Clinical trial NCT00324415
Conditions: Anal Cancer
Keywords: stage I anal cancer stage II anal cancer stage IIIA anal cancer stage IIIB anal cancer squamous cell carcinoma of the anus basaloid carcinoma of the anus cloacogenic carcinoma of the anus
Sponsor: AIDS Malignancy Consortium
Start date: 2006-09-01; Completion date: 2016-05-01
Enrollment: 45 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Drugs used in chemotherapy, such as cisplatin and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving cisplatin, fluorouracil, and cetuximab together with radiation therapy may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving cisplatin, fluorouracil, and cetuximab together with radiation therapy works in treating patients with HIV and stage I, stage II, or stage III anal cancer.

Detailed description:
OBJECTIVES:

Primary

* Determine the 2-year local failure rate in patients with HIV-associated stage I-IIIB anal carcinoma treated with cisplatin, fluorouracil, cetuximab, and radiotherapy.
* Determine the objective response rate (complete and partial), progression-free survival, relapse-free survival, colostomy-free survival, overall survival, quality of life, and overall toxicity in patients treated with this regimen.

Secondary

* Characterize the effect of this regimen on the underlying HIV condition by describing changes in viral load, CD4 counts, and the incidence of opportunistic illnesses, including the development of AIDS during and in the first year after treatment.
* Evaluate the effect of this regimen on anogenital human papilloma virus (HPV) infection and anal cytology.

OUTLINE: This is an open-label, multicenter study.

Patients receive cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, and 35\*, fluorouracil IV continuously on days 1-4 and 29-32, and cisplatin IV over 1 hour on days 1 and 29. Beginning on day 1, patients undergo concurrent radiotherapy to the primary tumor 5 days a week for 5-7 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

NOTE: \*Patients receiving 7 weeks of radiotherapy also receive cetuximab on days 42 and 49.

Quality of life is assessed at baseline, at the completion of study treatment, and then at months 3, 6, 12, 24, and 36.

After completion of study treatment, patients are followed periodically for 5 years.

PROJECTED ACCRUAL: A total of 47 patients will be accrued for this study.

Arms: arm 1: All patients will receive combined modality therapy (CMT) with 2 cycles of cisplatin and 5-FU chemotherapy, given concurrently with radiation therapy. CMT consists of:

* Cetuximab 400 mg/m2 IV Day -7 (1 week before the cycle 1, Day 1 cisplatin/5-FU and RT), then 250 mg/m2 IV Days 1, 8, 15, 22, 29, 36 and 43 (a minimum of 6 and a maximum of 8 doses of cetuximab will be administered, including the loading dose).
* Cisplatin 75 mg/m2 IV on Day 1 (cycle 1) and Day 29 (cycle 2)
* 5-FU 1000 mg/m2/day by continuous intravenous infusion on Days 1-4 (cycle 1) and Days 29-32 (cycle 2)
Interventions: intervention 1: cetuximab intervention 2: cisplatin intervention 3: fluorouracil intervention 4: radiation therapy
Intervention descriptions: intervention 1: 400 mg/m2 IV Day -7 (1 week before the cycle 1, Day 1 cisplatin/5-FU and RT), then 250 mg/m2 IV Days 1, 8, 15, 22, 29, 36 and 43 (a minimum of 6 and a maximum of 8 doses of cetuximab will be administered, including the loading dose) intervention 2: 75 mg/m2 IV on Day 1 (cycle 1) and Day 29 (cycle 2) intervention 3: 1000 mg/m2/day by continuous intravenous infusion on Days 1-4 (cycle 1) and Days 29-32 (cycle 2) intervention 4: Irradiation to tumor site and inguinal nodes beginning on cycle 1, Day 1 cisplatin/5-FU (minimum 45.0 Gy \[5 weeks if given on schedule and without interruption\], maximum 54.0 Gy \[6 weeks if given on schedule and without interruption). IMRT may be used at the discretion of the treating physician.

Protocol documents:
Prot_SAP_001.pdf: 
AMC #045 (Version 10.0) 04/30/2014 
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SUMMARY OF CHANGES 
Phase II Trial of Combined Modality Therapy plus Cetuximab in HIV-Associated Anal 
Carcinoma 
 
Version 10.0 
 
NCI Protocol #:  AMC-045 
Local Protocol #:  AMC-045 
 
NCI Version Date: 04/30/2014 
Update Date: 04/30/2014 
 
# 
Section 
Change Description  
1. 
Cover 
Page, 
 
Protocol 
Signature 
Page, 
 
Footer 
AMC # 045(Version 9.0) 01/20/2011 
Changed from: 
NCI Version Date 01/20/2011 
 
AMC # 045 (Version 10.0) 04/30/2014 
Changed to: 
NCI Version Date 04/30/2014 
2. 
Cover 
Page, 
 
Protocol 
Roster 
Lashmi Radjev, MD 
Changed from: 
 
Lakshmi Radjev, MD 
Changed to: 
3. 
Global 
All references to “Adverse Event Expedited Reporting System (AdEERS)” and “AdEERS” 
were updated to “CTEP Adverse Event Reporting System (CTEP-AERS)” and “CTEP-
AERS.” 
4. 
5.4.1 
http://ctep.info.nih.gov/protocolDevelopment/default.htm#adverse_events_ctepaers 
Changed from: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
Changed to: 
5. 
7.1.1 
Reference to section number was corrected: 
Section 7.1.3 to Section 7.2.3 
6. 
7.2.4.1 
Reference to section number was corrected: 
Section 5.2.2.1 to Section 7.2.4.2 
7. 
8.3.1 
Reference to section number was corrected: 
Section 8.3.2 to Section 8.4 
8. 
9.1 
Reference to section number was corrected: 
Appendix XIII to Appendix IV 
9. 
10.4 
Reference to section number was corrected: 
Section 8.3.2 to Section 8.4 


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Change Description  
10. 
8.3 
In the rare occurrence when internet connectivity is lost, an AE report may be submitted 
using CTEP’s Adverse Event Expedited Report-Single Agent or Multiple Agent paper 
template (available at http://ctep.cancer.gov) and faxed to 301-230-0159. Once Internet 
connectivity is restored, an AE report submitted on a paper template must be entered 
electronically into CTEP-AERS by the original submitter at the site. 
Changed from: 
A 24-hour notification is to be made to the AMC ODMC by telephone at 301-251-1161, only 
when Internet connectivity is disrupted. Once Internet connectivity is restored, a 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original 
submitter at the site. 
Changed to: 
11. 
8.5 
Reporting Secondary AML/MDS/ALL 
Changed from: 
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 the AMC and other appropriate regulatory 
agencies according to the instructions in section 8.0. 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  
• 
A copy of the pathology report confirming the AML/MDS/ALL; and 
• 
A copy of the cytogenetics report (if available). 
 
AMC Operations Center 
Fax: (240) 238-2842 
Phone: (301) 251-1161 
E-mail: amcpm@emmes.com 
 
Reporting Secondary Malignancies 
Changed to: 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe 
the event: 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML]) 
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. 
12. 
8.6 
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 the AMC and. Submit the following 
information within 30 days of an AML/MDS/ALL diagnosis occurring after treatment for 
cancer on NCI-sponsored trials: 
Changed from: 
 
• 
A completed NCI/CTEP Secondary AML/MDS/ALL Report Form (do not use CTEP-


AMC #045 (Version 10.0) 04/30/2014 
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# 
Section 
Change Description  
AERS); 
• 
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 NCI. 
 
ECOG Coordinating Center Mailing Address 
ECOG Coordinating Center 
FSTRF 
ATTN:  Adverse Event 
900 Commonwealth Avenue 
Boston, MA  02215 
ECOG Fax Number: (617) 632-2990 
 
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 the AMC and ECOG in accordance with 
Section 8.5. 
Changed to: 
13. 
Appendix 
X 
Changed from
APPENDIX X: DATA SAFETY AND MONITORING PLAN 
: 
(Version 3.0  September 4, 2008) 
 
Changed to
APPENDIX X: DATA SAFETY AND MONITORING PLAN 
: 
(Version 5.0  January 28, 2014) 
 
Appendix replaced. Revisions to Version 4.0 of the DSMP included updates to the AMC’s 
procedures for report distribution, medical monitor review, review of dose escalation 
studies, description of nonvoting DSMB members, and procedures for assuring compliance 
with adverse event reporting requirements. Revisions to Version 5.0 of the DSMP are limited 
to the CTEP-AERS change described in Item #3. 
 


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AIDS MALIGNANCY 
CLINICAL TRIALS CONSORTIUM 
 
 
 
AMC PROTOCOL #045: 
Phase II Trial of Combined Modality Therapy plus Cetuximab 
in HIV-Associated Anal Carcinoma 
 
A Trial of the AIDS Malignancy 
Clinical Trials Consortium (AMC) 
 
 
Funded by: 
The National Cancer Institute 
Division of Cancer Treatment and Diagnosis 
 
 
Pharmaceutical support  
provided by: 
 
Bristol-Myers Squibb Company 
 
Agent: 
Cetuximab (Erbitux) 
 
 
Protocol Chairs: 
Joseph Sparano, MD 
Lisa Kachnic, MD 
David Aboulafia, MD 
 
 
ECOG Study Coordinator: 
Lakshmi Rajdev, MD 
 
 
Version 10.0, April 30, 2014 
NCI Version Date: April 30, 2014 
 
 


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AMC PROTOCOL SIGNATURE PAGE 
 
I,                           , Principal Investigator at site            , agree to conduct and follow this 
protocol: AMC Protocol #045 - Phase II Trial of Combined Modality Therapy Plus 
Cetuximab in HIV-Associated Anal Carcinoma (Version 10.0 dated 04/30/2014), as written 
according to AMC, NCI and FDA guidelines.  I understand that no deviations from the above 
protocol may be made without written permission from the Protocol Chair (s). 
 
