Clinical trial NCT00068692
Conditions: Rectal Mucinous Adenocarcinoma Rectal Signet Ring Cell Adenocarcinoma Recurrent Rectal Carcinoma Stage IIA Rectal Cancer AJCC v7 Stage IIB Rectal Cancer AJCC v7 Stage IIC Rectal Cancer AJCC v7 Stage IIIA Rectal Cancer AJCC v7 Stage IIIB Rectal Cancer AJCC v7 Stage IIIC Rectal Cancer AJCC v7 Stage IVA Rectal Cancer AJCC v7 Stage IVB Rectal Cancer AJCC v7
Keywords: rectal cancer chemotherapy irinotecan oxaliplatin
Sponsor: National Cancer Institute (NCI)
Start date: 2003-10-15; Completion date: 2016-11-15
Enrollment: 225 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase III trial is comparing the effectiveness of three adjuvant combination chemotherapy regimens in treating patients who are receiving radiation therapy and fluorouracil either before or after surgery for stage II or stage III rectal cancer. Drugs used in chemotherapy, such as irinotecan, fluorouracil, leucovorin, and oxaliplatin, use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. It is not yet known which adjuvant combination chemotherapy regimen is more effective in treating patients who are receiving radiation therapy and fluorouracil either before or after surgery for rectal cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To compare the overall survival of patients treated with irinotecan, 5-FU and leucovorin versus those treated with oxaliplatin, leucovorin and 5-FU versus those treated with leucovorin and 5-FU for patients with stage II and III rectal cancer.

SECONDARY OBJECTIVES:

I. To determine sphincter preservation, tolerance of treatment and patterns of failure.

II. To describe patterns of failures

OTHER PRE-SPECIFIED OBJECTIVES:

I.To prospectively assess rectal function using the Patient Bowel Function/Uniscale questionnaire and the FACT Diarrhea Subscale in patients treated with an adjuvant program of pelvic radiation therapy and chemotherapy.

II. To correlate expression of key targets for 5-FU, leucovorin, oxaliplatin and irinotecan from tumor tissue biopsies with treatment efficacy III. To correlate tumor molecular prognostic markers with survival. IV. To determine physician preference in regard to the radiation-chemotherapy sequence in the Intergroup.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to ECOG performance status (0 vs 1), chemotherapy/radiotherapy sequence (preoperative vs postoperative), and risk group (high risk \[T3, N+, M0 or T4, any N, M0\] vs low risk \[T1-2, N+, M0 or T3, N0, M0\]). Patients are treated in 1 of 2 groups according to physician preference and then randomized to 1 of 3 treatment arms.

GROUP I (preoperative chemoradiotherapy and additional adjuvant chemotherapy): Preoperative chemoradiotherapy: Patients receive 1 of 3 treatment regimens, determined by the treating physician.

REGIMEN A (radiotherapy and fluorouracil): Patients undergo external beam radiotherapy once daily 5 days a week for 5 1/2 weeks (total of 28 fractions). Patients also receive concurrent fluorouracil intravenously (IV) continuously 7 days a week for 5 1/2 weeks.

REGIMEN B (radiotherapy, fluorouracil, and leucovorin calcium): Patients undergo external beam radiotherapy as in regimen A. Patients also receive concurrent fluorouracil IV and leucovorin calcium IV continuously for 4 days on weeks 1 and 5.

REGIMEN C (radiotherapy and capecitabine)\*: Patients undergo external beam radiotherapy as in regimen A. Patients also receive concurrent oral capecitabine twice daily for 5 1/2 weeks.

NOTE: \*Regimen C is allowed only for patients enrolled on protocol NSABP-R-04.

Surgery: Within 21-56 days after the completion of chemoradiotherapy, patients undergo surgical resection.

Additional adjuvant chemotherapy: Within 21-56 days after complete surgical resection, patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive irinotecan IV over 90 minutes and leucovorin calcium IV over 2 hours followed immediately by fluorourcil IV bolus on day 1. Patients also receive fluorouracil IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 8 courses.

ARM II: Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours followed immediately by fluorourcil IV bolus on day 1. Patients also receive fluorouracil IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 8 courses.

ARM III: Patients receive leucovorin calcium IV over 2 hours and fluorouracil IV over 1 hour on days 1, 8, 15, 22, 29, and 36. Treatment repeats every 8 weeks for 3 courses.

In all arms, treatment continues in the absence of disease progression or unacceptable toxicity.

GROUP 2 (postoperative chemoradiotherapy and additional adjuvant chemotherapy): Within 21-56 days after complete surgical resection, patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive irinotecan, leucovorin calcium, and fluorouracil as in group 1, arm I for 4 courses.

ARM II: Patients receive oxaliplatin, leucovorin calcium, and fluorouracil as in group 1, arm II for 4 courses.

ARM III: Patients receive leucovorin calcium and fluorouracil as in group 1, arm III for 1 course.

Within 4 weeks after the completion of chemotherapy, all patients undergo concurrent pelvic chemoradiotherapy as described in group 1 preoperative chemoradiotherapy Regimen A, B, or C, followed 4-6 weeks later by 4 additional courses of adjuvant chemotherapy for arms I and II and 2 additional courses of adjuvant chemotherapy for arm III.

Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 3 years, every 6 months for 2 years, and then annually for 5 years.

Arms: arm 1: Patients receive 1 of 3 preoperative chemo and radiotherapy treatment regimens, determined by the treating physician. Within 21-56 days after the completion of chemoradiotherapy, patients undergo surgical resection. Patients receive irinotecan IV over 90 minutes and leucovorin calcium IV over 2 hours followed immediately by fluorourcil IV bolus on day 1. Treatment continues in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive 1 of 3 preoperative chemo and radiotherapy treatment regimens, determined by the treating physician. Within 21-56 days after the completion of chemoradiotherapy, patients undergo surgical resection. Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours followed immediately by fluorourcil IV bolus on day 1. Patients also receive fluorouracil IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 8 courses. Treatment continues in the absence of disease progression or unacceptable toxicity. arm 3: Patients receive 1 of 3 preoperative chemo and radiotherapy treatment regimens, determined by the treating physician. Within 21-56 days after the completion of chemoradiotherapy, patients undergo surgical resection. Patients receive leucovorin calcium IV over 2 hours and fluorouracil IV over 1 hour on days 1, 8, 15, 22, 29, and 36. Treatment repeats every 8 weeks for 3 courses. Treatment continues in the absence of disease progression or unacceptable toxicity. arm 4: Patients receive irinotecan, leucovorin calcium, and fluorouracil as in group 1, arm I for 4 courses. Within 4 weeks after the completion of chemotherapy, all patients undergo concurrent pelvic chemoradiotherapy as described in group 1 preoperative chemo and radiotherapy Regimen A, B, or C, followed 4-6 weeks later by 4 additional courses of adjuvant chemotherapy for arms I and II and 2 additional courses of adjuvant chemotherapy for arm III.

Treatment continues in the absence of disease progression or unacceptable toxicity. arm 5: Patients receive oxaliplatin, leucovorin calcium, and fluorouracil as in group 1, arm II for 4 courses. Within 4 weeks after the completion of chemotherapy, all patients undergo concurrent pelvic chemoradiotherapy as described in group 1 preoperative chemo and radiotherapy Regimen A, B, or C, followed 4-6 weeks later by 4 additional courses of adjuvant chemotherapy for arms I and II and 2 additional courses of adjuvant chemotherapy for arm III.

Treatment continues in the absence of disease progression or unacceptable toxicity. arm 6: Patients receive leucovorin calcium and fluorouracil as in group 1, arm III for 1 course. Within 4 weeks after the completion of chemotherapy, all patients undergo concurrent pelvic chemoradiotherapy as described in group 1 preoperative chemo and radiotherapy Regimen A, B, or C, followed 4-6 weeks later by 4 additional courses of adjuvant chemotherapy for arms I and II and 2 additional courses of adjuvant chemotherapy for arm III. Treatment continues in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Radiotherapy intervention 2: Fluorouracil intervention 3: Leucovorin Calcium intervention 4: Oxaliplatin intervention 5: Irinotecan
Intervention descriptions: intervention 1: Undergo external beam radiation therapy intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
E3201 
Revised 3/07, Update #2 
Revised 9/08, Addendum #5  
 
 
 
 
Eastern Cooperative Oncology Group 
 
Intergroup Randomized Phase III Study of Postoperative Irinotecan, 5-Fluorouracil 
and Leucovorin vs Oxaliplatin, 5-Fluorouracil and Leucovorin vs 5-Fluorouracil and 
Leucovorin for Patients with Stage II or III Rectal Cancer Receiving Either 
Preoperative Radiation and 5-Fluorouracil or 
Postoperative Radiation and 5-Fluorouracil 
STUDY CHAIR: 
Al B. Benson III, MD 
STUDY CO-CHAIRS: 
Neal J. Meropol, MD  
Bruce Giantonio, MD 
RADIATION THERAPY CO-CHAIR: 
James Martenson Jr., MD 
SURGERY CO-CHAIR: 
Elin Sigurdson, MD 
PATHOLOGY CO-CHAIR: 
Stanley R. Hamilton, MD 
LABORATORY CO-CHAIR: 
Robert Diasio, MD 
OUTCOMES CO-CHAIR: 
Jeffrey Sloan, PhD 
COMMUNITY CO-CHAIR: 
Patrick Flynn, MD 
STATISICIAN: 
Paul Catalano, ScD 
LABORATORY SCIENCE AND PATHOLOGY 
COMMITTEE CO-CHAIR: 
 
Stanley R. Hamilton, MD 
RADIATION THERAPY COMMITTEE CHAIR: 
Richard Whittington, MD 
SURGERY COMMITTEE CHAIR: 
Elin Sigurdson, MD 
OUTCOMES COMMITTEE CHAIR: 
David F. Cella, PhD 
GASTROINTESTINAL COMMITTEE CHAIR: 
Al B. Benson III, MD 
NCCTG CO-CHAIR: 
Frank A. Sinicrope, MD 
Oxalplatin (NSC 266046) (IND 57004) will be supplied by the NCI for this study. 
Version Date:  June 26, 2008 
NCI Update Date: March 7, 2007 
 
STUDY PARTICIPANTS 
ACTIVATION DATE 
 
 
 
 
Rev. 3/07 
ECOG Entire Group 
CTSU 
NCCTG* 
 
*This 
study 
is 
supported 
by 
the 
NCI 
Cancer 
Trials 
Support 
Unit 
(CTSU). 
Institutions not aligned with ECOG will 
participate through the CTSU mechanism. 
(Please see Table of Contents and Appendix 
VII for details.) 
 
October 15, 2003 
 
Addendum #1 incorporated prior to activation 
Update #1 incorportated prior to activation 
Addendum #2 – 4/04 
Addendum #3 – 4/05 
ENTIRE DOCUMENT REVISED 
Addendum #4 – 11/05 
Update #2 – 3/07 
Addendum #5 – 9/08 


Eastern Cooperative 
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REVISED 
Revised 4/05, Addendum #3 
Revised 11/05, Addendum #4 
 
Table of Contents 
Schema .................................................................. i 
1. 
Introduction .................................................... 1 
2. 
Objectives ...................................................... 7 
3. 
Selection of Patients ...................................... 7 
4. 
Registration and Randomization Procedures10 
5. 
Treatment Plan ............................................13 
6. 
Measurement of Effect ................................42 
7. 
Study Parameters ........................................43 
8. 
Drug Formulation and Procurement ............46 
9. 
Statistical Considerations ............................60 
10. Pathology Review ........................................64 
11. Correlative Studies ......................................67 
12. Records to Be Kept .....................................73 
13. Patient Consent and Peer Judgment ..........74 
14. References ..................................................75 
Appendix I  Suggested Patient Consent Form ...... 1 
Study Plan ...........................................................17 
Appendix II Pathology Submission Guidelines ...... 1 
Appendix III  Patient Thank You Letter ................. 1 
Appendix IV  ECOG Checklist for Submission of 
Radiation Oncology Quality Assurance 
Matierials ....................................................... 1 
Appendix V  Staging Criteria- Rectum .................. 1 
Appendix VI  Comparision of Symptoms and 
Treatment Pharyngo-Laryngodesthesias and 
Platinum Hypersensitivity Reactions ............. 1 
Appendix VII  Cancert Trials Support Unit (CTSU) 
Participation Procedures ............................... 1 
 Appendix VIII  Cooperative Research and 
Development Agreement (CRADA) ............... 1 
 Appendix IX  Diarrhea Management Instructions . 1 
Rev. 11/05 
Rev. 11/05 


Eastern Cooperative 
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Oncology Group 
REVISED 
Revised 11/05, Addendum #4 
Revised 3/07, Update #2 
 
 
STUDY CHAIRS 
 
Al B. Benson III M.D. 
Northwestern University 
676 N. St. Clair; Suite 850 
Chicago, IL 60611-2998 
Phone:  312-695-6180 
Fax:  312-695-6189 
E-mail:  a-benson@northwestern.edu  
 
Neal J. Meropol, M.D. 
Fox Chase Cancer Center 
7701 Burholme Avenue 
Philadelphia, PA 19111-9111 
Phone: 215-728-2450 
Fax: 215-728-3639 
Email: nj_meropol@fccc.edu 
 
STUDY CHAIR LIAISON (SCL) 
 
STUDY CHAIR LIAISON (SCL) 
 
Bridget Elise O’Brien, ND, RN, CS-FNP, OCN 
Northwestern 
676 North St. Clair Suite 850 
Chicago, IL 60611-2998 
Phone: 312-695-6841 
Fax: 312-695-6189 
E-mail: bobrien1@nmff.org 
Rev. 
11/05 
 
Lisa Stucky-Marshall, MSN, AOCN 
Elmhurst Memorial Healthcare 
1200 S. York Road #4140 
Elmhurst, IL 60126-0000 
Phone:  630-758-8640 
Fax:  630-758-8642 
E-mail: lstucky@emhc.org 
 
 
 
 
Rev. 3/07 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
Institutions not aligned with ECOG will participate through the CTSU mechanism as outlined below and 
detailed in the CTSU logistical appendix. 
• 
The study protocol and all related forms and documents must be downloaded from the protocol-
specific Web page of the CTSU Member Web site located at https://members.ctsu.org 
• 
Send completed site registration documents to the CTSU Regulatory Office. Refer to the CTSU 
logistical appendix for specific instructions and documents to be submitted.  
• 
Patient enrollments will be conducted by the CTSU. Refer to the CTSU logistical appendix for specific 
instructions and forms to be submitted. 
• 
Data management will be performed by the ECOG. Case report forms (with the exception of patient 
enrollment forms), clinical reports, and transmittals must be sent to ECOG unless otherwise 
directed by the protocol. Do not send study data or case report forms to the CTSU Data Operations.  
• 
Data clarification forms and delinquency reports will be sent directly to the enrolling site by ECOG.  
Please send data clarification form responses and delinquent data to ECOG and do not copy CTSU 
Data Operations.  Please mail data clarification form responses and delinquent data directly to ECOG 
unless otherwise directed.  Each site should have a designated CTSU Administrator and Data 
Administrator and must keep their CTEP AMS account contact information current. This will ensure 
timely communication between the clinical site and the ECOG data center. 
 
 


Eastern Cooperative 
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REVISED 
Revised 3/07, Update #2 
 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
Rev. 3/07 
To submit site registration 
documents: 
For patient enrollments:  
Submit study data  directly to the 
Lead Cooperative Group unless 
otherwise specified in the protocol:  
 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone - 1-888-823-5923 
Fax – 215-569-0206 
CTSU Patient Registration 
Voice Mail – 1-888-462-3009 
Fax – 1-888-691-8039  
Hours: 8:00 AM – 8:00 PM 
Eastern Time, Monday – Friday 
(excluding holidays) 
 
[For CTSU patient enrollments 
that must be completed within 
approximately one hour, or 
other extenuating 
circumstances, call 301-704-
2376.  Please use the 1-888-
462-3009 number for ALL other 
CTSU patient enrollments.] 
ECOG Coordinating Center, FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215  
(ATTN: DATA). 
Phone # 617-632-3610 
Fax # 617-632-2990 
Data should be sent via postal mail 
(preferred); however fax is accepted. 
Do not submit study data or forms to 
CTSU Data Operations. Do not copy 
the CTSU on data submissions.   
 
For patient eligibility or treatment-related questions:  Contact the Study PI of the Coordinating Group.  
 
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help 
Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
The CTSU Public Web site is located at: www.ctsu.org  
The CTSU Registered Member Web site is located at https://members.ctsu.org 
CTSU logistical information is located in Appendix VII. 


Eastern Cooperative 
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REVISED 
i 
Schema 
R
E
G
I
S
T
E
 R1
Chemo1
XRT2
R
A
N
D
O
M
I
Z
    E3,4
Arm A:
Administer
8 cycles
Arm C:
Administer
3 cycles
All doses based on actual weight.
1.
See Section 5.1 for allowed regimens to be administered with radiation pre-op or post-op; must be declared at time of registration.
2.
Patients must receive minimum radiation dose of 50.4 Gy (see section 5.5 for guidelines).
3.
Patients will be stratified by ECOG performance status (0 vs 1), High risk (T3N+M0, T4Nany M0) vs Low Risk (T1-2 N+ M0, T3N0M0)
and Pre-operative chemotherapy/XRTvs Post-operative chemotherapy/XRT. (See Section 4.25)
4.
Patients who have reveived treatment as specified in "Arm S" may join the study, if they present post-surgery. They will be
registered and randomized to Group I (only) at the same time. [This group is referenced as "Group I PS".]
Arm B:
Administer
8 cycles
See Following Page for Dosing Details
Step 1
Step 2
Arm S
Surgery
21 - 56 days
21 - 56 days
R
E
G
I
S
T
E
R
1
R
A
N
D
O
M
I
Z
 E1
&
Step 1/2
Arm D:
Administer
4 cycles
Arm E:
Administer
4 cycles
Arm F:
Administer
1 cycle
Chemo1
XRT2
MD
Choice
Group I
Pre-Op
Chemo +
XRT
Group II
Post-Op
Chemo +
XRT
Surgery
21 - 56 days
Chemo1
XRT2
Chemo1
XRT2
Arm D:
Administer
4 cycles
Arm E:
Administer
4 cycles
Arm F:
Administer
2 cycles
 


Eastern Cooperative 
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Oncology Group 
REVISED 
ii 
 
Arm A/Arm D*
Irinotecan: 180 mg/m2, IV over 90- minutes
Leucovorin: 400 mg/m2, IV over 2 hours.
5-FU: 400 mg/m2, IV bolus injection,
immediately following leucovorin dose.
Continuous infustion 5-FU: 2.4 gm/m2 over 46
hours by ambulatory infusion pump beginning
immediately following bolus 5-FU.
Cycle = 2 treatment days every 2 weeks.
Arm B/Arm E**
Oxaliplatin: 85 mg/m , IV over 2 hours
Leucovorin: 400 mg/m2 , IV over 2 hours.
5-FU:400 mg/m2 , IV bolus injection,
immediately following leucovorin dose.
Continuous infusion 5-FU: 2.4 gm/m2 , over 46
hours by ambulatory infusion pump beginning
immediately following bolus 5-FU.
Cycle = 2 treatment days every 2 weeks.
Arm C/Arm F
Leucovorin: 500 mg/m2 , IV over 2 hours once
a week for 6 weeks, followed by 2 weeks rest.
5-FU: 500 mg/m2 , bolus IV 1 hour after the
start of the leucovorin infusion, once a week
for 6 weeks followed by 2 weeks rest.
Cycle =  8 weeks.
*   See Section 5.4.1 for dose escalation
**  See Section 5.4.2 for dose escalation
 
 


Eastern Cooperative 
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Oncology Group 
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1 
1. 
Introduction 
1.1 
The treatment for patients with resectable rectal cancer is evolving in the United States and 
Canada. Surgeons have increasingly offered patients preoperative combined 5-FU based 
chemotherapy and radiation to down-stage a patient prior to surgery, increase the possibility of a 
sphincter-sparing surgery, and to reduce combined modality toxicity by removing irradiated tissue 
at the time of resection. 
Many patients, however, continue to receive surgery as their initial treatment intervention and are 
candidates for postoperative combined modality therapy.  Although there have been a number of 
trials using preoperative combined modality therapy, particularly in Europe, few have been 
randomized and few have used conventional radiation doses.  The NSABP (R03) and the 
Gastrointestinal Intergroup (INT0147) each designed a randomized trial of preoperative versus 
postoperative combined modality therapy for resectable rectal cancer in an effort to employ 
conventional radiation dosing, to determine whether preoperative chemotherapy and radiation 
improves disease-free and overall survival compared to postoperative therapy, and to evaluate 
local recurrence rates, sphincter preservation, down staging, and quality of life.  Unfortunately, 
both trials were terminated prior to completion because of inadequate patient accrual.  The 
NSABP has reported on the status of the 267 patients randomized with data one year after 
randomization, suggesting similar disease-free survival (83% versus 78%, p=0.29) with similar 
postoperative complications, although a larger proportion of preoperative patients had sphincter-
saving surgery (1).  Grade 4-5 toxicity was greater in the preoperative arm (34% versus 23%, 
p=0.07).  It is evident that both pre- and postoperative strategies have been embraced in the 
United States, and it remains likely that a preoperative versus postoperative trial will never be 
completed with sufficient numbers of patients.  Both approaches are now viewed as acceptable 
alternatives de facto. 
The predominant chemotherapy regimens for rectal cancer patients include 5-FU, with or without 
leucovorin, and protracted venous infusion 5-FU.  There also is interest in substituting oral 5-FU 
regimens for protracted venous infusion 5-FU.  The first intergroup rectal trial (NCCTG 86-47-51) 
showed that protracted venous infusion of 5-FU during pelvic irradiation administered in the 
postoperative setting increased the time to relapse and improved survival compared to those 
treated with bolus 5-FU(2).  Results from the second intergroup trial (INT0114), with a median 
follow-up of survivors at 7.4 years, suggest that overall and disease-free survival are not 
statistically different among the four treatment groups.  All patients received two cycles of 5-FU-
based chemotherapy followed by pelvic radiation with 5-FU and two additional cycles of 
chemotherapy.  Chemotherapy was bolus 5-FU, 5-FU and leucovorin, 5-FU and levamisole, and 
5-FU, leucovorin, and levamisole (3-5).  The data do suggest that local recurrence is significantly 
less for lower risk patients (T1-2 N+ T3N0) compared to high risk (T3 N+ T4 Nany) with overall survival 
and disease-free survival favoring the lower-risk group.  Males also had a poorer outcome. 
Available survival data from the first two intergroup trials include: 
 
NCCTG 86-47-51 4-year survival (2) 
Bolus 5-FU = 60% 
PVI 5-FU = 70% 
INT 0114 (3) 
 
Good Risk 
Poor Risk 
All Patients 
5 Year Survival 
7 Year Survival 
76% 
55% 
64% 
70% 
45% 
56% 
 


Eastern Cooperative 
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REVISED 
2 
The third intergroup trial (INT0144) is a three-arm, postoperative evaluation of 5-FU by bolus 
injection versus 5-FU by prolonged venous infusion prior to and following combined prolonged 
venous infusion plus pelvic radiation versus bolus 5-FU plus leucovorin plus levamisole prior to 
and following combined pelvic radiation.  The study reached its accrual goal in August 2000 and 
will require at least three more years before analysis can begin. Therefore, pending the analysis of 
the third Intergroup trial, INT0144, an optimal 5-FU-based regimen has yet to be defined. 
Recent advanced disease colorectal cancer trials have suggested that a regimen of irinotecan, 5-
FU, and leucovorin is superior to 5-FU and leucovorin (6-7).  The intergroup adjuvant colon trial 
(INT0089) has confirmed that 5-FU and leucovorin is the favored regimen (8-13).  The recently 
completed colon intergroup adjuvant trial (C89803) compares irinotecan, 5-FU, and leucovorin 
versus 5-FU and leucovorin. The results are pending.  The survival advantage of irinotecan, 5-FU, 
and leucovorin in the advanced disease setting justifies further evaluation of the combination, not 
only in the adjuvant setting for colon cancer but also for rectal cancer patients.  There are limited 
data describing the use of post-radiation irinotecan, 5-FU and leucovorin for resected rectal cancer 
patients.  In a study of 17 patients receiving post-radiation and post-surgery weekly irinotecan, 5-
FU and leucovorin for four weeks repeated every six weeks for three cycles, there was no 
evidence of grade 4 neutropenia or other grade 3-4 non-hematologic toxicities (14).  Recent 
morbidity and mortality data from advanced disease trials and the intergroup protocol (C89803) 
suggest that the bolus regimen of irinotecan, 5-FU and leucovorin produces a level of toxicity 
which would warrant dose reductions or alternative schedules (6,15).  An alternative schedule 
includes infusion regimens of 5-FU combined with irinotecan which have been widely employed in 
Europe and approved by the Food and Drug Administration (7).  A recent report of infusion 
regimens of 5-FU with irinotecan suggest a median survival of greater than 20 months for 
advanced colorectal cancer patients with acceptable toxicity (16).   
Oxaliplatin (trans-l-1,2-diaminocyclohexane oxalatoplatinum) is a novel antineoplastic platinum 
derivative with a 1,2-diaminocyclohexane [DACH] carrier ligand.  Although the precise mechanism 
of action is unknown, platinum compounds are thought to exert their cytotoxic effects through the 
formation of DNA adducts that block both DNA replication and transcription. Like cisplatin, 
oxaliplatin reacts with DNA, forming mainly platinated intra-strand links with two adjacent guanines 
or a guanine adjacent to an adenine (17-19).  However, DACH-platinum adducts formed by 
oxaliplatin are apparently more effective at inhibiting DNA synthesis (19,20) and are more 
cytotoxic than cis-diammine-platinum adducts formed from cisplatin and carboplatin (19-21). 
The safety profile of oxaliplatin was evaluated in a phase I intra-patient escalation study of 44 
patients with advanced cancer, who received 116 courses of oxaliplatin through seven levels, 
from 45 mg/m² to 200 mg/m² every four weeks (22).  Oxaliplatin was administered without pre-
hydration or post-hydration.  Initially, all patients experienced nausea and vomiting.  As a result, 
systematic pretreatment with antiemetics was given to all patients receiving >90 mg/m² oxaliplatin, 
which reduced Grade 3 or 4 nausea and vomiting to 11%.  Diarrhea was mild (primarily Grade 1 
or 2 in 24% of therapy courses).  Hematologic toxicity was moderate.  Grade 1 or 2 
thrombocytopenia was dose related and occurred in 13% of patients receiving from 135 to 150 
mg/m², and 28.5% of patients receiving from 175 to 200 mg/m².  Similarly, only Grade 1 or 2 
neutropenia was observed, and hemoglobin levels remained unchanged. The dose-limiting side-
effect of oxaliplatin therapy was a transient peripheral neuropathy.  This toxicity usually appeared 
at doses >90 mg/m² and affected up to 75% of patients treated with 200 mg/m².  The 
recommended phase II dose was 135 mg/m² administered over at least 1 hour every four weeks. 
A review of several studies to evaluate overall safety in 682 patients who had received oxaliplatin 
either as a single agent or in combination with 5-FU was done to delineate the character and 
severity of oxaliplatin-induced neurotoxicity (23).  Grade 3 neurotoxicity presenting as fine 
movement disturbance or moderate sensitive ataxia was observed in 12% of patients at a median 
cumulative dose of 900 mg/m² oxaliplatin.  (Total cumulative doses of 780, 1170, and 1560 mg/m² 
were correlated with an incidence of 10%, 50% and 75% neurotoxicity, respectively.)  The total 
cumulative dose of oxaliplatin was the most significant prognostic factor for the occurrence of 
neurotoxicity and inversely related to the likelihood of recovery from toxicity.  Symptoms resulting 


Eastern Cooperative 
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Oncology Group 
REVISED 
3 
from Grade 1 and 2 neuropathy regressed in 82% of patients within 4 to 6 months, and 
disappeared entirely in 41% of patients within 6 to 8 months.  In summary, all studies reported to 
date that the neurotoxicity resulting from oxaliplatin treatment was specific, cumulative and, unlike 
cisplatin-induced neuropathy, reversible in most patients. 
The efficacy of oxaliplatin monotherapy in patients with advanced colorectal cancer was evaluated 
in five phase II trials, two with 63 previously untreated patients and three with 139 patients with 
metastatic disease previously treated with and mostly refractory to 5-FU (23-27).  The objective 
response rate achieved with oxaliplatin as first-line therapy was approximately 20% while that of 
oxaliplatin as second-line therapy was approximately 10%. 
Two randomized studies have compared the combination of oxaliplatin, 5-FU, and leucovorin to 5-
FU and leucovorin alone as initial therapy for metastatic colorectal cancer.  In one trial oxaliplatin 
was administered at 125 mg/m² every three weeks with daily x 5 5-FU plus leucovorin, and in the 
other oxaliplatin was administered at 85 mg/m² every two weeks with infusional 5-FU/ leucovorin 
on days 1-2 (28, 29).  Both studies showed improved time to progression (q 2 weeks: 9.0 vs. 6.2 
months, p=0.0003; q 3 weeks: 8.7 vs. 6.1 months, p=0.048) and response rates (q 2 weeks: 
50.7% vs. 22.3%, p=0.0001; q 3 weeks 53% vs. 16% p<0.001) in the oxaliplatin arms.  Although a 
trend in favor of oxaliplatin was reported, there was no statistically significant difference in overall 
survival between the arms. 
In order to evaluate the safety and efficacy of regimens based on the following combinations:  5-
FU+ leucovorin + irinotecan; 5-FU+ leucovorin + oxaliplatin; oxaliplatin + irinotecan, in newly 
diagnosed patients with advanced (metastatic) colorectal cancer an intergroup study, N9741, 
(NCCTG, ECOG, CALGB, NCIC-CTG, SWOG) was initiated. Initially, this was a 6-arm study. 
However, 3 arms (those administering 5-FU for 4 or 5 consecutive days) were discontinued early 
because of inferior efficacy or excessive toxicity. Recently, preliminary results of a planned interim 
analysis of the 3 remaining arms were released by the National Cancer Institute. The analysis, 
based on 795 patients enrolled in the study between March 1999 and April 2001, showed that 
patients receiving the infusional regimen (oxaliplatin with infusional 5-FU and leucovorin) had 
significantly longer time to disease progression (8.8 months vs 6.9 months; p = 0.0009), 
significantly better overall survival (18.6 months vs 14.1 months; p = 0.002) , a significantly higher 
response rate (38% vs 29%; p = 0.03) and lower toxicity than patients receiving irinotecan, with 
bolus 5-FU and leucovorin (IFL) (30, 31). 
Various modifications of the combination of oxaliplatin with 5-FU/leucovorin regimens (FOLFOX 1-
FOLFOX 6) have been evaluated (30-34). The more recent modifications have simplified the 
schedule of administration and improved patient convenience without compromising the efficacy 
of the regimen. Maindrault-Goebel et al. reported on a Phase II study of oxaliplatin (100 mg/m2) 
and leucovorin (400 mg/m2) as a 2-hour infusion on Day 1 followed by bolus (400 mg/m2) and a 
46-hour infusion (2.4-3 g/m2) of 5-FU every 2 weeks (FOLFOX 6) as second line treatment for 
metastatic colorectal cancer (35). Sixteen of 60 patients treated had a partial response (27%) and 
an additional 45% had stable disease. Median progression-free survival was 5.3 months and 
median survival was 10.8 months. Ryan et al. evaluated biweekly oxaliplatin in combination with a 
modified de Gramont regimen (oxaliplatin 85 mg/m2 as a 2-hour infusion on Day 1 of each 2-week 
cycle, immediately followed by leucovorin, 500 mg/m2 as a 2-hour infusion followed by bolus FU, 
400 mg/m2 and a 46-hour infusion of 5-FU, total dose 2.4 mg/m2) in heavily pre-treated patients 
with advanced colorectal cancer. Preliminary data showed a response rate of 7% (36). Updated 
information reveals a response rate of 11% (5%-22%), all in patients who had received prior 
irinotecan. When only second-line patients are considered, the response rate was 25% (8%-43%). 
1.2 
Rectal Function in Patients Treated with Adjuvant Radiation Therapy 
Administration of pelvic radiation therapy is associated with significant potential for both acute and 
long term adverse effects on rectal function. Despite this, no rectal adjuvant trial has prospectively 
undertaken a detailed evaluation of rectal function. In this clinical trial, we plan to prospectively 
evaluate rectal function with validated tools. Information derived in this way can be used in future 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
4 
studies on interventions of treatments designed to mitigate the adverse effect of adjuvant 
treatment on rectal function. 
In a clinical trial of postoperative adjuvant pelvic radiation therapy and bolus 5-fluorouracil for 
rectal cancer, 35% of the patients experienced $ grade 2 diarrhea (37).  The incidence of  $ grade 
3 diarrhea was 20%. Administration of 5-FU by continuous infusion results in a higher rate of 
grade 3 or worse diarrhea than administration by bolus (2). In a randomized comparison of these 
two approaches to postoperative adjuvant therapy, grade 3 or worse diarrhea was observed in 
24% of patients during radiation therapy who received concurrent 5-FU by continuous infusion 
compared to only 14% of patients treated with 5-FU by bolus infusion during radiation therapy. A 
number of randomized trials have been conducted in an effort to identify agents that prevent or 
decrease diarrhea during pelvic radiation therapy. Three trials have assessed the value of 
salicylate preparations (38-40). Two studies suggested a beneficial effect (38-40) and one 
NCCTG study suggested a large harmful effect. Two double blind clinical trials evaluated oral 
sucralfate (41,42). In one trial, sucralfate was associated with a decrease in diarrhea (41). In the 
other trial, performed by the NCCTG, sucralfate was not associated with a decrease in diarrhea, 
and some gastrointestinal symptoms were exacerbated by the use of this agent (42). A trial 
evaluating cholestyramine provided evidence that this agent can decrease diarrhea, but only at 
the expense of unacceptable gastrointestinal side effects (43). Taken together, evidence from 
these studies indicates that acute diarrhea is a significant clinical problem in patients receiving 
pelvic radiation therapy. These studies also indicate that there is no class of agents that 
consistently demonstrates the ability to prevent diarrhea in these patients with an acceptable 
toxicity profile. 
Long term adverse effects on rectal function as a result of combined postoperative chemotherapy 
and radiation therapy were studied by Kollmorgen and colleagues from the Mayo Clinic (44). 
Forty-one patients who had received this treatment were contacted and questioned about their 
bowel function, as were 59 patients who had not received this treatment.  Highly statistically 
significant adverse effects on bowel function were observed in the irradiated group across a broad 
spectrum of 11 different parameters. For example, 46% of the irradiated patients experienced 
nocturnal bowel movements, compared to only 14% of the non-irradiated patients (P<0.001). Fifty-
six percent of the irradiated patients experienced at least occasional incontinence, compared to 
only 7% of non-irradiated patients (P<0.001). Protective clothing was used by 41% of irradiated 
patients and 10% of non-irradiated patients (P<0.001).  Because interviewers were not blinded, 
and because the patients were not randomized to receive or not receive pelvic irradiation, the 
results of this study must be interpreted with caution. 
Lundby and colleagues evaluated rectal function 11 years after completion of a randomized 
clinical trial comparing adjuvant postoperative pelvic radiation therapy (50 Gy in 25 fractions, with 
a two week break after 30 Gy) with observation (45).  103 of the 494 patients originally entered 
onto the trial were alive without recurrence at the time of the evaluation.  The study design called 
for patients to be contacted by phone for a structured interview regarding their bowel function. 
Eight patients were excluded because of dementia or deafness.  Two could not be contacted.  
The remaining 93 patients, 49 in the radiation group and 44 in the control group, were included in 
the evaluation of rectal function. Individuals interviewing patients were blinded as to the treatment 
received at the beginning of the interview.  Blinding was maintained in 89% of the interviews. 
Findings of this study are strikingly similar to those observed in the Mayo Clinic study.  For 
example, 49% of irradiated patients experienced fecal incontinence, compared to only 5% of 
control patients (P<0.001).  Protective clothing was used by 26% of the irradiated patients 
compared to none of the control patients (P<0.001).  Because of the randomized nature of the 
original treatment allocation and because of the fact that interviewers, in the vast majority of 
cases, remained blinded as to the treatment received by the patients, it is unlikely that bias can 
account for these results.  This study, therefore, provides strong corroboration of the Mayo Clinic 
study and indicates that a very high proportion of patients experience clinically significant, long 
term rectal toxicity following postoperative adjuvant pelvic radiation therapy for rectal cancer. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
5 
A review of the literature on the measurement of bowel function uncovered no standard uniform 
approach or measurement scale.  A number of studies report assessing “bowel function” but 
remain primarily concerned with the number of stools per day or use a varied assortment of 
questionnaire formats (46-52). 
Prospective assessment of rectal function will be an integral part of this clinical trial, in view 
of the extensive body of research providing unequivocal evidence of both acute and long 
term adverse effects on rectal function in patients receiving pelvic radiation therapy.  A 
simple bowel function questionnaire has been developed for assessment of several 
measures of rectal function, such as stool frequency, continence, “clustering” (the need to 
have a second bowel movement, 30 minutes after defecation), and the ability to defer 
defecation 15 minutes.  The questionnaire is based on the Mayo Clinic study mentioned 
above, in which bowel function was assessed in a group of patients with resected rectal 
cancer who either had or had not received adjuvant pelvic RT (44).  As indicated previously, 
findings from this study suggest that this questionnaire is able to discriminate between 
patients that have received and not received pelvic radiation therapy. For each of the eight 
measures of bowel function addressed by the questionnaire, a highly significant difference 
was noted between the group of patients who had received prior RT and those who had not 
(44).  Further evidence of the ability of this questionnaire to discriminate between groups of 
patients may be found in the NCCTG study of sucralfate, which demonstrated statistically 
significant worse outcome in the sucralfate group with regard to fecal incontinence, need for 
protective clothing, and overall gastrointestinal symptoms (42).  Use of this questionnaire will 
provide more detailed information on long-term bowel function than would be provided by 
common toxicity criteria alone. 
The primary construct we are targeting with the questionnaire is problems with bowel 
function as perceived by the patient.  This construct is more relevant and precise than asking 
for a simple incidence measure of various bowel function parameters.  If the patient 
perceives that bowel function is a problem, then it is a problem (46, 53). Hence it is important 
to capture this patient-reported outcome as an indicator of treatment efficacy. 
Face validity of the bowel function questionnaire derives from a content analysis of the 
literature and the framework used in the application of the original questionnaire (44, 50-60). 
We will carry out further psychometric evaluation of the bowel function questionnaire in this study. 
Specifically, we will assess the reliability and validity of the bowel function questionnaire according 
to standard methods (47) and analogous to specific methodology used to validate a tool for 
measuring constipation in cancer patients (46). 
A function questionnaire with a more general quality-of-life (QOL) measure is known as the 
Uniscale (48).  The Uniscale is a single-item visual analogue tool intended to measure overall 
QOL, which has been used successfully in a number of NCCTG trials. These studies have 
demonstrated that this global measure of quality of life is reliable and valid, and also has some 
advantages over more complex instruments (49).  Discriminant validity will be examined by 
correlating toxicity incidence with individual items of the bowel function questionnaire. 
We will also use the FACT Diarrhea Subscale, a subscale of FACT-G, to assess bowel function in 
this study. The FACT Diarrhea Subscale is a simple eleven item instrument which covers a range 
of problems encountered by patients who experience diarrhea related to cancer treatment. A key 
difference between the FACT Diarrhea Subscale and the bowel function questionnaire is that the 
FACT Diarrhea Subscale uses a Likert scale, while the bowel function questionnaire uses a 
dichotomous scale for most questions. A general description of the extensive measures that have 
been undertaken to validate the FACT quality of life scales has been reported by Cella and 
colleagues (61). 
It generally takes patients less than 5 minutes to complete the short twelve-item bowel function 
questionnaire.  We believe this is an efficient means to obtain more detailed bowel function data.  
The extra effort should not be overly burdensome to either the patients in terms of time or the trial 
in terms of cost.  The Uniscale has been added to the end of the bowel function questionnaire for 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
6 
the convenience of the patient. Similarly, it will take less than five minutes to complete the FACT 
Diarrhea Subscale. Hence, in total the FACT, Uniscale and bowel function questionnaires require 
less than ten minutes for the patient to complete the combined 24 items 
1.3 
Correlative Studies 
Numerous studies of molecular prognostic and predictive markers have been reported (62-88), 
but none of the markers has reached routine clinical usage because their value is not proven (89-
91).  As a result of successful clinical trials (92), the current standard of care for rectal cancer 
patients in stage II and III is pre- or post-operative chemoradiation.  Identification of high- and low-
risk patients within the stage groupings would be helpful. 
In addition, predictive markers for response or resistance to chemoradiation have broad 
implications for treatment of patients with rectal carcinoma.  Therapy results in morbidity and 
mortality in some patients, and cancer can progress despite therapy.  Therefore, markers that 
predict survival are needed (62). 
The sensitivity and resistance of cancers to chemoradiation are complex characteristics affected 
by pharmacology, pharmacokinetics, tumor biology, radiation biology, and tumor cell phenotypes 
and genotypes.  Recent advances in molecular biology have directed attention at genetic 
pathways involved in control of the cell cycle and apoptosis which are affected by therapeutic 
agents (93-95).  In vitro studies suggested that the p53 pathway is important:  responses to most 
agents, including anti-metabolites such as 5-FU, the mainstay of chemotherapy for colorectal 
cancer, and radiation, were in large part dependent on wild-type p53 (96). Cells with abnormal 
mismatch repair showed resistance to a wide variety of chemotherapeutic agents and radiation 
(97-98).  In addition, genes that encode enzymes involved in metabolism of chemotherapeutic 
agents and repair of their DNA adducts may affect drug efficacy and also serve as predictive 
markers for sensitivity and resistance to the agents (123).  Few studies, however, have addressed 
markers in clinical trials of chemoradiation. 
In patients who undergo resection of a rectal carcinoma with curative intent, it is the presence of 
undetected residual disease which is responsible for recurrence and ultimately death of the patient 
(99).  These occult metastases are the target of pre-operative neoadjuvant and post-operative 
adjuvant chemoradiation in rectal cancer (100,101).  Patients who have occult metastasis may 
benefit if the adjuvant chemoradiation is effective, but those patients who lack occult metastasis 
derive no benefit and are nonetheless subjected to the toxicity of treatment (102).  Ideally, markers 
for risk-adapted therapy would identify the patients at high risk and low risk, thereby helping to 
guide treatment decisions. 
Improved prediction of outcome by identification of the high-risk minority and the low-risk majority 
of patients would be helpful in both groups of rectal cancer patients to identify appropriate 
candidates for chemoradiation and those who do not need therapy because of inherently high 
survival rates.   
Dr. Hamilton’s laboratory was the first to report that 18q allelic loss was an unfavorable prognostic 
marker in stage II colorectal cancer (103), a finding that was confirmed in numerous subsequent 
studies (62, 65, 71, 73, 75, 78, 79).  In a collaborative study with the ECOG of stage III colon 
cancer, Dr. Hamilton’s laboratory reported that retention of chromosome 18q alleles in 
microsatellite-stable cancers and mutation of the transforming growth factor beta type II receptor 
gene (TGF beta RII) in cancers with high levels of microsatellite instability were favorable markers 
for disease-free and overall survival.  Therefore, we will evaluate the molecular predictive markers 
identified in our and others’ previous studies (chromosome 18q allelic loss, p53 gene mutation and 
microsatellite instability) in order to evaluate the relative strengths of the markers. 
The cooperative groups and others have conducted a series of retrospective trials correlating 
expression of key targets of 5-FU-based therapy with response to therapy in the adjuvant setting.  
In rectal cancer, a retrospective analysis demonstrated decreased survival for those patients with 
high thymidylate synthetase (TS) expression, although the patients who received the most benefit 
from chemotherapy had high TS expression (104).  Other investigators have confirmed that high 


Eastern Cooperative 
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Oncology Group 
REVISED 
7 
TS correlates with worse survival.  However, more recent analyses for metastatic colorectal 
cancer suggest that low TS mRNA expression in tumor tissue is associated with a much higher 
response to therapy compared to those patients who have high TS mRNA expression.  
Preliminary data suggest that patients who have rectal tumor resection after preoperative 5-FU 
and radiation therapy not only will demonstrate tumor downstaging, but polymorphisms of the 
repeat sequences in the enhancer region of thymidylate synthase gene promoter may predict 
tumor downstaging (105, 106). In addition, recent analyses suggest colorectal cancer responding 
to 5-FU have low gene expression levels of dihydropyrmidine dehydrogenase (DPD) and 
thymidine phosphorylase (TP) (88).  We will evaluate expression of these three enzymes (TS, 
DPD and TP) as potential markers.   
This protocol includes therapy with oxaliplatin in Arm B and Arm E.  Excision repair cross-
complementing 1 (ERCC1), ERCC2 and XPF are enzymes involved in nucleotide excision repair, 
and their activity could affect the ability of tumor cells to remove platinum adducts from their DNA 
and influence the efficacy of the drug.  Colorectal cancer patients with low levels of ERCC1 
expression in their tumor have been reported to have improved survival after oxaliplatin therapy 
(123).  We will evaluate expression of these three genes (ERCC1, ERCC2 and XPF) as potential 
markers. 
1.4 
Gender and Ethnicities Statement 
This study is open to both men and women and to all racial/ethnic groups.  The patient enrollment 
pattern is expected to be similar to that of typical ECOG colorectal cancer studies.  According to 
the most recent ECOG experience, there is no evidence for outcome to be affected by either race 
or gender.  Thus, the study will not have separate accrual targets for different subgroups.  We will, 
however, conduct subset analyses to assess gender and racial/ethnic effects when possible. 
2. 
Objectives 
2.1 
To compare the overall survival of patients treated with irinotecan, 5-FU and leucovorin versus 
those treated with oxaliplatin, leucovorin and 5-FU versus those treated with leucovorin and 5-FU 
for patients with stage II and III rectal cancer. 
2.2 
Secondary endpoints will include sphincter preservation, tolerance of treatment and patterns of 
failure. 
2.3 
To prospectively assess rectal function using the Patient Bowel Function/Uniscale questionnaire 
and the FACT Diarrhea Subscale in patients treated with an adjuvant program of pelvic radiation 
therapy and chemotherapy. 
2.4 
To correlate TS, DPD and TP expression (key targets for 5-FU); retention of chromosome 18q 
alleles and MSI with TGFβ1RII mutation (markers for 5-FU efficacy); ERCC1, ERCC2 and XPF 
expression (participants in repair of adducts from oxaliplatin); and p53 gene mutation in tumor 
tissue specimens with treatment efficacy.   
2.5 
To correlate tumor molecular prognostic markers (chromosome 18q allelic loss and MSI) with 
survival. 
2.6 
To determine physician preference in regard to the radiation-chemotherapy sequence in the 
Intergroup. 
3. 
Selection of Patients 
NOTE: All questions regarding eligibility should be directed to the ECOG Coordinating Center at 
(617) 632-3610. 
NOTE: Patients who have received treatment as specified in "Arm S" of the protocol--specifically having 
undergone concurrent chemotherapy/radiation (refer to Section 5.1 for allowed regimens of 
chemotherapy and Section 5.5 for radiation guidelines) followed by surgery--and present post-


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
8 
surgery may join/participate in this trial.  These patients will be assigned to Group I (only).  
Hereinafter, this group will be referenced as "Group I PS" (post surgery).  Group I PS is required to 
satisfy the eligibility criteria defined in Section 3.2 (except 3.25) and Section 3.3 at the time of 
registration, since registration and randomization are performed at the same time. 
3.1 
Group I (Pre-operative) Registration 
3.1.1 
Patients must have histologically proven adenocarcinoma of the rectum with no distant 
metastases. Clinical staging is required (T3N0M0, T4N0M0, TanyN1-3M0).  See Appendix V 
for staging criteria. 
3.1.2 
Patients must not have evidence of tumor outside of the pelvis including liver metastases, 
peritoneal seeding, or metastatic inguinal lymphadenopathy. 
3.1.3 
Patients must have ECOG performance status 0-1. 
3.1.4 
The distal border of the tumor must be at or below the peritoneal reflection, defined as 
within 12 centimeters of anal verge by proctoscopic examination. In addition, patients who 
have had a portion of their tumors confirmed to be below the peritoneal reflection at the 
time of surgery are eligible regardless of the distance determined by endoscopy. 
3.1.5 
Transmural penetration of tumor through the muscularis propria must be demonstrated 
by CT scan, endo-rectal ultrasound or MRI. 
3.1.6 
Tumors must be defined prospectively by the surgeon as clinically resectable or not. 
3.1.6.1 
Clinically resectable tumors will be defined by the surgeon as not fixed and 
completely resectable with negative margins based on the routine 
examination of the non-anesthetized patient. 
3.1.6.2 
Before pre-op treatment, the surgeon should estimate and record the type of 
resection anticipated: APR, LAR or LAR/coloanal anastomosis. 
3.1.7 
The tumor may be clinically fixed or initially not completely resectable, clinical stage  
T4 N0-2 M0 based on the presence of at least one of the following criteria: 
3.1.7.1 
Clinically fixed tumors on rectal examination with tumor adherent to the pelvic 
sidewall or sacrum. 
3.1.7.2 
Hydronephrosis on CT scan or IVP or ureteric or bladder invasion as 
documented by cystoscopy and cytology or biopsy, or invasion into prostate. 
3.1.7.3 
Vaginal or uterine involvement. 
3.1.8 
Patients must not have received prior chemotherapy or pelvic irradiation therapy. 
3.1.9 
Patients must not have a previous or concurrent malignancy, with the exception of: 
3.1.9.1 
Nonmelanoma skin cancer or in situ cervical cancer. 
3.1.9.2 
Treated non-pelvic cancer from which the patient has been continuously 
disease-free more than five years. 
3.1.10 Patients must not have an active inflammatory bowel disease or other serious medical 
illness which might limit the ability of the patient to receive protocol therapy. 
3.1.11 Patients must be > 18 years of age. 
3.1.12 Female patients must not be pregnant or breast-feeding because of the potentially 
teratogenic and abortifacient effects of this regimen and there is no information on the 
excretion of the agents or other metabolites into breast milk. All females of childbearing 
potential must have a blood or urine test within 2 weeks prior to registration to rule out 
pregnancy. 


Eastern Cooperative 
E3201 
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9 
3.1.13 Sexually-active women of childbearing potential and sexually active males are strongly 
advised to use an accepted and effective method of contraception. 
3.2 
Group II (Post-operative) Registration 
NOTE: Group II patients are required to satisfy the eligibility criteria defined in Sections 3.2 and 
3.3 at the time of registration since registration and randomization are performed at the 
same time. 
3.2.1 
Patients must have had histologically proven adenocarcinoma of the rectum with no 
distant metastases.  Pathologic staging is required (T3N0M0, T4N0M0, TanyN1-3M0).  See 
Appendix V for staging criteria. 
3.2.2 
Patients must not have evidence of tumor outside of the pelvis including liver metastases, 
peritoneal seeding, or metastatic inguinal lymphadenopathy. 
3.2.3 
Patients must have ECOG performance status 0-1. 
3.2.4 
The distal border of the tumor must have been at or below the peritoneal reflection, 
defined as within 12 centimeters of anal verge by proctoscopic examination. In addition, 
patients who have had a portion of their tumors confirmed to be below the peritoneal 
reflection at the time of the surgery are eligible regardless of the distance determined by 
endoscopy. 
3.2.5 
Patients must not have received prior chemotherapy or pelvic irradiation therapy. 
3.2.6 
Patients must not have a previous or concurrent malignancy, with the exception of: 
3.2.6.1 
Non-melanoma skin cancer or in situ cervical cancer. 
3.2.6.2 
Treated non-pelvic cancer from which the patient has been continuously 
disease-free more than five years. 
3.2.7 
Patients must not have an active inflammatory bowel disease or other serious medical 
illness which might limit the ability of the patient to receive protocol therapy. 
3.2.8 
Patients must be > 18 years of age. 
3.2.9 
Female patients must not be pregnant or breast-feeding because of the potentially 
teratogenic and abortifacient effects of this regimen and there is no information on 
the excretion of the agents or their metabolites into breast milk. All females of 
childbearing potential must have a blood or urine test within 2 weeks prior to 
registration to rule out pregnancy. 
3.2.10 Sexually active women of childbearing potential and sexually active males are 
strongly advised to use an accepted and effective method of contraception. 
3.3 
Randomization (Groups I and II) 
3.3.1 
Patients must have a completely resected tumor and be within 21 - 56 days from the date 
of surgery. 
3.3.2 
Patients who received combination chemotherapy/radiation prior to randomization (Group 
I) must have had a minimum radiation dose of 50.4 Gy. 
3.3.3 
Patients must have ECOG performance status 0-1. 
3.3.4 
Patients must have adequate renal function (creatinine < 1.5 x ULN) obtained < 4 weeks 
prior to randomization. 
3.3.5 
Patients must have adequate hepatic function (bilirubin < 1.5 x ULN, SGOT (AST) < 3 x 
ULN) obtained < 4 weeks prior to randomization). 
3.3.6 
Patients must have absolute neutrophil count > 1500/mm 3 and platelet 
count > 100,000/mm3  < 4 weeks prior to randomization. 


Eastern Cooperative 
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3.3.7 
Patients must not have an active inflammatory bowel disease or other serious 
medical illness which might limit the ability of the patient to receive protocol therapy. 
4. 
Registration and Randomization Procedures 
Submitting Regulatory Documents 
 
Before an ECOG Institution may enter patients, protocol specific regulatory documents must 
be submitted to the CTSU Regulatory Office at the following address:   
 
 
 
 
CTSU Regulatory Office 
 
 
 
Coalition of National Cancer Cooperative Groups 
 
 
 
1818 Market Street, Suite 1100 
 
 
 
Philadelphia, PA 19103 
 
 
 
FAX: (215) 569-0206 
 
Required Protocol Specific Regulatory Documents 
 
1.  
CTSU Regulatory Transmittal Form. 
 
2.  
Copy of IRB Informed Consent Document. 
 
NOTE:  Any deletion or substantive modification of information concerning risks or 
alternative procedures contained in the sample informed consent document 
must be justified in writing by the investigator and approved by the IRB. 
 
3.  
A. CTSU IRB Certification Form. 
 
 
 
 
 
 
 
Or  
 
 
 
 
 
B.  
HHS 310 Form. 
 
 
 
 
 
 
 
 
Or  
C.  
IRB Approval Letter 
 
 
 
 
 
NOTE: 
The above submissions must include the following details: 
 
•  
Indicate all sites approved for the protocol under an assurance number. 
•  
OHRP assurance number of reviewing IRB 
•  
Full protocol title and number 
•  
Version Date 
•  
Type of review (full board vs. expedited) 
•  
Date of review. 
•  
Signature of IRB official 
 
The CTSU encourages you to link to the following RSS2.0 webpage so that more 
information on RSS2.0 as well as the submission forms can be accessed 
http://www.ctsu.org/rss2_page.asp. If you have questions regarding regulatory document 
submission, please telephone the CTSU Help Desk at 1-888-823-5923 or E-mail 
CTSUContact@westat.com.  Monday through Friday, 9:00am - 6:00pm. 
 
Patients must not start protocol treatment prior to registration. 
 
 
Treatment should start within three working days after registration. 


Eastern Cooperative 
E3201 
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REVISED 
 
Revised 3/07, Update #2 
11 
Institutions may register eligible patients to this study via the ECOG webpage 24 hours a 
day, 
7 
days 
a 
week, 
using 
the 
Web-based 
Patient 
Registration 
Program 
(https://webreg.ecog.org). If you need assistance or have questions, please telephone the 
Central Randomization Desk at the ECOG Coordinating Center at (617) 632-2022, Monday 
through Friday 9:00am – 5:00pm Eastern Time.  Please note that a password is required to 
use this program.  The following information will be requested: 
4.1 
Registration 
NOTE: The choice of pre-operative versus post-operative chemotherapy/XRT is at the treating 
physician’s discretion.  However, the physician must declare the selected regimen at the 
time of registration.  (See Section 5.0) 
4.1.1 
Protocol Number 
4.1.2 
Investigator Identification  
4.1.2.1 
Institution and affiliate name 
4.1.2.2 
Investigator’s name 
4.1.3 
Patient Identification  
4.1.3.1 
Patient’s initials and chart number 
4.1.3.2 
Patient’s Social Security number 
4.1.3.3 
Patient demographics 
4.1.3.3.1 
Sex 
4.1.3.3.2 
Birth date (mm/yyyy) 
4.1.3.3.3 
Race 
4.1.3.3.4 
Ethnicity 
4.1.3.3.5 
Nine-digit ZIP code 
4.1.3.3.6 
Method of payment 
4.1.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 3.0.  An 
eligibility checklist has been appended to the protocol.  A confirmation of registration 
will be forwarded by the ECOG Coordinating Center. 
4.1.5 
Additional Requirements  
4.1.5.1 
Patient must provide signed and dated written informed consent. 
4.1.5.2 
Physician will select and declare the regimen of chemotherapy/XRT. (See 
Section 5.0) 
4.1.5.3 
For Group I only, physician must also identify the surgical procedure to be 
performed. (see Section 5.7 Surgery) 
4.1.5.4 
The pathology materials should be submitted for correlative studies as 
outlined in Section 10. 
4.1.5.5 
[Deleted in Update #2] 
4.1.6 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and follow-up 
data will still be collected and must be submitted according to the instructions in the 
E3201 Forms Packet.  Document the reason for not starting protocol treatment on one 
Rev. 3/07 


Eastern Cooperative 
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12 
of the baseline forms.  Also report the date and type of the first non-protocol treatment 
that the patient receives and first progression. 
4.2 
Randomization 
NOTE: Randomization must occur between 21 and 56 days from the date of surgery. 
NOTE: Group II patients will be registered and randomized at the same time. 
Institutions may register eligible patients to this study via the ECOG webpage 24 hours a 
day, 
7 
days 
a 
week, 
using 
the 
Web-based 
Patient 
Registration 
Program 
(https://webreg.ecog.org).  If you need assistance or have questions, please telephone the 
Central Randomization Desk at the ECOG Coordinating Center 617-632-2022.  Please note 
that a password is required to use this program.  The following information will be requested: 
4.2.1 
Protocol Number 
4.2.2 
Investigator Identification 
4.2.2.1 
Institution name and/or affiliate 
4.2.2.2 
Investigator’s name 
4.2.3 
Patient Identification 
4.2.3.1 
Patient’s initials and chart number 
4.2.3.2 
Patient’s Social Security Number 
4.2.3.3 
Patient Demographics 
4.2.3.3.1 
Sex 
4.2.3.3.2 
Birthdate (MM/YYYY) 
4.2.3.3.3 
Race 
4.2.3.3.4 
Ethnicity 
4.2.3.3.5 
Nine-digit zip code 
4.2.3.3.6 
Method of payment 
4.2.4 
Eligibility Verification 
Patients must meet all of the eligibility requirements listed in Section 3.3.  An 
eligibility checklist has been appended to the protocol.   A confirmation of 
registration will be forwarded by the ECOG Coordinating Center. 
4.2.5 
Stratification Factors 
4.2.5.1 
ECOG Performance Status 0 vs. 1. 
4.2.5.2 
Pre-operative chemotherapy/XRT vs Post-operative chemotherapy/XRT 
4.2.5.3 
High risk(T3 N+ M0, T4 Nany M0) vs low risk (T1-2 N+M0, T3N0 M0) 
4.2.6 
Additional Requirements 
4.2.6.1 
The samples for laboratory studies should be submitted as outlined in 
section 10.0. 
4.2.6.2 
For Group I and Group II, physician must indicate the surgical procedure 
performed. (See Section 5.7 Surgery) 
4.2.7 
Instructions for Patients Who Do Not Start Assigned Protocol Treatment 
If a patient does not receive any assigned protocol treatment, baseline and follow-up 
data will still be collected and must be submitted according to the forms packet 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
13 
referenced in the Records to be Kept section (see Section 12.0).  Document the 
reason for not starting protocol treatment on one of the baseline forms.  Also report 
the date and type of the first non-protocol treatment that the patient receives. 
 
5. 
Treatment Plan 
Group I patients will receive concurrent chemotherapy (Section 5.1) and radiation (Section 5.5) prior 
to surgery. Twenty-one (21) to 56 days post-surgery, patients will be randomized to receive 
irinotecan/leucovorin/5-FU, oxaliplatin/leucovorin/5-FU or  leucovorin/5-FU (Section 5.2). 
Group 1 PS patients are registered and randomized 21 to 56 days following surgery. At 
randomization, patients will receive one of the following: irinotecan/leucovorin/5-FU, oxaliplatin/ 
leucovorin/ 5-FU or leucovorin/5-FU (Section 5.2.). 
Group II patients will be registered and randomized 21 to 56 days following surgery. Upon 
randomization, patients will receive an initial treatment cycle of irinotecan/leucovorin/5-FU, 
oxaliplatin/leucovorin/5-FU or leucovorin/5-FU.  Concurrent chemotherapy (Section 5.1) and 
radiation therapy (Section 5.5) will then be administered followed by further cycles of 
irinotecan/leucovorin/   5-FU, oxaliplatin/leucovorin/5-FU or  leucovorin/5-FU. 
5.1 
Chemotherapy Regimens Allowed During Radiation Therapy 
NOTE: All doses are based on actual weight 
Patients will receive concurrent radiation and chemotherapy, which will consist of one of the 
following regimens, either pre-operatively or post-operatively.  Please note that the radiation 
plus capecitabine regimen is open only to those patients enrolled on NSABP R-04.  The 
radiation regimen is defined in Section 5.5. 
Physicians must select and report the chosen chemotherapy regimen at the time of 
registration. The regimens allowed are: 
XRT + continuous infusion 5-FU  
FU 225 mg/m2 over 24 hours 7 days/week during XRT 
NOTE: Patients entered on R-04 may have been randomized to protracted venous 
infusion (PVI) 5-FU. Treatment with XRT and PVI 5-FU must therefore 
follow R-04 specifications. 
XRT + 5-FU/LV  
5-FU 400 mg/m2 + Leucovorin 20 mg/m2 for 4 days during Weeks 1 and 5 of XRT   
 
XRT + Capecitabine 
825 mg/m2 PO BID throughout course of XRT (beginning 2 hours before start of 
XRT and ending with the last dose of XRT). This regimen is allowed only if 
patient is enrolled on NSABP R-04 
 
5.2 
Administration Schedule 
NOTE: All doses are based on actual weight. Postoperative chemotherapy should begin 
within 8 weeks after surgery. 
5.2.1 
Group 1 (Preoperative Chemotherapy/XRT) 
Upon registration, patients are to receive concurrent chemotherapy (Section 5.1) 
and radiotherapy (Section 5.5) prior to surgery.  Patients will then be randomized to 
one of the following three treatments.  Post-operative chemotherapy should begin 21 
to 56 days after surgery. (Post-operative chemotherapy should begin 21 to 56 days 
after surgery for Group 1 PS, also.) 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
14 
5.2.1.1 
Arm A 
Irinotecan 
180 mg/m², IV over 90 minutes 
Leucovorin 
400 mg/m², IV over 2 hours 
5-FU  
400 mg/m², IV bolus injection immediately following 
leucovorin dose 
5-FU 
 2.4 gm/m² over 46 hours, by ambulatory infusion pump, 
immediately following bolus 5-FU. 
A cycle is comprised of a 2-day treatment period administered every 2 
weeks.  Eight (8) cycles will be administered. 
NOTE: 
Dose escalation is allowed; see section 5.4.2. 
5.2.1.2 
Arm B 
Oxaliplatin  
85 mg/m2, IV over 120 minutes 
Leucovorin  400 mg/m2, IV over 2 hours 
5-FU 
400 mg/m2, IV bolus injection immediately following 
leucovorin dose. 
5-FU  
2.4 gm/m2 over 46 hours, by ambulatory infusion pump, 
immediately following bolus 5-FU. 
A cycle is comprised of a 2-day treatment period administered every 2 
weeks.  Eight (8) cycles will be administered. 
NOTE: 
Dose escalation is allowed; see section 5.4.3. 
5.2.1.3 
Arm C 
Leucovorin  500 mg/m², IV over 2 hours once a week for 6 weeks 
5-FU 
500 mg/m², IV bolus injection 1 hour after the start of the 
leucovorin infusion, once a week for 6 weeks   
A cycle is comprised of 6 weeks of treatment followed by 2 weeks of rest. 
Three (3) cycles will be administered. 
 
5.2.2 
Group II (Post-operative Chemotherapy/XRT) 
Patients are to be registered and randomized 21 to 56 days after surgery.  Upon 
registration, patients will be randomized to one of the following three treatments.  
Concurrent chemotherapy (Section 5.1) and radiation therapy (Section 5.5) will then 
be administered followed by further courses of the chemotherapy assigned at 
randomization. 
5.2.2.1 
Arm D 
Irinotecan  
180 mg/m², IV over 90 minutes 
Leucovorin  
400 mg/m², IV over 2 hours 
5-FU  
400 mg/m², IV bolus injection immediately following each 
leucovorin dose 
5-FU  
2.4 gm/m² over 46 hours by ambulatory infusion pump 
immediately following bolus 5-FU. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
15 
A cycle is comprised of a 2-day treatment administered 
every 2 weeks. Four cycles will be administered followed by 
concurrent pelvic XRT + chemotherapy,  followed by an 
additional 4 cycles of irinotecan/leucovorin/5-FU. 
NOTE: Dose escalation is allowed; see section 5.4.2. 
NOTE:  Concurrent pelvic XTR + chemotherapy should 
begin within 4 weeks of the completion of the first 4 
cycles of chemotherapy.  Four to 6 weeks after the 
completion 
of 
concurrent 
pelvic 
XTR 
+ 
chemotherapy, 
the 
second 
4 
cycles 
of 
chemotherapy will be administered.  
5.2.2.2 
Arm E 
Oxaliplatin  
85 mg/m2, IV over 120 minutes 
Leucovorin  400 mg/m2, IV over 2 hours 
5-FU  
400 mg/m2, IV bolus injection immediately following 
leucovorin dose. 
5-FU  
2.4 gm/m2 over 46 hours, by ambulatory infusion pump, 
immediately following bolus 5-FU. 
A cycle is comprised of a 2-day treatment period administered every 2 weeks, 
Four cycles will be administered followed by concurrent pelvic XRT + 
chemotherapy, followed by an additional 4 cycles of oxaliplatin/leucovorin/5-
FU. 
NOTE: Dose escalation is allowed; see section 5.4.3. 
NOTE:  Concurrent pelvic XTR + chemotherapy should begin within 4 
weeks of the completion of the first 4 cycles of chemotherapy.  
Four to 6 weeks after the completion of concurrent pelvic XTR + 
chemotherapy, the second 4 cycles of chemotherapy will be 
administered.  
5.2.2.3 
Arm F 
Leucovorin 
500 mg/m², IV over 2 hours once a week for 6 weeks 
5-FU  
500 mg/m², IV bolus injection one hour after the start of the 
leucovorin infusion, once a week for 6 weeks   
A cycle is comprised of 6 weeks of treatment followed by 2 weeks of rest. 
One cycle will be administered followed by concurrent pelvic XRT + 
chemotherapy followed by an additional 2 cycles of leucovorin/5-FU. 
NOTE:  Concurrent pelvic XTR + chemotherapy should begin within 4 
weeks of the completion of the first cycle of chemotherapy.  Four to 
6 weeks after the completion of concurrent pelvic XTR + 
chemotherapy, the final 2 cycles of chemotherapy will be 
administered. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
16 
5.3 
Dose Specifics 
5.3.1 
Dose Specifics (Arms A and D) –Groups I, I PS, and II 
5.3.1.1 
Irinotecan 
The starting dose of irinotecan will be 180 mg/m2 (infused over 90 
minutes) given once every 2 weeks. 
For the first 2 cycles of irinotecan, patients should remain in the treatment 
area for a minimum of one hour following completion of irinotecan infusion 
in case acute abdominal cramping develops. 
5.3.1.2 
Leucovorin 
The dose of leucovorin will remain fixed at 400 mg/m2, administered over 
two hours and may be given during the irinotecan infusion. 
5.3.1.3 
5-Fluorouracil 
The starting dose of 5-FU will be 400 mg/m2, given as an intravenous 
bolus injection immediately following leucovorin dose. 
The starting dose of continuous infusion 5-FU is 2.4 grams administered 
over 46 hours using an ambulatory infusion pump to begin immediately 
following bolus 5-FU. 
5.3.2 
Dose Specifics (Arms B and E) – Groups I, I PS and II 
5.3.2.1 
Oxalplatin 
The starting dose of oxaliplatin will be 85 mg/m2 (infused over 2 hours) 
given once every two weeks. 
5.3.2.2 
Leucovorin 
The dose of leucovorin will remain fixed at 400 mg/m2  and administered 
over 2 hours 
5.3.2.3 
5-Fluorouracil 
The starting dose of 5-FU will be 400 mg/m2, given as an intravenous 
bolus injection immediately following leucovorin dose. 
The starting dose of continuous infusion 5-FU is 2.4 grams administered 
over 46 hours using an ambulatory infusion pump to begin immediately 
following bolus 5-FU. 
5.3.3 
Dose Specifics (Arms C and F) – Groups I, I PS and II 
5.3.3.1 
Leucovorin 
500 mg/m2 diluted in 250 cc of normal saline and administered IV as a 2 
hour infusion weekly for six consecutive weeks followed by a two week 
rest period. 
5.3.3.2 
5-FU 
500 mg/m2 administered bolus IV one hour after the start of the leucovorin 
infusion, weekly for six weeks followed by two weeks rest. 
5.4 
Dose Modifications 
NOTE: All toxicities should be graded according to the Common Terminology Criteria 
for Adverse Events (CTCAE) (version 3.0). 
Rev. 4/04


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
17 
5.4.1 
Dose Modifications for Combined Chemotherapy and Radiation - Group I (Pre-Op) 
and Group II (Post-Op) 
NOTE: Dose Modifications for Radiation Toxicity: Refer to Section 5.58. 
NOTE: All patients who are randomized on NSABP R-04 and receive capecitabine 
or continuous infusion 5-FU must follow dose mods as written in R-04 
NOTE: If toxicities have not resolved within 3 weeks, the patient’s protocol 
treatment will be discontinued. 
 
Patients must have WBC > 3500/μl and platelet count > 100,000/μl prior to 
initiation of combined XRT-continuous infusion 5-FU.  Dose modification 
should be based upon worst grade of toxicity experienced. 
5.4.1.1 
Concurrent XRT and Continuous Infusion 5-FU 
5.4.1.1.1 
Hematologic Toxicities 
 
WBC (/µl) 
Platelets (/µl) 
Modification 
< 2000 
< 50,000 
Hold until WBC > 2000 
and PLT > 50,000; 
resume at full dose 
5.4.1.1.2 
Stomatitis of Diarrhea 
 
Grade 
Toxicities/Symptoms 
Modification 
1 
 
Continue current dose 
level 
>2 
Mucositis, stomatitis or 
esophagitis 
Hold** until < grade 1 
and decrease dose by 
50 mg/m2/d 
>3 
Diarrheas > 7 
stools/day above 
baseline 
Hold** until < grade 1; 
resume at same dose 
** 
In the event of a dose “hold”, the central venous catheter should be flushed 
daily to prevent catheter occlusion. 
5.4.1.2 
Concurrent XRT and Bolus 5-FU/Leucovorin 
If radiation therapy is delayed, the chemotherapy should be similarly 
delayed so that chemotherapy is always given during the first and fifth 
week of radiation therapy.  Different drug modifications will be made 
depending on whether the toxicity is the maximum seen during the 
interval between the two doses of chemotherapy or the toxicity at the time 
of delivery of the second dose of chemotherapy (with week 5 radiation 
therapy). 
Maximum toxicity during interval between courses of 5-FU given 
during radiation therapy: 
5.4.1.2.1 
Hematologic Nadirs 
 
WBC (/µl) 
Platelets (/µl) 
Modification 
1000-2500 
 
< 1000 
25,000-75,000 
 
< 25,000 
Reduce by 20% 
 
Reduce by 30% 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
18 
5.4.1.2.2 
Stomatitis or Diarrhea 
 
Grade 
Toxicities/Symptoms 
Modification 
> 1 
 
Continue current dose 
level 
2 
Stomatitis 
Reduce by 20% 
3 
Diarrhea 
Stomatitis 
Reduce by 20% 
Reduce by 30% 
4 
Diarrhea/Stomatitis 
Reduce by 30% 
Toxicity at time of second dose of chemotherapy during radiation 
therapy: 
5.4.1.2.3 
Hematologic Toxicites 
 
WBC (/µl) 
Platelets (/µl) 
Modification 
< 3500 
< 75,000 
Do not administer  
2nd course 
5.4.1.2.4 
Stomatitis or Diarrhea 
 
Grade 
Toxicities/Symptoms 
Modification 
2-4 
Stomatitis 
Do not administer  
2nd course 
2*-4 
Diarrhea 
Delay chemotherapy 
with radiation therapy 
delay until diarrhea 
returns to Grade 1. 
Reinitiate XRT and 
chemotherapy with 
appropriate 5-FU dose 
reductions after 
diarrhea resolution. 
* Grade 2 diarrhea with loose, watery bowel movements. 
5.4.2 
Dose Modifications – Arms A and D (Groups I & II) 
The final dose modification according to the following tables should be made based 
upon the worst grade of toxicity experienced.  Note that the leucovorin dose remains 
constant and without modification. IF patients require dose reductions lower than 
level -2, protocol therapy will be discontinued. 
 