 
_________________________________ 
_____________________ 
 
Signature 
Date (mm/dd/yyyy) 
 


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TABLE OF CONTENTS 
 
SUMMARY OF CHANGES ........................................................................................................ i 
AMC PROTOCOL SIGNATURE PAGE ................................................................................. 2 
PROTOCOL ROSTER ............................................................................................................... 6 
SITES PARTICIPATING IN AMC-045 ................................................................................... 7 
SCHEMA ...................................................................................................................................... 8 
1.0 
INTRODUCTION........................................................................................................... 10 
1.1 
Epidemiology ......................................................................................................... 10 
1.2 
Treatment of Anal Carcinoma in Immunocompetent Patients .............................. 11 
1.3 
Anal Carcinoma in Patients with HIV Infection .................................................... 12 
1.4 
Rationale for Combining Cetuximab with CMT for Anal Carcinoma .................. 13 
1.5 
Rationale for the Proposed Trial Design ................................................................ 14 
1.6 
Laboratory Correlates ............................................................................................ 16 
2.0 
OBJECTIVES ................................................................................................................. 19 
2.1 
Primary Objective .................................................................................................. 19 
2.2 
Secondary Objective .............................................................................................. 19 
2.3 
Correlative Science Objectives .............................................................................. 19 
3.0 
PATIENT SELECTION ................................................................................................ 20 
3.1 
Inclusion Criteria ................................................................................................... 20 
3.2 
Exclusion Criteria .................................................................................................. 20 
3.3 
Enrollment Procedures ........................................................................................... 21 
4.0 
REQUIRED DATA ......................................................................................................... 24 
4.1 
Records to be Kept ................................................................................................. 24 
4.2 
Data Submission Schedule - ECOG Institutions ................................................... 24 
4.3 
Role of Data Management ..................................................................................... 24 
5.0 
TREATMENT PLAN ..................................................................................................... 25 
5.1 
Summary of Treatment Plan .................................................................................. 25 
5.2 
5-Fluorouracil (5-FU) ............................................................................................ 26 
5.3 
Cisplatin (CDDP) ................................................................................................... 28 
5.4 
Cetuximab .............................................................................................................. 29 
5.5 
Radiation Therapy .................................................................................................. 37 
5.6 
Concurrent Medications ......................................................................................... 49 


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5.7 
Criteria for Treatment Discontinuation .................................................................. 50 
5.8 
Criteria for Study Discontinuation ......................................................................... 50 
6.0 
STUDY EVALUATIONS ............................................................................................... 52 
6.1 
Baseline/Pretreatment Evaluation .......................................................................... 52 
6.2 
Evaluations During and Immediately after Treatment........................................... 54 
6.3 
Evaluations after Completion of Therapy .............................................................. 57 
6.4 
Off Study Evaluation ............................................................................................. 60 
7.0 
DOSE MODIFICATION/TOXICITY MANAGEMENT ........................................... 61 
7.1 
Hematologic Toxicity ............................................................................................ 61 
7.2 
Non-Hematologic Chemotherapy-Associated, Radiation-Associated, and 
Cetuximab-Associated Toxicity ............................................................................ 62 
8.0 
ADVERSE EVENTS ...................................................................................................... 69 
8.1 
Classification of Adverse Events by Severity and Relationship to Study Drug .... 69 
8.2 
Reporting of AEs ................................................................................................... 70 
8.3 
Expedited AE Reporting ........................................................................................ 70 
8.4 
Safety and Treatment Monitoring .......................................................................... 72 
8.5 
Reporting Secondary Malignancies ....................................................................... 72 
8.6 
Adverse Event Reporting for ECOG Investigators ................................................ 72 
9.0 
END POINT DEFINITIONS AND RESPONSE CRITERIA .................................... 74 
9.1 
Toxicity Criteria and Definitions ........................................................................... 74 
9.2 
Response Criteria ................................................................................................... 74 
9.3 
Quality Of Life Assessments ................................................................................. 76 
9.4 
HPV and Anal Cytology ........................................................................................ 77 
10.0 STATISTICAL CONSIDERATIONS .......................................................................... 78 
10.1 Rate of Accrual ...................................................................................................... 78 
10.2 Patient Characteristics ............................................................................................ 78 
10.3 Sample Size Estimation ......................................................................................... 78 
10.4 Safety and Additional Toxicity Analysis ............................................................... 78 
10.5 Efficacy Analysis ................................................................................................... 79 
10.6 HPV Response and Anal Cytology ........................................................................ 80 
10.7 Quality of Life Analysis ........................................................................................ 80 
10.8 AMC Policy for Monitoring of Phase II Trials ...................................................... 81 


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11.0 ETHICAL AND REGULATORY CONSIDERATIONS ........................................... 82 
11.1 Publication of Research Findings .......................................................................... 82 
11.2 Discipline Review .................................................................................................. 82 
11.3 Institutional Review Board (IRB) Review and Informed Consent ........................ 82 
11.4 Subject Confidentiality .......................................................................................... 82 
11.5 Study Discontinuation ............................................................................................ 82 
11.6 Biohazard Containment ......................................................................................... 82 
11.7 Women and Minorities .......................................................................................... 83 
12.0 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) ..  
 
........................................................................................................................................... 84 
13.0 REFERENCES ................................................................................................................ 85 
 
APPENDIX I:  
SCHEDULE OF EVALUATIONS ............................................................... 89 
APPENDIX II:  
ANAL CANCER STAGING CRITERIA ..................................................... 91 
APPENDIX III:  KARNOFSKY PERFORMANCE SCALE .................................................. 92 
APPENDIX IV:   RTOG/EORTC LATE RADIATION MORBIDITY SCORING SCHEME 93 
APPENDIX V:  
QUALITY OF LIFE INSTRUMENTS ......................................................... 96 
APPENDIX VI:  HPV, CYTOLOGY & PATHOLOGY SPECIMENS ................................ 107 
APPENDIX VII:   INFORMED CONSENT ............................................................................. 109 
APPENDIX VIII:  ACSR INFORMED CONSENT ................................................................. 122 
APPENDIX IX:   ACSR SPECIMEN PREPARATION & SHIPPING INSTRUCTIONS .... 125 
APPENDIX X:   AMC DATA SAFETY MONITORING PLAN ......................................... 128 


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PROTOCOL ROSTER 
 
AMC #045 
 
Phase II Trial of Combined Modality Therapy plus Cetuximab in HIV-Associated Anal 
Carcinoma  
 
Protocol Chairs: 
Joseph A. Sparano, MD 
Statistician: 
Jeannette Y. Lee, PhD 
Albert Einstein Cancer Center 
AMC Statistical Center 
Montefiore Medical Center-Weiler Division 
University of Arkansas for Medical Sciences 
1825 Eastchester Rd, 2 South, Rm 47-48 
4301 W. Markham, #781 
Bronx, NY  10461 
Little Rock, Arkansas 72205-7199 
Phone: 718-904-2555 
Phone: 501-526-6712 
Fax: 718-904-2892 
Fax: 501-526-6729 
Email: jsparano@montefiore.org 
E-mail: jylee@uams.edu 
 
 
David Aboulafia, MD 
University of Washington 
Study Coordinator: 
Una Hopkins, RN, CFNP 
Hematologist-Oncologist 
Albert Einstein Cancer Center 
Virginia Mason Medical Center 
Montefiore Medical Center 
1100 Ninth Avenue 
1825 Eastchester Rd, Rm 47-48 
Seattle, WA  98101 
Bronx, NY 10461 
Phone: 206-223-6193 
Phone: 718-405-8522 
Fax: 206-223-6914 
Fax: 718-904-2892 
Email: hemdma@vmmc.org 
Email: uhopkins@montefiore.org 
 
 
Lisa S. Kachnic, MD 
Boston Medical Center 
Data Operations/Management: 
AMC Operations Center 
830 Harrison Avenue 
The EMMES Corporation 
Boston, MA  02118 
401 N. Washington Street, Suite 700 
Phone: 617-638-7070 
Rockville, MD  20850 
Fax: 617-638-7144 
Phone:  301-251-1161 
Email: lisa.kachnic@bmc.org 
Fax: 240-238-2842 
 
Email: amcpm@emmes.com 
 
ECOG Study Coordinator 
Lakshmi Rajdev, MD 
 
1825 Eastchester Road, 2S-50 
 
Division of Oncology 
 
Bronx, NY  10461 
 
Phone:  718-904-2558 
 
Fax: 718-904-2892 
 
Email: lrajdev@montefiore.org 
 
 


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SITES PARTICIPATING IN AMC-045 
This trial is open for patient accrual at all AMC sites and participating ECOG institutions. 


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SCHEMA 
AMC Protocol # 045 
 
TITLE: 
Phase II Trial of Combined Modality Therapy plus 
Cetuximab in HIV-Associated Anal Carcinoma 
 
STUDY DESIGN: 
A phase II trial of combined modality therapy (CMT) 
consisting of cisplatin, 5-flourouruacil, and irradiation plus 
cetuximab. 
 
PRIMARY ENDPOINT: 
The primary endpoint is local failure rate at 3 years. This 
trial is designed to detect whether the addition of cetuximab 
to standard chemoradiation reduces the local failure rate by 
at least 50%. Secondary endpoints include objective 
response rate (complete and partial), progression-free 
survival, relapse-free survival, colostomy-free survival, 
overall survival, quality of life, and overall toxicity. 
 
SECONDARY ENDPOINTS: 
1. Characterize the effect of CMT plus cetuximab on the 
underlying HIV condition by describing changes in 
viral load, CD4 counts, incidence of opportunistic 
illnesses including the development of AIDS during 
and in the first year after CMT. 
2. Evaluate the effect of CMT of anal cancer on 
anogenital HPV infection and anal cytology. 
3. Evaluate EGFR, PI3K, and P-Akt expression in HIV-
associated anal carcinoma, and determine whether 
moderate strong expression is associated with an 
increased risk of local failure. 
 
POPULATION: 
HIV-infected adults with biopsy-proven squamous cell 
carcinoma of the anus who are candidates to receive CMT 
with curative intent.  
 
TREATMENT REGIMEN: 
All patients will receive CMT with 2 cycles of cisplatin and 
5-FU chemotherapy, given concurrently with radiation 
therapy. CMT consists of: 
• 
Cetuximab 400 mg/m2 IV Day –7 (1 week before the 
cycle 1, Day 1 cisplatin/5-FU and RT), then 250 mg/m2 
IV Days 1, 8, 15, 22, 29, 36 and 43 (a minimum of 6 
and a maximum of 8 doses of cetuximab will be 
administered, including the loading dose). 
• 
Cisplatin 75 mg/m2 IV on Day 1 (cycle 1) and Day 29 
(cycle 2) 


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• 
5-FU 1000 mg/m2/day by continuous intravenous 
infusion on Days 1-4 (cycle 1) and Days 29-32 (cycle 
2) 
NOTE: All patients will be seen by the radiation oncologist 
prior to induction chemotherapy. The radiation therapy 
treatment planning will be based on pre-chemotherapy 
tumor volumes. Irradiation to tumor site and inguinal nodes 
beginning on cycle 1, Day 1 cisplatin/5-FU (minimum 45.0 
Gy [5 weeks if given on schedule and without interruption], 
maximum 54.0 Gy [6 weeks if given on schedule and 
without interruption). IMRT may be used at the discretion 
of the treating physician. 
 
Treatment modifications
• 
The second cycle of chemotherapy may be reduced 
and/or delayed due to hematologic toxicity or other 
toxicities (see 
: 
sections 7.1, 7.2.1, and 7.2.2) 
• 
Irradiation 
held 
for 
excessive 
bone 
marrow, 
gastrointestinal, or cutaneous toxicity (see section 
7.2.3) 
• 
Cetuximab held if irradiation held (or chemotherapy 
plus irradiation held) because of toxicity (see sections 
7.1.1 and 7.2.4) 
 
DURATION: 
Patients will be followed on study for up to 5 years.  
 
SAMPLE SIZE: 
45 eligible and evaluable patients (50 total assuming 10% 
ineligibility).  
 
EXPECTED ACCRUAL RATE: Two eligible/evaluable patients per month. The trial is 
expected to take approximately 24 months to complete.


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1.0 
INTRODUCTION 
1.1 
Epidemiology 
The incidence of anal cancer in the general population is nearly a log lower than the 
current rate of cervical cancer at only 0.9 cases/100,000. It is expected that there were 
approximately 4,000 cases diagnosed in 2004, with nearly 600 deaths.[1] This represents a 
doubling in incidence in recent decades, and is likely due to changing sexual behavior 
within the general population.[2] Correlates of homosexual behavior in men (for instance 
never having been married) were shown to correlate with an increased risk of anal cancer 
nearly two decades ago.[3, 4] A number of studies have since confirmed the relationship 
between anal cancer and receptive anal intercourse in men. Even before HIV became 
widely epidemic, the incidence in men with a history of receptive anal intercourse 
exceeded the incidence of cervical cancer prior to the introduction of Pap smear 
screening at 35 per 100,000.[5] Merged cancer and AIDS registry data indicate that anal 
cancer is 80-fold more frequent than expected in individuals with a diagnosis of AIDS.[6, 
7] Other support includes data from the U.S. AIDS-Cancer registry match.[8] This study 
linked AIDS and cancer registries for both HIV-positive men and women from 11 state or 
metropolitan locations between 1995 and 1998 to study cancer incidence in more than 
309,000 HIV-infected individuals. The overall risks of HPV-associated cancers and their 
in situ precursor lesions were elevated for all anogenital sites studied. The relative risks 
for cervical cancer, vulva or vaginal cancer, and penile cancer were elevated at 5.4, 5.8 
and 3.7 respectively. The relative risk of 6.8 (of 134 individuals) for anal cancer in 
women included a tremendously increased risk for young HIV-positive women under the 
age of 30. At this age, the risk is normally extremely low in the absence of HIV infection. 
The relative risk for HIV-positive men was 37.9, again with the greatest increased risk 
seen in the youngest group. As expected, the HIV exposure category of homosexual 
contact had the strongest association with anal cancer, but it was notable that all HIV 
exposure categories, including intravenous (IV) drug use, transfusion and for women, 
heterosexual contact, were associated with increased risks of anal cancer. 
 
HPV infections of the anogenital tract are sexually transmitted and endemic worldwide.[9] 
HPV is believed to be the primary initiating event for anogenital neoplasia as validated 
by histological, molecular, and epidemiological evidence. HPV DNA has been identified 
in more than 99% of cervical squamous cell carcinomas and in most anal cancers. In a 
case control study by Frisch, HPV DNA was detected in 88% of 388 cases of anal cancer 
and in none of 20 colon cancer control specimens.[10] HPV 16, the most common HPV 
type found in cervical cancer, was found in 73% of these cases. There are nearly 100 
HPV subtypes that differ in tissue tropism (mucosal or cutaneous) and oncogenecity 
(high and low risk). Most cases of anal and cervical dysplasia or cancer contain high risk 
HPV such as 16 or less frequently 18, 31, 33, or 45. Oncogenic HPV types have E6 and 
E7 gene products that have tight binding efficiencies to p53 and pRb, respectively. The 
reduced levels and function of p53 and pRb within the cell lead to inhibition of apoptosis, 
cell cycle dysregulation, and genetic instability. 
 


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1.2 
Treatment of Anal Carcinoma in Immunocompetent Patients 
Standard therapy consists of chemotherapy and radiation therapy, which results in about 
60-70% disease-free survival and local failure rates of about 30-40%.[11] Randomized 
trials have clearly established that combined modality therapy (CMT) consisting of 
mitomycin-C, 5-fluorouracil (5-FU), and irradiation results in improved local control and 
disease-free survival compared with irradiation alone (Table 1). In addition, one phase III 
trial has demonstrated that the addition of mitomycin-C to 5-FU and irradiation further 
improves local control and disease-free survival. 
Table 1: Phase III Trials of Combined Modality Therapy  
of Anal Carcinoma in Immunocompetent Patients 
Study/Arms 
No. 
Local Failure 
Disease-free 
Survival 
Overall Survival 
UKCCCR[12] 
  RT alone 
  RT + 5-FU + mitomycin 
 
290 
295 
 
59% 
36% (p<0.0001) 
 
61% 
72% 
 
58% 
65% 
EORTC[13] 
  RT alone 
  RT + 5-FU + mitomycin 
110 
 
 
50% 
40% (p=0.02) 
 
NR 
 
52% 
59% 
Intergroup [14] 
  RT + 5-FU 
  RT = 5-FU + mitomycin 
 
145 
146 
 
NR 
 
51% 
73% (p=0.0003) 
 
ND  
Abbreviations: NR - not reported; ND – no difference 
 
Several phase II trials have evaluated substituting cisplatin for mitomycin-C. Mitomycin-
C has only modest anti-tumor activity when used alone for squamous cell cervical cancer 
(SCCA), and is associated with long term toxic effects on the kidney, lung, and bone 
marrow. The platinum compounds are considered more effective than mitomycin in the 
treatment of other squamous cell carcinomas, and are now commonly used as a 
component of the first line therapy for cervical cancer, head and neck cancer, and 
esophageal cancer. Several phase II trials in anal cancer have shown very promising 
results in anal carcinoma when cisplatin was combined with irradiation, and/or used as 
component of neoadjuvant therapy prior to irradiation.[15] [16, 17] An ongoing phase III 
RTOG trial (R9811) is comparing mitomycin-C (10 mg/m2 Days 1 and 29) and 5-FU 
(1000 mg/m2 Days 1-4 and 29-32) versus cisplatin (75 mg/m2 Days 1, 29, 57, 85) and 5-
FU (1000 mg/m2 Days 1-4, 29-32, 57-60, 85-88) in combination with radiation therapy 
in immunocompetent patients with anal carcinoma given concurrently with radiation 
therapy. For the mitmoycin-C/5-FU arm, irradiation begins on Day 1 of cycle 1. For 
cisplatin/5-FU arm, irradiation begins concurrently beginning on Day 1 of cycle 3 (or 
Day 57 of therapy). All patients receive an initial radiation dose of 30.6 Gy in 17 1.8 Gy 
fractions to a large pelvic field (superior border at L5-S1), followed by a field reduction 
(reduce superior border to inferior level of S1) for an additional 14.4 Gy in eight 1.8 Gy 
fractions. For patients with high-risk disease (T3, T4, or N+ lesions and T2 lesions with 
residual cancer after 45Gy), an additional 10-14 Gy (2 Gy/fraction) is delivered to gross 
primary or nodal disease plus a 2-2.5 cm margin for a total dose of 55-59 Gy within the 
boost field. As of January 2004, a total of 502 of the required 650 patients have been 


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enrolled on the study. Thus far, there appears to be less toxicity associated with the 
cisplatin/5-FU arm that would be of particular concern in an HIV-positive population, 
including grade 4 bone marrow toxicity (34% vs. 49%), grade 3-4 infection/febrile 
neutropenia (14% vs. 27%), and less overall grade 4 toxicity (43% vs. 62%) and grade 5 
toxicity (0% vs. < 1%). Preliminary data from this ongoing study and multiple previous 
phase II studies indicates that cisplatin/5-FU and irradiation is a reasonable treatment 
option for anal carcinoma. 
 
1.3 
Anal Carcinoma in Patients with HIV Infection 
As previously described in section 1.1, the risk of invasive squamous cell carcinoma of 
the anus is substantially increased in patients with HIV infection.[18] All available data 
regarding treatment of HIV-infected individuals with anal cancer have been retrospective 
in nature, and patients were treated in the era prior to the routine use of highly active 
antiretroviral therapy (HAART). The studies published or presented thus far are outlined 
in the Table 2. This summary outlines the limitations of the available information, and 
highlights the need for a prospective clinical trial performed in the HAART era. In most 
studies, patients received combined modality therapy consisting of mitomycin-C, 5-FU, 
and variations of standard doses/fractions of irradiation. HIV-positive patients seem to 
experience more acute toxicity and poorer survival than immunocompetent patients with 
anal carcinoma. The largest study was a retrospective review (personal communication, 
T. Allen-Mersch) that included 68 patients treated with combined modality therapy at 
four different centers in London and New York, including Montefiore Medical Center. 
The mean age was 44 years, median CD4 count was 255/µL, and 76% were receiving 
HAART at the time of diagnosis. Most patients received mitomycin-C, 5-FU, and 
irradiation. At the time of the analysis, 21 patients (31%) had died, including 14 from 
disseminated anal carcinoma (21%), and 7 patients (10%) from other causes. 
Approximately 35% had local failure at one year. The incidence of grade 3-4 
gastrointestinal, cutaneous, and hematologic toxicity was approximately, 21%, 41%, and 
34%, respectively. The majority of the toxic effects were grade 3 events, with grade 4 
gastrointestinal, cutaneous, and hematologic toxicity occurring in only 0%, 7%, and 13%, 
respectively (although there may have been under-ascertainment of toxicity in this 
retrospective study). Fifteen patients (22%) required radiation treatment breaks due to 
toxicity.  
Table 2: Treatment of Anal Carcinoma in HIV-Infected Individuals 
Reference 
No. 
Conclusion 
Hoffman[19]  
17 
Patients with CD4> 200 have a better outcome 
Holland [20] 
7 
HIV+ patients have more toxicity than HIV- controls 
Chadha [21] 
9 
HIV+ patients have more toxicity than HIV- controls but 
comparable local control 
Peddada [22] 
8 
Good local control and acceptable toxicity with 5-FU  
plus reduced dose irradiation (30Gy) 
Hocht [23] 
4 
Mild acute reactions, short followup 
Place [24] 
23 
40% one year mortality, 80% 5 year mortality 
Kim  [25] 
13  
HIV+ patients have more acute toxicity (80% vs. 30%) 


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Reference 
No. 
Conclusion 
and poorer disease control (62% vs. 85%)  
Cleator[26] 
12 
60% 2 year survival and 50% grade 3-5 acute toxicity 
Allen-Mersch 
68 
66% disease-free survival and 85% overall survival at 1 year 
 
1.4 
Rationale for Combining Cetuximab with CMT for Anal Carcinoma 
The epidermal growth factor receptor (EGFR), whose ligands include EGF and 
transforming growth factor (TGF)-alpha, is a member of the ErbB family of receptors 
that is broadly expressed in epithelial cancers, including squamous cell carcinoma of the 
anus. Cetuximab is chimeric IgG1 monoclonal antibody that binds EGFR with high 
specificity and with greater affinity than its ligands, thus blocking ligand-induced 
activation of EGFR. Cetuximab was recently approved by FDA in combination with 
irinotecan for patients with EGFR-expressing metastatic colorectal carcinoma who have 
developed resistance to irinotecan therapy.[27, 28] The response rate for cetuximab alone 
was 11%, compared with 23% for cetuximab plus irinotecan (23%; p=0.007). There was 
no correlation between response and EGFR expression, either as a percentage of EGFR-
positive tumor cells or as the maximal staining intensity per cell. However, there was a 
significantly higher response rate among patients with developed acneform skin reactions 
compared with those who did not in both the combination group (26% vs. 6%; p=0.005) 
and the monotherapy group (13% vs. 0%).  
 