Irinotecan 
(mg/m2) 
Leucovorin 
(mg/m2) 
Bolus 5-FU 
(mg/m2) 
Infusion 5-FU 
(mg/m2) 
Level +1 
180 
400 
400 
3 
Starting 
Dose** 
180 
400 
400 
2.4 
Level –1 
150 
400 
320 
2 
Level –2 
90 
400 
200 
2* 
* 
In case of hand-foot syndrom, the dose of infusional 5-FU, only, may be further reduced 20% 
as needed. 
** 
All patients will start cycle 1 with doses list in the “starting dose” row. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
19 
Dose escalation to “dose level +1” should be performed if the following conditions 
are met: the full course of cycle 1 must have been associated with no greater than 
grade 1 diarrhea and/or neutropenia and cycle 1 did not require omission of a dose 
or dose reduction. Any dose reduction is continued for all subsequent cycles. Dose 
re-escalation on Arms A and D is not allowed following a dose reduction. 
5.4.2.1 
Neutropenia and Other Hematologic Toxicities 
 
Grade 
ANC1 
(/mm3) 
 
Platelets1 
(/mm3) 
Modification 
1 
> 1500 
Or 
> 75,00 
Continue current dose level 
2 
> 1000 - 
<1500 
Or 
> 50,000- 
<75,000 
Hold until < grade 1 and decrease dose 
level 
> 3 
<1000 
Or 
<50,000 
Hold until < grade 1 and decrease 2 dose 
levels 
1 
Within 24 hours of day of treatment 
5.4.2.2 
Diarrhea 
 
Grade 
Without colostomy1 
With colostomy1 
Modification2 
1 
Increase of < 4 
stools/day over 
baseline 
Mild increase in loose, 
watery colostomy output 
compared with 
pretreatment 
Continue current 
dose level 
2 
Increase of 4-6 stools 
per day from baseline 
or nocturnal stools 
Moderate increase in loose, 
watery colostomy output 
compared with 
pretreatment, but not 
interfering with normal 
activity 
Hold until < grade 1 
and decrease 1 
dose level 
3 
Increase of 7 or more 
stools per day from 
baseline or 
incontinence or need 
dor parenteral support 
Severe increase in loose, 
watery colostomy output 
compared with 
pretreatment, interfering 
with normal activity 
Hold until < grade 1 
and decrease 1 
dose level 
4 
Physiologic 
consequences 
requireing intesive 
care or hemodynamic 
collapse 
Physiologic consequences, 
requireing intesive care; or 
hemodynamic collapse 
Hold until < grade 1 
and decrease 2 
dose levels 
1 
Within 24 hours of day of treatment 
2 
Any dose reduction is continued for all subsequent cycles. Dose re-escalation on 
Arms A and D is not allowed following a dose reduction. 
See Section 5.4.5 for the treatment of diarrhea. 
5.4.2.3 
All Other Toxicities 
All other toxicities should be managed by grade according to the 
modifications described for diarrhea in section 5.4.2.2. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
20 
5.4.2.4 
Adjustments to Treatment Schedule Following the ‘Withhold’ of Treatment 
for Toxicity 
In order to maintain dose intensity, the schedule of treatment should be 
adjusted for any treatment days that are withheld, such that no dose is 
ever omitted from the schedule. 
5.4.3 
Dose Modifications – Arms B and E (Groups I andII) 
The final dose modification according to the following tables should based upon the worst 
grade of toxicity experienced. If patients require dose reductions lower than level-2, 
protocol therapy will be discontinued.  Any dose reduction is continued for all subsequent 
cycles. Dose re-escalation on Arms B and E is not allowed following a dose reduction. 
Note that leucovorin dose remains constant and without modification. 
 
 
Oxalplatin 
(mg.m2) 
Leucovorin 
(mg/m2) 
Bolus 5-FU 
(mg/m2) 
Infusional 5-FU 
(gm/m2) 
Level +1 
100 
400 
400 
3 
Starting Dose** 
85 
400 
400 
2.4 
Level –1 
65 
400 
320 
2 
Level –2 
50 
400 
200 
2* 
* 
In case of hand foot syndrom, the dose of infusional 5-FU may be further reduced by 20% as 
needed. 
** 
All patients will start cycle 1 with doses listed in the “Starting Dose” row. 
Dose escalation to level +1 is allowed following cycle 1, provided the following 
criteria are met: 
1) 
Cycle 
was 
tolerated 
with 
diarrhea, 
neutropenia 
and 
thrombocytopenia no worse than grade 1 
2) 
The start of cycle 2 did not require a delay. 
5.4.3.1 
Neutropenia and Other Hematologic Toxicities 
 
Grade 
ANC1 
(/mm3) 
 
Platelets1 
(/mm3) 
Modification 
1 
> 1500 
Or 
> 75,00 
Continue current dose level 
2 
> 1000 - 
<1500 
Or 
> 50,000- 
<75,000 
Hold until < grade 1 and decrease dose 
level 
> 3 
<1000 
Or 
<50,000 
Hold until < grade 1 and decrease 2 dose 
levels 
1 
Within 24 hours of day of treatment 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
21 
5.4.3.2 
Diarrhea 
 
Grade 
Without colostomy1 
With colostomy1 
Modification2 
1 
Increase of < 4 stools/day over 
baseline 
Mild increase in loose, watery 
colostomy output compared 
with pretreatment 
Continue current 
dose level 
2 
Increase of 4-6 stools per day 
from baseline or nocturnal 
stools 
Moderate increase in loose, 
watery colostomy output 
compared with pretreatment, 
but not interfering with normal 
activity 
Hold until < grade 1 
and decrease 1 
dose level 
3 
Increase of 7 or more stools 
per day from baseline or 
incontinence or need dor 
parenteral support 
Severe increase in loose, 
watery colostomy output 
compared with pretreatment, 
interfering with normal activity 
Hold until < grade 1 
and decrease 1 
dose level 
4 
Physiologic consequences 
requireing intesive care or 
hemodynamic collapse 
Physiologic consequences, 
requireing intesive care; or 
hemodynamic collapse 
Hold until < grade 1 
and decrease 2 
dose levels 
1 
Within 24 hours of day of treatment 
See Section 5.4.5 for the treatment of diarrhea. 
5.4.3.3 
Dose Modifications for Neurologic Toxicity of Oxaliplatin 
 
Toxicity (Grade) 
Duration of Toxicity 
Duration of Toxicity 
Persistent 
Between 
Doses2 
 
1-7 Days 
> 7 Days 
 
Paresthesias/dysesthesias1 of short 
duration that resolve and do not 
interfere with function (Grade 1) 
No change 
No change 
No change 
Paresthesias/dysesthesias1 interfering 
with function, but not activities of daily 
living (ADL) (Grade 2) 
No change 
No change 
Reduce 
oxalplatin 1 
dose level 
Paresthesias/dysesthesias1 with pain or 
with functional impairment that also 
interferes with ADL (Grade 3) 
1st time: reduce oxaliplatin 1 
dose level 
2nd time: reduce oxaliplatin 
another dose level 
1st time: reduce oxaliplatin 
1 dose level 
2nd time: reduce 
oxaliplatin another dose 
level 
Discontinue 
protocol 
therapy 
Persistent Paresthesias/dysesthesias1 
that is disabling or life-threatening 
(Grade 4) 
Discontinue protocol therapy 
Discontinue protocol 
therapy 
Discontinue 
protocol 
therapy 
Pharyngo-laryngeal dysesthesias 
 
 
 
Grade 1 (mild) 
No change 
Increase duration of 
infusion to 6 hours 
Increase 
duration of 
infusion to 6 
hours 
Grade 2 (moderate) and Grade 3 
(severe).  Management of grade 2-3 
pharyngo-laryngeal dysesthesias occurs 
while treatment is being administered 
-Stop oxaliplatin infusion 
-Administer benzodiazepine 
and give patient reassurance. 
-At the discretion of the 
investigator, the infusion can 
be restarted at 1/3 the 
original rate of infusion 
Discontinue oxaliplatin 
permanently 
Discontinue 
oxaliplatin 
permanently 
1 
May be cold-induced 
2 
Not resolved by the beginning of the next cycle. 
NOTE:  See Appendix VI for a comparative table outlining the differentiation of platinum hypersensitivity from toxicity unqiue to 
oxaliplatin and pharngolaryngodyesthesias. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
22 
5.4.3.4 
Hemolytic Uremic Syndrome 
There have been several reports of hemolytic uremic syndrome (HUS) 
associated with oxaliplatin use.  The hemolytic uremic syndrome should 
be suspected in individuals who experience the following unexplained 
severe hemolysis, hemoglobinemia, and renal failure as demonstrated by 
an increase in serum creatinine. 
Oxaliplatin should be discontinued permanently for any suspected 
occurrence of hemolytic uremic syndrome. 
Patients suspected of experiencing HUS must have the following 
laboratory analyses conducted: 
Creatinine, BUN 
Urinalysis with microscopic evaluation 
CBC with differential and platelets 
PT/PTT 
Fibrinogen, Fibrinogen Degradation Products (FDP) 
Anti-thrombin III (ATIII) 
von Willebrand Factor (VWF)  
Anti-nuclear antibodies (ANA) 
Rheumatoid Factor (RhF) 
C3, C4, CH50 
Anti-platelet antibodies 
Platelet associated IgG 
Circulating immune complexes 
5.4.3.5 
Pulmonary Fibrosis 
There have been reports of pulmonary fibrosis associated with oxaliplatin 
use.  Patients receiving oxaliplatin should be instructed to promptly report 
any respiratory difficulties 
Pulmonary toxicities of grade 3 or worse will require that oxaliplatin be 
withheld until resolved to grade 1 or less.  Signs and symptoms 
associated with pulmonary fibrosis (cough, dyspnea, rales, hypoxia and 
tachypnea) should be investigated to rule out pulmonary fibrosis as their 
cause.  The investigation for pulmonary fibrosis should include (but not be 
limited to): chest radiography, oxygen saturation by pulse oximetry or 
arterial blood gas evaluation and pulmonary function testing to include 
DLCO. 
The diagnosis of pulmonary fibrosis will result in the discontinuation of 
oxaliplatin. These patients may continue to receive fluorouracil and 
leucovorin. 
5.4.3.6 
All Other Toxicities 
All other toxicities should be managed by grade according to the 
modifications described for diarrhea in section 5.4.3.2. 
5.4.3.7 
Adjustments to Treatment Schedule Following the ‘Withhold’ of Treatment 
for Toxicity 
In order to maintain dose intensity, the schedule of treatment should be 
adjusted for any treatment days that are withheld, such that no dose is ever 
omitted from the schedule. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
23 
5.4.4 
Dose Modifications- Arms C and F (Groups I & II) 
The final dose modification according to the following tables should be made based 
upon the worst grade of toxicity experienced. Note that the leucovorin dose remains 
constant and without modification. 
5.4.4.1 
Neutropenia and Other Hematologic Toxicites 
 
Grade 
ANC1 
(/mm3) 
 
Platelets1 
(/mm3) 
Modification2 
1 
> 1500 
Or 
> 75,00 
Continue current dose level 
2 
> 1000 - 
<1500 
Or 
> 50,000- 
<75,000 
Hold until < grade 1 then resume 5-FU at a 100mg/m2 
dose reduction to complete the cycle.3,4 
> 3 
<1000 
Or 
<50,000 
Hold for at least 3 weeks from last dose and < grade 1 
then resume 5-FU at a 100mg/m2 dose reduction to 
complete the cycle. 3,4 
1 
Within 24 hours of day of treatment 
2 
Leucovorin dose remains fixed at 500mg/m2. 
3 
If occurs after week 4 of any cycle, begin the rest period. 
4 
5-FU dose re-escalation in subsequent cycles will be allowed at 100mg/m2 
increments per cycle. 
5.4.4.2 
Diarrhea, Vomiting,Stomatitis 
 
Grade1 
Modification2 
1 
Hold until resolved, then resume 5-FU at at a 100mg/m2 dose reduction 
to complete the cycle. 3,4 
2 
Hold for at least 2 weeks AND until resolved, then resume the 5-FU at a 
100mg/m2 dose reduction to complete the cycle. 3,4 
3 and 4 
Discontinue protocol therapy and initate appropriate supportive care. 
1 
Within 24 hours of day of treatment 
2 
Leucovorin dose remains fixed at 500mg/m2. 
3 
If occurs after week 4 of any cycle, begin the rest period. 
4 
5-FU dose re-escalation in subsequent cycles will be allowed at 100mg/m2 
increments per cycle. 
See Section 5.4.5 for diarrhea control 
5.4.4.3 
All other toxicites 
All other toxicities should be managed by grade according to the 
modifications described for hematologic toxicity in Section 5.4.4. 
5.4.5 
Management of Gastrointestinal Toxicity (All Patients) 
Patients will be instructed to begin taking loperamide at the earliest signs of a poorly 
formed or loose stool.  Loperamide should be taken in the following manner:  4 mg at 
the first onset of diarrhea, then 2 mg every two hours around the clock until the 
patient is diarrhea-free for at least 12 hours.  Patients may take loperamide 4 mg (2 
capsules) every four hours during the night.  If there is no relief within 24-36 hours, 
add deodorized Tincture of Opium 4 drops in 1/4 to 1/2 cup of bland liquid or juice 
every 4 hours around the clock. In addition, begin oral fluoroquinolone and continue 
for 7 days. 


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24 
If diarrhea persists for greater than 48 hours, parenteral hydration is recommended 
(including hospitalization for such). Oral fluroquinolone treatment also should be 
initiated for patients who develop an ANC < 500mm3 (even in the absence of fever or 
diarrhea) or a fever that occurs with diarrhea (even without neutropenia). Antibiotics 
should continue until resolution of diarrhea.  (Refer to Appendix IX, Diarrhea 
Management Instructions.) 
Diarrhea or abdominal cramping that occurs during or within one hour after receiving 
irinotecan can be treated with atropine (0.25 to 1 mg IV as indicated).  Patients 
having recurrent problems with cholinergic symptoms may receive atropine 
prophylactically (SC or IV).   Additional antidiarrheal measures may be used at the 
discretion of the treating physician. 
Patients who experience diarrhea during treatment may benefit from dietary 
modification and/or consultation with a clinical dietitian.  Examples of foods which 
may exacerbate diarrhea include milk, ice cream, whole bran bread and cereal, nuts, 
seeds, fried or fatty foods, fresh and dried fruit, prune juice, raw vegetables, popcorn, 
potato chips, chocolate, coffee, teas, alcoholic beverages and cooked fruits and 
vegetables with seeds or skins such as berries, corn and tomatoes.  Foods which 
may mitigate problems with diarrhea include fish, poultry and meat that is cooked, 
broiled or roasted, bananas, apple sauce, peeled apples, white bread, macaroni and 
noodles, baked, boiled or mashed potatoes, cooked vegetables that are mild, such as 
asparagus tips, green and waxed beans, carrots, spinach, squash, mild processed 
cheese, eggs and smooth peanut butter. 
5.4.6 
Dose Modification for Obese Patients 
There is no clearly documented adverse impact of treatment of obese patients when 
dosing is performed according to actual body weight.  Therefore, all dosing is to be 
determined solely by (1) the patient’s BSA as calculated from actual weight or (2) 
actual weight without any modification unless explicitly described in the protocol.  
This will eliminate the risk of calculation error and the possible introduction of 
variability in dose administration.  Failure to use actual body weight in the calculation 
of drug dosages will be considered a major protocol deviation.  Physicians who are 
uncomfortable with administering chemotherapy dose based on actual body weight 
should not enroll obese patients. 
5.4.7 
Interruption of Chemotherapy for Reasons Other Than Toxicity 
Closure of Colostomy: The time for closure of the colostomy will be at the discretion 
of the surgeon and should be arranged to minimize time off chemotherapy.  Closure 
of colostomy following completion of chemotherapy is encouraged.  The total number 
of cycles should be retained. 
5.5 
Radiation Therapy 
All patients will receive a total of 50.4 Gy external beam radiation therapy at 1.8 Gy per 
fraction per day for 28 fractions over a total of 5 1/2 weeks.  Pelvic fields will receive 45 Gy in 
25 fractions, followed by a boost of 5.4 Gy in 3 fractions.  Intraoperative radiation therapy 
and/or brachytherapy are strictly prohibited. 
The Quality Assurance Review Center (QARC) will perform a Final Review at the completion 
of radiation therapy. Please see sections 5.5.11, 12.3 and Appendix IV for the quality 
assurance documentation requirements. 
Standard and conformal techniques will be allowed in this study.  Institutions using conformal 
techniques must complete a 3D benchmark.  The benchmark materials may be obtained from 
the QARC website (www.QARC.org) and must be submitted to QARC prior to final review.
Rev. 11/05 


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5.5.1 
Patient Positioning and Setup/Treatment Planning and Verification 
Multiple fields technique (usually either 3 fields with a posterior and 2 lateral fields 
with wedges or 4 fields with anterior, posterior and 2 lateral fields) is mandatory.  
Custom shielding is mandatory to exclude as much small bowel as possible. Prone 
position is recommended, and “belly-drop” devices should be considered. It is 
recommended that the buttocks be taped apart to decrease self-bolus effect. It is also 
recommended that patients be treated with a full bladder. They should be instructed 
to void 1 hour before XRT and immediately drink 16 ounces of a non-caffeinated 
beverage and then not void until after treatment is complete for that day.  All fields 
must be treated daily. 
As part of the treatment planning process, all patients will undergo simulation for all 
fields to be treated with a machine that duplicates the geometry of the actual 
treatment machine.  Conventional simulation or the use of CT based simulation linked 
to software that allows "virtual simulation" are both allowed as long as the simulation 
process provides for duplication of the geometry of the actual treatment machine. It is 
recommended that oral gastrointestinal contrast material be given between 1 and 2 
hours prior to simulation to facilitate definition of the small bowel, so that as much as 
possible of this normal structure can be shielded. At the time of simulation, barium or 
other contrast materials should be placed in the rectum. The anal verge should be 
marked with a radio-opaque marker. 
5.5.2 
Target Volume – Initial Fields 
5.5.2.1 
Preoperatively Irradiated Patients 
The target volume will include the entire tumor and nodal groups at risk for 
metastatic disease.  This will include the internal iliac and pre-sacral lymph 
nodes.  The external iliac nodes will be included when tumors extend to the 
uterus, cervix, vagina, bladder or prostate.  Exclusion of as much bowel as 
possible through the use of custom shielding is required. 
5.5.2.2 
Postoperatively Irradiated Patients 
The target volume will include the entire preoperative tumor and nodal 
groups at risk for metastatic disease.  Determination of the preoperative 
tumor volume will be based on findings from preoperative and 
intraoperative evaluations, including preoperative endoscopy studies, 
preoperative imaging studies (such as CT scans or barium enema), the 
operative note and the pathology report.  Clips placed by the surgeon to 
mark the tumor bed may also be used for determining the preoperative 
tumor volume.  This will include the internal iliac and pre-sacral lymph 
nodes.  The external iliac nodes will be included for tumors that extended 
to the uterus, vagina, bladder or prostate. Exclusion of as much bowel as 
possible through the use of custom shielding is required. 
5.5.3 
PA and AP Fields 
5.5.3.1 
PA and AP Fields in Preoperatively Irradiated Patients 
The superior border of the fields will extend at least 3 cm superior to the 
tumor, and will be no lower than L5-S1 interspace.  The inferior border will 
be at least 2 cm distal to the tumor.  The lateral border of the fields will be 
at least 1.5 cm lateral to the greater sciatic notch on each side.  
Customized blocking is recommended for all fields.  Blocks will provide at 
least 3 cm margin around the tumor.  Superiorly, the blocks will be on or 
lateral to the sacroilliac joints. Inferiorly, the blocks will be on or lateral to a 
line connecting the ischial tuberosities to the field edge at the widest 


Eastern Cooperative 
E3201 
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REVISED 
26 
separation of the pelvis at the level of the greater sciatic notch. As outlined 
in Section 5.5.1, AP fields need not be used in patients treated with PA 
and lateral fields. 
5.5.3.2 
PA and AP Fields in Postoperatively Irradiated Patients 
5.5.3.2.1 
PA and AP Fields for Postoperatively Irradiated Patients 
Who Have Had An Anterior Resection 
The superior border of the fields will extend at least 3 cm 
superior to the tumor bed, and will be no lower than L5-
S1 interspace.  The inferior border will be at least 2 cm 
distal to the tumor bed.  The lateral border of the fields 
will be at last 1.5 cm lateral to the greater sciatic notch 
on each side.  Customized blocking is recommended for 
all fields.  Blocks will provide at least 3 cm margin 
around the tumor bed.  Superiorly, the blocks will be on 
or lateral to the sacroiliac joints. Inferiorly, the blocks will 
be on or lateral to a line connecting the ischial 
tuberosities to the field edge at the widest separation of 
the pelvis at the level of the greater sciatic notch. As 
outlined in Section 5.51, AP fields need not be used in 
patients treated with PA and lateral fields. 
5.5.3.2.2 
PA and AP Fields For Postoperatively Irradiated 
Patients Who Have Had An Abdominal Perineal 
Resection 
The superior border of the fields will extend at least 3 cm 
superior to the tumor bed, and will be no lower than L5-
S1 interspace.  The inferior border will include the entire 
perineal scar.  It is recommended that the perineal scar 
be identified with radio-opaque markers prior to 
simulation to assist with identification and inclusion in 
the RT field.  The lateral border of the fields will be at 
last 1.5 cm lateral to the greater sciatic notch on each 
side.  Customized blocking is recommended for all 
fields.  Blocks will provide at least 3 cm margin around 
the tumor bed.  Superiorly, the blocks will be on or 
lateral to the sacroiliac joints. Inferiorly, the blocks will be 
on or lateral to a line connecting the ischial tuberosities 
to the field edge at the widest separation of the pelvis at 
the level of the greater sciatic notch. 
5.5.4 
Lateral Fields 
5.5.4.1 
Lateral Fields For Preoperatively Irradiated Patients 
The superior and inferior borders of the lateral fields will be the same as 
the AP-PA fields.  The posterior border/blocking will provide for a margin of 
at least 1.5 cm on the anterior sacrum.  The anterior border/blocking will 
extend at least 2.5 cm anterior to the tumor and will also include the 
internal iliac nodes.  In most patients, this will mean that the anterior 
border is such that the anterior half to one-third of the femoral heads lie 
anterior to the anterior border of the lateral RT field.  In patients at risk for 
external iliac lymph node involvement, because of involvement of the 
bladder, prostate, vagina, cervix or uterus, the field will extend to the 
anterior symphysis pubis, to allow for inclusion of the external iliac lymph 
nodes. 


Eastern Cooperative 
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27 
5.5.4.2 
Lateral Fields For Postoperatively Irradiated Patients 
5.5.4.2.1 
Lateral Fields For Postoperatively Irradiated Patients 
Who Have Had An Anterior Resection: 
The superior and inferior borders of the lateral fields will 
be the same as the AP-PA fields.The posterior 
border/blocking will provide for a margin of at least 1.5 
cm on the anterior sacrum.  The anterior border/blocking 
will extend at least 2.5 cm anterior to the tumor bed and 
will also include the internal iliac nodes.  In most 
patients, this will mean that the anterior border is such 
that the anterior half to one-third of the femoral heads lie 
anterior to the anterior border of the lateral RT field.  In 
patients at risk for external iliac lymph node involvement, 
because of involvement of the bladder, prostate, vagina, 
cervix or uterus, the field will extend to the anterior 
symphysis pubis, to allow for inclusion of the external 
iliac lymph nodes. 
5.5.4.2.2 
Lateral Fields For Postoperatively Irradiated Patients 
Who Have Had An Abdominal Perineal Resection 
The superior and inferior borders of the lateral fields will 
be the same as the AP-PA fields. The inferior border 
and the posterior border will include the entire perineal 
scar.  It is recommended that the perineal scar be 
identified with radio-opaque markers prior to simulation 
to assist with identification and inclusion in the RT field.  
The posterior border/blocking will also provide for a 
margin of at least 1.5 cm on the anterior sacrum.  The 
anterior border/blocking will extend at least 2.5 cm 
anterior to the tumor bed and will also include the 
internal iliac nodes.  In most patients, this will mean that 
the anterior border is such that the anterior half to one-
third of the femoral heads lie anterior to the anterior 
border of the lateral RT field.  In patients at risk for 
external iliac lymph node involvement, because of 
involvement of the bladder, prostate, vagina, cervix or 
uterus, the field will extend to the anterior symphysis 
pubis, to allow for inclusion of the external iliac lymph 
nodes. 
5.5.5 
Target Volume-Boost Fields 
After a dose of 45 Gy is delivered to the pelvic field, the fields will be reduced to 
include the primary tumor (or tumor bed, for postoperatively irradiated patients) with a 
minimum 2 cm margin in all directions.  Exclusion with custom shielding of as much 
of small bowel (defined by oral contrast) as possible is strongly encouraged.  The 
boost fields will be given a dose of 5.4 Gy at 1.8 Gy/fraction. The total cumulative 
dose delivered within the boost fields will be to a total dose of 50.4 Gy in 28 fractions.  
Patients may be treated with opposed fields or a multiple field technique during the 
boost phase of treatment.   
5.5.6 
Equipment 
5.5.6.1 
Modality: X-rays with nominal energy of 4 MV or greater.  The minimum 
allowable treatment distance is 80 cm SAD.  Co-60 is not allowed on this 
study. 


Eastern Cooperative 
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Oncology Group 
REVISED 
28 
5.5.6.2 
Calibration: The calibration of therapy machines used in this protocol shall 
be verified by the Radiological Physics Center (RPC). 
5.5.7 
Target Dose 
5.5.7.1 
Prescription Point: The prescription point is at or near the isocenter. 
5.5.7.2 
Dose Definition: Dose is specified in cGy to muscle. 
5.5.7.3 
Tissue Heterogeneity: Density corrections are not required, however, 
inhomogeneity correction for air or bone attenuation may be applied.  This 
is optional and would typically be in the setting of CT-based treatment 
planning where radiation dose distributions and treatment calculations are 
automatically generated based upon the CT densities of the treatment-
planning scan. 
5.5.7.4 
Prescribed Dose and Fractionation: Initial fields will be given 45 Gy at 1.8 
Gy per day.  The boost fields will receive 5.4 Gy at 1.8 Gy per day. 
5.5.7.5 
Dose Uniformity: The dose variation in the PTV will be +7% and -5% of the 
prescription point dose. This applies to all photon treatment techniques.  
Wedges, compensators, and other methods of generating a uniform dose 
distribution are encouraged. 
5.5.7.6 
Therapy Interruptions: Interruptions that are required because of RT or 
chemotherapy-related toxicity or major holidays shall not result in protocol 
violation.  Interruptions that are due to a major intervening illness (for 
example, myocardial infarction) shall not result in protocol violation.  
Interruptions for other reasons that prolong treatment by 5-8 days shall 
constitute a minor protocol deviation, and interruptions for other reasons 
that prolong treatment by 9 or more treatment days shall constitute a major 
protocol deviation.  Because it is not possible to anticipate every 
interruption that may be required during a course of RT, the principle 
radiation therapy investigator will be given discretion to not assess a 
protocol violation for interruptions for toxicity other than those described in 
section 5.5.8.1, if such interruption is felt to be in the best interest of the 
patient. 
5.5.8 
Radiation Toxocity 
5.5.8.1 
Chemoradiation will be interrupted for Grade 3 acute skin, hematologic or 
GU toxicity or diarrhea, as defined in the Common Toxicity Criteria 
(version 2.0). 
5.5.8.2 
In the event of such an interruption, chemoradiation can resume when 
there is recovery to Grade 2 or less toxicity. (See Section 5.4 for 
chemotherapy dose modifications.) 
5.5.9 
Normal Tissue Sparing 
As previously described, every effort must be made to limit the dose to the small 
bowel.  It is expected that portions of the bladder will receive full dose. 
5.5.10 Dose Calculation and Reporting 
If conformal techniques are used to treat patients on this study, a 3D 
benchmark needs to be completed and submitted to QARC. 
5.5.10.1 Prescription Point: The monitor units required to deliver the prescribed dose 
to 
the 
prescription 
point 
shall 
be 
calculated 
and 
submitted.


Eastern Cooperative 
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29 
5.5.10.2 Dose Uniformity: The maximum and minimum doses in the PTV shall be 
calculated and reported. These may be extracted from isodose 
distributions, calculated separately or derived from DVH’s. 
5.5.10.3 Reference Point: The daily dose reference point calculated on this study is 
the isocenter. The total dose to this point shall be calculated and reported. 
5.5.10.4 Isodose Distribution: For 2-D plans a color isodose plot of the dose 
distribution in a transverse plane through the prescription point (isocenter) 
shall be submitted. The prescription point and the outlines of the planning 
target volume and critical organs shall be shown. Isodose values must be 
clearly labeled. The effects of shielding blocks shall be included. 
For volume based treatment planning, a color hard copy isodose 
distribution for the total dose plan in the axial, sagittal, and coronal planes, 
which includes the isocenter of the planning target volume (PTV) must be 
submitted. If sagittal and coronal planes are not available, then five axial 
distributions may be submitted (central axis, two superior and two inferior 
planes). These dose distributions must include the following: 
A sufficient number of isodose contours should be shown to determine that 
the dose distribution conforms to the protocol guidelines. These isodoses 
should be superimposed over treatment planning CT or MR images. 
However, if such hard copy presents difficulty, similar plots without the 
gray scale image are acceptable if enough critical contours are identifiable 
to verify the dose distribution to target volumes and critical normal 
structures. Specifically, include those volumes for which there are dose 
volume histograms. 
5.5.11 QA Documentation 
Data should be forwarded to: 
Quality Assurance Review Center 
272 West Exchange Street, Suite 101 
Providence, Rhode Island 02903-1025 
Telephone 401-454-4301 
FAX 401-454-4683 
5.5.11.1 For standard planning techniques, submit the following within 1 week of 
the completion of radiotherapy. 
 NOTE: Materials listed below for Group I PS must be submitted within 1 
week of randomization. 
• 
Copy of Appendix IV: Checklist For Submission of Radiation 
Oncology QA Materials 
• 
Prescription Sheet for Entire Treatment 
• 
Completed Daily Treatment Record 
• 
Preoperative imaging studies: CT with contrast and barium enema 
(if available). 
• 
Copies of the planning CT and/or the diagnostic imaging utilized in 
defining the gross target volume. 
• 
Copies of simulator films and /or digitally reconstructed radiographs 
(DRR’s) for each field. 
• 
Copies of verification (portal) films (or hard copy of real time portal 
images) for each field. 
Rev. 11/05 
Rev. 11/05 
Rev. 11/05 
Rev. 11/05 
Rev. 11/05 


Eastern Cooperative 
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30 
• 
Photographs of the patient in the treatment position with the fields 
marked. 
• 
Copies of worksheets and/or printouts used for calculations of 
monitor units and for calculating the dose to normal structures. 
• 
Color copies of isodose distributions to demonstrate that the dose 
variation is within specification. The target volume, and the 
prescription point must be clearly shown.  (See Section 5.5.10.4) 
5.5.11.2 For 3D conformal treatment planning submit the following within 1 week of 
the completion of radiotherapy. 
 NOTE: Materials listed below for Group I PS must be submitted within 1 
week of randomization. 
• 
Copy of Appendix IV: Checklist For Submission of Radiation 
Oncology • QA Materials 
• 
Prescription Sheet for Entire Treatment 
• 
Partial Daily Treatment Record 
• 
Preoperative imaging studies: CT with contrast and barium enema 
(if available). 
• 
Copies of the planning CT and/or the diagnostic imaging utilized in 
defining the gross target volume. 
• 
Copies of simulator films and /or digitally reconstructed radiographs 
(DRR’s) for each field. 
• 
Copies of verification (portal) films (or hard copy of real time portal 
images) for each field. 
• 
Photographs of the patient in the treatment position with the fields 
marked. 
• 
Copies of worksheets and/or printouts used for calculations of 
monitor units and for calculating the dose to normal structures. 
• 
Complete description of each portal, including energy, gantry, 
couch, and collimator position, wedge description (if used), and 
equivalent field size.  
• 
One set of orthogonal anterior/posterior and lateral films for 
isocenter localization for each group of concurrently treated beams. 
If portals being submitted contain an orthogonal set, this is 
sufficient. 
• 
Beam’s Eye Views (BEV’s) for all fields and showing the PTV and 
critical structures.  BEV hard copies must be in color to enable 
reviewers to identify structures. 
• 
A room view display of all fields should be submitted. 
• 
Dose volume histograms for the total treatment of the PTV and 
normal critical structures. 
• 
Color hard copy isodose distributions for the total dose plan in the 
axial, sagittal, and coronal planes, which includes the isocenter of 
the planning target volume. The target volume, critical structures, 
and the prescription point must be clearly shown.  (See Section 
5.5.10.4)


Eastern Cooperative 
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31 
5.5.11.3 Questions regarding the dose calculations or documentation should be 
directed to: 
ECOG Protocol Dosimetrist 
Quality Assurance Review Center 
272 West Exchange Street, Suite 101 
Providence, RI  02903-1025 
5.5.11.4 Questions regarding the radiotherapy section of this protocol should be 
directed to: 
James Martenson Jr., MD 
Charlton Building, Desk R 
Mayo Clinic/Rochester 
Rochester MN  55905 
Phone: 507-284-4561 
Fax: 507-284-0079 
5.5.12 Definitions of Deviations in Protocol Performance: 
 
Prescription Dose: 
Minor Deviation: The dose to the prescription point differs from that in the protocol 
by between 6% and 10%. 
Major Deviation: The dose to the prescription point differs from that in the protocol 
by more than 10%. 
 
Dose Uniformity: 
Minor Deviation: The variation of dose in one of the target volumes exceeds +7% 
and –5% of the dose to the planning target volume. 
 
Treatment Interruptions: 
Minor Deviation: Total duration of treatment more than 5-8 days longer than 
protocol specifications (excluding interruptions for major holidays, 
toxicity or major intervening illness, as per section 5.5.7.6). 
Major Deviation: Total duration of treatment more than 8 days longer than protocol 
specifications (excluding interruptions for major holidays, toxicity 
or major intervening illness, as per section 5.5.7.6). 
 