Cetuximab has been shown to prolong survival in patients with locally advanced 
squamous cell carcinoma of the head and neck[28] and enhance the effectiveness of 
cisplatin in advanced head and neck carcinoma[29] (Table 3), and may be safely combined 
with oxaliplatin and 5-FU in colorectal cancer.[30] In the head and neck trial, patients were 
randomized to receive irradiation alone or in combination with cetuximab (400 mg/m2 IV 
week 1, then 250 mg/m2 weekly in weeks 2-8). Physicians could select the radiation 
fractionation schedule, which was equally distributed in the two arms, and which were 
substantially higher than the doses typically used for anal carcinoma (45-54 Gy for anal 
carcinoma compared with 70-76.8 Gy for the head and neck trial [70 Gy in 35 daily 
fractions over 7 weeks; 72-76.8 Gy in 60-64 fractions twice daily over 6 – 61/2 weeks; or 
concomitant boost, with 72 Gy given in 42 fractions over 6 weeks]). The addition of 
cetuximab led to improved local regional control at 1 year (69% vs. 59%; p=0.02) and 2 
years (56% vs. 48%; p=0.02), as well as significantly improved survival (57% vs. 44% at 
3 years p=0.002). Although there were significantly more skin reactions and infusion 
reactions associated with cetuximab, there were no significant differences in the 
incidence of mucositis/stomatitis, xerostomia, dysphagia, or fatigue. 
 
Table 3. Phase III Trials of Cetuximab in Squamous Cell Carcinoma of the Head and Neck 
Study/ 
Patient Population 
Arms 
No. 
Efficacy 
Comment 
Bonner et al (ASCO, 
2004) 
Locally advanced 
disease at Initial 
 
RT alone 
RT + cetuximab 
 
212 
211 
Median survival 
28 mo. 
58 mo. (p=0.02) 
More grade 3-4 skin reaction  
with cetuximab  (34% vs. 18%; 
p=0.0003)  


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Study/ 
Patient Population 
Arms 
No. 
Efficacy 
Comment 
presentation 
but no difference in grade 3-4  
mucositis (55% vs. 52%) 
Burtness (ASCO 2002) 
Metastatic disease or 
locally Recurrent after 
prior RT 
 
Cisplatin + placebo 
Cisplatin + cetuximab 
 
60 
63 
Response rate 
9% 
23% (=0.0508) 
Trend toward improved 
2 year survival (29% vs. 17%) for 
cetuximab 
 
1.5 
Rationale for the Proposed Trial Design 
We propose a phase II trial of cetuximab plus cisplatin, 5-FU, and irradiation in patients 
with anal carcinoma and HIV infection. Given the potential for less bone marrow 
suppression and more favorable safety profile reported for cisplatin/5-FU/RT, this will be 
the treatment regimen employed in our trial rather than mitomycin-C and 5-FU. Given 
the high prevalence and degree of EGFR expression by squamous cell carcinoma of the 
anus and the promising data for combining cetuximab with either cisplatin or irradiation 
in squamous cell carcinoma of the head and neck, there is clear rationale for evaluating 
this strategy in anal carcinoma. The results of this phase II trial may form the basis for an 
experimental arm of a future phase III trial evaluating cisplatin/5-FU/RT +/- cetuximab, 
or perhaps cetuximab/RT +/- cisplatin/5-FU. This trial is designed to detect whether the 
addition of cetuximab to standard chemoradiation reduces the local failure rate by at least 
50% at 3 years. 
 
In this proposed trial, we will give cisplatin and 5-FU for only two cycles concurrently 
with irradiation and cetuximab; this differs slightly from the R9811 trial, in which two 
cycles of induction cisplatin/5-FU are given alone, followed by two cycles of cisplatin/5-
FU followed given concurrently with irradiation. The reasons for using only two cycles 
of chemotherapy is justified in patients with HIV infection and anal carcinoma on the 
following grounds: (1) the duration of treatment will be reduced by 50%, which should 
result in less chemotherapy-related toxicity, a particular concern in patients with HIV 
infection; (2) the concurrent administration of cetuximab, chemotherapy, and radiation 
therapy offers greater potential for cetuximab to enhance the effects of both 
chemotherapy and irradiation; and (3) there is no evidence for a benefit from a course of 
induction chemotherapy prior to combined chemoradiotherapy in squamous cell 
carcinoma arising in other sites. For example, in head and neck carcinoma, induction 
chemotherapy has had little impact on reducing locoregional and distant failures despite 
rapid reduction of tumor size in most patients treated with induction chemotherapy.[31] 
Should the results of this trial indicate that this combination to be feasible, tolerable, and 
effective, we will consider amendment of this study to evaluate administration of two 
cycles of cisplatin/5-FU given before combined modality therapy, as given in trial R9811 
 
Anal carcinoma and its treatment may produce significant morbidity that is not 
adequately captured by adverse event (AE) grading systems, including issues such as 
continence and sexual function. This study will therefore include quality of life 
instruments that are specifically designed for individuals with anal carcinoma, and will 
provide useful information regarding these important issues. 


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IMRT (Intensity Modulated Radiation Therapy) has become the standard way to deliver 
radiation therapy in the treatment of head-and-neck [40-43] and prostate cancers [44]. In anal 
cancer, IMRT has the potential to reduce prescription dose to normal structures such as 
small and large bowel, bladder, external genitalia, femoral head, bone marrow and skin, 
thereby reducing toxicity. However, very little has been published using IMRT for the 
treatment of this disease. This is mainly due to complexities associated with accurate 
target delineation of both primary and sub-clinical disease in the pelvis region.  
 
There have been two published studies looking into the advantages of IMRT in treating 
anal cancer. Milano, et al. [45] reported that the dose to normal structures is reduced when 
using IMRT as compared to 3-D AP-PA planning. IMRT yielded excellent local control 
(82% at 2 years) and was well tolerated with most patients experiencing only mild or 
moderate side effects and few patients experiencing treatment breaks (13 of 17 had no 
treatment breaks). A dosimetric study by Chen, et al.[46], demonstrated that conformal 
avoidance IMRT technique achieves comparable planning target volume (PTV) coverage 
compared with other approaches while at the same time significantly sparing the 
surrounding Organs at Risk.  
 
Boston Medical Center and Massachusetts General Hospital have recently developed a 
method of delivering a single-phase IMRT plan using a dose-painting (DP-IMRT) 
technique. Six patients with squamous cell carcinoma (stage T2N0 and above) of the anal 
canal were treated with DP-IMRT and concurrent chemotherapy.[47] The DP-IMRT dose 
prescriptions were 50.4 Gy at 1.8 Gy/fraction to the primary tumor and 42 Gy at 1.5 
Gy/fx to the elective nodes for T2 N0 disease, or 54 Gy at 1.8 Gy/fx to the tumor and 45 
Gy at 1.5 Gy/fx to the elective nodes for T3-4/N+ disease. Involved nodes were 
prescribed 54 Gy at 1.8 Gy/fx if > 3 cm in size or 50.4 Gy at 1.68 Gy/fx if < 3 cm. For 
the dosimetric analysis, the DP-IMRT plans were compared with optimal, 3-D CT-based 
conformal therapy (CRT) per RTOG 98-11 design and doses. For the early clinical 
analysis, acute toxicity was assessed using the RTOG scoring system. The mean 
percentage of the primary clinical target volume receiving the prescription dose was 97% 
for both the DP-IMRT and CRT plans. DP-IMRT provided better tissue sparing of most 
normal structures. The acute toxicity experienced by the six patients treated with DP-
IMRT was generally well-tolerated. All patients completed therapy as prescribed, and no 
patient required a treatment break of over one week. Four patients experienced grade > 2 
skin toxicity; three had grade > 3 hematologic toxicity, and no patients had grade > 3 GI 
toxicity. No patient experienced inguinal skin desquamation; however since perianal 
tissue is target, moist desquamation in the anus was observed. All patients achieved a 
complete tumor response based on clinical and radiographic assessment. 
 
Because of the potential advantages of IMRT, this protocol allows use of both standard 
and conformal planning techniques. The efficacy endpoint will be evaluated using all 
patients treated, included conventional RT and IMRT. Toxicity will be evaluated in the 
entire group, and separately in the IMRT group and conventional RT group. An 
exploratory analysis of the primary endpoint (local failure) will be conducted based on 
the type of radiation received (RT and IMRT); local failure will be monitored 


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continuously for both treatment strata (conventional RT vs. IMRT) throughout the course 
of the study. The trial may be amended to exclude IMRT if it becomes apparent that 
IMRT results in inferior disease control or worse toxicity. For conformal techniques, 
approved benchmarks must be on file at QARC. Centers participating in this protocol 
using 3D conformal techniques are required to complete the 3D Benchmark; those 
treating with IMRT must complete the IMRT Questionnaire and either the QARC 
Benchmark or irradiate the RPC’s IMRT head and neck phantom. The Benchmark 
material can be obtained from the Quality Assurance Review Center (www.QARC.org). 
Contact the RPC (http://rpc.mdanderson.org/rpc) for information regarding their 
IMRT phantoms. 
 
1.6 
Laboratory Correlates 
Few studies have evaluated the effect of biological features of anal carcinoma and disease 
control. Bonin, et al. evaluated p53 expression in tumor specimens from patients enrolled 
on an RTOG trial evaluating 5-FU/radiation +/- mitomycin; 48% of the 64 specimens 
evaluated over-expressed p53 by immunohistochemistry, with a trend for inferior local 
control, disease-free survival, and overall survival for those patients having tumors that 
demonstrated p53 overexpression.[32] However, squamous cell carcinoma of the anus 
shares several biological characteristics with head and neck carcinoma that may be 
relevant to this proposal, including a high prevalence of EGFR expression (nearly all in 
both cases) and HPV infection (most anal carcinoma [33] compared with about 35% for 
head and neck carcinoma.[34, 35]) Several studies have evaluated the role of signal 
transduction pathways and prognosis in head and neck cancer, and in particular their 
relation to treatment resistance and local control. For example, Gupta, et al. reported that 
expression of phosphorylated Akt (P-Akt), a downstream target of PI3K, was associated 
with inferior local control in patients with squamous cell carcinoma of the head and neck 
treated with irradiation (2 year local control rate 71% for 2-3+ P-Akt staining by IHC, 
compared with 100% local control rate for 0-1% staining).[36] Of the 38 head and neck 
cancers evaluated, 79% demonstrated strong (3+) EGFR expression, and 66% 
demonstrated moderate to strong (2+ - 3+) expression of P-Akt. In addition, Gupta, et al. 
reported that pharmacological inhibition of EGRF, Ras, and PI3K led to 
radiosensitization of SQ20B squamous cell carcinoma in vitro. 
In this trial, we plan to evaluate EGFR, PI3K, and P-Akt expression in paraffin-
embedded tumor specimens, and to perform anal swabs for HPV detection and 
genotyping, with all studies to be performed in the Palefsky laboratory. We hypothesize 
that similar to the findings reported by Gupta in a relatively small number of patents with 
head and neck carcinoma (N=38), moderate to strong P-AKT expression will be 
associated with an increased risk of local failure. Polymerase chain reaction (PCR) for 
anal HPV testing will be performed as published previously and will detect 39 different 
HPV types.[37] The swab material provides a sampling of the entire anal canal but this 
may or may not directly reflect the HPV type in the tumor. For this reason, we will also 
perform HPV testing from the anal biopsy specimens using methods published 
previously.[38] EGFR, PI3K, and P-Akt expression will be studied using quantitative 
real-time PCR (Q-RT-PCR). RNA will be extracted from the samples in the Palefsky 
laboratory. Quantitative PCR will be done on anal tissues using techniques performed by 