Volume: 
Minor Deviation: Margins less than specified or fields excessively large as deemed 
by the study. 
Major Deviation: Transection of tumor (GTV) or potentially. 
5.6 
Assessment of Bowel Function 
5.6.1 
Assessment of Bowel Function in Preoperatively Irradiated Patients (Group I) 
Bowel function will be measured in preoperatively irradiated patients, using the 
Patient Bowel Function/Uniscale Questionnaire and the FACT Diarrhea Subscale, 
completed at the following time-points: 
 
1. 
Prior to radiation therapy (baseline) 
2. 
During the last week of radiation therapy 
3. 
Immediately prior to surgery 
4. 
18 + 2 months following completion of radiation therapy 
 
If a patient is not assessed due to a non-functioning rectum, please report this to the 
ECOG data center, using the QOL Assessment Compliance Form. This information 
is only to be collected in patients with a functioning rectum, i.e. do not collect it 
in patients with a colostomy, permanent or temporary. 
Rev. 11/05 
Rev. 11/05 


Eastern Cooperative 
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32 
5.6.1.1 Assessment of Bowel Function in Preoperatively Irradiated Patients (Group 
IPS) 
Patients who joined study post-surgery (Group II) will complete the Patient 
Bowel Function /Uniscale Questionnaire and the FACT Diarrhea Subscale at 
the following time-points: 
1. 
Time of registration/randomization (baseline) 
2. 
18 + 2 months following completion of radiation therapy 
 
This information is only to be collected in patients with a functioning 
rectum, i.e. do not collect it in patients with a colostomy, permanent or 
temporary.   If a patient is not assessed due to a non-functioning rectum, 
please report this to the ECOG data center, using the QOL Assessment 
Compliance Form. 
5.6.2 
Assessment of Bowel Function in Postoperatively Irradiated Patients (Group I PS) 
Bowel function will be measured in postoperatively irradiated patients, using the 
Patient Bowel Function/Uniscale Questionnaire and the FACT Diarrhea Subscale 
completed at the following time-points: 
1. 
Prior to surgery (if possible) 
2. 
Prior to beginning adjuvant postoperative chemotherapy (baseline) 
3. 
Immediately prior to starting radiation therapy (RT) 
4. 
During the last week of RT 
5. 
18 + 2 months following completion of RT 
 
This information is only to be collected in patients with a functioning rectum, 
i.e. do not collect it in patients with a colostomy, permanent or temporary.  If a 
patient is not assessed due to a non-functioning rectum, please report this to the 
ECOG data center, using the QOL Assessment Compliance Form. 
5.6.3 
Administration Instructions 
5.6.3.1 
The FACT Diarrhea Subscale (FACT-D) is available in Spanish; the Patient 
Bowel Function/Uniscale Questionnaire is not. Patients who do not speak 
English or who prefer Spanish to English, may be offered a Spanish 
version of the FACT-D. 
5.6.3.2 
Instructions at the top of the questionnaires should be read to the patient. 
Assure patient’s understanding and ask him/her to complete every item 
without overlooking any items. 
5.6.3.3 
If patients are unable to complete the forms independently because 
language, literacy, or physical condition is a barrier, the form should be 
administered by a trained staff member. Note on the Assessment 
Compliance Form the degree of assistance required and the mode of 
administration: interview or self-administration. 
5.6.3.4 
It is very important to review the questionnaires after the patient has 
completed them to be sure that all questions have been answered and that 
only one answer has been marked for each question. If the patient has 
marked more than one answer for a question, ask the patient which 
answer best reflects how he/she is feeling. If the patient skipped a 
question, inform the patient and ask him/her to answer the question. 
Always give the patient the option to refuse and indicate on the measure 
itself, next to the question that was not answered, that the patient did not 
want to answer the question. 


Eastern Cooperative 
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5.6.3.5     If the patient misses an appointment or is too sick to complete the 
questionnaires, they can be mailed to the patient or sent home with 
him/her. A telephone interview can be conducted when the patient is 
looking at his/her copy of the forms. Please note on the Assessment 
Compliance 
Form 
that 
a 
telephone 
interview 
was 
conducted. 
Questionnaire data should be collected within one week of the missed 
assessment. 
5.6.3.6     While it is preferable for the patient to complete the questionnaires, it is 
acceptable for them to be completed with the assistance of a family 
member/companion, health care provider or via a phone call to the patient 
by a health care provider or research associate. The 18-month 
questionnaires may be obtained at the time of a follow-up visit, may be 
mailed in by the patient or completed via a phone call, as described above. 
5.6.3.7     If the patient fails to complete an assessment for any reason, he/she 
should still be asked to complete the remaining scheduled assessments. 
5.6.3.8    The Assessment Compliance Form should be completed and attached to 
the questionnaires each time they are scheduled to be completed. Mail the 
form to the ECOG Coordinating Center (Reference Records to be Kept, 
Section 12.0) 
5.7 
Surgery 
Prior to randomization (for patients registered prior to surgery), patients will be evaluated and 
cleared by the surgeon to determine if their medical condition will tolerate the planned 
operation. 
The surgeon should determine whether or not the tumor is fixed or mobile, resectable or not, 
and, if resectable, which operation will be performed should the patient go directly to the 
operating room (LAR, APR, LAR/coloanal anastomosis). 
Patients with any symptoms suggesting an obstruction should have a diverting colostomy 
placed prior to beginning preoperative therapy. 
5.7.1 
Surgery Schedule 
Surgical resection should occur between 21-56 days (3 - 8 weeks) after the patient 
completes preoperative 5-FU and radiation therapy. 
5.7.2 
General Operative Evaluation 
All patients will be explored at least for palliative intent even if there is no clinical 
evidence of tumor regression, because palliation is superior if tumor is resected, 
providing there is no clinical evidence of metastatic disease. An exam under 
anesthesia should be performed and evaluation of tumor size and location reported.  
At the time of surgery, the procedure should begin with close inspection of the liver 
and peritoneal surfaces for any evidence of metastatic disease.  Any suspicious 
areas should be biopsied prior to beginning resection of the primary tumor.  If any of 
the biopsies are positive, the patient will be considered to have extensive disease 
and the surgeon will select the procedure to be performed. 
5.7.3 
Surgical Resection 
If the preoperative evaluation demonstrates extrapelvic metastatic disease, a 
palliative procedure may be selected by the operating surgeon to provide the 
maximal control of symptoms for the greatest duration of the patient’s anticipated 
survival.  In almost all cases, this will be an LAR or APR. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
34 
The choice of the operative procedure (APR, LAR or LAR/coloanal anastomosis) is at 
the discretion of the surgeon.  It is strongly recommended that the entire mesorectum 
be removed and that the distal rectal margin of 2 cm be obtained for sphincter 
preserving procedures.  The surgical procedure will be determined by the extent of 
the tumor prior to preoperative therapy.  Adjacent organs involved with tumor at the 
time of pre-registration evaluation should be resected even if there is no evidence of 
residual tumor in those tissues at the time of surgery. 
The pathologist will ink the specimen for evaluation of the radial margin. 
Following the resection of the tumor specimen, when feasible, biopsies will be taken 
from the adjacent tissues near the resection margin and sent separately for 
evaluation of the surgical bed for residual tumor. 
When APR is performed, some form of closure of the perineum will be performed 
unless contraindicated. 
If the patient has a diverting colostomy, it should not be closed until after the 
completion of chemotherapy.  During this time, the patient should be seen monthly by 
the surgeon and the anastomosis digitally dilated.  Patients should be followed for at 
least four weeks after surgery. 
5.8 
Adverse Event Reporting Requirements 
5.8.1 
Purpose 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as well 
as those who will enroll in future studies using similar agents. Adverse events are 
reported in a routine manner at scheduled times during a trial (please refer to the 
E3201 Forms Packet for the list of forms with directions for routine adverse event 
reporting).  Additionally, certain adverse events must be reported in an expedited 
manner for more timely monitoring of patient safety and care. The following sections 
provide information about expedited reporting. 
5.8.2 
Determination of reporting requirements 
Reporting requirements may include the following considerations: 1) whether the 
patient has received an investigational or commercial agent; 2) the characteristics of 
the adverse event including the grade (severity), the relationship to the study 
therapy (attribution), and the prior experience (expectedness) of the adverse event; 
3) the phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization or 
prolongation of hospitalization was associated with the event. 
An investigational agent is a protocol drug administered under an Investigational 
New Drug Application (IND). In some instances, the investigational agent may be 
available commercially, but is actually being tested for indications not included in the 
approved package label. 
Commercial agents are those agents not provided under an IND but obtained 
instead from a commercial source. The NCI, rather than a commercial distributor, 
may on some occasions distribute commercial agents for a trial. 
When a study arm includes both investigational and commercial agents, the 
following rules apply. 
Concurrent administration: When an investigational agent(s) is used in combination 
with a commercial agent(s), the combination is considered to be investigational 
and expedited reporting of adverse events would follow the guidelines for 
investigational agents. 
Rev. 11/05 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 11/05, Addendum #4 
35 
Steps to determine if an adverse event is to be reported in an expedited 
manner: 
Step 1: Identify the type of event using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) Version 3.0. The CTCAE provides descriptive terminology 
and a grading scale for each adverse event listed. A copy of the CTCAE can be 
downloaded from the CTEP home page (http://ctep.cancer.gov). Additionally, if 
assistance is needed, the NCl has an Index to the CTCAE that provides help for 
classifying and locating terms. All appropriate treatment locations should have 
access to a copy of the CTCAE. 
Step 2: Grade the event using the NCI CTCAE. 
Step 3: Determine whether the adverse event is related to the protocol therapy 
(investigational or commercial). Attribution categories are as follows: Unrelated, 
Unlikely, Possible, Probable, and Definite. 
Step 4: Determine the prior experience of the adverse event. Expected events are 
those that have been previously identified as resulting from administration of the 
agent. An adverse event is considered unexpected, for expedited reporting purposes 
only, when either the type of event or the severity of the event is NOT listed in:  
• 
Arm A, C, D, F, and S – the drug package insert or protocol 
• 
Arm B and E – the current NCI Agent-Specific Adverse Event List for the 
investigational agent or package insert/protocol for the commercial agents 
NOTE: The NCI AgentSpecific Adverse Event List (ASAEL) is included in Section 
5.9 of the protocol. The ASAEL is a list of events that should be considered 
‘expected’ for adverse event reporting purposes. The ASAEL is presented in 
the third column of the Comprehensive Adverse Event and Potential Risks 
List (CAEPR) and identified with bold and italicized text. 
Step 5: Review the ”Additional instructions, requirements, and exceptions for 
protocol E3201” table in section 5.8.6 and footnote b in Section 5.8.7 for protocol 
and/or ECOG specific requirements for expedited reporting of specific adverse 
events that require special monitoring.   
NOTE: For general questions regarding expedited reporting requirements, please 
contact the NCI Medical Help Desk:  301-897-7497. 
5.8.3 
Reporting methods 
Arm A, B, C, D, E, F, and S – This study requires that expedited adverse event 
reporting use the NCI’s Adverse Expedited Reporting System (AdEERS). The 
NCI’s guidelines for AdEERS can be found at http://ctep.cancer.gov.  For 
questions regarding the use of the AdEERS application, please contact the NCI 
Technical Help Desk:  301-840-8202. 
An AdEERS report must be submitted to ECOG and the appropriate regulatory 
agencies by one of the following methods: 
Electronically submit the report via the AdEERS Web-based application located at 
http://ctep.cancer.gov 
or 
Fax the completed NCI Adverse Event Expedited Report – Single Agent or Multiple 
Agents 
paper 
template 
located 
at 
http://ctep.cancer.gov 
to 
ECOG 
(617-632-2990), Attention: AE.  In addition, fax the completed AdEERS report to 
the NCI (301-230-0159) for Arms B and E and to the FDA (800-332-0178) for 
Arms A, C, D, F, and S. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 11/05, Addendum #4 
36 
NOTE: Paper copies of AdEERS reports will only be accepted if the AdEERS 
system is down.  Once the system is restored, a report submitted on a 
paper template must be entered into the AdEERS system by the 
original submitter of the report at the site.   
Any supporting or follow up documentation must be faxed to ECOG (617-632-2990), 
Attention: AE.  In addition, supporting or follow up documentation must be faxed to 
the NCI (301) 230-0159 for Arms B and E and the FDA (800)-332-0178) for Arms A, 
C, D, F, and S. 
5.8.4 
When to report an event in an expedited manner 
Some adverse events require 24-hour notification (refer to Section 5.8.6). Please 
complete a 
24-Hour Notification Report 
via the NCl 
AdEERS 
website 
(http://ctep.cancer.gov/reporting/adeers.html) within 24 hours of learning of the 
event.  The full AdEERS report must be completed and submitted via AdEERS 
within 5 calendar days.   
If the AdEERS system is down, a 24-hour notification call must be made to ECOG 
(617-632-3610) and to NCI (301-897-7497).  Once the system is restored, a 24-hour 
Notification Report must be entered into the AdEERS system by the original 
submitter of the report at the site.   
When an adverse event requires expedited reporting, submit a full AdEERS report 
within the timeframes outlined in Sections 5.8.6 and 5.8.7. 
NOTE: Adverse events that meet the reporting requirements in Sections 5.8.6 or 
5.8.7 and occur within 30 days of the last dose of protocol treatment must 
be reported on an expedited adverse event report form (using AdEERS). 
For any adverse events that occur more than 30 days after the last dose of 
treatment, only those that have an attribution of possibly, probably, or 
definitely AND meet the reporting requirements in Sections 5.8.6 or 5.8.7 
must be reported on an expedited adverse event report form (using 
AdEERS). 
5.8.5 
Other recipients of adverse event reports 
ECOG will forward AdEERS reports to the appropriate regulatory agencies and 
pharmaceutical company, if applicable.    
Adverse events determined to be reportable must also be reported by the institution, 
according to the local policy and procedures, to the Institutional Review Board 
responsible for oversight of the patient. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 11/05, Addendum #4 
37 
5.8.6 
Expedited reporting for investigational agents 
Phase 2 and 3 Trials Utilizing an Agent under a CTEP IND:  AdEERS Expedited 
Reporting Requirements for Adverse Events That Occur Within 30 Days1 of the 
Last Dose of Investigational Agent (Oxaliplatin) in this Study (Arm B and E) 
OR Within 30 Days of the Last Dose of Any Protocol Treatment. 
 
 
Attribution 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected 
and 
Expected 
 
 
Unexpected 
 
 
Expected 
Unexpected 
Expected 
Unexpected  
Expected 
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 Calendar 
Days 
10 Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
10 Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of 
treatment with an agent under a CTEP IND require reporting as follows: 
AdEERS 24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 4 and Grade 5 unexpected events  
 
AdEERS 10 calendar day report: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 5 expected events 
2 Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a full report is required 
as outlined in the table. 
Please see additional information below under section entitled “Additional instructions, requirements, 
and exceptions for protocol E3201” 
March 2005 
NOTE: All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to treatment or other cause should be provided. 
• 
Expedited AE reporting timelines: 
 24 Hours; 5 calendar days – The investigator must initially report the AE via 
AdEERS within 24 hours of learning of the event followed by a complete AdEERS 
report within 5 calendar days of the initial 24-hour report. 
 10 calendar days – A complete AdEERS report on the AE must be submitted within 
10 calendar days of the investigator learning of the event. 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization* 
(or prolongation of existing hospitalization) must be reported regardless of attribution 
and designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions. 
• 
Any event that results in persistent or significant disability/incapacity, congenital 
anomaly, or birth defect must be reported via AdEERS if the event occurs following 
treatment with an agent under a CTEP IND 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
* Hospitalizations are defined as lasting 24 hours or longer and these events must be 
reported via AdEERS. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 11/05, Addendum #4 
38 
 
Additional instructions, requirements and exceptions for protocol E3201 
1.  Additional Instructions: 
 With respect to determining the specific day by which the event must be reported, the day 
the reporter learns of the adverse event constitutes “Day 0” 
 For grade 2 and 3 unexpected events, AdEERS reporting is only required if the event is 
related to the investigational agent(s);  it is not required if the event is related only to the 
commercial agent(s) included in the protocol treatment.   
NOTE: For grade 3 unexpected events with hospitalization lasting ≥ 24 hours (or prolonged 
hospitalization), an AdEERS report is required even if the event is unrelated to the 
investigational agent(s). 
 For instructions on how to specifically report events that result in persistent or significant 
disability/incapacity, congenital anomaly, or birth defect events via AdEERS, please contact 
the NCI Medical Help Desk at 301-897-7497 or adeersmd@tech-res.com. 
2.  ECOG and Protocol Specific expedited reporting requirements: 
The adverse events listed below also require expedited reporting for this trial: 
ECOG specific expedited reporting requirements: 
 Hospitalizations:  Any grade 1 or 2 adverse event with precipitates a hospitalization 
lasting > 24 hours (or prolongs hospitalization) must be reported via AdEERS within 
10 calendar days of learning of the event regardless of the attribution and 
designation as expected or unexpected.   
3.  Protocol specific expedited reporting exceptions: 
For study arms B and E, the adverse events listed below do not require expedited reporting 
via AdEERS, including hospitalization for these events: 
• 
Grade 1-4 Constipation, Ileus, or Bowel obstruction 
• 
Grade 1-4 Dehydration 
• 
Grade 1-4 Diarrhea with and without colostomy and associated electrolye imbalances 
• 
Grade 1-4 Mucositis, esophagitis, stomatitis/pharyngitis, dysphagia 
• 
Grade 1-4 Nausea or vomiting 
• 
Grade 1-4 Febrile neutropenia 
• 
Grade 1-4 Fever without neutropenia 
• 
Grade 1-4 Infection with or without neutropenia or infection with unknown ANC 
• 
Grade 1-3 Hand/foot skin reaction 
• 
Grade 1-4 Pain- including abdominal pain/cramping 
• 
Grade 1-4 Sensory neuopathy 
• 
Grade 1-4 SGOT/SGPT 
• 
Grade 1-4 Thrombosis/Embolism- including pulmonary embolism 
• 
Grade 1-4 Fatigue (lethargy, malaise, asthenia) 
• 
Grade 1-4 Neutrophils, leukocycles, hemoglobin, platelets 
• 
Grade 1-3 Cardiac Ischemia/infarction 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 11/05, Addendum #4 
39 
5.8.7 
Expedited reporting for commercial agents 
Commercial reporting requirements are provided below. The commercial agents 
used in arms A, C, D, F and S of this study Irinotecan, Leucovorin, 5-FU, 
Capecitabine (only for those in NSABP protocol R-04). 
 
Expedited reporting requirements for adverse events experienced by patients on arm(s) with commercial agents only – Arms A, 
C, D, F, and S. 
Attribution 
Grade 4 
Grade 5a 
ECOG and 
Protocol-Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special 
requirements. 
 
Unrelated or 
Unlikely 
 
 
7 calendar days 
7 calendar days 
Possible,  
Probable,  
Definite 
7 calendar days 
 
7 calendar days 
7 calendar days 
7 Calendar Days: 
Indicates a full AdEERS report is to be submitted within 7 calendar days of learning of the event. 
a 
This includes all deaths within 30 days of the last dose of treatment regardless of attribution. NOTE:  Any death that 
occurs > 30 days after the last dose of treatment and is attributed possibly, probably, or definitely to the treatment 
must be reported within 7 calendar days of learning of the event.   
 
b 
Protocol-specific expedited reporting requirements: The adverse events listed below also require expedited reporting for 
this trial: 
 
Serious Events: Any event following treatment that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via AdEERS within 7 calendar days of learning of the 
event.  For instructions on how to specifically report these events via AdEERS, please contact the NCI 
Medical Help Desk at 301-897-7497.   
 
5.8.8 
Reporting secondary AML/MDS/ALL 
All cases of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and 
acute lymphocytic leukemia (ALL) that occur in patients on NCI-sponsored trials 
following their chemotherapy for cancer must be reported to ECOG. Submit the 
following information within 30 days of an AML/MDS/ALL diagnosis occurring after 
treatment for cancer on NCI-sponsored trials: 
a completed NCI/CTEP Secondary AML/MDS/ALL Report Form (do not use 
AdEERS); 
a copy of the pathology report confirming the AML/MDS/ALL; and 
a copy of the cytogenetics report (if available). 
ECOG will forward copies to the Investigational Drug Branch (IDB) of the NCI 
Cancer Therapy Evaluation Program (CTEP).  
NOTE: If a patient has been enrolled in more than one NCI-sponsored study, the 
NCI/CTEP Secondary AML/MDS/ALL Report Form must be submitted for 
the most recent trial. ECOG must be provided with a copy of the report even 
if ECOG was not the patient's most recent trial. 
5.8.9 
Reporting of other second primary cancers 
All cases of new primary cancers that occur on ECOG protocols during or after 
protocol must be reported to ECOG, according to the follow up schedule outlined in 
the E3201 Forms Packet, on the ECOG Second Primary Form within 30 days of 
diagnosis, regardless of relationship to protocol treatment. This form is not for use 
for reporting recurrence or development of metastatic disease. A copy of the 
pathology report should be sent, if available. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 11/05, Addendum #4 
Revised 3/07, Update #2 
Revised 9/08, Addendum #5 
40 
NOTE:  Once data regarding survival and remission status are no longer required by 
the protocol, no follow-up data should be submitted, including the NCI 
AML/MDS/ALL form and ECOG Second Primary Form. 
Submit AML/MDS/ALL and Second Primary information to: 
ECOG Coordinating Center 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
[Deleted NOTE in Update #2] 
5.9 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Oxaliplatin  
(NSC 266046) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single, 
complete list of reported and/or potential adverse events (AE) associated with an agent 
using a uniform presentation of events by body system. In addition to the comprehensive  
list, a subset, the Agent Specific Adverse Event List (ASAEL), appears in a separate column 
and is identified with bold and italicized text. This subset of AEs (ASAEL) contains  
events 
that 
are 
considered 
'expected' 
for 
expedited 
reporting 
purposes 
only.  
Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/reporting/adeers.html for further clarification. Frequency is provided 
based on 869 patients. Below is the CAEPR for Oxaliplatin. 
Version 2.0, December 10, 20071 
 
Adverse Events with Possible 
Relationship to Oxaliplatin 
(CTCAE v3.0 Term) 
[n=869 patients] 
 
 
Agent Specific Adverse Event 
List' 
(ASAEL) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
ALLERGY/IMMUNOLOGY 
 
Allergic 
reaction/hypersensitivity 
(including drug fever) 
 
Allergic 
reaction/hypersensitivity 
(including drug fever) 
 
Allergic rhinitis (including sneezing, 
nasal stuffiness, postnasal drip) 
 
Allergic rhinitis (including sneezing, 
nasal stuffiness, postnasal drip) 
AUDITORY/EAR 
 
Hearing: patients without baseline 
audiogram and not enrolled in a 
monitoring program 
 
Hearing: patients without baseline 
audiogram and not enrolled in a 
monitoring program 
 
Otitis, middle ear (non-infectious) 
 
Otitis, middle ear (non-infectious) 
BLOOD/BONE MARROW 
Hemoglobin 
 
 
Hemoglobin 
 
Hemolysis (e.g., immune hemolytic 
anemia, drug-related hemolysis) 
 
Hemolysis (e.g., immune hemolytic 
anemia, drug-related hemolysis) 
 
Leukocytes (total WBC) 
 
Leukocytes (total WBC) 
 
Lymphopenia 
 
Lymphopenia 
Neutrophils/granulocytes 
(ANC/AGC) 
 
 
Neutrophils/granulocytes 
(ANC/AGC) 
Platelets 
 
 
Platelets 
 
Rev. 11/05, 9/08 
Rev. 3/07 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 9/08, Addendum #5 
40a 
 
CARDIAC ARRHYTHMIA 
 
Supraventricular 
and 
nodal 
arrhythmia:  Atrial fibrillation 
 
 
 
Supraventricular 
and 
nodal 
arrhythmia:  Sinus tachycardia 
 
Supraventricular 
and 
nodal 
arrhythmia:  Sinus tachycardia 
 
Supraventricular 
and 
nodal 
arrhythmia: 
 
Supraventricular 
arrhythmia NOS 
 
Supraventricular 
and 
nodal 
arrhythmia: 
 
Supraventricular 
arrhythmia NOS 
 
Ventricular arrhythmia:  Ventricular 
arrhythmia NOS 
 
Ventricular arrhythmia:  Ventricular 
arrhythmia NOS 
CARDIAC GENERAL 
 
Hypertension 
 
Hypertension 
 
Hypotension 
 
Hypotension 
COAGULATION 
 
DIC 
(disseminated 
intravascular 
coagulation) 
 
DIC 
(disseminated 
intravascular 
coagulation) 
 
INR (International Normalized Ratio 
of prothrombin time) 
 
INR (International Normalized Ratio 
of prothrombin time) 
 
PTT (Partial Thromboplastin Time) 
 
PTT (Partial Thromboplastin Time) 
 
 
Thrombotic microangiopathy 
(e.g., 
thrombotic 
thrombocytopenic 
purpura 
[TTP] or hemolytic uremic 
syndrome [HUS]) 
 
CONSTITUTIONAL SYMPTOMS 
Fatigue 
(asthenia, 
lethargy, malaise) 
 
 
Fatigue (asthenia, lethargy, malaise) 
 
Fever 
(in 
the 
absence 
of 
neutropenia, where neutropenia is 
defined as ANC <1.0 x 10e9/L) 
 
Fever 
(in 
the 
absence 
of 
neutropenia, where neutropenia is 
defined as ANC <1.0 x 10e9/L) 
 
Insomnia 
 
Insomnia 
 
Rigors/chills 
 
Rigors/chills 
 
Sweating (diaphoresis) 
 
Sweating (diaphoresis) 
 
Weight gain 
 
Weight gain 
 
Weight loss 
 
Weight loss 
DERMATOLOGY/SKIN 
 
Dry skin 
 
Dry skin 
 
Flushing 
 
Flushing 
 
Hair loss/alopecia (scalp or body) 
 
Hair loss/alopecia (scalp or body) 
 
Injection site reaction/extravasation 
changes 
 
Injection site reaction/extravasation 
changes 
 
Pruritus/itching 
 
Pruritus/itching 
 
Rash/desquamation 
 
Rash/desquamation 
 
Rash: hand-foot skin reaction 
 
Rash: hand-foot skin reaction 
 
Urticaria (hives, welts, wheals) 
 
Urticaria (hives, welts, wheals) 
ENDOCRINE 
 
Hot flashes/flushes 
 
Hot flashes/flushes 
GASTROINTESTINAL 
 
Anorexia 
 
Anorexia 
 
Ascites (non-malignant) 
 
Ascites (non-malignant) 
 
Colitis 
 
Colitis 
 
Constipation 
 
Constipation 
 
Dehydration 
 
Dehydration 
Diarrhea 
 
 
Diarrhea 
 
Dry 
mouth/salivary 
gland 
(xerostomia) 
 
Dry 
mouth/salivary 
gland 
(xerostomia) 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 9/08, Addendum #5 
40b 
 
Dysphagia (difficulty swallowing) 
 
Dysphagia (difficulty swallowing) 
 
Enteritis (inflammation of the small 
bowel) 
 
Enteritis (inflammation of the small 
bowel) 
 
Esophagitis 
 
Esophagitis 
 
Flatulence 
 
Flatulence 
 
Gastritis 
(including 
bile 
reflux 
gastritis) 
 
Gastritis 
(including 
bile 
reflux 
gastritis) 
 
Heartburn/dyspepsia 
 
Heartburn/dyspepsia 
 
Ileus, GI (functional obstruction of 
bowel, i.e., neuroconstipation) 
 
Ileus, GI (functional obstruction of 
bowel, i.e., neuroconstipation) 
 
Mucositis/stomatitis 
(functional/symptomatic): oral cavity 
 
Mucositis/stomatitis 
(functional/symptomatic): oral cavity 
Nausea 
 
 
Nausea 
 
Necrosis, GI - Select 
 
Necrosis, GI - Select 
 
 
Gastrointestinal 
- 
Other 
(pneumatosis intestinalis) 
 
 
Obstruction, GI: small bowel NOS 
 
Obstruction, GI: small bowel NOS 
 
Taste alteration (dysgeusia) 
 
Taste alteration (dysgeusia) 
 
Ulcer, GI - Select 
 
Ulcer, GI - Select 
Vomiting 
 
 
Vomiting 
HEMORRHAGE/BLEEDING 
 
Hemorrhage, CNS 
 
Hemorrhage, CNS 
 
Hemorrhage, GI: Select 
 
Hemorrhage, GI: Select 
 
Hemorrhage, GU: Select 
 
Hemorrhage, GU: Select 
 
Hemorrhage, 
pulmonary/upper 
respiratory: respiratory tract NOS 
 
Hemorrhage, 
pulmonary/upper 
respiratory: respiratory tract NOS 
 
Hemorrhage/bleeding 
- 
Other 
(hemorrhage 
with 
thrombocytopenia) 
 
 
 
 
 
 
Hemorrhage/bleeding 
- 
Other 
(hemorrhage 
with 
thrombocytopenia) 
HEPATOBILIARY/PANCREAS 
 
 
Cholecystitis 
 
 
Hepatobiliary/Pancreas 
- 
Other 
(Hepatic enlargement) 
 
Hepatobiliary/Pancreas 
- 
Other 
(Hepatic enlargement) 
 
Hepatobiliary/Pancreas 
- 
Other 
(Veno-occlusive disease) 
 
Hepatobiliary/Pancreas 
- 
Other 
(veno-occlusive disease) 
 
Liver dysfunction/failure (clinical) 
 
Liver dysfunction/failure (clinical) 
 
Pancreatitis 
 
Pancreatitis 
INFECTION 
 
Febrile 
neutropenia 
(fever 
of 
unknown origin without clinically or 
microbiologically 
documented 
infection)(ANC <1.0 x 10e9/L, fever 
>=38.5 degrees C) 
 
Febrile 
neutropenia 
(fever 
of 
unknown origin without clinically or 
microbiologically 
documented 
infection)(ANC <1.0 x 10e9/L, fever 
>=38.5 degrees C) 
 
Infection 
with 
Grade 
3 
or 
4 
neutrophils - Select 
 
Infection 
with 
Grade 
3 
or 
4 
neutrophils - Select 
 
Infection with normal ANC or Grade 
1 or 2 neutrophils - Select 
 
Infection with normal ANC or Grade 
1 or 2 neutrophils - Select 
 
Infection with unknown ANC - 
Select 
 
Infection with unknown ANC - Select 
LYMPHATICS 
 
Edema: head and neck 
 
Edema: head and neck 
 
Edema: limb 
 
Edema: limb 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 9/08, Addendum #5 
40c 
 
METABOLIC/LABORATORY 
 
Acidosis (metabolic or respiratory) 
 
Acidosis (metabolic or respiratory) 
 
Albumin, 
serum-low 
(hypoalbuminemia) 
 
Albumin, 
serum-low 
(hypoalbuminemia) 
 
Alkaline phosphatase 
 
Alkaline phosphatase 
ALT, 
SGPT 
(serum 
glutamic 
pyruvic 
transaminase) 
 
 
ALT, SGPT (serum glutamic pyruvic 
transaminase) 
 
AST, 
SGOT 
(serum 
glutamic 
oxaloacetic transaminase) 
 
AST, 
SGOT 
(serum 
glutamic 
oxaloacetic transaminase) 
 
Bilirubin (hyperbilirubinemia) 
 
Bilirubin (hyperbilirubinemia) 
 
Calcium, serum-low (hypocalcemia) 
 
Calcium, serum-low (hypocalcemia) 
 
Creatinine 
 
Creatinine 
 
GGT 
(gamma-glutamyl 
transpeptidase) 
 
GGT 
(gamma-glutamyl 
transpeptidase) 
 
Glucose, 
serum-high 
(hyperglycemia) 
 
Glucose, 
serum-high 
(hyperglycemia) 
 
Glucose, serum-low (hypoglycemia) 
 
Glucose, serum-low (hypoglycemia) 
 
Magnesium, 
serum-low 
(hypomagnesemia) 
 
Magnesium, 
serum-low 
(hypomagnesemia) 
 
Phosphate, 
serum-low 
(hypophosphatemia) 
 
Phosphate, 
serum-low 
(hypophosphatemia) 
 
Potassium, 
serum-low 
(hypokalemia) 
 
Potassium, 
serum-low 
(hypokalemia) 
 
Sodium, serum-low (hyponatremia) 
 
Sodium, serum-low (hyponatremia) 
 
Uric 
acid, 
serum-high 
(hyperuricemia) 
 
 
 
Uric 
acid, 
serum-high 
(hyperuricemia) 
MUSCULOSKELETAL/SOFT TISSUE 
 
Extremity-lower (gait/walking) 
 
Extremity-lower (gait/walking) 
 
Trismus (difficulty, restriction or pain 
when opening mouth 
 
 
 
 
 
 
 
 
 
 
 
Trismus (difficulty, restriction or 
pain when opening mouth) 
NEUROLOGY 
 
Ataxia (incoordination) 
 
Ataxia (incoordination) 
 
CNS cerebrovascular ischemia 
 
CNS cerebrovascular ischemia 
 
Confusion 
 
Confusion 
 
Dizziness 
 
Dizziness 
 
Extrapyramidal/involuntary 
movement/restlessness 
 
Extrapyramidal/involuntary 
movement/restlessness 
 
Mood alteration:  Anxiety 
 
Mood alteration: Anxiety 
 
Mood alteration:  Depression 
 
Mood alteration: Depression 
 
Neuropathy: cranial - Select 
 
Neuropathy: cranial - Select 
 
Neuropathy: motor 
 
Neuropathy: motor 
 
Neurology - Other:  (multiple cranial 
nerve palsies) 
 
Neurology  Other (multiple cranial 
nerve palsies) 
Neuropathy: sensory 
 
 
Neuropathy: sensory 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 9/08, Addendum #5 
40d 
 
 
Seizure 
 
Seizure 
 
Somnolence/depressed 
level 
of 
consciousness 
 
Somnolence/depressed 
level 
of 
consciousness 
 
Speech impairment (e.g. dysphagia 
or aphasia) 
 
Speech impairment (e.g. dysphagia 
or aphasia) 
 
Syncope (fainting) 
 
 
OCULAR/VISUAL 
 
Dry eye syndrome 
 
Dry eye syndrome 
 
Eyelid dysfunction 
 
Eyelid dysfunction 
 
Ocular surface disease 
 
Ocular surface disease 
 
Ocular/Visual - Other (Cold-induced 
transient visual abnormalities) 
 
Ocular/Visual - Other (cold-induced 
transient visual abnormalities) 
 
Ocular/Visual - Other (Amaurosis 
fugax) 
 
Ocular/Visual - Other (Amaurosis 
fugax) 
 
Optic disc edema 
 
Optic disc edema 
PAIN 
 
Pain - Abdomen NOS 
 
Pain - Abdomen NOS 
 
Pain - Back 
 
Pain - Back 
 
Pain - Bone 
 
Pain - Bone 
 
Pain - Chest/thorax NOS 
 
Pain - Chest/thorax NOS 
 
Pain - Eye 
 
 
 
Pain - Head/headache 
 
Pain - Head/headache 
 
Pain - Joint 
 
Pain - Joint 
 
Pain - Muscle 
 
Pain - Muscle 
PULMONARY/UPPER RESPIRATORY 
 
Adult respiratory distress syndrome 
(ARDS) 
 
Adult respiratory distress syndrome 
(ARDS) 
 
Bronchospasm, wheezing 
 
Bronchospasm, wheezing 
 
Cough 
 
Cough 
 
Dyspnea (shortness of breath) 
 
Dyspnea (shortness of breath) 
 
Hiccoughs (hiccups, singultus) 
 
Hiccoughs (hiccups, singultus) 
 
Hypoxia 
 
 
 
Nasal 
cavity/paranasal 
sinus 
reactions 
 
Nasal 
cavity/paranasal 
sinus 
reactions 
 
Pneumonitis/pulmonary infiltrates 
 
Pneumonitis/pulmonary infiltrates 
 
Pulmonary 
fibrosis 
(radiographic 
changes) 
 
Pulmonary 
fibrosis 
(radiographic 
changes) 
 
Voice 
changes/dysarthria 
(e.g. 
hoarseness, loss or alteration in 
voice, laryngitis) 
 
Voice 
changes/dysarthria 
(e.g. 
hoarseness, loss or alteration in 
voice, laryngitis) 
RENAL/GENITOURINARY 
 
Renal failure 
 
Renal failure 
 
Urinary frequency/urgency 
 
Urinary frequency/urgency 
 
Urinary 
retention 
(including 
neurogenic bladder) 
 
Urinary 
retention 
(including 
neurogenic bladder) 
SYNDROMES 
 
Syndromes - Other (Hepato-renal 
syndrome) 
 
 
 
 
 
Syndromes - Other (Hepato-renal 
syndrome) 
VASCULAR 
 
Phlebitis 
(including 
superficial 
thrombosis) 
 
Phlebitis 
(including 
superficial 
thrombosis) 
 
Thrombosis/thrombus/embolism 
 
Thrombosis/thrombus/embolism 
 
Thrombosis/thrombus/embolism 
(vascular access-related) 
 
 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 9/08, Addendum #5 
40e 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
ADEERSMD@tech-res.com.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
Also reported on oxaliplatin trials but with the relationship to oxaliplatin still undetermined: 
GASTROINTESTINAL - GI perforation 
METABOLIC/LABORATORY - amylase; lipase 
MUSCULOSKELETAL/SOFT TISSUE - generalized muscle weakness 
SYNDROMES - tumor lysis syndrome 
 
Note: Oxaliplatin in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 11/05, Addendum #4 
40f 
5.10 
Supportive Care (Chemotherapy Toxicity) 
All supportive measures consistent with optimal patient care will be given throughout the 
study. 
Loperamide (Imodium):  Patients will be instructed to begin taking loperamide at the earliest 
signs of a poorly formed or loose stool.  Loperamide should be taken in the following manner:  
4 mg at the first onset of diarrhea, then 2 mg every two hours around the clock until the 
patient is diarrhea-free for at least 12 hours.  Patients may take loperamide 4 mg (2 capsules) 
every four hours during the night.  (Refer to Appendix IX, Diarrhea Management Instructions.) 
Atropine:  Diarrhea or abdominal cramping that occurs during or within one hour after 
receiving irinotecan can be treated with atropine (0.25 to 1 mg IV as indicated).  Patients 
having recurrent problems with cholinergic symptoms may receive atropine prophylactically 
(sc or IV).  Additional antidiarrheal measures may be used at the discretion of the treating 
physician. 
Antiemetics:  Patients may receive dexamethasone 10 mg IV as a pretreatment antiemetic 
before irinotecan doses, unless there is a relative or absolute contraindication to 
corticosteroids (i.e., diabetes, known sensitivity to corticosteroids, severe muscle weakness or 
myalgias, etc.).  Other antiemetics may be used in addition to the suggested regimen, if 
clinically indicated.  As the majority of patients on previous trials have not experienced 
significant nausea, antiemetics other than decadron are recommended only for those patients 
who demonstrate nausea and/or vomiting despite treatment with decadron. 
Routine use of antiemetics prior to treatment with standard dose 5-FU and leucovorin is rarely 
indicated.  It is recommended that patients not be given routine antiemetics for the standard 
arms of the study (Arms C and F) and that antiemetics be prescribed by the treating physician 
as clinically indicated if a patient develops nausea and/or vomiting. 
Oxaliplatin is emetogenic.  All patients receiving oxaliplatin (Arms B and E) should be pre-
medicated with an acceptable anti-emetic regimen. 
Antibiotics (for patients with persistent diarrhea): Begin oral fluoroquinolone and continue for 7 
days. If diarrhea persists for greater than 48 hours, parenteral hydration is recommended 
(including hospitalization for such). Oral fluroquinolone treatment also should be initiated for 
patients who develop an ANC < 500 /mm³ (even in the absence of fever or diarrhea) or a 
fever that occurs with diarrhea (even without neutropenia). Antibiotics should continue until 
resolution of diarrhea. (15) 
Rev. 11/05 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 11/05, Addendum #4 
41 
Anticoagulants:  Patients who are taking Coumadin may participate in this study; however, it 
is recommended the prothrombin time be monitored carefully (at least weekly).  
Subcutaneous heparin is permitted. 
Hypersensitivity: Platinum hypersensitivity can cause dyspnea, bronchospasm, itching and 
hypoxia.  Appropriate treatment includes supplemental oxygen, steroids, antihistamines, and 
epinephrine; bronchodilators and vasopressors may be required.  Platinum hypersensitivity is 
an extremely rare event and should be treated promptly. 
Oxaliplatin hypersensitivity occurs in approximately 0.5% of patients receiving this 
investigational agent.  See Appendix VI for the "Comparison of the Symptoms and Treatment 
of Pharyngo-Laryngodysesthesias and Platinum Hypersensitivity Reactions. 
Pharyngo-laryngodysesthesias: Oxaliplatin may cause discomfort in the larynx or pharnyx 
associated with dyspnea, anxiety, swallowing difficulty and is exacerbated by cold.  
Appropriate therapy includes use of anxiolytics, cold avoidance and monitoring.  See 
Appendix VI for the  "Comparison of the Symptoms and Treatment of Pharyngo-
Laryngodysesthesias and Platinum Hypersensitivity Reactions." 
5.11 
Duration of Therapy  
Patients will continue to be monitored for toxicity but will discontinue protocol therapy in the 
following situations: 
5.11.1 Patient experiences unacceptable  toxicity, in spite of dose modifications as outlined 
in Section 5.4. 
5.11.2 If the patient requests discontinuation of therapy. 
5.11.3 If the patient’s attending physician believes that it is in the patient’s best interest to 
stop therapy. 
5.11.4 Disease recurrence while on therapy. 
5.11.5 Severe hypersensitivity reaction. 
5.11.6 If a patient is removed from study treatment, that patient should be evaluated for 
continuing radiation therapy +/- standard chemotherapy or surgery at the discretion of 
the treating physician. 
5.12 
Duration of Follow-up 
All patients, including those who discontinue protocol therapy early, will be followed for 
response until progression and for survival until 10 years from the date of registration. All 
patients must also be followed through completion of all protocol therapy. 
 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
42 
6. 
Measurement of Effect 
6.1 
Local, Regional Recurrence 
The development of a local or regional recurrence of rectal cancer. 
6.2 
Distant Recurrence 
The development of a distant recurrence of rectal cancer. 
6.3 
Disease-Free Survival 
Date of randomization to the date of the first treatment failure (recurrance or death before 
recurrance). 
6.4 
Survival 
Date of Randomization to date of death 
NOTE:  Recurrance must be doumented by biopsy and/or evidence of disease on radiologic 
studies. Abnormal blood studies alon (e.g., eleveated transaminases or alkaline 
phosphase) are not sufficent evidence of relapse. Whenever possible, histologic 
proof of recurrance should be obtained. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
43 
7. 
Study Parameters 
NOTE: Section 7.1 refers to therapeutic parameters required of the institutions for patient 
monitoring. Section 7.2 pertains to the requested sample submissions for the correlative 
studies described in Section 10.0. 
7.1 
Therapeutic Parameters  
7.1.1 
Group I (Patients Treated with Preoperative Radiation Therapy) 
1. 
Prestudy CXR and/or scans should be done < 4 weeks prior to definitive 
surgery. 
2. 
Prestudy CBC (with differential and platelet count) should be done < 4 weeks 
before randomization. 
3. 
All required prestudy chemistries, as outlined in Section 3.0, should be done < 4 
weeks before randomization. 
 
Evaluation 
Prior to 
Registration 
Weekly 
during 
XRT 
Post –
Chemo/XRT 
Pre-Op 
Post-Op/ 
Pre-
Chemo 
Prior to Each 
Chemo 
Cycle  
(Post-Op) 
Every 3 
Months 
after chemo 
x 8 
Every 6 
months. 
Years 3-
5 after 
treatment 
18 + 2 
months 
after 
completion 
of XRT 
Yearly 
After 
Surgery 
History and Physical 
X 
X 
X 
 
X 
X 
X 
 
 
Peformance Status 
X 
X 
X 
 
 
X 
X 
 
 
CBC1 
X 
X 
 
 
X1,3 
 
 
 
 
Creatinine, SGOT, 
(AST), Bilirubin 
X 
 
X 
 
X 
 
 
 
 
CEA 
X 
 
X 
X 
 
X 
X 
 
 
Pregnancy Test2 
X 
 
 
 
 
 
 
 
 
CT, Transrectal MRI 
or Endo-rectal 
Ultrasound4 
X 
 
 
 
 
 
 
 
 
Colonoscopy or 
Barium Enema 
X7 
 
 
 
 
 
 
 
X5 
Fact-Diarrhea 
Subscale 
Questionnaire6 
X6 
X6 
X6 
 
 
 
 
X6 
 
Patient Bowel 
Function/Uniscale 
Questionnaire 
X6 
X6 
X6 
 
 
 
 
X6 
 
 
1  
CBCs (with differential and platelet count) which includes WBC, ANC, Platelets and Hgb required for protocol 
therapy must be done < 24 hours prior to the treatment cycle. 
2  
Required for premenopausal women who have not been surgically sterilized.  All females of childbearing potential 
should undergo GYN pelvic exam and Pap smear before receiving protocol therapy. 
3  
Patients will be monitored for toxicity weekly during the first cycle of postoperative chemotherapy. 
4  
CT-scan, transrectal MRI or endo-rectal ultrasound may be used. 
5  
One year after surgery then recommended every 3 years. 
6  
Using the specified tool, bowel function will be measured 4 times: prior to radiation therapy (baseline), during the last 
week of RT, immediately prior to surgery and 18 + 2 months following completion of RT.  Bowel function of Group I 
PS will be measured 2 times: at registration/randomization (baseline) and 18 + 2 months following completion of RT. 
This information is only to be collected in patients with a functioning rectum, i.e. do not collect it in patients with a 
colostomy.  Please refer to Section 5.6.  
7  
Does not need to be repeated if performed pre-op or intra-op. 
 
 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
44 
7.1.2 
Group II (Patients Treated with Postoperative Radiation Therapy) 
1. 
Prestudy CXR and/or scans should be done < 4 weeks prior to definitive 
surgery. 
2. 
Prestudy CBC (with differential and platelet count) should be done < 4 
weeks before randomization. 
3. 
All required prestudy chemistries, as outlined in Section 3.0, should be done 
< 4 weeks before randomization. 
 
Evaluation 
Prior to 
Registration 
Weekly 
during 
XRT 
Post –
Chemo/XRT 
Pre-Op 
Post-Op/ 
Pre-
Chemo 
Prior to Each 
Chemo 
Cycle  
(Post-Op) 
Every 3 
Months 
after chemo 
x 8 
Every 6 
months. 
Years 3-
5 after 
treatment 
18 + 2 
months 
after 
completion 
of XRT 
Yearly 
After 
Surgery 
History and Physical 
X 
X 
X 
 
X 
X 
X 
 
 
Peformance Status 
X 
X 
X 
 
 
X 
X 
 
 
CBC1 
X 
X 
 
 
X1,3 
 
 
 
 
Creatinine, SGOT, 
(AST), Bilirubin 
X 
 
X 
 
X 
 
 
 
 
CEA 
X 
 
X 
X 
 
X 
X 
 
 
Pregnancy Test2 
X 
 
 
 
 
 
 
 
 
CT, Transrectal MRI 
or Endo-rectal 
Ultrasound4 
X 
 
 
 
 
 
 
 
 
Colonoscopy or 
Barium Enema 
X7 
 
 
 
 
 
 
 
X5 
Fact-Diarrhea 
Subscale 
Questionnaire6 
X6 
X6 
X6 
 
 
 
 
X6 
 
Patient Bowel 
Function/Uniscale 
Questionnaire 
X6 
X6 
X6 
 
 
 
 
X6 
 
 
1  
CBCs (with differential and platelet count) which includes WBC, ANC, Platelets and Hgb required for protocol 
therapy must be done < 24 hours prior to the treatment cycle. 
2  
Required for premenopausal women who have not been surgically sterilized.  All females of childbearing potential 
should undergo GYN pelvic exam and Pap smear before receiving protocol therapy. 
3  
Patients will be monitored for toxicity weekly during the first cycle of postoperative chemotherapy. 
4  
CT-scan, transrectal MRI or endo-rectal ultrasound may be used. 
5  
One year after surgery then recommended every 3 years. 
6  
Using the specified tool, bowel function will be measured 4 times: prior to radiation therapy (baseline), during the last 
week of RT, immediately prior to surgery and 18 + 2 months following completion of RT.  Bowel function of Group I 
PS will be measured 2 times: at registration/randomization (baseline) and 18 + 2 months following completion of RT. 
This information is only to be collected in patients with a functioning rectum, i.e. do not collect it in patients with a 
colostomy.  Please refer to Section 5.6.  
7  
Does not need to be repeated if performed pre-op or intra-op. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
 
Revised 3/07, Update #2 
45 
7.2 
Biological Material Submissions 
7.2.1 
Pathology samples have been requested for the correlative studies described in 
Section 11.0.  Collection and submission of correlative samples should be limited to 
those patients who have agreed to participate in the correlative studies.  Samples 
should be submitted as outlined in Section 10.0. 
7.2.2 
ECOG’s diagnostic review project for secondary AML/MDS ended December 1, 
2005.  Submission of diagnostic slides upon diagnosis of secondary AML/MDS for 
central diagnostic review and classification is no longer required. 
 
Rev. 3/07 
 
Pre-Treatment Biopsy1 
Surgical Resection2 
Tumor Tissue Block3 
X 
X 
Mucosa Tissue Block3 
 
X 
 
1 
To be submitted from patients receiving preoperative treatment (Group I). 
2 
Group I PS and Group II (pre-registration surgical resection) materials are to be submitted within one 
month of registration. Group I (post-registration surgical resection) materials are to be submitted within 
one month of surgery. 
3 
If paraffin-embedded blocks cannot be provided, please contact the PCO regarding the appropriate 
alternative sample submission. 
Rev. 3/07 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
46 
8. 
Drug Formulation and Procurement 
8.1 
Irinotecan - For more information, please refer to the package insert. 
8.1.1 
Other Names  
Camptothecin-11, CPT-11, Camptosar® 
8.1.2 
Classification  
Topoisomerase I inhibitor. 
8.1.3 
Mode of Action  
Topoisomerase I is intimately involved in DNA replication and RNA transcription as it 
relieves the torsional strain introduced ahead of the moving replication fork.  The 
cytotoxicity of irinotecan results from single and double strand DNA breaks that are 
produced by the inhibited topoisomerase I during the course of DNA and RNA 
synthesis.  Irinotecan is an inactive prodrug and must be metabolized in vivo by 
carboxyesterases to the active compound SN-38.    
8.1.4 
Storage and Stability  
Undiluted vials are stored at room temperature (15-30EC), and protected from light.  
Irinotecan diluted with 5% dextrose is stable at refrigerated temperatures for 48 hours 
when protected from light. 
8.1.5 
Dose Specifics  
Arms A and D: 180 mg/m2 IV over 90 minutes. Repeat every 2 weeks. 
8.1.6 
Preparation  
Irinotecan must be diluted before infusion.  The recommended dilutant for short 
intravenous administration of irinotecan is 500 mL of dextrose 5% or a concentration 
range between 0.12 to 2.8 mg/mL.  Stability is less in normal saline.  The diluted 
solution should be inspected visually for particulate matter. 
8.1.7 
Administration  
IV over 90 minutes 
8.1.8 
Availability 
Irinotecan is a commercially marketed product which has been approved by the FDA 
for the treatment of metastatic carcinoma of the colon or rectum and metastatic 
carcinoma of the colon or rectum where disease has recurred or progressed following 
initial fluorouracil-based therapy. However, its use in patients with advanced (stage II 
or III) rectal cancer is not currently approved by the FDA. When used as directed by 
this protocol, irinotecan is classified as an “unapproved use of an approved agent” 
and, by definition, considered as an investigational agent. However, while it is not an 
indication currently approved by the FDA, the use of irinotecan in this protocol is 
exempt from the requirements of an IND, as described under Title 21 CFR 312.2(b). 
Commercially available in 100 mg single dose 5 mL vials and 40 mg single dose 2 ml 
vials containing 20 mg/mL. 
8.1.9 
Incompatabilites 
Solutions other than dextrose 5% or normal saline should not be used for dilution.  
Other compatibility information is not available. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
47 
8.1.10 Drug Interactions 
Dexamethasone when administered concurrently with irinotecan causes increased 
lymphopenia and hyperglycemia.   
Laxative use should be curtailed during irinotecan administration and in the 
immediate days following irinotecan administration.   
Simultaneous administration of prochlorperazine and irinotecan has increased the 
incidence of akathesia.   
Diuretic use with irinotecan may exacerbate dehydration induced by diarrhea and 
chemotherapy-induced nausea and vomiting.   
St. John’s wort decreases the AUC of SN-38 presumably by induction of CYP3A4 
activity. 
Ketoconazole via inhibition of CYP3A4 signficantly increase exposure of the active 
metabolite SN-38, which could result in exaggerated toxicity.  Consideration of dose 
reduction in patients on ketoconazole and other agents known to inhibit CYP3A4 
should be considered for irinotecan. 
 
8.1.11 Side Effects  
Hematologic: Leukopenia, neutropenia, anemia, thrombocytopenia, neutropenic 
fever, hemorrhage 
Gastrointestinal: Diarrhea, nausea and vomiting, anorexia, abdominal pain, 
flatulence, stomatitis, dyspepsia, dehydration 
Hepatic: Elevated transaminases 
Cardiovascular:  Vasodilation, hypotension, myocardial infarction, stroke, edema  
Neurologic:  Dizziness, confusion, somnolence, insomnia, back pain 
Respiratory: Pulmonary embolism 
Dermatologic: Alopecia, rash 
Other: Asthenia, thrombophlebitis, sweating, weight loss, chills 
8.1.12 Nursing/Patient Implications  
Premedicate with dexamethasone in anticipation of mild to moderate nausea and 
vomiting. When used in combination with 5-fluroruracil and leucovorin the nausea 
and vomiting will likely be worse. 
Fatalities have been reported with thromboembolic events and neutropenic sepsis in 
patients receiving 5-fluorouracil, leucovorin and irinotecan. 
Monitor for diarrhea. For diarrhea occurring during or immediately after the infusion 
of irinotecan, atropine 0.25 to 1mg can be administered IV or SC (anticipate 
mydriasis and tachycardia). For more delayed diarrhea, usually beginning 5-7 days 
after starting treatment, the patient should take 4 mg loperamide orally at the first 
loose stool. Loperamide dosing should continue at 2 mg q 2h (4 mg q 4h at night) 
until 12 hours after the first formed stool. (NOTE: this loperamide regimen is in 
excess of the labeled “maximum” dose of 16 mg/day.) 
Monitor CBC, platelets, and liver function tests. 
Dose modifications per the protocol or the package insert should be followed for 
hematologic and gastrointestinal toxicity. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 11/05. Addendum #4 
48 
Administration of a oral quinolone antibiotic may decrease the risk of neutropenic 
sepsis in patients receiving 5-fluorouracil/leucovorin and irinotecan. 
Advise patient of likely post-treatment neutropenia and instruct in appropriate 
neutropenic precautions. 
Advise patient of possible alopecia and inform patient of various cosmetic strategies. 
(See Section 5.10). 
8.1.13 References  
Negoro S et al. Phase I study of weekly intravenous infusions of CPT-11, a new 
derivative of camptothecin, in the treatment of advanced NSCLC. J Natl Cancer Inst 
1991;16:1164-8. 
Armand JP et al. CPT-11 (irinotecan) in the treatment of colorectal cancer. Eur J 
Cancer 1995; 7/8:1283-7. 
Cunningham D, Pyrhonen S, James R et al: Randomised trial of irinotecan plus 
supportive care versus supportive care alone after fluorouracil failure for patients 
with metastatic colorectal cancer. Lancet 1998; 352:1413-1418. 
Mathijssen RHJ, Verweij J, DeBruijn P et al: Effects of St. John's Wort on irinotecan 
metabolism. J Natl Cancer Inst 2002; 94(16):1247-1249. 
Noda K, Nishiwaki Y, Kawahara M et al: Irinotecan plus cisplatin compared with 
etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 2002; 
346(2):85-91. 
Sargent DJ. Niedzwiecki D. O'Connell MJ. Schilsky RL. Recommendation for 
caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer. New 
England Journal of Medicine. 2001;345(2):144-5. 
Saltz LB. Cox JV. Blanke C. Rosen LS. Fehrenbacher L. Moore MJ. Maroun JA. 
Ackland SP. Locker PK. Pirotta N. Elfring GL. Miller LL. Irinotecan plus fluorouracil 
and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. New 
England Journal of Medicine. 2000;343(13):905-14. 
Kehrer DF. Mathijssen RH. Verweij J. de Bruijn P. Sparreboom A. Modulation of 
irinotecan metabolism by ketoconazole. Journal of Clinical Oncology. 2002; 
20(14):3122-9.
Rev. 11/05 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 4/05, Addendum #3 
49 
8.2 
Oxaliplatin (266046) - For more information, please refer to the package insert. 
8.2.1 
Chemical Name 
cis -[(1R,2R)-1,2-cyclohexanediamine- N,N’] [oxalate(2-)- 0,0’]  platinum. 
8.2.2 
Other Names  
Trans-l-diaminocyclohexane oxalatoplatinum 
Cis-[oxalato (trans-I-1 ,2-diaminocyclohexane) platinum(lI)] 
l-OHP 
Eloxatin TM 
Eloxatine TM 
Dacplat TM 
5R96669 
8.2.3 
Classification  
Platinum Derivative 
8.2.4 
CAS Registry Number 
63121-00-6 
8.2.5 
Molecular Formula/Weight 
C8H14N204 Pt 
397.3 
8.2.6 
Approximate Solubility 
Oxaliplatin is slightly soluble in water at 6 mg/mL, very slightly soluble in methanol, 
and practically insoluble in ethanol and acetone. 
8.2.7 
Mode of Action  
Oxaliplatin is biotransformed to a reactive species which complex with (crosslink) 
DNA, amino acids, proteins, and other macromolecules and cause tumor cell death 
by preventing cellular replication and transcription and stimulating cells to undergo 
apoptosis. 
8.2.8 
Description 
Oxaliplatin is a novel antineoplastic platinum derivative with an oxalato ligand as 
group and a 1 ,2-diaminocyclohexane (DACH) carrier. 
8.2.9 
How Supplied 
Oxaliplatin is available in two distinct dosage forms:  
• 
Oxaliplatin for injection (lyophilized sterile powder) is a preservative-free, 
lyophilized powder as a white to off-white cake or powder contained in clear 
vials, sealed with an elastomeric stopper and a flip-off cover.   It is available in 
50 mg and 100 mg vials containing 450 mg and 900 mg of lactose monohydrate, 
respectively.   
 
• 
Oxaliplatin injection (sterile solution) is a preservative-free, aqueous solution 
containing 5 mg of oxaliplatin per mL in water for injection.  It is available in 50 
mg and 100 mg vials containing 50 mg in 10 mL of water for injection and 100 
mg in 20 mL of water for injection, respectively.  The primary package is a clear 
glass (Type I) vial sealed with an elastomeric stopper and flip-off cover.  
 
 
Both formulations must be further diluted in D5W before administration. 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 4/05, Addendum #3 
50 
8.2.10 Preparation 
• 
Oxaliplatin for injection:  Reconstitute the lyophilized powder by adding 10 mL 
(for the 50 mg vials) or 20 mL (for the 100 mg vials) of Water for Injection or 
Dextrose 5% in Water to yield a 5 mg/mL solution.  After reconstitution in the 
original vial, withdraw the required amount of reconstituted solution from the 
vial(s) and then dilute with 250 mL to 500 mL Dextrose 5% in Water to give an 
oxaliplatin concentration of not less than 0.2 mg/mL. Do not reconstitute or 
dilute oxaliplatin with a sodium chloride solution. 
• 
Oxaliplatin injection:  Withdraw the calculated dose of the 5 mg/ml solution from 
the vial(s)  and then dilute with 250 mL to 500 mL Dextrose 5% in Water to give 
an oxaliplatin concentration between 0.2 mg/mL and 2.0 mg/mL.  Do not 
reconstitute or dilute oxaliplatin with a sodium chloride solution.    
Do not use administration needles or intravenous infusion sets containing 
aluminum items (risk of degradation of oxaliplatin upon contact with 
aluminum) for the preparation or administration of either the oxaliplatin 
for injection or the oxaliplatin injection. 
8.2.11 Incompatibilites (Both Formulations) 
Do not mix or administer with saline or other chloride containing solutions.  
Oxaliplatin is unstable in the presence of chloride. 
The infusion line should be flushed with D5W prior to administration of any 
concomitant medication.   
Oxaliplatin is unstable under alkaline conditions.  Do not mix with alkaline drugs or 
solutions (in particular 5-fluorouracil basic solution, trometamol and folinic products 
containing trometamol as an excipient).  When oxaliplatin is administered with 5-
fluorouracil, the oxaliplatin infusion should precede that of 5-fluorouracil.  Ensure the 
infusion lines are adequately flushed with 5% Dextrose between administration of 
the two drugs. 
When oxaliplatin is administered with folinic acid, separate infusion bags and lines 
must be used, with Y-tubing to connect the two lines prior to the single injection site.  
Under these conditions of administration, the two products have been shown to be 
chemically compatible.   
Do not use components containing aluminum for the preparation or administration of 
oxaliplatin.  There is a risk of drug degradation when in contact with aluminum. 
8.2.12 Storage/Stability 
8.2.12.1 Intact Vials 
• 
Oxaliplatin for injection:  Store between 15°C and 30°C (59°F-86°F).  
Do not exceed 30°C.  Stable for 3 years under these conditions.   
• 
Oxaliplatin injection:  Store between 20°C and 25°C (68°F-77°F) with 
excursion permissible between 15°C and 30°C (59°F-86°F).  Do not 
freeze.  For long-term storage, protect product from light (keep vial in 
outer carton).   Stable for 3 years under these conditions. 
8.2.12.2 Reconstituted and Diluted Solutions 
• 
Reconstituted 
solution 
(oxaliplatin 
for 
injection 
only): 
 
After 
reconstitution in the original vial, the reconstituted solution may be 
stored up to 24 hours under refrigeration (2°-8°C /36°-46°F). 
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• 
Both formulations, after final dilution in 250-500 mL of 5% Dextrose in 
Water, are stable for 6 hours at room temperature (20°C to 25°C; 68°F -
77°F) or up to 24 hours under refrigeration (2°C to 8°C; 36°F-46°F). 
8.2.13 Dose Specifics  
Oxaliplatin will be administered to patients registered on Arms B and E. Dose is 
85 mg/m² IV infusion over 2 hours, given once every 2 weeks. Use actual, rather 
than ideal, body weight to calculate dose. If ascites is present, however, use 
estimated “dry” body weight. 
8.2.14 Route of Administration  
Intravenous. 
8.2.15 Availability 
Investigational agent to be obtained from Division of Cancer Treatment and 
Diagnosis, NCI. Oxaliplatin is supplied to the NCI under a Cooperative Research and 
Development Agreement (CRADA) between Sanofi-Aventis and the NCI, DCTD. 
Drug Ordering: Oxaliplatin (NSC #266046) may be requested by the Principal 
Investigator (or their authorized designees) at each participating institution.  
Pharmaceutical Management Branch (PMB) policy requires that drug be shipped 
directly to the institution where the patient is to be treated.  PMB does not permit the 
transfer of agents between institutions (unless prior approval from PMB is obtained - 
see general information).  The responsible investigator at each participating institution 
must be registered with CTEP, DCTD through an annual submission of FDA form 
1572 (Statement of Investigator), Curriculum Vitae, Supplemental Investigator Data 
Form (IDF) and Financial Disclosure Form (FDF).  If there are several participating 
investigators at one institution, CTEP-supplied investigational agents for the study 
should be ordered under the name of one lead investigator at that institution.  
Completed Clinical Drug Requests (NIH-986) should be submitted to  the PMB by fax 
(301) 480-4612 or mailed to the Pharmaceutical Management Branch, CTEP, 
DCTDC, NCI, 9000 Rockville Pike, EPN, Rm. 707, Bethesda, M.D. 20892.  The NCI 
Clinical Drug Request form is available on the NCI home page (www.cancer.gov) or 
by calling the PMB at (301) 496-5725. 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling 301-496-5725 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time. 
Drug Returns:  All unused drug supplies must be returned to the PMB.  When it is 
necessary to return study drug (e.g., sealed vials remaining when a patient 
permanently discontinues protocol treatment, expired vials recalled by the PMB), 
investigators must return the study drug to the PMB using the NCI Return Agent 
Form available on the NCI home page (http://ctep.info.nih.gov) or by calling the PMB 
at (301) 496-5725. 
Drug Accountability:  The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of 
all drugs received from the PMB using the NCI Investigational Agent Accountability 
Record available on the NCI home page (www.cancer.gov) or by calling the PMB at 
(301) 496-5725. 
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52 
8.2.16 Reported Adverse Events and Potential Risks 
 
Please refer to the Oxaliplatin CAEPR in Section 5.9. 
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8.2.17 Potential Drug Interactions (Both Formulations) 
In vitro, oxaliplatin is not metabolized by, nor does it inhibit, human cytochrome 
P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP3A4, CYP2D6, or 
CYP2E1.  Metabolically mediated drug-drug interactions of oxaliplatin on co-
administered drugs cleared by these CYP isoforms are not anticipated in humans. 
No significant pharmacokinetic interactions between oxaliplatin and 5-fluorouracil, 
irinotecan, topotecan, or gemcitabine have been observed in patients. 
Since platinum-containing compounds are eliminated primarily through the kidney, 
oxaliplatin clearance may be decreased by co-administration of potentially 
nephrotoxic compounds, although this has not been specifically studied. 
In vitro, platinum was not displaced from plasma proteins by the following 
medications:  erythromycin, salicylate, sodium valproate, granisetron, and paclitaxel. 
No plasma protein binding displacement interaction are anticipated in humans. 
8.2.18 Contraindications 
Oxaliplatin should not be administered to patients with a known allergy to other 
platinum compounds. 
8.2.19 Nursing/Patient Implications 
• 
Premedicate with antiemetics (5 HT3 antagonist and steroid) to prevent severe 
nausea and vomiting. 
• 
Monitor for diarrhea and treat symptomatically. 
• 
Monitor for neuropathies (parasthesias of hands, feet and toes and pharynx 
and occasionally cramps), if they occur, tend to be brief (less than one week) 
during the first course but longer with subsequent courses. Advise patients to 
avoid cold exposure and against touching cold objects. Sensory neuropathies 
develop with continued treatment. Ask patient if changes in ambulation, 
swallowing, breathing or fine motor activity have been noted. 
• 
Prolonging the oxaliplatin infusion time to 6 hours may alleviate acute 
neurologic toxicities. 
• 
Monitor for respiratory changes such as shortness of breath. 
 
WARNING: The hemolytic uremic syndrome should be suspected in individuals who 
experience the following: unexplained severe hemolysis, hemoglobinemia and renal 
failure, as demonstrated by an increase in serum creatinine. (See section 8.2.16). 
8.2.20 References 
Investigator’s Brochure: Oxaliplatin. Sanofi Winthrop 1996 
Prescribing Information: Oxaliplatin (Eloxatin) Sanofi- Sythelabo Inc., November 
2004
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8.3 
5-Fluorouracil - For more information, please refer to the package insert. 
8.3.1 
Other Names 
5-FU, Adrucil, Efudex 
8.3.2 
Classification  
Antimetabolite. 
8.3.3 
Mode of Action  
Fluorouracil is a pyrimidine antagonist that interferes with nucleic acid biosynthesis.  
The deoxyribonucleotide of the drug inhibits thymidylate synthetase, thus inhibiting 
the formation of thymidylic acid from deoxyuridylic acid and thus interfering in the 
synthesis of DNA.  It also interferes with RNA synthesis. 
8.3.4 
Storage and Stability 
Stable for prolonged periods of time at room temperature if protected from light.  
Inspect for precipitate; if apparent, agitate vial vigorously or gently heat to not greater 
than 140EF in a water bath.  Do not allow to freeze. 
8.3.5 
Dose Specifics 
Arms A, B, D, E:400 mg/m² then 2.4 gm/m² over 46 hours. 
Arms C and F: 500 mg/m² over 1 hour. 
8.3.6 
Administration 
Arms A, B, D, E:IV bolus followed by continuous infusion. 
Arms C and F: IV bolus. 
8.3.7 
Availability 
Commercially available in 500 mg/10 ml ampules and vials, and 1 gm/20 ml, 
2.5 gm/50 ml, and 5 gm/100 ml vials. 
8.3.8 
Side Effects 
Hematologic:  Leukopenia, thrombocytopenia, anemia; can be dose limiting; less 
common with continuous infusion. 
Dermatologic:  Dermatitis, nail changes, hyperpigmentation, Hand-Foot Syndrome 
with protracted infusions, alopecia. 
Gastrointestinal:  Nausea, vomiting, anorexia; diarrhea, can be dose limiting; 
mucositis occasionally dose limiting; severe, cholera-like diarrhea which can be fatal 
when given with leucovorin. 
Neurologic:  Cerebellar Syndrome (headache and cerebellar ataxia). 
Cardiac:  Angina, noted with continuous infusion. 
Ophthalmic:  Eye irritation, nasal discharge, watering of eyes, blurred vision. 
Hepatic:  Hepatitis with hepatic infusion. 
8.3.9 
Nursing/Patient Implications  
Monitor CBC, platelet counts. 
Administer antiemetics as indicated. 
Monitor for diarrhea.  Encourage fluids and treat symptomatically - may be dose 
limiting. 


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Assess for stomatitis - oral care recommendations as indicated. 
Monitor for neurologic symptoms (headache, ataxia). 
Patients on continuous infusions may need instruction regarding central IV catheters 
and portable IV or IA infusion devices. 
Inform patient of potential alopecia. 
8.3.10 References 
Hansen R, Quebbeman E, Ausman R, et al.  Continuous systemic 5-fluorouracil in 
advanced colorectal cancer:  Results in 91 patients.  J Surg Oncol 1989; 40:177-181. 
Freeman NJ, Costanza ME.  5-Fluorouracil-associated cardiotoxicity.  Cancer 1988; 
61:36-45. 
8.4 
Leucovorin - For more information, please refer to the package insert. 
8.4.1 
Other Names  
Leucovorin Calcium, Wellcovorin‚ citrovorum factor, folinic acid, 5-formyl tetrahydrofolate, 
LV, LCV. 
8.4.2 
Classification  
Tetrahydrofolic acid derivative. 
8.4.3 
Mode of Action  
Leucovorin acts as a biochemical cofactor for 1-carbon transfer reactions in the 
synthesis of purines and pyrimidines.  Leucovorin does not require the enzyme 
dihydrofolate reductase (DHFR) for conversion to tetrahydrofolic acid. 
Leucovorin can potentiate the cytotoxic effects of fluorinated pyrimidines (i.e., 
fluorouracil and floxuridine).  After 5-FU is activated within the cell, it is accompanied 
by a folate cofactor, and inhibits the enzyme thymidylate synthetase, thus inhibiting 
pyrimidine synthesis.  Leucovorin increases the folate pool, thereby increasing the 
binding of folate cofactor and active 5-FU with thymidylate synthetase. 
8.4.4 
Storage and Stability 
All dosage forms are stored at room temperature.  At concentrations of 0.5-0.9 mg/ml 
the drug is chemically stable for at least 24 hours at room temperature under normal 
laboratory light. 
8.4.5 
Dose Specifics 
Arms A, B, D, E: 400 mg/m² IV over 2 hours. 
Arms C and F: 
500 mg/m² IV over 2 hours. 
8.4.6 
Preparation 
The 50 and 100 mg vials for injection are reconstituted with 5 and 10 ml of sterile 
water, respectively, resulting in a 10 mg/ml solution.  The 350 mg vial is reconstituted 
with 17 ml of sterile water resulting in a 20 mg/ml solution.  Due to the increased 
preservative content with the higher doses of bacteriostatic water, only sterile water 
should be used for reconstitution of leucovorin doses greater than 10 mg/m2 (i.e. 
doses utilized in this protocol). 
8.4.7 
Administration 
Intravenous infusion over 2 hours. 