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Dr. Palefsky’s group and the UCSF Comprehensive Cancer Center Genome Analysis 
Core. We will use two-step Q-RT-PCR. For evaluation by Q-RT-PCR, RNA will be 
extracted from the formalin-fixed paraffin-embedded (FFPE) anal epithelium tissues. 
RNA obtained from each sample will be reverse transcribed and amplified in triplicate 
for assessment of the above genes as well as three housekeeping genes. The resulting 
cDNA will be amplified in a two-step real-time PCR to quantify gene expression of our 
target genes. Each sample will be evaluated in triplicate. The outcome of interest will be 
the mean Ct value (the cycle number at which the increase in fluorescence, and therefore 
cDNA, is logarithmic) for each anal sample that will be analyzed by either the standard 
curve method or the comparative Ct method. The comparative Ct method is preferred and 
will be used if possible. The results of these studies with anal cancer samples will be 
compared with those of normal tissues and different grades of anal intraepithelial 
neoplasia (AIN) obtained either from Dr. Palefsky’s Anal Neoplasia Clinic or from the 
AIDS Clinical Specimen Resource (ACSR). We will study three samples each of normal, 
AIN 1, AIN 2 and AIN 3 tissues for comparison with the anal cancer samples. In addition 
to Q-RT-PCR, we will examine levels of EGFR, PI3K and P-Akt expression using 
immunohistochemistry (IHC) in the FFPE tissues using the method of Gupta, et al. In 
these studies, strength of IHC staining will be graded and the results correlated with 
treatment outcome. We will also compare the IHC results to the Q-RT-PCR results. In 
addition to the above, the EGFR gene from anal cancer specimens will be sequenced to 
determine if mutations are present. Finally, cDNA will be stored should we wish to study 
expression of other genes in the future. Relative expression levels or DNA copy number 
measurements of genes are performed using the 5’ fluorogenic nuclease assay in Q-RT-
PCR. The basis for this system is to continuously measure PCR product accumulation 
using a dual-labeled fluorogenic oligonucleotide probe, called a TaqMan™ probe. This 
probe is composed of a short (ca. 20-25 bases) oligonucleotide that is labeled with two 
different fluorescent dyes. On the 5’ terminus is a reporter dye and on the 3’ terminus is a 
quenching dye. The oligonucleotide sequence is homologous to a target sequence in the 
genome and PCR primers encompassing the probe sequence are added. Briefly, the 
protocol involves: (1) Tissue isolation, RNA purification and reverse transcription – 
Tissue samples are obtained from FFPE anal biopsy specimen. For total RNA isolation 
from FFPE tissues, three 10 µm thick sections will be cut from each tissue block. The 
High Pure RNA Paraffin Kit (Roche) will be used as reported by Bibikova, et al.[39] 
Samples are first deparaffinized and RNA isolation then performed. Proteinase K 
digestion time will be 12 hours for each sample. All purification, DNase treatment, and 
other steps were performed according to the manufacturer’s protocol. After total RNA 
isolation, samples will be stored at -80°C until use. Deparaffinization is performed using 
800 µl Hemo-De (or Xylol) and ethanol. Total RNA from entire sections of tissue is 
assessed with a Bioanalyser to determine RNA quality. Purified RNA (1/3 of total 
obtained) is reverse transcribed in 20 µl volume following the manufacturer’s instructions 
to yield cDNA (80 U RNase H- Superscript II), 250 ng random hexamers (Invitrogen), 20 
nmoles dNTPs each, 20 U RNase inhibitor (Superase In, Ambion). Following reverse 
transcription, an amplification step is performed. (2) cDNA Amplification – Individual 
RT-PCR reactions are set up using individual sets of “inner” primers for each gene of 
interest. This includes separate reactions for the housekeeping genes. Amplification 
occurs on a 7700 or 7900 Sequence Detection System (Applied Biosystems): 1 cycle at 


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50°C for 2 minutes, 1 cycle at 95°C for 10 minutes, 40 cycles at 95°C for 15 seconds, 
60°C for 1 minute. Great care is given to the analysis of all raw Ct values obtained from 
these amplifications. Amplifications resulting in Ct values <6 (threshold 0.04) are 
repeated with smaller amounts of input pre-amplification cDNA to ensure that 
amplification plateaus are not reached. Outer and inner primers were designed with the 
“Primer Express” software (Applied Biosystems). Amplicon lengths for outer primers are 
kept <250 bp. The analysis will be primarily exploratory because of the limited sample 
size. From the Q-RT-PCR data, an average Ct value is calculated from triplicate reactions 
and analyzed by the standard curve approach. Averaged Ct values are then normalized (to 
adjust for different amounts of cDNA in each reaction) using the raw values obtained for 
each separate collection of the housekeeping control gene from the same patient. Relative 
expression levels of the same gene between two samples are determined according to ∆ 
Ct values. A ∆Ct value < 1 is considered no change. Statistical evaluation is conducted 
using the rank test. After Ct values are normalized using the raw housekeeping control 
gene values, log Ct values are obtained for all three genes because of the logarithmic 
correlation between Ct value and gene expression levels. Another quantitative approach 
to evaluate relative gene expression is termed the comparative Ct method. This involves 
comparing the average Ct values of the samples of interest with the average of a control 
or calibrator such as RNA from normal tissue. The Ct values of both the calibrator and 
the samples of interest are normalized to an appropriate endogenous housekeeping gene. 
The comparative Ct method is also known as the 2–∆ ∆ Ct method, where ∆ ∆ Ct = ∆ 
Ct,sample - ∆ Ct,reference. Here, ∆ Ct,sample is the Ct value for any test sample 
normalized to the endogenous housekeeping gene and ∆Ct, reference is the Ct value for 
the calibrator (e.g., normal tissue sample) also normalized to the endogenous 
housekeeping gene. For the ∆∆ Ct calculation to be valid, the amplification efficiencies 
of each target gene and the endogenous reference must be approximately equal. This 
must be established by a validation experiment looking at how ∆ Ct varies with template 
dilution. If the plot of cDNA dilution versus delta Ct is close to zero, it implies that the 
efficiencies of the target and housekeeping genes are very similar. If a housekeeping gene 
cannot be found whose amplification efficiency is similar to the target genes, then the 
standard curve method is preferred. The comparative Ct method will be used if possible 
as the need for a standard curve is eliminated. This increases throughput because wells no 
longer need to be used for the standard curve samples. It also eliminates the adverse 
effect of any dilution errors made in creating the standard curve samples as the target and 
endogenous control amplifications are run in separate tubes. 


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2.0 
OBJECTIVES 
2.1 
Primary Objective 
The primary endpoint is local failure rate at 3 years. 
 
2.2 
Secondary Objective  
Secondary endpoints include objective response rate (complete and partial), progression-
free survival, relapse-free survival, colostomy-free survival, overall survival, quality of 
life, and overall toxicity.  
 
2.3 
Correlative Science Objectives 
1. Characterize the effect of CMT on the underlying HIV condition by describing 
changes in viral load, CD4 counts, and incidence of opportunistic illnesses including 
the development of AIDS during and in the first year after CMT 
2. Evaluate the effect of CMT of anal cancer on anogenital HPV infection and anal 
cytology. 
3. Evaluate EGFR, PI3K, and P-Akt expression in HIV-associated anal carcinoma, and 
determine whether moderate strong expression is associated with an increased risk of 
local failure.  
 
 


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3.0 
PATIENT SELECTION 
3.1 
Inclusion Criteria 
1. 
Histologically proven stage I-IIIB (see Appendix II) invasive anal canal or perianal 
(anal margin) squamous cell carcinoma. This may include tumors of non-
keratinizing histology such as basoloid, transitional cell, or cloacogenic histology. 
Patients with well differentiated Stage I anal margin cancer are not eligible. 
2. 
Documented HIV infection. Documentation may be by antibody detection, culture, 
or quantitative assay of plasma HIV RNA.  
3. 
No prior chemotherapy and no prior irradiation for this malignancy. Patients with a 
history of prior irradiation to the planned irradiation field for another condition 
(e.g., Kaposi’s sarcoma) may be eligible after consultation with the radiation 
oncology study co-chair. 
4. 
Adult patients, 18 years of age or older. 
5. 
Karnofsky Performance Status > 60 %. 
6. 
Adequate hematologic function within 14 days of study enrollment: Hemoglobin > 
10 g/dL; Platelet count > 100,000/mm3; ANC > 1500/mm3. Patients receiving 
transfusion, erythropoietin, or myeloid growth factor support will be eligible for 
this study as long as these requirements have been stable for a minimum of 2 weeks 
prior to enrollment.  
7. 
Creatinine < 1.5 X the upper limits of normal (ULN) or a creatinine clearance above 
60 mL/min within 14 days of study enrollment. 
8. 
Adequate hepatic function within 14 days of study enrollment: AST and ALT < 3 X 
ULN, total bilirubin < 2 X ULN unless related to antiretroviral use, then the direct 
bilirubin must be < 2 X ULN. 
9. 
Able and willing to provide written consent. 
 
3.2 
Exclusion Criteria 
1. Acute active, serious, uncontrolled opportunistic infection. Patients with a CD4 count 
< 50/µL will be excluded if they have had an opportunistic infection within the past 6 
months, or if there is evidence of resistance to antiretroviral therapy (i.e., HIV viral 
load > 400 copies/mL despite antiretroviral therapy). 
2. Prior invasive malignancy diagnosed within the past 24 months, excluding in situ 
cervical cancer, anal dysplasia or carcinoma in situ, non-melanoma skin carcinoma, 
Kaposi’s sarcoma that has not required systemic chemotherapy within the past 24 
months. 
3. Grade 2, 3, or 4 neuropathy. 
4. Severe (grade 3 or 4) or poorly controlled diarrhea. 
5. Pregnancy or breast-feeding. Radiation therapy to the pelvis is contraindicated during 
any stage of pregnancy. Both chemotherapy drugs (5-FU and cisplatin) are 
contraindicated during pregnancy and breast-feeding. The 5-FU package insert states 
“compounds that inhibit DNA, RNA and protein synthesis might be expected to have 


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adverse effects on post-natal as well as pre-natal development. The effects of 
cetuximab on a developing fetus are unknown, and may cause harm.” 
6. A medical or psychiatric illness that precludes ability to give informed consent or is 
likely to interfere with the ability to comply with the protocol stipulations. 
 
3.3 
Enrollment Procedures 
3.3.1 AMC Investigators 
This study will be available for enrollment at all AIDS Malignancy Clinical Trials 
Consortium (AMC) sites. Sites must have this protocol approved by their 
Institutional Review Boards (IRBs) and be registered with the AMC Operations 
Center before they may enroll patients. The site must identify at the time of 
registration whether the patient is being treated with standard RT or IMRT. 
 
After it has been determined that the patient is eligible and an informed consent 
has been signed by the patient, the patient must be registered on-line via the AMC 
AdvantageEDCSM internet data entry system. Registration will be accepted from 
the AMC main or affiliated institutions. 
 