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8.4.8 
Compatibilites 
Leucovorin (0.5-0.9 mg/ml) is chemically stable for at least 24 hours in normal saline, 
5% dextrose, 10% dextrose, Ringer's injection or lactated Ringer's injection. 
Leucovorin is also compatible with fluorouracil. 
8.4.9 
Availability 
Commercially available in parenteral formulations (50 mg, 100 mg and 350 mg vial). 
8.4.10 Side Effects 
Hematologic:  Thrombocytosis. 
Dermatologic:  Skin rash. 
Gastrointestinal:  Nausea, upset stomach, diarrhea. 
Allergic:  Skin rash, hives, pruritus. 
Pulmonary:  Wheezing (possibly allergic in origin). 
Other: Headache; may potentiate the toxic effects of fluoropyrimidine therapy, 
resulting in increased hematologic and gastrointestinal (diarrhea, stomatitis) 
adverse effects. 
8.4.11 Nursing/Patient Implications  
Observe for sensitization reactions. 
When given with fluoropyrimidines, monitor closely for diarrhea and stomatitis. 
8.4.12 References 
Arbuck SG.  Overview of clinical trials using 5-fluorouracil and leucovorin for the 
treatment of colorectal cancer.  Cancer 1989; 63: 1036-1044. 
Bleyer WA.  New vistas for leucovorin in cancer chemotherapy.  Cancer 1989; 63: 
995-1007. 
Grem JL.  5-Fluorouracil plus leucovorin in cancer therapy.  In:  Cancer: Practices 
and Principles of Oncology Updates. Devita VT, Hellman S, Rosenberg SA, editors. 
1988; 2(7): 1-12. 
8.5 
Capecitabine - For more information, please refer to the package insert. Only available for 
patients on NSABP R-04. 
8.5.1 
Other Names 
Xeloda  
8.5.2 
Classification 
Orally administered prodrug of Fluorouracil which is an antimetabolite 
8.5.3 
Mode of Action 
Capecitabine is a prodrug, which is readily absorbed Intact from the GI tract, then 
converted in the liver by carboxyesterase to  5-deoxy-5-fluorocytidine, and ultimately 
to 5-fluorouracil by thymidylate synthetase. This enzymatic conversion occurs in all 
tissues, but is higher in colorectal tumors due to increased intratumoral levels of 
thymidylate synthetase. Capecitabine produces plasma concentrations of fluorouracil 
comparable to equivalent doses of intravenous fluorouracil administered by 
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8.5.4 
Storage and Stability 
Store tablets at controlled room temperature. The drug is stable as per the 
manufacturer’s expiration date. 
8.5.5 
Dose Specifics 
As per protocol. Recommended daily dosage is 825 mg/ m2 divided into two doses. 
8.5.6 
Preparation 
Orally administered drug. Needs no preparation other than dispensing the proper 
amount of medication for that dosing period. 
8.5.7 
Administration 
Drug is administered orally with food in two divided daily doses. Dose should be 
taken with water. 
8.5.8 
Compatabilites 
Drug – Drug Interactions: 
Folic Acid may increase fluorouracil concentrations and may increase the toxicity. 
8.5.9 
Availability 
Commercially available as 150 mg and 500 mg tablets, in bottles of 120 and 240 mg 
respectively. Only available for patients on NSABP R-04. 
8.5.10 Side Effects 
Gastrointestinal: Nausea, vomiting, diarrhea, mucositis, stomatitis. abdominal pain, 
cachexia, anorexia. Diarrhea can be life threatening and is dose limiting 
Dermatological:Hand – Foot Syndrome (dose limiting), photosensitivity, radiation 
recall 
Cardiovascular: Angina, Cardiac Sudden death (reported with fluorouracil) 
Hematologic: Neutopenia, thrombocytopenia, anemia, lymphopenia 
Immune System: Susceptibility to infections 
Muscolosketetal: Myalgias 
Hepatobilliary: Hyperbillirubinemia 
8.5.11 Nursing/Patient Implications 
Monitor CBC 
Assess for hand-foot syndrome, oropharyngeal lesions 
Reinforce importance of taking medication as instructed. Various patient aids are 
provided by manufacturer to assist patient and caregivers 
Assess for diarrhea. Instruct patient to report any symptoms immediately 
Reinforce  any dosage changes/ reductions which are ordered due to side effects 
8.5.12 References 
Xeloda product information 
Kerr, R Capcitabine/ irinotecan Combinations in Colorectal Cancer. Oncology 
(supplement ) 2002, 16: 27-29 


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Freeman NJ, Costanza ME. 5- Fluorouracil associated cardiotoxicity. Cancer 1988 
61: 36-45 
Budman DR Mropol NJ Reigner B, et al: Preliminary studies of a novel 
fluoropyrimidine carbamate: Capecitabine . J Clin Oncol 16: 1795-1802 1998 
Gradishar WJ: Clinical status of capecitabine in the treatment of breast cancer. 
Oncology 15 (1) supplement: 69-72 2001 
Prepared by Gary Mead 5/2002 


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9. 
Statistical Considerations 
9.1 
Clinical Endpoints 
The main endpoint of this trial is overall survival (OS). We expect OS to be 75% at three 
years for the control arm (5-FU/LV, Arms C [Group 1]/F [Group 2]) and the study is designed 
to target a hazard ratio of 1.3 (75% vs 80% OS at 3 years; 62% vs 69% at 5 years) in either of 
the experimental arms, Irinotecan/5-FU/LV (Arms A [Group 1]/D [Group 2]) or Oxaliplatin/5-
FU/LV (Arms B [Group 1]/E [Group 2]). 
With all major cooperative groups participating in this study, we expect to achieve an accrual 
rate in the range of 600 patients per year (200 patients per arm per year).  With the expected 
accrual and failure rates given above, the study will have over 82% power to detect a hazard 
ratio of 1.3 for OS between either experimental arm and control with 3,000 total eligible 
patients (600 eligible patients per year for 5 years) and follow-up of 1.5 years after closure to 
accrual. With an expected ineligibility rate of 5%, this trial may enter 3,150 total registrations. 
This design incorporates 7 interim analyses and one final analysis at 6.5 years post activation 
for overall survival. One interim analysis will occur every six months corresponding to 
scheduled ECOG Data Monitoring Committee (DMC) meetings, once the trial achieves 25% 
expected information (142 total failures, at roughly 36 months post activation). Analyses will 
use stratified log rank tests (stratified on the factors listed in section 4.26) with an overall 
0.0167 (=0.05/3) one-side type I error. Full information will occur at 564 total deaths.  The 
O'Brien-Fleming group sequential boundary will be used to adjust for the sequential testing 
and the use function methodology of Lan and DeMets will be employed to adjust the 
boundaries if the actual interim analyses do not correspond with the projected information 
times given here. Group sequential O'Brien-Fleming boundaries for the first three interim 
analyses will be truncated at 0.00033. Simulation studies conducted by the ECOG Statistical 
Center and others (Friedlin, Korn and George) (108) suggest that overall test size is inflated 
by a negligible factor from the truncation, but there may be a small gain in terms of expected 
stopping time. 
Assuming one of the experimental arms is no different from the control arm and the other 
experimental arm is active, power for a true hazard ratio of 1.30 to compare the two 
experimental arms using a two-sided 0.0167 level test is 74% (power is 82% for a hazard 
ratio of 1.33). If both of the experimental arms are active (at least 80% OS at 3 years), the 
power to detect a hazard ratio of 1.30 between experimental arms, using a two-sided 0.0167 
level test is 64% (power is 80% for a hazard ratio of 1.37). Power to compare the 
experimental arms will also be higher with longer follow-up. 
This study will be monitored for early stopping in favor of the null hypothesis using repeated 
confidence interval methodology similar to that described by Jennison and Turnbull (109). At 
each interim analysis nominal one-sided (1-alpha) confidence intervals on the overall survival 
hazard ratios comparing the experimental arms to control will be computed, where alpha is 
the nominal one-sided significance level of the use function boundary at the information 
fraction at the particular analyis time. If the confidence intervals do not contain the target 
alternative of 1.3, the ECOG DMC may consider closing an experimental arm or stopping the 
trial early for overall lack of a treatment difference. Conversely, if an experimental arm is 
found to be statistically superior to the control arm at a particular interim analysis before 
accrual is completed, the ECOG DMC may consider closing the control arm to further accrual. 
Patient follow-up will be completed per section 7.0. All patients will be followed at least yearly 
for survival for a period of 10 years post registration. 
9.2 
Laboratory Correlates 
Objectives 2.4 and 2.5 seek to determine the prognostic and predictive significance of TS and 
other key targets of 5-FU, ERCC1 and other enzymes involved in repair of oxaliplatin adducts  
and molecular markers (18q allelic loss, MSI and p53 gene mutation) for overall survival in 


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rectal cancer. We base power calculations for these endpoints on our previous ECOG 
experience in adjuvant colon cancer with TS and 18q allelic loss. Results in adjuvant colon 
cancer have shown that roughly 80% of cases showed high levels of expression (2+/3+) and 
20% of patients showed no or low levels of expression (0/1+). Also, we observed an absolute 
10% difference in OS at 5 years in the colon series, with highly expressing patients exhibiting 
worse survival. Using these figures, we anticipate having at least 85% power to detect an 8% 
absolute difference in OS at 5 years in this study (from 63% in the highly expressing group to 
71% in the low/no expression group; a 35% increase in median overall survival). Calculations 
are based on the accrual and follow-up assumptions given in the previous section and a two-
sided 0.05 level logrank test for overall survival, assuming 85% of the patients contribute 
evaluable samples to the correlative component of the trial. If the split between low and high 
expression groups is more evenly distributed (50% in each group) then the power will be 
higher to compare these groups, greater than 95%.  We expect that the other targets of 5-FU 
will have power similar to that described above for TS. 
For molecular marker analysis we use 18q allelic loss to estimate power and expect that other 
molecular markers will have similar power. In our previous adjuvant colon correlative study 
we found that roughly 50% of samples showed 18q loss of heterozygosity (LOH) and 50% 
showed no loss, with an absolute difference in overall survival at 5 years of 19% (69% for no 
loss group versus 50% in the LOH group). Assuming that the rectal cases in this study will 
exhibit similar patterns of LOH, we anticipate that there will be greater than 95% power to 
detect a smaller difference, 63% versus 73% at 5 years, again assuming that 85% of the 
samples will be available for this analysis. If the 18q LOH split is different from 50:50, say 
25% of cases with LOH and 75% of cases with no loss, then the power will still be high, 
greater than 95%. With 50% of cases showing LOH, there will be 83% power to detect an 
absolute difference as small as 30% in overall survival (63% versus 70% at 5 years). 
9.3 
Bowel Function and Quality of Life Endpoints 
9.3.1 
Quality of Life (QOL) Data Analysis 
Analytical processing of the patient bowel function questionnaire (PBF), Uniscale, 
and FACT Diarrhea Subscale (FACT-D) will be comparable. We will calculate 
summary scores for the PBF and FACT-D as prescribed by the tool authors. The 
PBF will provide a score representing the number of problems experienced by the 
patient with bowel functioning as well as with individual aspects of bowel function. 
The FACT-D produces a single total score transformed onto a 0-100 point range. The 
Uniscale is a single-item score from 0-100. 
Each of the endpoints mentioned in the previous paragraph will be compared across 
the two treatment groups. The main statistical comparison across treatment arms will 
be the change score from baseline to last assessment (18 month post treatment) in 
each group. The summated scores from the PBF, FACT-D, and Uniscale will be 
compared via ANOVA and two-sample t-tests (two-sample tests will be performed at 
a two-sided significance level of 0.05/3=0.0167). Supplementary analyses will include 
analysis of covariance modeling of the differences between groups over time in each 
of the QOL endpoints while holding constant the various demographic and treatment 
covariates. The proportion of patients that report problems with different aspects of 
bowel function will be compared across groups using equality of binomial proportions 
testing. Further analysis will involve an examination of the clinical significance for 
changes over time by calculating the percentage of patients in each treatment group 
that report an improvement of more than 10 points on the 0-100 point scale for any 
QOL endpoint (110-112).  These percentages will be compared via chi-square 
testing. All testing will be done using a two-tailed overall 5% Type I error rate (0.0167 
level for each of three pairwise comparisons). 
Concurrent validity of the QOL measures will be ascertained by calculating the 
difference in scores between the Uniscale, PBF, and FACT-D values for each patient 


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followed by a number of approaches.  First, simple correlational data will be obtained 
via the use of Spearman's rho correlation coefficient with validity being determined to 
have been established if the monthly correlation coefficients are all within the range 
of 0.5 to 0.75 (113). Simple paired comparison procedures (t-tests, Wilcoxon 
procedures) will be used based on the results of normality testing (114) and the 
measurement comparison procedures of Bland and Altman (115). Equality of trends 
over time analysis will be carried out by calculating the slope of the QOL scores over 
time and testing for equality of slopes across the two measures and by subsequently 
testing for a zero slope for the trend of different scores over time.  Finally, area under 
the curve analysis will be completed by calculating the difference of the area under 
the curves for the two measures and using the same simple univariate tests for 
measures of central tendency specified above. 
9.3.2 
Power considerations for QOL data 
A two-sample t-test with 1000 patients per group provides over 90% power to detect 
a difference of 20% times the standard deviation. This effect size has been classified 
as small and minimally clinically significant by various authors.  Hence, we will have 
sufficient power to detect all clinically significant differences between individual 
treatment groups. With 1000 patients per group, we will have over 90% power to 
detect differences of 10% in the rate of bowel function problems reported between 
groups by standard equality of binomial proportions testing. 
9.3.3 
Handling of Missing QOL Data 
Several approaches to missing data will be employed including alternatives that carry 
forward the mean, minimum, maximum, last value, and zero value (in the case of 
death) for the purposes of verifying that the results for treatment comparisons are 
consistent relative to various assumptions and impact of the randomness of the 
missing data (117, 116). Previous experience with imputation in clinical trials has 
demonstrated that the use of various imputation methods compared to complete 
cases analysis provides evidence of the degree of robustness of the results relative 
to the assumptions of the analytical procedure (118). We do not expect the amount of 
missing data to exceed 20% and therefore the results should remain relatively 
resistant to missing data. We will examine the data for any influence that would be 
likely to cause data to be missing for any other reason than simple random chance. In 
other words, we will explore the dataset for evidence to suggest that any concomitant 
influence may cause the data to not be missing completely at random. 
(117, 116, 119) 


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63 
9.4 
Ethnicity/Racial Breakdown by Gender 
Expected accrual: 50 per month (600 per year). Accrual goal is 3000 eligible patients. 
 
Ethnic Category 
Gender 
Males 
Females 
Total 
Hispanic or Latino 
21 
34 
55 
Not Hispanic or Latino 
1950 
995 
2945 
Ethnic Category: Total of all subjects 
1971 
1029 
3000 
Racial Category 
American Indian or Alaskan Native 
11 
8 
19 
Asian 
77 
43 
120 
Black or African American 
95 
80 
175 
Native Hawaiian or other Pacific Islander 
10 
6 
16 
White 
1778 
892 
2670 
Racial Category: Total of all subjects 
1971 
1029 
3000 
Estimates are based on past protocols E1297, E4290, S9304, R9401. 


Eastern Cooperative 
E3201 
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64 
10. 
Pathology Review 
NOTE: ECOG’s diagnostic review project for secondary AML/MDS ended December 1, 2005.  
Submission of secondary slides upon diagnosis of secondary AML/MDS for central 
diagnostic review and classification is no longer required.  Submit materials requested for 
correlative studies per patient consent. 
10.1 
The clinical investigator and the submitting pathologist are responsible for submitting 
representtative diagnostic materials for correlative studies.  When a patient is registered to 
receive protocol therapy, the submitting pathologist and clinical research associate should 
refer to Appendix II (Pathology Submission Guidelines) which provides the following: 
10.1.1 Instruction Sheet from ECOG Pathology Coordinating Office providing details for the 
Submission of Pathology Materials. 
10.1.2 Memorandum to the submitting pathologist from Stanley Hamilton, M.D., chair, 
ECOG Pathology Committee, providing details for the Submission of Pathology 
Materials. 
10.1.3 A list of required materials. 
10.1.4 An ECOG Pathology Material Submission Form (#638). 
10.2 
The materials required for this protocol are: 
10.2.1 ECOG Pathology Material Submission Form (#638), Parts A & B completed. Please 
identify the clinical status of the submitted material (i.e., pretreatment as opposed to 
remission and relapse). 
10.2.2 A copy of the surgical pathology report. 
It is imperative that the number of lymph nodes retrieved in the surgical specimen is 
mentioned within the surgical pathology report. In addition to the surgical pathology 
report, if immunologic studies have been performed at the home institution, it is 
necessary that these be forwarded as well.  
10.2.3 Sample Submission  
For Correlative Study 
Analysis of 18q allelic loss status and MSI status requires evaluation of DNA from 
tumor tissue and control non-neoplastic tissue, preferably mucosa, in routine 
formalin-fixed, 
paraffin-embedded histologic sections. 
Immuno-histochemistry 
requires tissue sections on positively charged slides. 
The requested specimens are: 
• 
In patients receiving pre-operative treatment (Group I): formalin-fixed, paraffin-
embedded block from pre-treatment biopsy tissue including cancer 
• 
In all patients: from surgical resection specimen 
o 
One block containing tumor tissue 
o 
One block containing mucosa tissue 
NOTE: 
If tissue blocks cannot be submitted, contact the PCO regarding the 
appropriate alternative sample submission. Contact information is provided 
in Section 10.3.2. 
Rev. 3/07 
Rev. 3/07 


Eastern Cooperative 
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65 
[Deleted in Update #2] 
NOTE: 
If pathology materials cannot be submitted, please indicate the reason on 
the ECOG Pathology Material Submission Form (#638) and include a letter 
of explanation. 
NOTE: 
A copy of the completed submission form will be sent to the Coordinating 
Center by the Pathology Coordinating Office. 
10.3 
Shipping Procedures  
10.3.1 Submission Schedule  
10.3.1.1 Pretreatment biopsy materials (Group I) and surgical resections (Group II) 
are to be submitted within one month after registration 
10.3.1.2 On study surgical resections (Group I) are to be submitted within one 
month following the surgery. 
[Deleted in Update #2] 
10.3.2 Submit materials to: 
ECOG Pathology Coordinating Office 
Robert H. Lurie Comprehensive Cancer Center  
of Northwestern University Medical School 
Olson Pavilion - Room 8501 
710 North Fairbanks Court 
Chicago, IL 60611 
Tel: (312) 503-3384 
FAX: (312) 503-3385 
The ECOG Pathology Coordinating Office will forward the appropriate pathology 
materials to Dr. Stanley Hamilton’s laboratory at MD Anderson Cancer Center for 
microdissection, DNA extraction and molecular analysis, and to Dr. Robert Diasio’s 
laboratory at the University of Alabama at Birmingham for RNA extraction and 
immunohistochemistry. 
Rev. 3/07 
Rev. 3/07 


Eastern Cooperative 
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66 
10.4 
Processing and Routing by the Pathology Coordinating Office 
10.4.1 For the correlative studies (defined in section 11.0), the PCO will section the blocks 
and forward the appropriate materials to Dr Hamilton and Dr. Rashid for analysis. 
Section Number  
Processing 
Purpose 
1 
H&E-stained slide 
Documentation 
of 
block 
status upon receipt at PCO 
2 
H&E-stained slide 
Microdissection guidance at 
MDACC 
3-12 
unstained slides 
DNA extraction for marker 
analysis at MDACC 
13-17 
unstained slides 
For future analysis of TS, 
TPD, etc. 
18 
1 unstained slide 
Archive at PCO 
19 
H&E-stained slide 
Documenation of block status 
completion of selectioning at 
PCO 
10.4.2 [Deleted in Update #2] 
10.5 
Banking  
The residuals tissue blocks and/or slides collected for the correlative studies described in 
Section 10.0 will be retained at the ECOG Central Tissue Repository for possible future use in 
GI Intergroup approved studies.  Any residual blocks will be available for purposes of 
individual patient management upon specific written request.  If future use is denied or 
withdrawn by the patient, the samples will be removed from consideration for use in any 
future study. 
Rev. 3/07 


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67 
11. 
Correlative Studies 
11.1 
Marker Analysis 
The correlative studies will evaluate chromosome 18q allelic loss, microsatellite instability 
including mutation of the gene for transforming growth factor beta 1 type II receptor 
(TGFβ1RII), p53 gene mutation, and expression of thymidylate synthase (TS), dipyrimidine 
dehydrogenase (DPD), thymidine phosphorylase (TP), excision repair cross-complementing 1 
(ERCC1), ERCC2 and XPF genes.  The correlative studies are summarized in the following 
table:   
Marker 
Method 
Results format 
Laboratory 
Chromosome 18q 
allelic loss 
PCR and automated 
sequencing of 
D18S69, D18S64, 
D18S55, D18S61, 
D18S58 in tumor and 
control DNA 
Shift, no shift + loss, no shift + no 
loss, or unsatisfactory for each 
marker 
Complete loss, partial loss, no 
loss, or unsatisfactory for each 
tumor 
Molecular Diagnostics 
Laboratory, M.D. 
Anderson Cancer 
Center 
MSI including 
TGFβ1RII gene 
mutation 
PCR and automated 
sequencing of BAT25, 
BAT26, D2S123, 
D5S346, D17S250 & 
TGFβ1RII in tumor 
and control DNA 
Shift or no shift for each marker 
MSI-H + TGFβ1RII mutation, 
MSI-H + no TGFβ1RII mutation, 
MSI-L or MSS from 11 markers 
(18q and MSI sets) for each 
tumor 
Molecular Diagnostics 
Laboratory, M.D. 
Anderson Cancer 
Center 
p53 gene mutation 
PCR amplification and 
automated 
sequencing of exons 
5-8 
Mutation or no mutation 
Molecular Diagnostics 
Laboratory, M.D. 
Anderson Cancer 
Center 
TS, DPD, TP 
expression 
Kinetic quantitative 
RT-PCR 
Immunohistochemistry 
with Roche antibody 
kits 
Crossing point values with 
algorithm for RT-PCR 
Semi-quantitative scoring of 
intensity (0-4+) and proportion of 
cells (0-100%) for score of 0-400 
for immunohistochemistry 
Laboratory of Dr. 
Robert Diasio, 
University of Alabama-
Birmingham 
ERCC1, ERCC2 and 
XPF expression 
Kinetic quantitative 
RT-PCR 
Quantitative RT-PCR 
Crossing point values with 
algorithm for RT-PCR 
Laboratory of Dr. 
Robert Diasio, 
University of Alabama-
Birmingham 
Five polymorphic dinucleotide markers on 18q (D18S69, D18S64, D18S55, D18S61 and 
D18S58 from centromere to telomere) and the National Cancer Institute Consensus MSI 
Panel of two mononucleotide markers (BAT25, BAT26) and three dinucleotide markers 
(D2S123, D5S346 and D17S250) and the mononucleotide marker in transforming growth 
factor beta type II receptor are amplified in DNA extracted from tumor and normal control 
tissue with multiplex PCR and sequenced with the ABI 3700 instrument in the Molecular 
Diagnostics Laboratory by the protocol-assigned technologist, as detailed in our previous 


Eastern Cooperative 
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68 
publication (43).  Peak sizes are quantitated and the chromatogram tracings and quantitative 
data are reviewed with Drs. Hamilton and/or Rashid. 
Mutation of the p53 gene in exons 5 through 8 will be evaluated by PCR amplification from 
tumor DNA and automated sequencing on the ABI 3700 instrument in the Molecular 
Diagnostics Laboratory by the protocol-assigned technologist, as in our previous publications 
(124, 125).  The chromatogram tracings will be reviewed with Drs. Hamilton and/or Rashid.   
Evaluation of TS, DPD, TP, ERCC1, ERCC2 and XPF expression will be carried out in the 
laboratory of Dr. Robert Diasio.  Drs. Diasio and Soong have laboratory space of 2000 square 
feet on the sixth floor of the Wallace Tumor Institute located on the School of Medicine 
Campus at the University of Alabama at Birmingham. The labs are modern, wet laboratories 
set up for biochemical and molecular studies with space dedicated for cell culture, PCR and 
biochemical assays. In these laboratories are two kinetic PCR (Roche LightCycler and 
ABI7700 Sequence Detector) Instruments, an ABI310 Genetic Analyzer for DNA sequencing, 
a PALM Robot-Microbeam Laser Capture Microdissector, a Pharmacia GeneQuant II 
Spectrophotometer and a WAVE Denaturing HPLC Instrument for the detection of sequence 
variants.   
Dr. Soong will be supervising the entire process from the receipt of samples, the design, 
validation and performance of assays to the compilation of the results. He has extensive 
expertise in assay design and translational studies and has developed a number of kinetic 
RT-PCR systems, application kits and quantification concepts used commercially and 
patented by Roche Diagnostics, including those to be used in this study. Dr. Soong has also 
published some of the largest series on the clinical relevance of p53 alterations, 
microsatellite instability and cytokeratin 20 in various cancer types, including colorectal 
cancer. 
RNA Extraction from Paraffin-Embedded Tissue (PET)  Microdissected PET from 10μm 
sections will be sent to the University of Alabama at Birmingham. RNA will be isolated from 
this tissue using the standardized protocols in the High Pure RNA Paraffin Kit (Roche 
Cat#3270289, Indianapolis, Indiana). Briefly, tissues are homogenized and digested overnight 
in a buffer containing Proteinase K. The digest is then loaded onto a spin column containing 
glass fibers that bind nucleic acids. Through successive washing steps, contaminants are 
removed and eventually nucleic acids are eluted from the column into a 50μl solution. This 
process also involves incubation with DNase I and a second Proteinase K digestion to 
maximize RNA purity. Using a prototype of this kit, an ability to amplify RNA from 
macrodissected paraffin-embedded tissue and a correlation between RNA levels obtained 
from these tissues and immunohistochemical results has been shown previously (126). 
Kinetic RT-PCR Quantification of RNA levels of markers of 5-fluorouracil and oxaliplatin 
response.  Quantification of DPD, TP and TS RNA levels will be performed by kinetic (or 
“real-time”) RT-PCR on the LightCycler Instrument (Roche, Indianapolis, Indiana) according 
to the assay systems described in the LightCycler - DPD mRNA Quantification KitPLUS (Roche 
Catalog#3302938), LightCycler - TP mRNA Quantification KitPLUS (Cat#3302946) and 
LightCycler - TS mRNA Quantification KitPLUS (Cat#3302954) kits respectively. In these kits, 
10μl of RNA eluate is converted to cDNA in a 30μl reaction including 1x reverse transcriptase 
reaction mix, deoxynucleotide triphosphates, RNAse inhibitor, a gene specific primer and 
AMV reverse transcriptase; incubated at 25oC for 10 minutes, 42oC for 60 minutes and 94oC 
for 5 minutes. Four μl cDNA is then submitted to kinetic PCR in a 20μl reaction containing 1 x 
PCR reaction mix, a “hotstart” Taq polymerase and gene-specific oligonucleotide primers and 
fluorescent probes. The incubation times are 95oC for 5 minutes, 40 cycles of 95oC for 10 
seconds, 62oC for 10 seconds and 72oC for 10 seconds before cooling at 40oC for 30 
seconds. 
In kinetic PCR, the addition of fluorescent probes allow monitoring of amplification kinetics 
and hence, determination of a crossing point (CP or “cycle threshold”) at a partial cycle 
number at which fluorescence becomes detectable above background levels. CP values are 


Eastern Cooperative 
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REVISED 
69 
linearly correlated to gene concentration (127) hence, gene quantities are determined using 
CP values and an algorithm included in the LightCycler Relative Quantification software 
(Roche). The algorithm calculates equivalent quantities to standard curve methods (120). To 
standardize kits and normalize for sample loading and inter-run variation, final quantities are 
expressed as ratios of target to a reference (or “housekeeping”) gene in the test sample, 
relative to the ratios of target to reference gene in a calibrator sample included in each run. 
Calibrator samples are included in each kit and production lot-standardized. 
The kits for DPD, TP and TS RNA quantification use the same kinetic RT-PCR system that 
has been validated previously (128). This system had a dynamic range of at least 1000000 
and was able to detect down to a single gene copy for different gene targets. From 27 
individual determinations, involving 3 different sample concentrations, 3 separate RT 
reactions and 9 individual PCR runs, the co-efficient of variation for the crossing point (CP) 
values of detection was 0.4-1.2% and the sample quantity was 12% for this system. 
Detection mixes containing oligonucleotide primers and fluorescent probes for DPD, TP, TS 
and the reference gene, glucose-6-phosphate dehydrogenase (G6PDH), are included in each 
kit. For the quantification of ERCC1, ERCC2 and XPF RNA levels, detection mixes will be 
designed and validated for analysis in the same kinetic-RTPCR system as the other kits. To 
facilitate amplification from PET, small PCR amplicon sizes will be designed.   
Immunohistochemical (IHC) analysis of DPD, TP and TS protein levels.  Five μm sections 
containing areas of normal and tumor tissue and continuous to those used for the analysis of 
other molecular markers will be sent to the University of Alabama at Birmingham for IHC 
analysis. IHC detection of DPD, TP and TS protein expression will be performed according to 
the protocols in the Anti-DPD Antibody, Formalin-Grade (Roche, Cat #3183645), Anti-TP 
Antibody, 
Formalin-Grade 
(Cat#3183653) 
and 
Anti-TS 
Antiserum, 
Formalin-Grade 
(Cat#3186008) kits respectively. Briefly, after deparaffinization and rehydration, sections 
undergo antigen retrieval by steaming for 5 minutes. They are then blocked with 20% normal 
goat serum for 20 minutes before overnight incubation at 4oC with either DPD, TP or TS 
antibody/antiserum diluted 1:100. Secondary Envision+ peroxidase antibody (Dako Inc., 
Glostrup, Denmark), specifically anti-rabbit for DPD, TS and anti-mouse for TP, are added to 
the sections for 30 minutes before color development with liquid DAB (Dako) for 20 minutes 
and counterstaining with Mayer’s haematoxylin. For DPD, sections are incubated with rabbit 
anti-rat immunoglobulins (Dako) diluted 1:100 for 30 minutes prior to the addition of the 
secondary antibody. Between each incubation step, sections are washed twice with 1xPBS 
for 5 minutes. A negative control section without the addition of DPD, TP or TS-specific 
antibodies/antisera will be included for each IHC run. A positive control section from a tissue 
with known immunostaining patterns for DPD, TP and TS will also be included with each run 
and will be examined for consistency of staining. 
Protein expression from the IHC stains will be evaluated using a semi-quantitative scoring 
strategy described previously that takes into account both the intensity and extent of staining 
(129). Immunostains are assessed on their intensity on a scale of 0 (no staining) to 4+ 
(strongest intensity). The proportion of cells of each intensity to a total of 100% is determined 
and the final score obtained by multiplying each intensity with the proportion of cells allotted to 
it, thus allowing a maximum score of 400 (100% at 4+ intensity). For each section, 8 
individual IHC scores will be determined based on the localization of stains in combinations of 
normal mucosa or tumor, epithelium or stroma and nucleus or cytoplasm. To reduce bias, 
scores will be determined by two independent investigators and averaged. 
It is recognized that there are additional predictive markers that may be of interest during the 
accrual period of this study.  The banking of tissue blocks and/or slides (Section 11.4) will 
provide the necessary flexibility to add additional tumor markers.  The study team and the 
Gastrointestinal Intergroup will consider the addition of future markers for analysis.   


Eastern Cooperative 
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70 
11.1.1 Tumor Marker Reporting 
11.1.1.1 Chromosome 18q allelic loss:  Loss of an 18q allele will be determined by 
a >50% reduction in the area under the peak for 1 allele in tumor DNA as 
compared to non-neoplastic tissue for at least 1 of 2 polymorphic 
markers.  The results for each marker will be recorded along with the 
summary interpretation.  (see Section 11.1.1.3 below) 
11.1.1.2 Microsatellite Instability (MSI) 
Microsatellite instability (MSI) status will be interpreted on the basis of 
shifts in allele size with the criterion of >50% increase in tumor DNA as 
compared to the corresponding peak in mucosal DNA on the 
chromatogram. The 8 dinucleotide and 3 mononucleotide markers will be 
assessed. Tumors are then classified using criteria from the National 
Cancer Institute-sponsored workshop on MSI in colorectal cancer (93). 
Results for each marker are recorded in the project database. 
Classification of the tumor is based on the following criteria:  microsatellite-
stable cancers have shift in none of a minimum of eight evaluable markers; 
cancers with low levels of microsatellite instability (MSI-L) have shift in less 
than 30% of evaluable markers among a minimum of eight; and cancers 
with high levels of microsatellite in stability (MIS-H) have shifts in >30% of 
evaluable markers among a minimum of eight. In microsatellite-stable 
cancers, loss of an 18q allele will be determined by a >50% reduction in 
the area under the peak in tumor of at least 1 of the 2 polymorphic 
markers, as compared to non-neoplastic tissue. 
11.1.1.3 Molecular Classification 
Each tumor is classified on the molecular pathway alterations and results 
of previous correlative studies.  A standardized report form is prepared 
including the list of each marker results and the interpretation of the case 
as: 
Microsatellite-stable with 18q allelic loss 
Microsatellite-stable without 18q allelic loss 
Low level of microsatellite instability (MSI-L) with 18g allelic loss 
Low level of microsatellite instability (MSI-L) without 18g allelic loss 
High level of microsatellite instability (MSI- with TGβ1RII mutation 
High level of microsatellite instability (MSI-H) without TGFβ1RII 
mutation 
High level of microsatellite instability (MSI-H) with TGFβ1RII 
mutation 
11.1.1.4 p53 
p53 mutation analysis will be reported as:   
No mutation 
Mutation (nucleotide change, codon, exon and amina acid change.) 
 
The report will be prepared by the technologist and the chromatogram 
reviewed and reports signed by Drs. Hamilton or Rashid. 
11.1.1.5 Thymidylate Synthase (TS), Dipyrimidine Dehydrogenase (DPD), and 
Thymidine Phosphorylase (TP) Expression 
TS, DPD and TP expression will be reported independently as gene 
quantity for RT-PCR and as score of 0-400 for immunohistochemistry. 


Eastern Cooperative 
E3201 
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71 
11.1.1.6  ERCC1, ERCC2, and XPF Expression 
ERCC1, ERCC2, and XPF expression will reported independently as gene 
quantity for RT-PCR.   
11.2 
Specimen Processing for Molecular Analysis 
Upon receipt in Dr. Hamilton’s office, the case is logged into the project database and the 
stained slide is examined histologically by Dr. Hamilton or Dr. Asif Rashid of the GI Pathology 
Research Laboratory for the presence of tumor and mucosa and for tissue quality for quality 
assurance/quality control purposes.  The review results are recorded in the database.  Tumor 
and mucosa tissue areas for DNA extraction are marked on the H&E slide to serve as the 
microdissection guidance slide.  The unstained slides and marked H&E slide are delivered to 
the Molecular Diagnostics Laboratory (CLIA-88 approved) at M.D. Anderson Cancer Center 
and logged into the project database.  The demarcated areas are scraped by scalpel (the vast 
majority of colorectal cancers can be microdissected satisfactorily by scalpel scraping rather 
than the more time-consuming method of laser capture microdissection) into separate tubes 
by the project-assigned technologist.  For unusual cases with difficult scalpel microdissection, 
Drs. Hamilton or Rashid will carry out laser capture microdissection in the Department of 
Pathology shared facility and the tubes will then be transported to the Molecular Diagnostics 
Laboratory for DNA extraction.  The microdissected slides and histologic guidance slide are 
filed in the GI Pathology Research Laboratory (Stan Hamilton, MD, Principal Investigator) for 
possible future review. 
11.2.1 DNA Extraction and Purification 
The tube of tumor and the tube of mucosa are processed to DNA separately by the 
project-assigned technologist using standard methods in the Molecular Diagnostic 
Laboratory (MDL).  An aliquot of DNA for marker analysis, an aliquot for collaborator 
analysis, and an aliquot for backup storage are prepared.   
11.3 
Banking 
11.3.1 Tissue blocks and slides 
The residuals tissue blocks and/or slides collected for the correlative studies 
described in Section 10.0 will be retained at the ECOG Central Tissue Repository for 
possible use in GI Intergroup approved future studies.  Any residual blocks will be 
available for purposes of individual patient management upon specific written 
request.  If future use is denied or withdrawn by the patient, the samples will be 
removed from consideration for use in any future study. 
11.3.2 Residual DNA Specimen 
The remaining DNA after analysis is stored in a -80EC freezer in the Molecular 
Diagnostics Laboratory in the event of additional need for additional analysis. 
11.3.3 Collaborators’ DNA Specimen 
The aliquot of DNA for each case is stored in a -80EC freezer in the Molecular 
Diagnostics Laboratory for batch shipping to the ECOG PCO for later shipping to 
approved collaborators’ laboratories when needed.  The ECOG PCO is notified of the 
storage specimens for logging in the Pathology Coordinating Office database. 
11.3.4 Backup DNA Aliquot 
The backup DNA aliquot is stored in a -80EC freezer in the Gastrointestinal Pathology 
Research Laboratory at M.D. Anderson Cancer Center. 
11.4 
Sample Inventory Submission Guidelines 
Inventories of all samples collected and the respective aliquots made and used on the above 
mentioned laboratory correlative studies will be submitted to the ECOG Coordinating Center


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
72 
on a monthly basis.  Inventories will be submitted electronically or by diskette by any 
laboratory holding and/or using any specimens associated with this study.  Electronic 
submissions 
should 
be 
submitted 
to 
ecog.labdata@jimmy.harvard.edu. 
All 
other 
correspondence should be addressed to the attention of the Correlative Science Team. 
11.5 
Lab Data Transfer Guidelines 
The data collected on the above mentioned laboratory correlative studies will be submitted to 
the ECOG Coordinating Center by the central laboratory on a quarterly basis. The quarterly 
cut-off dates are March 31, June 30, September 30 and December 31.  Lab data are due at 
the ECOG Coordinating Center one week after these cut-off dates.  Electronic submissions 
should be submitted to ecog.labdata@jimmy.harvard.edu. All other correspondence should 
be addressed to the attention of the Correlative Science Team. 
11.6 
CTSU Sample Submissions 
Submit samples to ECOG Pathology Coordinating Office and follow instructions in Section 10. 
 