The participating site will ensure the patient meets all eligibility criteria prior to 
completing the protocol-specific eligibility checklist. Patients will be enrolled on-
line via the AMC AdvantageEDCSM internet data entry system no more than one 
week prior to the initiation of treatment (enrollment one day prior to or on the day 
of treatment is strongly encouraged). Once the eligibility checklist is submitted 
and eligibility is confirmed, a system generated confirmation email will be sent to 
the enroller with a subject-specific ID that will be used to access the case report 
forms (CRFs). If the on-line system is inaccessible, the site should notify the 
AMC Operations Center (via email at amcpm@emmes.com or phone at 301-
251-1161) for further instructions. 
 
3.3.2 Registration – ECOG Investigators 
 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 19102 
Fax: 215-569-0206 
 
 Required Protocol Specific Regulatory Documents 
1. CTSU Regulatory Transmittal Form. 
2. Copy of IRB Informed Consent Document. 


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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, 9:00 a.m. to 6:00 p.m. 
 
Patients must not start protocol treatment prior to registration. 
 
Treatment should start within five working days after registration 
(enrollment one day prior to or on the day of treatment is strongly 
encouraged).  
 
Institutions may begin to register eligible patients to this study by 
completing the AMC-045 Eligibility Worksheet. A copy of this worksheet 
can be downloaded from the ECOG web site located under "Protocol - 
Complete Protocol Information" for AMC045. After completing these 
questions you must also complete the ECOG registration worksheet via 
the ECOG webpage 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. Please note that a password is 


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required to use this program. The following information will be requested: 
Protocol Number; Investigator Identification (including institution and/or 
affiliate name and investigator's name); Eligibility Verification and patient 
demographics. Patients must meet all of the eligibility requirements listed 
in Section 3.0. After completing the ECOG registration worksheet on the 
web, the institution must call the Central Randomization Desk at the 
ECOG Coordinating Center to provide the Transaction ID # at (617) 632-
2022, Monday-Friday, between the hours of 9:00 a.m. and 4:30 p.m. ET. 
ECOG members should not call the AMC directly. Immediately after 
phoning the ECOG Randomization Desk, the institution must fax the 
NCIC CTG Eligibility Worksheet to the NCIC CTG Central office at 
(613) 533-2941. 
 
The ECOG Randomization Desk will complete the randomization process 
and call the institution back to relay the treatment assignment for the 
patient. The ECOG Coordinating Center will forward a confirmation of 
treatment assignment to the ECOG participating institution. 
 


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4.0 
REQUIRED DATA 
4.1 
Records to be Kept 
CRFs will be provided for each subject via the AMC AdvantageEDCSM internet data 
entry system upon enrollment. Patients must not be identified by name on any study 
document. Data will be entered on the CRFs using the unique subject identification 
number assigned at registration. 
 
All signs, symptoms, HIV-related and AIDS-defining events, toxicities, laboratory results 
and deaths must be entered on the CRFs. Sample CRFs will be available on the AMC 
Operations Center website. 
 
4.2 
Data Submission Schedule - ECOG Institutions 
ECOG Institutions enrolling patients on AMC045 are required to use the AdvantageEDC 
internet data entry system for the submission of CRFs.  Do not use ECOG Forms for this 
study. 
 
Submissions to QARC for radiation therapy quality control are outlined in section 5.5.9.6. 
 
Note:  It is required that the site obtain instructions and training on the AdvantageEDC 
system prior to the enrollment of patients onto the trial.  Sites may contact the AMC 
Operations Center via e-mail (amcpm@emmes.com) to schedule a training session. 
 
4.3 
Role of Data Management 
Instructions concerning the recording of study data on CRFs will be provided by the 
Operations Center. It is the responsibility of the AMC Operations Center to assure the 
quality of data for this study. This role extends from protocol development to generation 
of the final study database. 


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5.0 
TREATMENT PLAN  
5.1 
Summary of Treatment Plan 
5.1.1 Chemotherapy and Cetuximab (see sections 5.2-5.4) 
Note: All patients will be seen by the radiation oncologist prior to induction 
chemotherapy. The radiation therapy treatment planning will be based on pre-
chemotherapy tumor volumes. 
 
Chemotherapy will consist of two courses of cisplatin (Days 1 and 29) and 5-FU 
given for 4 days (i.e., Days 1-4 and 29-32) given concurrently with irradiation. 
Cetuximab will be also be given concurrently with chemotherapy and radiation. 
The start date should be a Monday whenever possible so that chemotherapy can 
overlap with 5 doses of radiation during each cycle. The treatment plan is outlined 
below: 
• Cetuximab is given at a dose of 400 mg/m2 IV 7 days before the first cisplatin 
dose and first radiation dose (cycle 1, Day 1), then 250 mg/m2 on Days 1, 8, 
15, 22, 29, 36, and 43. A minimum of 6 and a maximum of 8 doses of 
cetuximab will be given (including the loading dose). Cetuximab 
administration may not conform exactly to this treatment schedule if toxicity 
develops that requires withholding cetuximab because of toxicity related to 
radiation, cetuximab, chemotherapy, or the combination (see section 5.4 for 
cetuximab administration guidelines and sections 7.1-7.2 for dose 
modification). Cetuximab will be given before the cisplatin/5-FU infusion on 
days when cisplatin is given and/or the 5-FU infusion is initiated. 
• 5-FU is given as a 96-hour continuous infusion (generally as an outpatient via 
a CADD pump and PIC line or Portacath) at a dose of 1000 mg/m2/day X 4 
days (see section 5.2). 5-FU will be given on Days 1-4 and Days 29-32 (i.e., 
begin on the same day of each cisplatin infusion). 
• Cisplatin is given at a dose of 75 mg/m2 IV over 60 minutes on the first day of 
each course of 5-FU (Day 1 and Day 29) with adequate hydration (3 liters of 
0.9% normal saline) (see section 5.3). 
• All patients treated with cisplatin should receive prophylactic antiemetics. 
• Chemotherapy and cetuximab dose delay guidelines are described in section 
7.0. When there has been a radiation therapy break, the chemotherapy and 
cetuximab schedule may be affected as described in section 7.0.  
• Hypomagnesemia is a known complication of cetuximab and of cisplatin. 
Patients must be monitored for hypomagnesemia (see Appendix I), and 
magnesium supplementation should be administered as clinically indicated at 
the discretion of the treating physician. 
 


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5.1.2 Radiation Therapy (see section 5.5) 
All patients will be treated with 1.8 Gy per day, 5 days per week for up to 5-6 
weeks. IMRT may be used at the discretion of the treating physician according to 
the guidelines outlined in this protocol. 
 
 Primary Tumor 
The total dose of irradiation to the primary tumor will be dependent upon T 
stage: 
• T1 or T2 disease: 45 Gy total dose 
• T3 or T4 disease or T2 disease with clinical evidence of residual disease 
after 45 Gy: treat to total dose of between 50.4 Gy – 54.0 Gy 
 
 Inguinal Lymph Nodes 
The total dose to the inguinal nodes will be dependent upon N stage: 
• N0 or N1 (perirectal disease): 30.6 Gy 
• N2 or N3: 45 Gy (plus 5.4 – 9.0 Gy to total dose of 50.4 – 54.0 Gy if there 
is clinical evidence of residual disease after 45 Gy, or for any lymph nodes 
> 3 cm). 
 
5.1.3 Supportive Care 
Supportive care measures (antiemetics, anti-diarrhea medicines, narcotics, 
opportunistic infection prophylaxis) will be given as described in section 5.5 of 
the protocol. Use of HAART is highly encouraged. 
 
5.1.4 Salvage/Secondary Therapy 
Patients who relapse, have progressive disease, or who have persistent disease 
after the completion of protocol therapy may be treated at the discretion of the 
treating physician, and will be followed for survival. 
 
5.2 
5-Fluorouracil (5-FU) 
5.2.1 Formulation, Pharmacology, Supplier, Storage, Potential Toxicity 
 Dose Formulation 
5-FU is available in 10-ml ampules, as a colorless to faint yellow aqueous 
solution containing 500 mg 5-FU, with pH adjusted to approximately 9.0 with 
sodium hydroxide. Administration of 5-FU should be only by the intravenous 
route taking care to avoid extravasation. 
 
 Pharmacology 
5-FU is a marketed drug available in 500 mg vials. It is a fluorinated 
pyrimidine belonging to the category of antimetabolites. 5-FU resembles the 
natural uracil molecule in structure, except that a hydrogen atom has been 


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replaced by a fluoride atom in the 5 position. There is evidence that the 
metabolism of fluorouracil in the anabolic pathway blocks the methylation 
reaction of deoxyuridylic acid to the thymidylic acid. In this fashion 5-FU 
interferes with the synthesis of DNA and to a lesser extent inhibits the 
formation of ribonucleic division and growth. The effect of fluorouracil may 
be to create a thymidine deficiency, which provides unbalanced growth and 
death of the cell. It is primarily metabolized to the inactive dihydro-5-FU by 
dihydropyrimidine dehydrogenase (DPD) in the liver. Rare patients with DPD 
deficiency have excessive toxicity following 5-FU. The route of elimination is 
renal. 
 
 Supplier 
5-FU is available commercially. 
 
 Storage 
Although 5-FU solution may discolor slightly during storage, the potency and 
safety are not adversely affected. Store at room temperature (49°-86° F). 
Protect from light. If a precipitate occurs due to exposure to low temperatures, 
resolubilize by heating to 140° F with vigorous shaking; allow it to cool to 
body temperature before using. 
 
 Side Effects and Toxicities 
The spectrum of toxicity includes stomatitis and esophagopharyngitis (which 
may lead to sloughing and ulceration), diarrhea with cramping and/or 
bleeding, anorexia, nausea and emesis are commonly seen during therapy. 
Leukopenia usually follows every course of adequate therapy with 
fluorouracil. The lowest white blood cell counts are commonly observed 
between the 9th and 14th days after the first dose, although uncommonly the 
maximal depression may be delayed for as long as 20 days. By the 30th day 
the count has usually returned to the normal range. Alopecia and dermatitis 
may be seen. The dermatitis most often seen is a pruritic maculopapular rash 
usually appearing on the extremities and less frequently on the trunk. Other 
side effects include myocardial ischemia, angina, lethargy, malaise, headache, 
allergic 
reactions, 
disorientation, 
confusion, 
euphoria, 
dizziness, 
incoordination, visual changes, photosensitivity of the eyes and skin, nail 
changes including loss of nails, skin thickening, cracking, dryness or 
sloughing, vein pigmentation, biliary sclerosis, or acalculus cholecystitis. 
Other toxicities included cardiac ischemia, angina, and cardiomyopathy Please 
refer to the approved package insert for complete prescribing and toxicity. 
 