Eastern Cooperative 
E3201 
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73 
12. 
Records to Be Kept 
Please refer to the E3201 Forms Packet for the forms submission schedule and copies of all forms.  
The E3201 Forms Packet may be downloaded by accessing the ECOG world wide web home page 
(http://www.ecog.org).  Forms must be submitted to the ECOG Coordinating Center, FSTRF, 900 
Commonwealth Avenue, Boston, MA 02215 (ATTN: DATA). 
12.1 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0.  
Cumulative CDUS data will be submitted quarterly (due dates January 31, April 30, July 31, 
October 31) from the ECOG Coordinating Center to CTEP electronically. 
12.2 
Records Retention  
FDA regulations (21 CFR 312.62) require clinical investigators to retain all trial-related 
documentation, including source documents, long enough to allow the sponsor to use the 
data to support marketing applications. 
This study will be used in support of a US marketing application (New Drug Application), all 
records pertaining to the trial (including source documents) must be maintained for: 
• 
two years after the FDA approves the marketing application, or 
• 
two years after the FDA disapproves the application for the indication being studied, or 
• 
two years after the FDA is notified by the sponsor of the discontinuation of trials and that 
an application will not be submitted. 
 


Eastern Cooperative 
E3201 
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REVISED 
Revised 11/05, Addendum #4 
74 
12.3 
ECOG Radiation Oncology Quality Assurance Materials  
All radiotherapy quality assurance materials should be submitted to QARC:* 
Quality Assurance Review Center 
ATTN: ECOG Materials 
272 West Exchange Street, Suite 101 
Providence, RI 02903-1025 
Tel:(401) 454-4301 
FAX: (401) 454-4683 
 
Radiation Oncology Materials 
QARC Due Date 
Copy of Appendix IV: 
Checklist For Submission of Radiation Oncology Quality  
 
 
 
Assurance Matierals 
ECOG Rectal Cancer On-Study Form 
E3201 Baseline Data Form 
Prescription Sheet for Entire Treatment 
Preoperative Imaging studies: CT with contrast and barium enema (if available) 
Treatment Planning CT/diagnostic imaging and reports 
Beam Verification (portal) Films of ALL Fields 
Simulation Films and/or DRR’s of ALL Fields (indicating any planned field 
reductions) 
Picture of patient in treatment position 
Color Copies of Isodose Distributions along with the corresponding beam data  
 
printouts from the planning system (see Section 5.104) 
Monitor Unit Calculations 
Completed Daily Treatment Record 
 
3D-Conformal Planning:  Submit the following in addition to the above materials 
Description of each treatment field 
Orthogonal anterior/posterior and lateral films if not part of portals 
BEV’s of each treatment field 
REV or overview diagram 
Dose Volume Histograms 
Within 1 week of 
the completion of 
radiation 
All materials must be labeled with the ECOG assigned Protocol and Sequence numbers 
Please contact QARC ECOG CRA TEL: 401-454-4301 or FAX: 401-454-4683 for clarification as 
necessary 
13. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed consent will be 
followed.
 
 
 
Rev. 11/05 
 
 
Rev. 11/05 
Rev. 11/05 
Rev. 11/05 
Rev. 11/05 
Rev. 3/07 


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14. 
References 
1. 
Roh MS, Petrelli N, Wieand S, Colangelo L, Smith R, Mamounas E, Hyams D, Wolmark N.  
Phase III randomized trial of preoperative versus postoperative multi-modality therapy in patients 
with carcinoma of the rectum (NSABP R-03).  American Society of Clinical Oncology, Abstract 
2001; 20(490). 
2. 
O’Connell MJ, Martenson JA, Wieand HS, Krook JE, Macdonald JS, Haller DG, Mayer RJ, 
Gunderson LL, Rich TA.  Improving adjuvant therapy for rectal cancer by combining protracted-
infusion fluorouracil with radiation therapy after curative surgery.  N Engl J Med 1994; 331:502-
507. 
3. 
Tepper JE, O’Connell MJ, Niedzwiecki D, Hollis DR, Mayer RJ, Benson AB, et al.  Final report of 
INT 0014 - adjuvant therapy in rectal cancer: analysis by treatment, stage and gender.  American 
Society of Clinical Oncology, Abstract 2001; 20(489):123a. 
4. 
Tepper JE, O’Connell MJ, Peteroni GR, Hollis D, Cooke E, Benson III AB, Cummings B, 
Gunderson LL, Macdonald JS, Martenson.  Adjuvant postoperative flourouracil-modulated 
chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of intergroup 
0114.  J of Clin Oncol 1997; 15:2030-2039. 
5. 
Tepper JE, O’Connell MJ, Niedzwiecki D, Hollis D, Compton C, Benson III AB, Cummings B, 
Gunderson L, Macdonald JS, Mayer.  Impact of number of nodes retrieved on outcome in 
patients with rectal cancer.  J of Clin Oncol 2001; 19:157-163. 
6. 
Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, 
Locker PK, Pirotta N, Elfring GL, Langdon LM.  Irinotecan plus fluorouracil and leucovorin for 
metastatic colorectal cancer.  N Engl J Med 2000; 343:905-914. 
7. 
Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, 
Carmichael J, Alakl M, Gruia G, Awad L, Rougier P. Irinotecan combined with fluorouracil 
compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a 
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127. Higuchi R, Fockler C et al. Kinetic PCR analysis: real-time monitoring of DNA amplification reactions. 
Biotechnology (N Y) 11(9): 1026-30, 1993. 
128. Soong R, Beyser K et al. Quantitative reverse transcription-polymerase chain reaction detection of 
cytokeratin 20 in noncolorectal lymph nodes. Clin Cancer Res 7(11): 3423-9, 2001. 
129. Frost AR, Sparks D & Grizzle WE. Methods of antigen recovery vary in their usefulness in 
unmasking specific antigens in immunohistochemistry. Appl Immunohistochem Mol Morphol 8: 236-
43, 2000. 
 
 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix I – Page 1 of 18 
Intergroup Randomized Phase III Study of Postoperative Irinotecan, 5-Fluorouracil and Leucovorin vs 
Oxaliplatin, 5-Fluorouracil and Leucovorin vs 5-Fluorouracil and Leucovorin 
 for Patients with Stage II or III Rectal Cancer Receiving Either Preoperative Radiation and 5-Fluorouracil  
or Postoperative Radiation and 5-Fluorouracil 
Version Date: June 26, 2008 
Appendix I 
 
Suggested Patient Consent Form 
 
You are being asked to take part in this study because you have rectal cancer and you may benefit 
from additional treatment.  This is a type of clinical trial (research study).  Clinical trials include only 
patients who choose to take part.  Please take your time to make your decision and discuss it with 
your friends and family. 
 
WHY IS THIS STUDY BEING DONE? 
 
This study involves treatment with chemotherapy, radiation therapy and surgery.  This research 
is being done to compare the effects (good and bad) of a combination of chemotherapy 
medications.  To date, there have been very few studies of different combinations of 
chemotherapies for patients with rectal cancer, who have already had surgery and radiation.  
This study will compare the investigational treatment combinations of irinotecan/leucovorin/5-
fluorouracil or oxaliplatin/leucovorin/5-fluorouracil with the standard therapy leucovorin/5-
fluorouracil. 
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
 
About 3000 people in the United States and Canada will take part in this study. 
 
WHAT IS INVOLVED IN THIS STUDY?   
 
This is a randomized study which means that the three chemotherapy treatment combinations 
are compared with each other to find out if one is better and also to see if the order in which 
therapies are given will affect outcome.  If you agree to enter this trial, you will be randomly 
assigned to receive one of the three chemotherapy combinations.  You have an equal chance 
of an assignment to any one.  This helps to make the results of the research more scientifically 
sound.  Neither you nor your doctor will have a say as to which schedule you are assigned to, 
but both you and your doctor will be informed as to which treatment you will receive. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix I – Page 2 of 18 
The majority of patients with newly-diagnosed rectal cancer are treated with a combined 
program of chemotherapy, radiation and surgery; however, the order or sequence in which 
these treatments are given may vary, as may the chemotherapy which is administered during 
radiation.  Patients and their physicians get to choose which of two treatment groups they will   
be in.   
There are two treatment groups in this trial.  One group receives radiation therapy combined 
with 5-fluorouracil chemotherapy before surgery.  The second group receives surgery first, 
followed by one of the combination chemotherapies, followed by radiation therapy with 5-FU, 
followed by more combination chemotherapy.  The radiation will be given Monday through 
Friday for about six weeks.  You and your doctor will have a choice as to how the 5-fluorouracil 
will be administered.  During the chemotherapy, the 5-fluorouracil may be administered by vein 
over several minutes with the leucovorin for four consecutive days of the first and fifth week of 
radiation OR the 5-fluorouracil may be administered continuously through a catheter in a large 
vein during the entire course of the combined radiation and chemotherapy (six weeks). If you 
are participating in a clinical trial (R-04) conducted by the National Surgical Adjuvant Project 
for Breast and Bowel Cancers (NSABP), you are potentially eligible to participate in this study. 
If you enter this study (E3201), you may receive a pill form of 5-fluorouracil (capecitabine), 
which you will take twice a day during the course of the radiation. The use of capecitabine with 
radiation is ONLY allowed for patients if they are receiving it by participating in R-04. In effect, 
you will be participating in both studies. 
Whether you receive radiation with 5-FU before or after surgery, there is a rest period of at 
least three weeks (usually four to eight weeks) until you have recovered adequately from your 
operation.  Group one patients (pre-operative radiation with 5-FU) will have surgery within 
three to six weeks after completing radiation.  All patients will be treated according to one of 
the treatment schedules described below after their surgery. 
[ Please note: If you have received chemotherapy and radiation followed by surgery as 
described in the treatment plan, you may be able to participate in this trial. Your doctor will 
determine if you can join. You, also, will receive treatment according to one of the schedules 
described below. ] 
Schedule A - this is a two day treatment given every 2 weeks for a total of eight 2-week cycles.  
Medications are given before chemotherapy to prevent nausea and vomiting.  All of the 
chemotherapy drugs will be given intravenously (through a vein).  Irinotecan is given over 90 
minutes; leucovorin is given over 2 hours, followed by 5-FU (5-fluorouracil) given as a quick 
infusion, followed by 5-FU given as a constant infusion through a portable pump over the next 
46 hours.   
Schedule B - this is a two day treatment given every 2 weeks for a total of eight 2-week cycles.  
Medications are given before chemotherapy to prevent nausea and vomiting.  All of the 
chemotherapy drugs will be given intravenously (through a vein).  Oxaliplatin is given over 2 
hours; leucovorin is given over 2 hours, followed by 5-FU (5-fluorouracil) given as a quick 
infusion, followed by 5-FU given as a constant infusion through a portable pump over the next 
46 hours.   
Schedule C - this treatment is given weekly for six weeks followed by a two-week break and is 
given for a total of three 8-week cycles.  All of the chemotherapy drugs will be given 
intravenously (through a vein).  Leucovorin is given over 2 hours; 5-FU (5-fluorouracil) is given 
as a quick infusion after the start of the leucovorin. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix I – Page 3 of 18 
Schedule D - this is a two day treatment given every two weeks for four 2-week cycles, 
followed by combined radiation therapy and chemotherapy.  After completion of radiation 
therapy, four more 2-week cycles of the chemotherapy will be given.  Medications are given 
before chemotherapy to prevent nausea and vomiting.  All of the chemotherapy drugs will be 
given intravenously (through a vein).  Irinotecan is given over 90 minutes; leucovorin is given 
over 2 hours, followed by 5-FU (5-fluorouracil) given as a quick infusion, followed by 5-FU 
given as a constant infusion through a portable pump over the next 46 hours.   
Schedule E - this is a two day treatment given every two weeks for four 2-week cycles, 
followed by combined radiation therapy with chemotherapy.  After completion of radiation 
therapy, four more 2-week cycles of chemotherapy will be given.  Medications are given before 
chemotherapy to prevent nausea and vomiting. All of the chemotherapy drugs will be given 
intravenously (through a vein).  Oxaliplatin is given over 2 hours; leucovorin is given over 2 
hours, followed by 5-FU (5-fluorouracil) given as a quick infusion, followed by 5-FU given as a 
constant infusion through a portable pump over the next 46 hours.   
Schedule F - this treatment is given weekly for six weeks followed by a two-week break.  One 
8-week cycle will be given followed by combined radiation therapy and chemotherapy.  After 
completion of radiation therapy, two more 8-week cycles of chemotherapy will be given. 
All of the chemotherapy drugs will be given intravenously (through a vein). Leucovorin is given 
over 2 hours; 5-FU (5-fluorouracil)  is given as a quick infusion one hour after the start of the 
leucovorin 
If you take part in the study, you will have the following tests and procedures. Some of the  
tests required for this study would be done even if you did not participate in the study.   
 
• Female patients will have a pregnancy test. 
• You will receive a complete physical exam and be seen by a physician at the beginning of 
each cycle of treatment and weekly during the course of radiation.   
• Samples of your blood will be obtained, along with chest x-rays, CT scans or MRI to 
evaluate your health status. 
In addition, you will be asked to fill out brief forms with questions about your bowel function.  
This will take about 10 to 15 minutes. 
If you are in the group receiving radiation therapy with 5-FU before surgery, you will complete 
the questionnaire four (4) times: 
1. 
Prior to radiation therapy 
2. 
During the last week of radiation therapy 
3. 
Immediately prior to surgery 
4. 
Between 16 and 20 months following completion of radiation therapy 
 
If you joined the study after your surgery, but received radiation therapy with 5-FU prior to 
surgery, you will complete the questionnaire two (2) times: 
1. 
At registration 
2. 
Between 16 and 20 months following completion of radiation therapy 
 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix I – Page 4 of 18 
If you are in the group receiving radiation therapy with 5-FU after surgery (and between cycles 
of chemotherapy), you will complete the questionnaire five (5) times: 
1. 
Prior to surgery (if possible) 
2. 
Prior to beginning adjuvant postoperative chemotherapy 
3. 
Immediately prior to starting radiation therapy (RT) 
4. 
During the last week of RT 
5.  
Between 16 and 20 months following completion of RT 
While you are on study, samples of your tissue, blood or bone marrow may be sent to a 
central laboratory to be examined by a central reviewer.  This review is to confirm the results 
of the local laboratory review. 
 
HOW LONG WILL I BE IN THE STUDY? 
 
The actual treatment period on the study is approximately 8 months.  We would like to keep 
track of your medical condition for a period of 10 years after entering the study,  to look at the 
long-term effects of the treatment.  You may stop participating at any time; however, we 
encourage you to talk to your doctor first.   
 
WHAT ARE THE RISKS OF THE STUDY?  
 
While on the study, you are at risk for the following side effects.  The chemotherapy and the 
radiation may cause some, all or none of the side effects listed.  You should discuss these with 
your doctor.  There may also be other side effects that we cannot predict.  Other drugs will be 
given to make side effects less serious and less uncomfortable.  Many side effects go away 
shortly after the chemotherapy drugs are stopped, but in some cases side effects can be 
serious, long-lasting, permanent or life threatening.  Death is rare, but possible. 
Your physician will check you closely to see if any of these side effects are occurring and 
routine blood tests will be done to monitor the effects of treatment.   
 
Treatment Schedules A and D (irinotecan, 5-fluorouracil and leucovorin) 
Likely 
• 
  Diarrhea (loose stools, increased number of bowel movements)* 
• 
  Mouth sores which may make swallowing difficult 
• 
  Nausea (feeling sick to your stomach) and vomiting (throwing up) 
• 
  Sweats 
• 
  Low white blood cells (may make you more likely to get infection) 
• 
  Low red blood cells (may make you feel tired or weak) 
• 
  Low platelets (may make you more likely to have bruising or bleeding) 
• 
  Peeling skin on hands and feet 
• 
  Sensitivity to sunlight 
• 
  Stomach cramps/pain 
• 
  Loss of appetite 
• 
  Fatigue, weakness or lack of body strength 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 4/05, Addendum #3 
Appendix I – Page 5 of 18 
• 
  Hair loss 
• 
  Watery eyes 
• 
  Taste changes 
 
*Diarrhea can occur with most chemotherapy drugs, but it is more common with 
irinotecan. The diarrhea associated with irinotecan can happen at 2 different times. 
First, diarrhea can happen the day that you receive it (by vein), which can be treated 
with a single injection (shot) of a drug called atropine. The diarrhea can occur again, 
several days after the completion of the chemotherapy, and may last for several days. 
The best way to deal with this second occurrence is to notify your doctor immediately. 
Instructions will be given to you on how to treat the diarrhea. 
 
Less Likely   
• 
  Skin rash 
• 
  Blurred vision 
• 
  Loss of nails 
• 
  Unsteadiness when walking 
• 
  Allergic reaction 
• 
  Headache 
• 
  Confusion 
• 
  Tingling of the fingers and toes 
• 
  Damage to the kidneys and liver 
• 
  Swelling of the colon, which could cause a life-threatening infection 
 
 
Rare But Serious 
• 
  Stroke 
• 
  Spasms of the blood vessels that supply the heart, possibly leading to heart 
  attacks 
• 
  Lung damage resulting in shortness of breath (may be permanent) 
• 
  Blood clots in legs and/or lungs 
• 
  Secondary cancers such as acute leukemia 
 
Although very rare, it is possible that the treatment-related side effects could result in 
death. 
 
Treatment Schedules B and E (oxaliplatin, 5-fluorouracil and leucovorin) 
Likely 
• 
  Lowered white blood cells (may make you more likely to get infections) 
• 
  Lowered platelets (may make you more likely to bruise or bleed) 
• 
  Lowered red blood cells (may make you feel tired or weak) 
• 
  Nausea (feeling sick to your stomach) and vomiting (throwing up) 
• 
  Diarrhea (frequent bowel movements) 
• 
  Numbness or tingling in your hands and/or feet (can feel stronger if exposed to 
  cold) 
• 
Feeling of tightness or fullness in the throat, making it feel like it is difficult to 
breath or swallow 
• 
  Soreness, pain, skin irritation or redness where the drug is injected 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 4/05, Addendum #3 
Revised 9/08, Addendum #5 
Appendix I – Page 6 of 18 
• 
  Temporary hair loss 
• 
  Swelling or infection of the bowel 
• 
  Mouth sores or sore throat which may make swallowing difficult 
• 
  Sunlight sensitivity 
• 
  Nail changes 
• 
  Constipation (having fewer bowel movements and harder stools) 
• 
Dehydration (decreased fluid in the body because of diarrhea or inability to drink 
fluids 
• 
  Appetite loss 
• 
  Skin darkening, hives, itchy or dry skin 
• 
Rash 
• 
Fever 
• 
Shortness of breath 
• 
Damage to the liver or kidneys 
• 
Pain that could be in the belly, chest, bones, muscles or joints, along the spine and 
legs 
• 
Fatigue (feeling tired all the time), weakness or lack of body strength 
• 
Headache 
• 
Trouble sleeping 
• 
Hearing loss 
Less Likely   
• 
Flu-like symptoms such as fevers, chills and muscle aches 
• 
Watery eyes, runny nose 
• 
Pain and the risk of infection where the drug is injected 
• 
High blood pressure 
• 
Changes in heart beat (rapid and/or jumpy heart beat) 
• 
Allergic reaction (symptoms vary but difficulty breathing, nausea, vomiting, 
diarrhea, skin rash and/or itching are common with allergic reactions) 
• 
Swelling, soreness or infection of the bowel 
• 
Vision changes (blurring), usually brief 
• 
Temporary blockage or paralysis of the bowels resulting in abdominal pain and 
cramping which may prevent normal bowel movements 
• 
Changes in the salts in the bloodstream such as phosphorous, calcium, 
magnesium, sodium and/or potassium  
• 
Swelling of the lungs 
• 
Swelling in the arms and legs 
• 
Blistering on the palms of the hands and soles of the feet 
• 
Changes in taste 
• 
Upset stomach, heartburn, gas 
• 
Dry mouth 
• 
Hot flashes or flushing (redness of face and neck) 
• 
Cough 
• 
Hiccups 
• 
Fluid collecting in the abdomen 
• 
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip) 
• 
Neuropathy: motor (muscle weakness due to nerve damage) 
• 
Adult respiratory distress syndrome (ARDS) (respiratory failure)  
• 
Hypoxia (a lower-than normal concentration of oxygen in the blood) 
• 
Thrombosis/thrombus/embolism (vascular access-related) (blood clot)  
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 9/08 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 9/08 
Rev. 9/08 
Rev. 9/08 
Rev. 9/08 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 4/05, Addendum #3 
Revised 11/05, Addendum #4 
Revised 9/08, Addendum #5 
Appendix I – Page 7 of 18 
Rare: 
• 
Confusion, memory loss, depression, anxiety or other mental changes 
• 
Lack of balance (feeling as if you might fall down), dizziness 
• 
Chest pain or heart attack 
• 
Blood clot(s) in the brain 
• 
Slurred speech 
• 
 
• 
Infection 
• 
Abnormal eye muscle movement 
• 
Muscle spasms or loss of normal muscular contractions 
• 
Abnormal liver function 
• 
Blood in the urine 
• 
Pain while peeing, inability to pee, frequent need to pee 
• 
Change in nerve function, lack of coordination, sleep disturbance, eyesight 
• 
Seizures, passing out 
• 
Hoarseness, laryngitis, loss or alteration in voice 
   
Rare But Serious: 
• 
Hemolytic Uremic Syndrome – a breakdown of red blood cells, low platelets and 
kidney failure together. 
• 
Pulmonary Fibrosis - lung problems such as cough, shortness of breath, trouble 
breathing, build-up of scar tissue in lungs; thickening and stiffening of lung tissue. 
Can be life threatening - tell your doctor right away if you experience any of these 
problems. 
• 
Disruption of blood proteins where bleeding and blood clots can occur at the same 
time, which could be life-threatening. 
• 
Bleeding from any source including stomach (throwing up blood or black stools), 
lung (coughing up blood), bowels (blood in the stool) or brain; which could be life-
threatening. 
• 
Veno-occlusive disease – liver injury which leads to an enlarged liver, enlarged 
spleen, swelling in the abdomen and jaundice (yellowing of the skin); could be life-
threatening. 
• 
Although very rare, it is possible that treatment-related side effects could result in 
death. 
• 
Tumor Lysis Syndrome – complication can occur when cancer cells are destroyed 
by treatment.  Cell destruction may damage kidneys and change calcium levels, 
which may lead to kidney dialysis, usually on a short-term basis. 
• 
Cholecystitis (inflammation of the gallbladder) 
• 
Gastrointestinal – other (pneumonitis intestinalis) (air in the bowel) 
Treatment Schedules C and F (5-fluorouracil and leucovorin) 
Likely 
• 
  Diarrhea (loose stools, increased number of bowel movements) 
• 
  Mouth sores, which may make swallowing difficult 
• 
  Nausea (feeling sick to your stomach) and vomiting (throwing up) 
• 
Temporary decrease in numbers of white blood cells (with possible risk of 
infection) 
• 
  Peeling skin on hands and feet 
• 
  Sensitivity to sunlight 
• 
  Loss of appetite 
• 
  Fatigue, weakness or lack of body strength 
• 
  Hair loss 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05, 11/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 4/05 
Rev. 11/05 
Rev. 9/08 
Rev. 9/08 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix I – Page 8 of 18 
• 
  Watery eyes 
• 
  Nail changes 
• 
Low platelet counts, causing you to bruise easily, develop spots on your skin that 
look like pinpricks or a rash, or bleed longer if you are hurt. 
• 
Low red blood cell counts, which could result in increasing tiredness, pale skin, 
loss of ability to do physical tasks or exercises and shortness of breath. 
 
Less Likely   
• 
  Skin rash 
• 
  Blurred vision 
• 
  Headache 
• 
  Allergic reaction 
• 
  Confusion 
• 
  Tingling of the fingers and toes 
• 
  Unsteadiness when walking 
• 
  Damage to the liver 
 
Rare But Serious 
 
• 
  Spasms of blood vessels that supply the heart, possibly leading to heart attacks. 
• 
Although very rare, it is possible that treatment-related side effects could result in 
death. 
 
Radiation Therapy 
 
Likely: 
• 
  General feeling of tiredness 
• 
  Loss of appetite 
• 
  Nausea 
• 
  Decrease in blood cell counts that can cause infection or bleeding problems 
• 
  Diarrhea 
• 
  Abdominal pain or cramping 
• 
  Bladder irritation with frequent urination 
• 
  Redness (or darkening) of the skin in the treatment area 
• 
  Rash, itching or peeling of the skin 
• 
  Hair loss in the treatment area, which may be permanent 
 
Less Likely But Serious: 
 
• 
  Injury to the bladder, bowel, or other tissues in the pelvis or abdomen. 
• 
  Intestinal or urinary obstruction 
 
Radiation will cause sterility (inability to bear a child) and lead to early menopause in women who 
have not yet gone through menopause. 
 
Reproductive Risks 
 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix I – Page 9 of 18 
If you are pregnant or breast feeding, you cannot take part in this study.  If you are a 
woman who has not gone through menopause, you will take a blood test to see if you are 
pregnant before you start treatment.  If you are sexually active, your doctor strongly 
recommends that you take precautions to avoid the possibility of becoming pregnant 
because this therapy could kill or seriously damage an unborn child.  Sexually active males 
are also strongly advised to use an accepted and effective method of contraception.  For 
more information about risks and side effects, ask the researcher or contact  
______________________________________________________________ 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
 
If you are taking part in this study, there may or may not be direct medical benefits to you.  If 
you receive study treatment and do not show any benefit, your doctor will discuss alternative 
treatments with you.  You have been told that, should your disease become worse, should side 
effects become very severe, should new scientific developments occur that indicate the 
treatment is not in your best interest or should your doctor feel that this treatment is no longer 
in your best interest, the treatment will be stopped.  Further treatment will be discussed. 
We hope the information learned in this study will benefit other patients with rectal cancer in the 
future. 
 
WHAT OTHER OPTIONS ARE THERE? 
 
Instead of being in this study, you have these options: 
• 
Standard chemotherapy alone 
• 
Radiation therapy alone 
• 
Standard chemotherapy with radiation 
• 
No therapy, with care to help you feel more comfortable. Treatments will reduce 
symptoms, relieve pain, and maximize comfort, diginity and control. Treatment is 
not directed at curing, slowing, or reversing the disease. 
Your doctor can provide information about your disease and will be available to answer any 
questions about the research study. 
 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix I – Page 10 of 18 
WHAT ABOUT CONFIDENTIALITY?  
 
This study is conducted by the Eastern Cooperative Oncology Group (ECOG).  ECOG is a 
cancer group that conducts studies for the National Cancer Institute.  Your doctor is a member 
of ECOG or another group that is participating in this study.  To help protect your privacy, 
ECOG has obtained a Confidentiality Certificate from the Department of Health and Human 
Services (DHHS). 
 
With this Certificate, ECOG cannot be forced (for example, by court subpoena) to disclose 
information that may identify you in any federal, state or local civil, criminal, administrative, 
legislative or other proceedings.  Disclosure will be necessary, however, upon request of 
DHHS for audit or program evaluation purposes. 
 
You should understand that a Confidentiality Certificate does not prevent you or a member of 
your family from voluntarily releasing information about you or your involvement in this 
research.  Note, however, that if an insurer or employer learns about your participation and 
obtains your consent to receive research information, then ECOG may not use the Certificate 
of Confidentiality to withhold this information.  This means that you and your family must also 
actively protect your privacy. 
 
Your identifiable health information is also protected by the Health Insurance Portability and 
Accountability Act (HIPAA) Privacy Rule, which was issued by the Department of Health and 
Human Services. Except as required by law, ECOG will not be able to disclose identifiable 
health information, expected to be collected in this study to anyone other than you without your 
authorization, by a separate document you have signed or will be asked to sign. 
 
Finally, you should understand that your doctor and ECOG are not prevented from taking 
steps, including reporting to authorities, to prevent serious harm to yourself or others and the 
Certificate does not prevent the review of your research records under some circumstances by 
certain organizations for an internal program audit or evaluation.  Organizations that may 
inspect and/or copy your research records for quality assurance and data analysis include 
groups such as: 
 
• 
Eastern Cooperative Oncology Group 
• 
National Cancer Institute (NCI) 
• 
Cancer Trials Support Unit (CTSU) – an NCI-sponsored organization designed to 
increase accrula by provideing greater access to phase III trials. 
• 
Food and Drug Administration 
• 
Other regulatory agencies and/or their designated representatives 
• 
Drug manufacturers, and/or their representatives 
• 
NCI Central Institutional Review Board (CIRB) 
• 
Central laboratories, reviewers, banks 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix I – Page 11 of 18 
WHAT ARE THE COSTS? 
 
If you are put in the study arm that gets oxaliplatin, the Division of Cancer Treatment and 
Diagnosis, NCI will provide you with oxaliplatin free of charge for this study. Every effort will be 
made to ensure adequate supplies of oxaliplatin will be available for all participants. If the drug 
becomes commercially available for this indication, there is a remote possibility that you will be 
asked to purchase subsequent supplies. Your physician will discuss this with you, should this 
situation arise. 
 
Taking part in this study may lead to added costs to you or your insurance company.  Please 
ask about any expected added costs or insurance issues. Medicare should be considered a 
health insurance provider. You may find the National Cancer Institute’s guide “Clinical Trials 
and Insurance Coverage - A Resource Guide” helpful. Ask your doctor for a copy. It is also 
available on the world wide web at http://www.nci.nih.gov/ClinicalTrials/Insurance. Click on the 
printable version. 
 
In the case of injury or illness resulting from this study, emergency medical treatment is 
available but will be provided at the usual charge. Although no funds have been set aside to 
compensate you in the event of injury or illness related to the study treatment or procedures, 
you do not give up any of your legal rights for compensation by signing this form. 
You or your insurance company will be charged for continuing medical care and/or 
hospitalization.  
 
You will receive no payment for taking part in this study. 
 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix I – Page 12 of 18 
 WHAT ARE MY RIGHTS AS A PARTICIPANT? 
 
Taking part in this study is voluntary.  You may choose not to take part or may leave the study 
at any time.  Leaving the study, or choosing not to take part, will not result in any penalty or 
loss of benefits to which you are entitled. 
 
We will tell you about new information that may affect your health, welfare, or willingness to 
stay in this study. 
 
A Data Safety and Monitoring Board, an independent group of experts, will be reviewing the 
data from this research throughout the study.  We will tell you about the new information from 
this or other studies that may affect your health, welfare, or willingness to stay in this study. 
 
 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about the study or a research-related injury, contact your cancer doctor  
 
                                                     at                                                              . 
                       NAME(S)                              TELEPHONE NUMBER  
 
For questions about your rights as a research participant, contact the                                        
NAME OF CENTER 
Institutional Review Board (which is a group of people who review the research to protect 
your rights) at                                        .   
   
 
TELEPHONE NUMBER 
 
WHERE CAN I GET MORE INFORMATION? 
 
You may call the National Cancer Institute's Cancer Information Service at:  
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 
 
You may also visit the NCI Web site at http://cancer.gov/ 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix I – Page 13 of 18 
SIGNATURE 
 
I agree to take part in this study._____________________________________________ 
 
Participant __________________________________________Date ________________ 
 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix I – Page 14 of 18 
SCIENTIFIC STUDIES 
This study includes laboratory tests  that will analyze small samples of your tissue.  The 
samples will be taken from the biopsy materials and/or the surgery tissue which has already 
been collected as a routine part of your diagnostic evaluation and surgical treatment.  If you 
participate in the laboratory studies associated with this protocol, some of the leftover tissue 
will be sent to a research laboratory  for analysis.  Researchers will be performing these 
tests in order to better understand the biology of rectal cancer.  They hope these studies 
will help them better understand this type of cancer.  The results of these tests will not be 
sent to you or your doctor and will not be used in planning your care.  These tests are only 
for research purposes and have no effect on your medical care.  The researchers have no 
access to your identity.  You and/or your insurance company will not be charged for these 
tests. 
 
 
Making Your Choice 
 
Please read the sentence below and think about your choice.  After reading the sentence, 
circle "Yes" or "No."  No matter what you decide to do, it will not affect your care.  You can 
participate in the treatment part of the study without participating in the laboratory studies.  
If you have any questions, please talk to your doctor or nurse, or call our research review 
board at    IRB's phone number   . 
 
I agree to participate in the scientific laboratory tests that are being done as a part of 
this study. 
Yes  
 
 
No 
 
Please print and sign your name here after you circle your answer. 
 
Your Name: 
Your Signature: 
Date: 
 
WILL ANY OF THE SAMPLES (E.G. TISSUE) TAKEN FROM ME BE USED FOR OTHER 
RESEARCH STUDIES? 
About Using Tissue for Research  
If you participate in the laboratory studies associated with this protocol, some of the tissue 
biopsy material obtained for the clinical study will be sent to a central laboratory for 
analysis.  Slides of your bone marrow and blood may be submitted for central review to 
confirm local laboratory reviews. 
We would like to keep some of the bone marrow and tissue that is left over for future 
research.  If you agree, this bone marrow and tissue will be kept and may be used in 
research to learn more about cancer and other diseases.  This bone marrow and tissue will 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix I – Page 15 of 18 
only be given to researchers approved by the Eastern Cooperative Oncology Group.  Any 
research done on the bone marrow and tissue must also be approved by the researcher's 
Institutional Review Board. 
Your bone marrow and tissue may be helpful for research whether you do or do not have 
cancer.  The research that may be done with your bone marrow and tissue will probably not 
help you.  It might help people who have cancer and other diseases in the future. 
 
Reports about research done with your bone marrow and tissue will not be given to you or 
your doctor.  These reports will not be put in your health record.  The research will not have 
an effect on your care. 
 
Things to Think About  
The choice to let us keep the left over bone marrow and tissue for future research is up to 
you.  No matter what you decide to do, it will not affect your care and you may still take part 
in the Eastern Cooperative Oncology Group study.  
If you decide now that your bone marrow and tissue can be kept for research, you can 
change your mind at any time.  Just contact your study doctor and let him or her know that 
you do not want us to use your bone marrow and tissue.  Then the bone marrow and tissue 
will no longer be used for research. It may be retained for diagnostic reviews related to the 
study. Tissue samples will be returned to the institutions upon written request. 
In the future, people who do research may need to know more about your health.  When 
the Eastern Cooperative Oncology Group gives them reports about your health, it will not 
give them your name. 
Sometimes bone marrow and tissue are used for genetic research (about diseases that are 
passed on in families).  Even if your bone marrow and tissue are used for this kind of 
research, the results will not be put in your health records. 
Your bone marrow and tissue will be used only for research and will not be sold.  You will 
not be paid for allowing your leftover bone marrow and tissue to be used in research even 
though the research done with your bone marrow and tissue may help to develop new 
products in the future.  Similarly there will be no cost to you for any bone marrow and tissue 
collected and stored by the  Eastern Cooperative Oncology Group. 
 
It is possible that, at some time in the future, as part of deciding on what therapy to give 
you, a new test might be available that could be performed on some of the bone marrow 
and tissue now thought of as leftover.  This situation is unusual, but it could happen.  In 
order to see that not all the leftover bone marrow and tissue are used up, the Eastern 
Cooperative Oncology Group will take care to see that some of your bone marrow and 
tissue are stored for 10 years so that it is available should it be needed by you or your 
doctors.  This will depend upon the amount of left over bone marrow and tissue that is 
submitted for this study; however, there may not be any left over bone marrow and tissue to 
store. 
 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix I – Page 16 of 18 
Benefits 
The benefits of research using bone marrow and tissue include learning more about what 
causes cancer and other diseases, how to prevent them, how to treat them, and how to 
cure them. 
Risks  
There are very few risks to you from using your bone marrow and tissue for research. One 
is the release of information from your health records.  The Eastern Cooperative Oncology 
Group will protect your records so that your name will be kept private.  The chance that this 
information will be given to someone else is very small. 
 