5.2.2 5-FU: Preparation, Dose, Schedule and Administration 
The 5-FU can be diluted in D5W or normal saline (NS) to the desired 
concentration. Diluted solutions are stable for up to 16 weeks if refrigerated. The 
5-FU dose is 1000 mg/m2/day for 4 days (total dose per cycle is 4000mg/m2) 
given as continuous infusion in 5% D5W or 0.5 NS for 96 hours continuously 


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starting Day 1. This is to be repeated starting on Day 29. If a patient requires a 
radiation therapy break for skin toxicity or other reason, chemotherapy should 
also be delayed. Once radiation is resumed, the chemotherapy should again begin 
on the first full week so that the 96 hour infusion overlaps with 5 doses of 
radiation whenever possible. Patients may either be admitted to the hospital for 
the 5-FU or receive it as an outpatient via a venous access device (such as a PIC 
line or Porta-Cath) with the use of a pump (i.e., CADD pump). This typically is 
supplied by a home infusion company and supported by a home nursing agency. 
The 5-FU is NOT compatible with cisplatin, which should either be given through 
a separate line or during a brief interruption in the 5-FU infusion.  
 
5.3 
Cisplatin (CDDP) 
5.3.1 Formulation, Pharmacology, Supplier, Storage, Potential Toxicities 
 Formulation 
Cisplatin (Platinol) is available as 10 mg and 50 mg vials of dry powder, 
which are reconstituted with 10 mL, and 50 mL of sterile water for Injection 
USP, respectively. Cisplatin is also available as a 1-mg/mL solution in 50 and 
100 mg vials. 
 
 Pharmacology 
This atypical alkylating agent’s dominant mode of action appears to involve 
the formation of a bifunctional adduct resulting in DNA crosslinks. Plasma 
levels of cisplatin decay in a biphasic mode with an initial half-life of 18 to 37 
minutes, and a secondary phase ranging from 44 to 190 hours. This prolonged 
phase is due to protein binding, exceeding 90%. Urinary excretion is 
incomplete with only 27 to 45% excreted in the first 5 days. The initial 
fractions are largely unchanged drugs. 
 
 Supplier 
Cisplatin is available commercially. 
 
 Storage 
The intact vials should be stored at room temperature. 
 
 Side Effects and Toxicity 
Include anorexia, nausea, vomiting, renal toxicity (with an elevation of BUN, 
creatinine, and impairment of endogenous creatinine clearance, as well as 
renal tubular damage which appears to be transient), neurotoxicity (may be 
severe and irreversible), ototoxicity (with hearing loss which initially is in the 
high-frequency range, as well as tinnitus), hyperuricemia, magnesium and 
potassium wasting, seizures, rash, ocular toxicities, rare cardiac abnormalities, 
or possible acute myeloid leukemia. Much more severe and prolonged toxicity 
has been observed in patients with abnormal or obstructed urinary excretion. 


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Myelosuppression, often with delayed erythrosuppression, is expected. In the 
high-dose treatment regimen with osmotic diuresis, the nadir of white cells 
and platelets occurred regularly at about 2 weeks with recovery generally at 
about 3 weeks after the initiation of therapy. Rare complications are loss of 
taste, allergic reactions, loss of muscle or nerve function, and vascular 
complications. Please refer to the approved package insert for complete 
prescribing and toxicity. 
 
5.3.2 Cisplatin: Preparation, Schedule, and Administration  
 Preparation 
The intact vials should be stored at room temperature. Once reconstituted, the 
solution should be kept at room temperature to avoid precipitation. Due to a 
lack of preservatives, the solution should be given immediately after 
preparation, or at least within eight hours of reconstitution, as a slow 
intravenous infusion. The solution may be further diluted in a chloride-
containing vehicle such as D5NS, NS, or D5-1/2NS (precipitation occurs in 
D5W). Cisplatin has been shown to react with aluminum needles, producing a 
black precipitate within 30 minutes. Cisplatin is incompatible with 5-FU, and 
thus it should either be given through a separate line or during a brief break in 
the 5-FU infusion. 
 
The CDDP dose is 75 mg/m2 in 250 mL NS intravenous infusion over a 
minimum of 60 min on the first day of each 5-FU infusion (Days 1 and 29). If 
required, the CDDP can be given another day during the week of 5-FU (i.e., 
for a Monday holiday or another scheduling reason). The CDDP may be given 
in either an outpatient infusion center or hospital setting. It must be given on a 
day that radiation therapy and 5-FU are to be given. Patients should receive up 
to 2,000 mL of an IV physiologic fluid prior to cisplatin therapy. This may be 
accomplished in the hours prior to dose administration or more gradually 
beginning the previous evening. Post-cisplatin IV hydration of at least 1,000 
mL of physiologic solution containing potassium and magnesium 
supplementation may follow. Patients should be recommended to drink 
generous amount of liquids orally before and after cisplatin therapy (suggested 
volume is 2L). 
 
5.4 
Cetuximab 
 Description 
Cetuximab is an anti-EGFR human-to-murine chimeric antibody. Cetuximab is 
expressed in SP2/0 myeloma cell line, grown in large scale cell culture bioreactors 
and purified to a high level purity using several purification steps including protein A 
chromatography, ion exchange chromatography, low pH treatment and nanofiltration. 
Cetuximab is not known to be a vesicant. 
 


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 Supplier/How Supplied 
Bristol-Myers Squibb (BMS) will supply cetuximab free of charge to the patient. The 
product is a sterile, clear, colorless liquid of pH 7.0 to 7.4, which may contain a small 
amount of easily visible, white, amorphous cetuximab particulates. Each single-use 
50-mL vial contains 100 mg of cetuximab at a concentration of 2 mg/mL and is 
formulated in a preservative-free solution containing 8.48 mg/mL sodium chloride, 
1.88 mg/mL sodium phosphate dibasic heptahydrate, 0.42mg/mL sodium phosphate 
monobasic monohydrate, and Water for injection, USP. 
 
 Packaging and Labeling 
Cetuximab for injection will be supplied by BMS in single-use, ready-to-use 50-mL 
vials containing 2 mg/mL of product. 
 
 Handling and Dispensing 
Cetuximab must be dispensed only from official study sites by authorized personnel 
according to local regulations. Cetuximab should be stored in a secure area according 
to local regulations. It is the responsibility of the Investigator to ensure that study 
drug is only dispensed to study patients. 
 
 Storage Requirement/Stability 
Store vials under refrigeration at 2° C to 8° C (36° F to 46° F). DO NOT FREEZE. 
Increased particulate formation may occur at temperatures at or below 0° C. This 
product contains no preservatives. Preparations of cetuximab in infusion containers 
are chemically and physically stable for up to 12 hours at 2° C to 8° C (36° F to 46° 
F) and up to 8 hours at controlled room temperature (20° C to 25° C; 68° F to 77° F). 
Discard any remaining solution in the infusion container after 8 hours at controlled 
room temperature or after 12 hours at 2° to 8° C. Discard any unused portion of the 
vial. 
 
 Preparation and Administration Techniques 
Cetuximab must NOT be administered as an IV push or bolus. Cetuximab must be 
administered with the use of a low protein binding 0.22-micrometer in-line filter. 
 
Cetuximab is supplied as a 50-mL, single-use vial containing 100 mg of cetuximab at 
a concentration of 2 mg/mL in phosphate buffered saline. The solution should be 
clear and colorless and may contain a small amount of easily visible white amorphous 
cetuximab particulates. DO NOT SHAKE OR DILUTE. 
 
Cetuximab can be administered via infusion pump or syringe pump. 
 
 Infusion Pump 
1. Draw up the volume of a vial using a sterile syringe attached to an appropriate 
needle (a vented spike or other appropriate transfer device may be used). 


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2. Fill cetuximab into a sterile evacuated container or bag such as glass containers, 
polyolefin bags (e.g., Baxter Intravia), ethylene vinyl acetate bags (e.g., Baxter 
Clintec), DEHP plasticized PVC bags (e.g., Abbott Lifecare), or PVC bags. 
3. Repeat procedure until the calculated volume has been put in to the container. Use 
a new needle for each vial. 
4. Administer through a low protein binding 0.22-micrometer in-line filter (placed as 
proximal to the patient as practical). 
5. Affix the infusion line and prime it with cetuximab before starting the infusion. 
6. Maximum infusion rate should not exceed 5 mL/min. 
7. Use 0.9% saline solution to flush line at the end of infusion. 
 
 Syringe Pump 
1. Draw up the volume of a vial using a sterile syringe attached to an appropriate 
needle (a vented spike may be used). 
2. Place the syringe into the syringe driver of a syringe pump and set the rate. 
3. Administer through a low protein binding 0.22-micrometer in-line filter rated for 
syringe pump use (placed as proximal to the patient as practical). 
4. Connect up the infusion line and start the infusion after priming the line with 
cetuximab. 
5. Repeat procedure until the calculated volume has been infused. 
6. Use a new needle and filter for each vial. 
7. Maximum infusion rate should not exceed 5 mL/min. 
8. Use 0.9% saline solution to flush line at the end of infusion. 
 
Cetuximab should be piggybacked to the patient’s infusion line. 
 
Following the cetuximab infusion, a 1-hour observation period is recommended. 
 
 Safety Precautions 
Appropriate mask, protective clothing, eye protection, gloves, and Class II vertical-
laminar-airflow safety cabinets are recommended during preparation and handling. 
Opened vials must be disposed of at the investigational center as chemotherapy or 
biohazardous waste provided documented procedures for destruction are in place. 
 
Cetuximab therapy should be used with caution in patients with known 
hypersensitivity to Cetuximab, murine proteins, or any component of this product. 
It is recommended that patients wear sunscreen and hats and limit sun exposure while 
receiving cetuximab as sunlight can exacerbate any skin reactions that may occur. 
 


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5.4.1 Comprehensive Adverse Events and Potential Risks list (CAEPR) for Cetuximab 
(NSC 714692) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single 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
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidel
ines.pdf for further clarification. Frequency is provided based on 2282 patients. 
Below is the CAEPR for Cetuximab. 
 of AEs (ASAEL) contains events that are considered 'expected' for 
expedited reporting purposes only. Refer to the 'CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements'  
 
Version 2.1, March 31, 20101 
 
 Adverse Events with Possible  
 Relationship to Cetuximab 
 (CTCAE 4.0 Term) 
[n= 2282] 
 
 
 
 EXPECTED AEs FOR 
CTEP-AERS 
REPORTING  
Agent Specific Adverse 
Event List 
(ASAEL) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Expected 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
  
EAR AND LABYRINTH DISORDERS 
  
 
External ear inflammation 
 
  
 
Tinnitus 
 
  
EYE DISORDERS 
  
 
Conjunctivitis 
 
 Conjunctivitis 
 
Dry eye 
 
 Dry eye 
 
Uveitis 
 
 Uveitis 
 
Watering eyes 
 
 Watering eyes 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain 
 
Cheilitis 
 
 Cheilitis 
 
Constipation 
 
 Constipation 
Diarrhea 
 
 
 Diarrhea 
 
Dry mouth 
 
 Dry mouth 
 
Dyspepsia 
 
 Dyspepsia 
 
Mucositis oral 
 
 Mucositis oral 
Nausea 
 
 
 Nausea 
 
Vomiting 
 
 Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills 
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue 


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 Adverse Events with Possible  
 Relationship to Cetuximab 
 (CTCAE 4.0 Term) 
[n= 2282] 
 
 
 
 EXPECTED AEs FOR 
CTEP-AERS 
REPORTING  
Agent Specific Adverse 
Event List 
(ASAEL) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Expected 
Fever 
 
 
 Fever 
 
Flu like symptoms 
 
 Flu like symptoms 
 
Infusion related reaction 
 
 Infusion related reaction 
 
Non-cardiac chest pain 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction 
 