Making Your Choice 
 
Please read each sentence below and think about your choice.  After reading each 
sentence, circle "Yes" or "No."  No matter what you decide to do, it will not affect your care.  
You can participate in the treatment part of the study without participating in all or part of 
the bone marrow and tissue research studies.  If you have any questions, please talk to 
your doctor or nurse, or call our research review board at                                       . 
       
 
 
 
 IRB's phone number 
 
1 My bone marrow and tissue may be kept for use in research to learn about, prevent, 
treat, or cure cancer. 
Yes 
 
No 
2 My bone marrow and tissue may be kept for research about other health problems 
(for example: causes of diabetes, Alzheimer's disease, and heart disease). 
Yes 
 
No 
3 My doctor (or someone from the Eastern Cooperative Oncology Group) may contact 
me in the future to ask me to take part in more research. 
Yes 
 
No 
 
Please print and sign your name here after you circle your answers. 
 
 
Your Name: 
________________________________________________ 
Your Signature: 
___________________________ 
Date: _____________ 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix I – Page 17 of 18 
Study Plan 
Page 1 
Group I: If you and your doctor chose this group, you will be registerd on-study & receive pre-operative radiation and chemotherapy. Then you will have surgery. About 3-8 weeks 
after surgery, you will receive 1 of 3 possible chemotherapy regimens. 
Group II: If you and your doctor chose the ‘sandwich’ approach, you will have (had) surgery first and then, about 3-8 weeks after surgery, you will be registered on-study. You will 
receive radiation with chemotherapy ‘sandwiched’ between 1 of 3 possible (repeating) chemotherapy regimens. 
See the boxes below and on page 2 for a ‘picture’ of the study plan 
Group I:
Chemotherapy &
Radiation Before
Surgery
Group II:
Chemotherapy &
Radiation After
Surgery
You & Your
Doctor
Choose
R
E
G
I
S
T
E
R1
Chemotherapy
and Radiation1
Randomly
Assigned to one
of 3 arms
Arm A:
Receive 8 cycles
of chemotherapy
Arm C:
Receive 3 cycles
of chemotherapy
R
E
G
I
S
T
E
R1
Arm D:
Receive 4
cycles of
chemotherapy
Arm F:
Administer 1
cycle
1. You will receive one of three allowed chemotherapy regimens with radiation.

5-FU over 24 hours 7 days a week during radiation

5-FU and leucovorin for 4 days during 1st and 5th week of radiation

Capecitabine by mouth 2x each day during radiation
This regimen is available only to patients enrolled in NSABP R-04
Arm B:
Receive 8 cycles
of chemotherapy
Arm E:
Receive 4
cycles of
chemotherapy
See Page 2 for Details on Chemotherapy Doses for Arms A, B, C, D, E, F
Surgery
21 - 56 days
21 - 56 days
Surgery
21 - 56 days
Randomly
Assigned to
one of 3 arms
Chemotherapy
and Radiation1
Chemotherapy
and Radiation1
Arm D:
Receive 4 (more)
cycles of
Chemotherapy
Arm F:
Receive 2 (more)
cycles of
Chemotherapy
Chemotherapy
and Radiation1
Arm E:
Receive 4 (more)
cycles of
Chemotherapy
 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix I – Page 18 of 18 
Page Two of Study Plan 
Arm A/Arm D
Irinotecan IV over 90 minutes.
Leucovorin IV over 2 hours.
5-FU IV bolus injection,
immediately following leucovorin dose.
Continuous infusion 5-FU over 46 hours by
ambulatory infusion pump beginning
immediately following bolus 5-FU.
Cycle = 2 treatment days every 2 weeks.
Arm B/Arm E
Oxaliplatin IV over 2 hours.
Leucovorin IV over 2 hours.
5-FU IV bolus injection,
immediately following leucovorin dose.
Continuous infusion 5-FU over 46 hours by
ambulatory infusion pump beginning
immediately following bolus 5-FU.
Cycle = 2 treatment days every 2 weeks.
Arm C/Arm F
Leucovorin IV over 2 hours once a week for
6 weeks followed by 2 weeks rest.
5-FU  bolus injection 1 hour after the start of
the leucovorin infusion, once a week for
6 weeks followed by 2 weeks rest.
Cycle =  8 weeks.
IV = intravenous = in vein
Bolus = higher amount of drug all at once
Continuous infusion = fluid put into a vein over time
Ambulatory infusion pump = portable pump that gives you the drug
Rest = no chemotherapy drugs
 
 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix II– Page 1 of 6 
Intergroup Randomized Phase III Study of Postoperative Irinotecan, 5-Fluorouracil and Leucovorin vs 
Oxaliplatin, 5-Fluorouracil and Leucovorin vs 5-Fluorouracil and Leucovorin 
 for Patients with Stage II or III Rectal Cancer Receiving Either Preoperative Radiation and 5-Fluorouracil  
or Postoperative Radiation and 5-Fluorouracil 
 
Appendix II 
Pathology Submission Guidelines 
 
The following items are included in Appendix II: 
1. 
Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. 
Instructional memo to submitting pathologists 
3. 
List of Required Materials for E3201 
4. 
ECOG Pathology Submission Form (#638)


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix II– Page 2 of 6 
Guidelines for Submission of Pathology Materials 
 
The following items should always be included when submitting pathology materials to the ECOG 
Pathology Coordinating Office: 
Institutional Surgical Pathology Report 
Pathology materials (see attached List of Required Material) 
ECOG Pathology Material Submission Form (# 638) 
Instructions: 
1. 
Place the Patient ID label provided by the ECOG Coordinating Center in Part A of the ECOG Pathology 
Material Submission Form. 
If a label is not available, TYPE or PRINT the following information in Part A of the form: 
Patient's name (last, first) 
Protocol number 
Protocol case number (the patient's ECOG sequence number; for intergroup studies, include both the ECOG 
and other group's sequence numbers) 
Patient's hospital number 
Institution 
Affiliate (if appropriate) 
2. 
Complete blank areas of the pathologist's instructional memo, and forward it, along with the List of 
Required Material and the ECOG Pathology Material Submission Form, to the appropriate pathologist.  
3. 
The pathologist should return to you the required pathologic samples and surgical pathology reports, 
along with the completed ECOG Pathology Material Submission Form (# 638) (Part B completed). If any 
other reports are required, they should be obtained from the appropriate department at this time. 
4. 
Keep a copy of the ECOG Pathology Material Submission Form (# 638) for your records (the original 
should be sent to the PCO). 
5. 
Double check that ALL required forms, reports, and pathology samples are included in the package to 
send to the Pathology Coordinating Office (see appropriate List of Required Material).   
Pathology specimens submitted for a patient WILL NOT be processed by the Pathology 
Coordinating Office until all necessary items are received. 
6. 
Mail pathology materials to: 
ECOG Pathology Coordinating Office 
Robert H. Lurie Comprehensive Cancer Center  
of Northwestern University Medical School 
Olson Pavilion - Room 8501 
710 North Fairbanks Court 
Chicago, IL  60611 
If you have any questions concerning the above instructions, or if you anticipate any problems in meeting the 
pathology material submission deadline of one month, contact the Pathology Coordinator at the ECOG 
Pathology Coordinating Office at Tel: (312) 503-3384 or Fax: (312) 503-3385. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix II– Page 3 of 6 
LIST OF REQUIRED MATERIAL 
 
E3201 
Intergroup Randomized Phase III Study of Postoperative Irinotecan, 5-Fluorouracil and 
Leucovorin vs Oxaliplatin, 5-Fluorouracil and Leucovorin vs 5-Fluorouracil and 
Leucovorin for Patients with Stage II or III Rectal Cancer Receiving Either Preoperative 
Radiation and 5-Fluorouracil orPostoperative Radiation and 5-Fluorouracil 
Original Biopsy (Group I): 
1. 
ECOG Pathology Material Submission Form (# 638) – Parts A & B completed.  
2. 
Institutional pathology report (must be included with EVERY pathology submission). 
3. 
A formalin-fixed, paraffin-embedded block from pre-treatment biopsy including cancer. 
 
NOTE: If tissue blocks cannot be submitted, contact the PCO regarding the appropriate 
alternative sample submission. 
Surgical Resection (All patients): 
1. 
ECOG Pathology Material Submission Form (# 638) – Parts A and B completed. 
2. 
Institutional pathology report (must be included with EVERY pathology submission). 
3. 
The following blocks are requested: 
• 
One block containing tumor tissue 
• 
One block containing mucosa 
NOTE: If tissue blocks cannot be submitted, contact the PCO regarding the appropriate 
alternative sample submission. 
NOTE: Since blocks are being used for correlative studies, in some cases material may be depleted, and 
therefore, the block may not be returned. 
NOTE: The Pathology Coordinating Office will forward a copy of the submission form to the ECOG 
Coordinating Center as well 
NOTE:  Paraffin blocks and/or slides submitted for this study will be retained at the ECOG Central Tissue 
Repository for possible use in future ECOG approved studies. Blocks will be available upon specific 
request for purposes of patient care. 
NOTE:  If pathology materials cannot be submitted, please indicate the reason for on the ECOG Pathology 
Material Submission Form (#638) and include a letter of explanation. 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 3/07, Update #2 
Appendix II– Page 4 of 6 
Upon Development of AML or MDS: 
NOTE: ECOG’s diagnostic review project for secondary AML/MDS ended December 1, 2005. Submissiom 
of diagnostic slides upon diagnosis of secondary AML/MDS for central diagnostic review and 
classification is no longer required. 
 
Rev. 3/07 


Eastern Cooperative 
Oncology Group 
Group Chair: Robert L. Comis, M.D. 
Group Statistician: Robert Gray, Ph.D. 
 
Appendix II– Page 5 of 6 
Coordinating Center 
Frontier Science 
900 Commonwealth Avenue • Boston, MA 02215 
(617) 632-3610 • Fax: (617) 632-2990 
Randomization: (617) 632-2022 
Director: Sheilah Hurley, M.A. 
MEMORANDUM 
TO:  _________________________________________  
 
(Submitting Pathologist) 
FROM: Stanley Hamilton, M.D. 
 
Chair 
 
ECOG Pathology Committee 
DATE:  ______________________________________  
SUBJECT: 
Submission of Pathology Materials for E3201: Intergroup Randomized Phase III Study of 
Postoperative Irinotecan, 5-Fluorouracil and Leucovorin vs Oxaliplatin, 5-Fluorouracil and Leucovorin vs 5-
Fluorouracil and Leucovorin for Patients with Stage II or III Rectal Cancer Receiving Either Preoperative 
Radiation and 5-Fluorouracil orPostoperative Radiation and 5-Fluorouracil 
 
The patient named on the attached ECOG Pathology Material Submission Form (# 638) has been 
entered onto an ECOG protocol by ______________________________ (ECOG Investigator).  This 
protocol requires the submission of pathology materials for laboratory studies. 
Please complete PART B of the Submission Form. Keep a copy for your own records, and return the 
completed Submission Form, the surgical pathology report(s), the slides and/or blocks, and any other 
required material (see attached List of Required Material) to the Clinical Research Associate (CRA).  The 
CRA will forward all required pathology material to the ECOG Pathology Coordinating Office. 
Please note: Since blocks are being used for laboratory studies, in some cases the material may 
be depleted, and, therefore, the block may not be returned. 
NOTE:  Paraffin blocks and/or slides submitted for this study will be retained at the ECOG Central Tissue 
Repository for possible use in future ECOG approved studies. Blocks will be available upon 
specific request for purposes of patient care. 
NOTE:  If pathology materials cannot be submitted, please indicate the reason for on the ECOG 
Pathology Material Submission Form (#638) and include a letter of explanation. 
If you have any questions regarding this request, please feel free to contact the Pathology Coordinating 
Office at Tel:  (312) 503-3384 OR FAX:  (312) 503-3385. 
The ECOG CRA at your institution is: 
Name: ______________________________________________  
Address: ____________________________________________  
Phone: ______________________________________________  
 
 
Thank you. 
 


 
Appendix II– Page 6 of 6 
 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix III – Page 1 of 1 
Intergroup Randomized Phase III Study of Postoperative Irinotecan, 5-Fluorouracil and Leucovorin vs 
Oxaliplatin, 5-Fluorouracil and Leucovorin vs 5-Fluorouracil and Leucovorin 
 for Patients with Stage II or III Rectal Cancer Receiving Either Preoperative Radiation and 5-Fluorouracil  
or Postoperative Radiation and 5-Fluorouracil 
 
Appendix III 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter thanking the patient  
for enrolling in this trial. The template is intended as a guide and can be downloaded from the ECOG web 
site at http://www.ecog.org. As this is a personal letter, physicians may elect to further tailor the text to their 
situation. 
This small gesture is a part of a broader program being undertaken by ECOG and the NCI to increase 
awareness of the importance of clinical trials and improve accrual and follow-through. We appreciate your 
help in this effort. 
_____________________________________________________________________________ 
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important clinical program.  Many questions remain unanswered in 
cancer.  With the help of people like you who participate in these programs, we will achieve our goal of 
effectively treating and ultimately curing cancer 
We believe this program will provide you with high quality, thorough care.  Your physician and research staff 
will maintain very close contact with you.  This is important to allow your physician to provide you with the 
best care while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the Eastern Cooperative Oncology Group, we thank you again and look 
forward to helping you. 
 
 
Sincerely, 
 
 
 
[PHYSICIAN NAME] 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Revised 11/05, Addendum #4 
Appendix IV – Page 1 of 1 
Intergroup Randomized Phase III Study of Postoperative Irinotecan, 5-Fluorouracil and Leucovorin vs 
Oxaliplatin, 5-Fluorouracil and Leucovorin vs 5-Fluorouracil and Leucovorin 
 for Patients with Stage II or III Rectal Cancer Receiving Either Preoperative Radiation and 5-Fluorouracil  
or Postoperative Radiation and 5-Fluorouracil 
 
Appendix IV 
 
ECOG Checklist for Submission of Radiation Oncology Quality Assurance Matierials 
Patient: 
 
Protcol: 
E3201 
Sequence # 
 
 
 
Send Material c/o 
For the Radiation Oncologist: 
 
Quality Assurnace Review Center 
Name: 
 
Attention: ECOG Materials 
Address: 
Rev. 
11/05 
272 West Exchange Street, Suite 101 
 
Rev. 
11/05 
Providence, RI 02903-1025 
Phone:                                 Fax: 
 
 
Email: 
Date Radiation Began: ____________________________________ 
Final Review materials must be submitted withing 1 week of completion of radiation: 
 
DATE SUBMITTED: 
Copy of Appendix IV: Checklist For Submission of Radiation Oncology QA Materials 
 
ECOG Rectal Cancer On-Study Form (copy) 
 
E3201 Baseline Data Form 
 
Prescription Sheet for Entire Treatment 
 
Preoperative imaging studies: CT with contrast and barium enema (if available) 
 
Treatment Planninf CT/diagnostic imaging and report 
 
Beam Verification (portal) Films of All Fields 
 
Simulation Films and/or DRRs of All Fields 
 
Picture of patient in treatment position 
 
Color Copies of Isodose Distributions along with the corresponding bean data 
 
Printouts from the planning system (see Section 5.1.0.4) 
 
Monitor Daily Treatment Record 
 
Partial Daily Treatment Record 
 
 
 
3D-Conformal Planning: Submit the following in addition to the above materials 
 
Description of each treatment field 
 
Orthogonal anterior/posterior and lateral films if not part of portals 
 
BEV’s of portals 
 
REV of overview diagram 
 
Dose Volume Histogram 
 
All materials must be labeled with the ECOG assigned Protocol and Sequence numbers 
Please contact QARC ECOG CRA – TEL: 401-454-4301 FAX: 401-454-4683 for clarification as necessary. 
Rev. 11/05 
Rev. 
11/05 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix V – Page 1 of 1 
Intergroup Randomized Phase III Study of Postoperative Irinotecan, 5-Fluorouracil and Leucovorin vs Oxaliplatin, 
5-Fluorouracil and Leucovorin vs 5-Fluorouracil and Leucovorin 
 for Patients with Stage II or III Rectal Cancer Receiving Either Preoperative Radiation and 5-Fluorouracil  
or Postoperative Radiation and 5-Fluorouracil 
 
Appendix V 
 
Staging Criteria- Rectum 
Primary Tumor (T) 
 
T1 
Tumor invades submucosa 
T2 
Tumor invades muscularis propria 
T3 
Tumor invades through the muscularis propria into the subserosa, or into nonperitonealized 
perirectal tissues 
T4 
Tumor perforates the visceral peritoneum or directly invades or is adherent to other organs 
or structures* 
 
*NOTE: 
Direct invasion of other organs or structures includes adherence to or invasion of 
other organs or structures including other segments of colorectum by way of 
extension beyond the serosa (e.g., invasion of the sigmoid colon by a carcinoma of 
the proximal (rectum). 
 
Regional Lymph Node(s) (N) 
 
N0 
No regional lymph node metastatsis 
N1 
Metastatsis in 1 to 3 pericolic or perirectal lymph nodes 
N2 
Metastatsis in 4 or more pericolic or preirectal lymph noes 
N3 
Metastatsis in any lymph node along the course of a named vascular trunk 
 
Distant Metastasis (M) 
 
M0 
No distant metastasis 
 
Modified Astler-Coller Stage Grouping 
 
Stage 
A 
T1 
N0 
M0 
 
B1 
T2 
N0 
M0 
Stage 
B2 
T3, T4a 
N0 
M0 
 
B3 
T4b 
N0 
M0 
Stage 
C1 
T1-2 
N1 – 3 
M0 
 
C2 
T3-4a 
N1 – 3 
M0 
 
C3 
T4b 
N1 – 3 
M0 
 
Note: 
Modified Astler-Coller B is a composite of better (T3, N0, M0) and worse (T4, N0, M0) 
prognostic groups as is Modified Astler-Coller C (Any T, N1, M0 and any T, N2-N3, M0). 
 
 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix VI – Page 1 of 1 
Intergroup Randomized Phase III Study of Postoperative Irinotecan, 5-Fluorouracil and Leucovorin vs 
Oxaliplatin, 5-Fluorouracil and Leucovorin vs 5-Fluorouracil and Leucovorin 
 for Patients with Stage II or III Rectal Cancer Receiving Either Preoperative Radiation and 5-Fluorouracil  
or Postoperative Radiation and 5-Fluorouracil 
 
Appendix VI 
 
Comparision of Symptoms and Treatment Pharyngo-Laryngodesthesias and Platinum 
Hypersensitivity Reactions 
Clinical Symptoms 
Pharyngo-Larygneal Dysesthesias 
Platinum Hypersensitivity 
 
Dyspnea 
Present 
Present 
Bronchospasm 
Absent 
Present 
Laryngospasm 
Absent 
Present 
Anxiety 
Present 
Present 
O2 saturation 
Normal 
Decreased 
Difficulty swallowing 
Present (loss of sensation) 
Absent 
Pruritis 
Absent 
Present 
Urticaria/rash 
Absent 
Present 
Cold-induced Sx 
Yes 
No 
BP 
Normal or increased 
Normal or decreased 
Treatment 
Anxiolytics, observation in a 
controlled clinical setting until 
symptoms abate or at the 
physican’s discretion 
Oxygen, steriods, epinephrine, 
antihistamines, bronchodilators; 
fluids and vascopressors, if 
appropriate. 
 
 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
Appendix VII – Page 1 of 4 
Intergroup Randomized Phase III Study of Postoperative Irinotecan, 5-Fluorouracil and Leucovorin vs 
Oxaliplatin, 5-Fluorouracil and Leucovorin vs 5-Fluorouracil and Leucovorin 
 for Patients with Stage II or III Rectal Cancer Receiving Either Preoperative Radiation and 5-Fluorouracil  
or Postoperative Radiation and 5-Fluorouracil 
 
Appendix VII 
 
Cancert Trials Support Unit (CTSU) Participation Procedures 
REGISTRATION/RANDOMIZATION 
Prior to the recruitment of a patient for this study, investigators must be registered members of the CTSU. 
Each investigator must have an NCI investigator number and must maintain an “active” investigator 
registration status through the annual submission of a complete investigator registration packet (FDA Form 
1572 with original signature, current CV, Supplemental Investigator Data Form with signature and Financial 
Disclosure Form with original signature) to the Pharmaceutical Management Branch, CTEP, DCTD, NCI. 
These forms are available on the CTSU registered member web site or by calling the PMB at 301-496-5725 
Monday through Friday between 8.30 am and 4.30 pm Eastern time. Each CTSU investigator or group of 
investigators at a clinical site must obtain IRB approval for this protocol and submit all IRB/regulatory 
documents to the CTSU before they can enroll patients. All forms and documents associated with this study 
can be downloaded from the E3201 Web page on the CTSU registered member Web site 
(http://members.ctsu.org). Patients can be registered only after pre-treatment evaluation is complete, all 
eligibility criteria have been met, and all pertinent forms and documents are approved and on file with the 
CTSU. 
Requirements for E3201 site registration: 
• 
CTSU IRB Certification 
• 
IRB/Regulatory Approval Transmittal Form 
• 
IRB-approved consent form 
• 
Radiation Therapy Facility Inventory Form 
Requirements for patient enrollment on E3201 
• 
Patient must meet all inclusion criteria and no exclusion criteria should apply. 
• 
Patient signed and dated consent. 
• 
All baseline laboratory tests and prestudy evaluations performed. 
• 
Pathology materials submitted per Section 10.0 (provided patient has given consent) 
• 
Patient completed baseline QOL forms. 
 
CTSU PROCEDURES FOR PATIENT ENROLLMENT 
 
The choice of pre-operative chemo/XRT (GROUP I) versus post-operative chemo/XRT (GROUP II) is at the 
discretion of the treating physician and must be declared at the time of registration.  The physician must also 
identify the surgical procedure to be performed.  (See Section 5.0 for details.) Please refer to Section 3 for 
explanation of Group I PS. 
 
GROUP I patients are registered but not randomized until 21-56 days from date of total resection. 
GROUP I PS (patients who have received chemotherapy/RT and surgery per protocol) are registered and 
randomized at the same time. 
GROUP II patients are registered and randomized at the same time. Treatment should start within five (5) 
working days after registration/randomization. 
 
Registration instructions for Group I (including Group I PS) and II patients and Randomization instructions for 
Group I PS and II patients: 
Contact the CTSU Patient Registration Office by calling 1-888-462-3009 to alert the CTSU Patient Registrar 
that an enrollment is forthcoming.  Complete the following forms: 


Eastern Cooperative 
E3201 
Oncology Group 
REVISED 
 
Revised 3/07, Update #2 
Appendix VII – Page 2 of 4 
 
• 
CTSU Patient Enrollment Transmittal Form 
• 
E3201 Eligibility Check (Step 1 - Registration) 
• 
E3201 Eligibility Check (Step 2 - Randomization) Group II patients only 
 
Fax these forms to the CTSU Patient Registrar at 1-888-691-8039 between the hours of 8:00 am and 4:30 
p.m., Mon-Fri, Eastern time. The CTSU registrar will check the investigator and site information provided to 
ensure that all regulatory requirements have been met. The registrar will also check the forms for 
completeness and follow-up with the site to resolve any discrepancies. Once investigator and patient 
eligibility are confirmed, the CTSU registrar will contact the Eastern Cooperative Oncology Group to obtain 
the patient ID assignment (to be used on all future forms and correspondence), and if this is a Group II 
patient, the CTSU registrar will also obtain a randomization assignment at this time. The CTSU registrar will 
convey this information to the enrolling site by phone followed by a confirmation e-mail or fax. 
 
Randomization instructions for Group I patients: 
 
Group I patients may not be randomized until 21-56 days from date of total resection. 
Complete the following forms: 
 
• CTSU Data Transmittal Form 
• E3201 Eligibility Check (Step 2 - Randomization) 
 
Fax this form to the CTSU Patient Registrar at 1-888-691-8039 between the hours of 8:00 am and 4:30 p.m., 
Mon-Fri, Eastern time.  The CTSU registrar will contact the Eastern Cooperative Oncology Group to obtain a 
randomization assignment. The CTSU registrar will convey this information to the enrolling site by phone 
followed by a confirmation e-mail or fax. 
 
DATA SUBMISSION AND RECONCILIATION  
1. All case report forms (CRFs) and transmittals associated with this study must be downloaded from the 
E3201 Web page located on the CTSU registered member Web site (https://members.ctsu.org). Sites 
must use the current form versions and adhere to the instructions and submission schedule outlined in 
the protocol.   
2. Submit all completed CRFs (with the exception of patient enrollment forms), clinical reports, and 
transmittals directly to the ECOG [refer to contacts table] unless an alternate location is specified in the 
protocol. Do not send study data to the CTSU. A completed CTSU-ECOG coversheet should accompany 
all data submissions. 
3. The ECOG Coordinating Center will mail query notices and delinquency reports directly to the site for 
reconciliation. Please send query responses and delinquent data to the ECOG Coordinating Center and 
do not copy the CTSU Data Operations. Each site should have a designated CTSU Administrator and 
Data Administrator and must keep their CTEP AMS account contact information current. This will 
ensure timely communication between the clinical site and the ECOG Coordinating Center. 
 
 
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Revised 3/07, Update #2 
Appendix VII – Page 3 of 4 
SPECIAL MATERIALS OR SUBSTUDIES 
 
Radiation materials submission 
 
The Quality Assurance Review Center (QARC) will perform a Final Review  of radiation oncology materials 
for E3201: at the completion of radiation oncology therapy .  Final Review materials are to be submitted 
within 1 week of completion of radiation.   
 
CTSU investigators should follow the instructions in section 5.0 and Appendix IV of the protocol and submit 
all requested RT materials and documentation directly to the QARC office (Note: CTSU investigators should 
not send RT dosimetry materials to the CTSU).  Please send a copy of the ECOG Checklist for Submission 
of Radiation Oncology Quality Assurance Materials (Appendix IV of protocol) to the CTSU accompanied by a 
CTSU Data Transmittal Form. 
 
Pathology Review and Correlative Studies  
 
• 
Participation in the correlative studies is optional and requires patient consent. 
• 
Do not send specimens, supporting clinical reports, or transmittals to the CTSU. 
 
Quality of Life 
 
The FACT Diarrhea Subscale Questionnaire, Bowel Function Questionnaire, and Uniscale will be used to 
assess rectal function in study participants.  Administration instructions and schedule are outlined in Section 
5.6 of the protocol.  
 
 
SERIOUS ADVERSE EVENT (AE) REPORTING  
 
1.  CTSU sites must comply with the expectations of their local Institutional Review Board (IRB) regarding 
documentation and submission of adverse events.  Local IRBs must be informed of all reportable 
serious adverse reactions.  
 
2.  CTSU sites will assess and report adverse events according to the guidelines and timelines specified in 
the protocol. You may navigate to the CTEP Adverse Event Expedited Report System (AdEERS) from 
either the Adverse Events tab of the CTSU member homepage (https://members.ctsu.org) or by 
selecting Adverse Event Reporting Forms from the document center drop down list on the E3201 Web 
page.  
 
3.  Do not send adverse event reports to the CTSU. 
 
4. 
Secondary AML/MDS/ALL reporting: Report occurrence of secondary AML, MDS, or ALL via the 
NCI/CTEP AML-MDS Report Form in lieu of AdEERS. Submit the completed form and supporting 
documentation as outlined in the protocol. 
 
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Appendix VII – Page 4 of 4 
 
DRUG PROCUREMENT 
CTSU investigators should refer to section 8.2 for detailed instructions on drug ordering, preparation, 
administration and accountability. Completed Clinical Drug Requests (NIH-986) for investigational IND 
agents should be faxed (301-480-4612) or mailed directly to the Pharmaceutical Management Branch 
(PMB). 
Investigational IND agents: Oxaliplatin (Note that the PMB will ship drug only to the shipping address 
specified by the CTSU investigator on their FDA form 1572.) 
Commercial Agents: Irinotecan, Leucovorin, 5-Fluorouracil, Capecitabine. 
REGULATORY COMPLIANCE AND MONITORING 
Study Audit 
To assure compliance with Federal regulatory requirements [CFR 21 parts 50, 54, 56, 312, 314 and HHS 45 
CFR 46] and National Cancer Institute (NCI)/ Cancer Therapy Evaluation Program (CTEP) Clinical Trials 
Monitoring Branch (CTMB) guidelines for the conduct of clinical trials and study data validity, all protocols 
approved by NCI/CTEP that have patient enrollment through the CTSU are subject to audit. 
Responsibility for assignment of the audit will be determined by the site’s primary affiliation with a 
Cooperative Group or CTSU. For Group-aligned sites, the audit of a patient registered through CTSU will 
become the responsibility of the Group receiving credit for the enrollment. For CTSU Independent Clinical 
Research Sites (CICRS), the CTSU will coordinate the entire audit process. 
For patients enrolled through the CTSU, you may request the accrual be credited to any Group for which you 
have an affiliation provided that Group has an active clinical trials program for the primary disease type being 
addressed by the protocol. (e.g., NSABP members may only request credit for protocols pertaining to breast 
or colorectal cancers).  Registrations to protocols for other disease sites may still take place through CTSU 
without receiving credit for your NSABP activities.  Per capita reimbursement will be issued directly from 
CTSU. 
Details on audit evaluation components, site selection, patient case selection, materials to be reviewed, site 
preparation, on-site procedures for review and assessment, and results reporting and follow-up are available 
for download from the CTSU Operations Manual located on the CTSU Member Web site. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA) 
The HIPAA Privacy Rule establishes the conditions under which protected health information may be used or 
disclosed by covered entities for research purposes. Research is defined in the Privacy Rule referenced in 
HHS 45 CFR 164.501. Templated language addressing NCI-U.S. HIPAA guidelines are provided in the 
HIPAA Authorization Form located on the CTSU website. 
The HIPAA Privacy Rule does not affect participants from outside the United States. Authorization to release 
Protected Health Information is NOT required from patients enrolled in clinical trials at non-US sites. 
Clinical Data Update System (CDUS) Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  Cumulative CDUS 
data will be submitted quarterly to CTEP by electronic means. The sponsoring Group fulfills this reporting 
obligation by electronically transmitting to CTEP the CDUS data collected from the study-specific case report 
forms. 
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Appendix VIII – Page 1 of 1 
 
Intergroup Randomized Phase III Study of Postoperative Irinotecan, 5-Fluorouracil and Leucovorin vs 
Oxaliplatin, 5-Fluorouracil and Leucovorin vs 5-Fluorouracil and Leucovorin 
 for Patients with Stage II or III Rectal Cancer Receiving Either Preoperative Radiation and 5-Fluorouracil  
or Postoperative Radiation and 5-Fluorouracil 
 
Appendix VIII 
 
Cooperative Research and Development Agreement (CRADA) 
The agent, Oxaliplatin, used in this protocol is provided to the NCI under a Cooperative Research and 
Development Agreement (CRADA) between Sanofi-Aventis (hereinafter referred to as “Collaborator”) and 
the NCI Division of Cancer Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in 
addition to the provisions in the “Intellectual Property Option to Collaborator” terms of award modifications, 
apply to the use of Oxaliplatin in this study: 
1. 
Oxaliplatin may not be used for any purpose outside the scope of this protocol, nor can Oxaliplatin be 
transferred or licensed to any party not participating in the clinical study.  Collaborator data for 
Oxaliplatin are confidential and proprietary to Collaborator and shall be maintained as such by the 
investigators.  The protocol documents for studies utilizing investigational agents are also confidential 
and should not be shared or distributed without the permission of the NCI. 
2. 
Clinical Trial Data and Results and Raw Data developed under a CRADA will be made available 
exclusively to Collaborator, the NCI and the FDA, as appropriate. 
3. 
When a Collaborator(s) wishes to initiate a data request, the request should first be sent to the NCI, who 
will then notify the appropriate investigators (Group Chair for cooperative group studies, or PI for other 
studies) of Collaborator’s wish to contact them. 
4. 
Any data provided to Collaborator for Phase III studies must be in accordance with the guidelines and 
policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial. 
5. 
Any manuscripts reporting the results of this clinical trial should be provided to CTEP for immediate 
delivery to Collaborator for advisory review and coment prior to submission for publication.  Collaborator 
will have 30 days from the date of receipt for review. Collaborator shall have the right to request that 
publication be delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential 
and proprietary data, in addition to Collaborator’s intellectual property rights, are protected.  Copies of 
abstracts should be provided to CTEP for forwarding to Collaborator for courtesy review as soon as 
possible and preferably at least three (3) days prior to submission, but in any case, prior to presentation 
at the meeting or publication in the proceedings. Press releases and other media presentations must 
also be forwarded to CTEP prior to release. Copies of any manuscript press release and/or abstract 
should be sent to: 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
6130 Executive Boulevard Suite 7111 
Rockville, MD 20852 
FAX (301) 402-1584 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, manuscript or 
other form of public disclosure shall contain any of Collaborator’s confidential/proprietary information. 
 
Rev. 
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Appendix IX – Page 1 of 2 
Intergroup Randomized Phase III Study of Postoperative Irinotecan, 5-Fluorouracil and Leucovorin vs 
Oxaliplatin, 5-Fluorouracil and Leucovorin vs 5-Fluorouracil and Leucovorin 
 for Patients with Stage II or III Rectal Cancer Receiving Either Preoperative Radiation and 5-Fluorouracil  
or Postoperative Radiation and 5-Fluorouracil 
 
Appendix IX 
 
Diarrhea Management Instructions 
How to Manage Diarrhea 
 
While you are receiving the chemotherapy drugs and radiation therapy, you may experience diarrhea.  In 
some individuals, diarrhea has been severe.  Therefore, it is important that you follow the instructions noted 
below if you experience diarrhea while being treated. 
 
What Is Diarrhea?  
 
Diarrhea is when your bowel movements are loose or watery and more frequent than is usual for you.  In order to 
help manage the diarrhea that your treatment may cause, you will need to keep track of your bowel movements.  
Keeping a diary may be the easiest way to do this.  The diary should record how many bowel movements you have 
during the day, when they occur and the consistency of the stool (formed, loose or watery).  Having diarrhea for a 
long period of time can result in problems such as dehydration.  It is best to treat it early when it first begins.  You 
should contact you doctor or nurse if you begin experiencing this side effect. 
 
What Do I Take To Stop the Diarrhea?  
 
The medication used to treat the diarrhea is called loperamide.  The most common brand of loperamide is 
Imodium.  Loperamide comes in the form of a 2 milligram (mg) caplet and is available without a prescription 
at most pharmacies and grocery stores in the health and beauty aids section.  
 
The loperamide may cause some side effects.  These side effects are drowsiness, tiredness and dizziness.  
It is important to avoid driving motorized vehicles or operating machinery if you experience any of these side 
effects. 
 
When Should I Start Taking the Loperamide and For How Long?  
 
At the first sign of diarrhea you will need to begin taking loperamide (Imodium) according to the directions 
below. (These will differ from the usual instructions found on the label.) If you do not start taking loperamide 
right away, severe diarrhea can occur that could require hospitalization.  It is also important to stop taking 
any laxatives (medications to treat constipation such as milk of magnesia, Colace, Dulcolax, or Senakot). 
 
Please follow these instructions carefully: 
 
• 
Take two caplets (4 mg) at the first sign of any change in your normal bowel movement as 
described above. 
• 
Continue taking one caplet (2 mg) every 2 hours until you have returned to your normal pattern of 
bowel movements for at least 12 hours.  It is important to continue taking the loperamide even 
during the night.  However, during the night you can take two caplets (4mg) every four hours 
instead of one caplet (2 mg) every two hours. 
• 
Be sure to drink plenty of fluids each day (several glasses of water, fruit juice, soda, soup, etc).  It is 
important to try to replace fluid that is being lost because of the diarrhea. This will help prevent 
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Appendix IX – Page 2 of 2 
dehydration and will not cause more diarrhea.  You should avoid caffeinated beverages (coffee, tea, 
cola), alcoholic beverages and dairy products. 
• 
Avoid high roughage foods like high-fiber cereals containing bran or whole grain, broccoli, cabbage, 
beans, fresh vegetables or fruit, fried food, chocolate or doughnuts. 
 
Please call your doctor or nurse if you have any questions about taking loperamide, if your diarrhea does not 
improve, or if you experience new symptoms.