 Allergic reaction 
 
 
 
Anaphylaxis  
  
INFECTIONS AND INFESTATIONS 
  
 
Infection2 
 
  
 
 
 Infections and infestations – 
Other (aseptic meningitis) 
  
INVESTIGATIONS 
  
 
Neutrophil count decreased 
 
  
 
Weight loss 
 
 Weight loss 
 
White blood cell decreased 
 
 White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia 
 
Dehydration 
 
 Dehydration 
 
Hypocalcemia 
 
  
 
Hypomagnesemia 
 
 Hypomagnesemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia 
 
Back pain 
 
 Back pain 
 
Myalgia 
 
 Myalgia 
NERVOUS SYSTEM DISORDERS 
  
Headache 
 
 
 Headache 
 
Syncope 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Allergic rhinitis 
 
 Allergic rhinitis 
 
Bronchospasm 
 
  
 
Cough 
 
 Cough 
 
Dyspnea 
 
 Dyspnea 
 
Hoarseness 
 
 Hoarseness 
 
 
Pneumonitis 
  
 
 
Respiratory, thoracic, and 
mediastinal disorders - Other 
(non-cardiogenic pulmonary 
edema) 
  


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 Adverse Events with Possible  
 Relationship to Cetuximab 
 (CTCAE 4.0 Term) 
[n= 2282] 
 
 
 
 EXPECTED AEs FOR 
CTEP-AERS 
REPORTING  
Agent Specific Adverse 
Event List 
(ASAEL) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Expected 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia 
Dry skin 
 
 
 Dry skin 
 
Nail loss 
 
 Nail loss 
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
  
 
Photosensitivity 
 
 Photosensitivity 
 
Pruritus 
 
 Pruritus 
 
Purpura 
 
  
Rash acneiform 
 
 
 Rash acneiform 
Rash maculo-papular 
 
 
 Rash maculo-papular 
 
Skin ulceration 
 
  
 
Urticaria 
 
 Urticaria 
VASCULAR DISORDERS 
  
 
Hypotension 
 
 Hypotension 
 
Thromboembolic event 
 
 Thromboembolic event 
 
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 PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2Infection could include all 75 sites of infections under the INFECTIONS AND 
INFESTATIONS SOC. 
 
Also reported on cetuximab trials but with the relationship to cetuximab still 
undetermined: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Disseminated intravascular 
coagulation; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Chest pain - cardiac; Left 
ventricular systolic dysfunction; Myocardial infarction; Paroxysmal atrial tachycardia; 
Pericardial effusion; Sinus bradycardia; Sinus tachycardia; Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired 
EYE DISORDERS - Blurred vision; Extraocular muscle paresis; Eyelid function disorder; 
Keratitis; Photophobia; Vitreous hemorrhage 
GASTROINTESTINAL DISORDERS 
- 
Colitis; Dysphagia; Esophagitis; Gastritis; 
Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal hemorrhage (including Colonic 
or Gastric hemorrhage or hemorrhage in other sites under the GASTROINTESTINAL 
DISORDERS SOC); Gastrointestinal perforation (Colonic perforation, Duodenal perforation, or 


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perforation 
in 
other 
sites 
under 
the 
GASTROINTESTINAL 
DISORDERS 
SOC); 
Gastrointestinal ulcer (ulcer includes Duodenal ulcer, Rectal ulcer, or ulcer in other sites under 
the GASTROINTESTINAL DISORDERS SOC); Ileus; Pancreatitis; Rectal fistula 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; 
Sudden death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Wound 
dehiscence 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; 
Aspartate aminotransferase increased; Blood bilirubin increased; Creatinine increased; Platelet 
count decreased; Serum amylase increased 
METABOLISM AND NUTRITION DISORDERS - Hyperkalemia; Hyperuricemia; 
Hypokalemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle 
weakness; Musculoskeletal and connective tissue disorder - Other (myasthenia); Musculoskeletal 
and connective tissue disorder - Other (Sudeck's Atrophy) 
NERVOUS SYSTEM DISORDERS - Ataxia; Dizziness; Dysgeusia; Extrapyramidal disorder; 
Intracranial hemorrhage; Nervous system disorders - Other (cholinergic syndrome); Neuralgia; 
Peripheral motor neuropathy; Peripheral sensory neuropathy; Seizure; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Depression 
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary disorders - Other 
(acute renal failure)  
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Reproductive system and breast 
disorders - Other (balanitis); Vaginal inflammation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory 
distress syndrome; Atelectasis; Bronchopulmonary hemorrhage; Epistaxis; Pleural effusion; 
Respiratory, thoracic and mediastinal disorders - Other (bronchiolitis obliterans-organized 
pneumonia [BOOP]) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hirsutism; Skin hypopigmentation; 
Skin and subcutaneous tissue disorders - Other (skin fissures) 
VASCULAR DISORDERS - Flushing; Hypertension; Lymphedema; Vasculitis 
 
Note: Cetuximab 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. 
 
 Cetuximab Administration 
All patients should be premedicated with diphenhydramine hydrochloride 50 
mg (or an equivalent antihistamine) by IV given 30-60 minutes prior to the 
first dose of cetuximab. Premedication may be administered prior to 
subsequent doses, but at the Investigator’s discretion, the dose of 
diphenhydramine (or a similar agent) may be reduced. 
 


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The initial dose of cetuximab is 400 mg/m2 intravenously administered over 
120 minutes, followed by weekly infusions at 250 mg/m2 IV over 60 minutes. 
The infusion rate of cetuximab must never exceed 5 mL/min. Patients must be 
continuously observed during the infusion for signs of anaphylaxis. 
 
Patients will be closely monitored for treatment-related AEs, especially 
infusion reactions (see section 5.2.1), during the infusion and the post-infusion 
observation hour. For the initial cetuximab infusion, vital signs should be 
monitored pre-infusion, 1/2 hour into the infusion, at the end of the infusion 
and 1 hour post-infusion. For subsequent infusions, vital signs should be taken 
pre- and post-infusion; however, it is recommended that the patient be 
observed for 1 hour post infusion. 
 
For the duration that patients are on study therapy, AE monitoring will be 
done continuously. Patients will be evaluated for AEs at each visit and are to 
be instructed to call their physician to report any clinically significant AEs 
between visits. 
 
Drug Ordering and Accountability: Following submission and approval of the 
required regulatory documents, a supply of cetuximab may be ordered from 
BMS. Please find the Cetuximab (ErbituxTM) Request for Drug Shipment 
form on the AMC Operations Center website (www.amcoperations.com). 
Quantities must be ordered in multiples of four (keeping in mind that you will 
need 7-9 vials for an initial dose, and 4-6 vials for weekly maintenance doses, 
dependent on patient's BSA). A suggested initial shipment is 20 vials. Allow 5 
business days for shipment of drug from receipt of the C225 (Cetuximab) 
Clinical Supply Shipment Request form. The Drug Supply Shipment Form 
can be downloaded from the AMC Operations Center website in MS Word 
format. 
 
All product will be shipped via Federal Express in a temperature-controlled 
container. Shipments will be made from BMS on Monday through Thursday 
for delivery onsite Tuesday through Friday. There will be no weekend or 
holiday delivery of drugs. Protocol specific stickers will be provided to the 
sites for placement on the vials during drug check-in. It is possible that sites 
may have more than one cetuximab clinical study ongoing at the same time. It 
is imperative that only product designated for AMC-045 be utilized for this 
study. 
 
Inside each shipping container will be a disposable electronic unit 
(TagAlert) to ensure the product has remained at the appropriate 
temperature during shipping. This unit will be attached to an information card. 
The LCD display will show OK (indicating no alarm has been triggered) or a 
black bar and the number(s) 1-4 (indicating an alarm/alarms have been 
triggered). Should an alarm be triggered, follow the instructions on the 
attached information card. Display results should be recorded on the packing 


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list. For questions regarding drug requisitioning contact BMS at 800 743-
9224. 
 
Important Reorder Instructions: Reorders should be emailed directly to BMS 
using cetuximab.drug@bms.com or via fax at 609 252-7856 for shipment 
within 5 days. 
 
When assessing need for re-supply, institutions should keep in mind the 
number of vials used per treatment dose (~7-9 for initial dose, ~4-6 for weekly 
maintenance doses, dependent on patient's BSA), and that shipments may take 
5 business days from BMS receipt of request. Quantities must be in multiples 
of four. 
 
Receipt of Drug Shipment:  Study drug shipments will include a TagAlert 
unit and attached information card (see above for description) and a clinical 
supply packing list (CSPL). The pharmacist/study personnel responsible for 
the clinical study product will need to indicate the condition of the shipment, 
record the TagAlert results, and sign the CSPL in the designated areas. The 
pharmacist/study personnel will keep a photocopy for the site's records, and 
return the original to BMS, using the enclosed, pre-addressed envelope. The 
TagAlert unit can be discarded after the reading is recorded on the CSPL. 
 
At the Completion of the Study: At the completion of the infusion all open 
study drug should be destroyed according to institution policy. At the end of 
the study, all unused drugs will be destroyed at the site according to the 
institution's policy for drug destruction. Please maintain appropriate records of 
the disposal, including dates and quantities. 
 
5.5 
Radiation Therapy 
All patients will be treated with 1.8 Gy per day, 5 days per week. Treatment breaks will 
only be allowed for toxicity. Dose adjustments for toxicity are discussed in section 7.0. 
There will be no scheduled breaks. Patients should receive their chemotherapy 
concurrently. If a patient is on a break for skin toxicity, the chemotherapy and cetuximab 
should be delayed until radiation therapy resumes. Patients should be seen and examined 
weekly to monitor tolerance to treatment, skin toxicity, and tumor response. Supportive 
care should be provided as appropriate. 
 
5.5.1 Standard Radiation Therapy Doses 
All patients will be treated with a daily dose of 1.8 Gy, 5 days per week, to a dose 
of 45 Gy in 25 fractions over 5 weeks. There are no scheduled treatment breaks. 
Treatment breaks of < 10-days will only be allowed for severe toxicity; dose 
adjustments for toxicity are discussed in section 7.0.  
 
Patients with T3, T4, or N+ lesions, or T2 lesions with clinical evidence of 
residual disease after 45 Gy, may receive an additional 5.4 – 9.0 Gy (1.8 Gy per 


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fraction) to a reduced field, per the treating radiation oncologist's discretion. A 
further radiation boost is discouraged, and must be discussed with the protocol 
chairs. 
 
Patients with N0 disease or patients with N1 disease (perirectal only involvement) 
will receive 30.6 Gy electively to the bilateral inguinal fossa. For patients with 
inguinal or pelvic metastases, or for lymph nodes greater than 3 cm, the entire 
metastatically involved nodal region is to be included to 45 Gy, and further boost 
irradiation of 5.4-9 Gy may be given for residual nodal disease as outlined in 
Section 5.5.3. 
 
5.5.2 Standard Radiation Simulation/Equipment 
Treatment for patients must be planned on a simulator, which exactly reproduces 
the geometry of the treatment machine and is capable of producing diagnostic 
quality radiographs. Patients are to be simulated in the supine or prone position. A 
radio-opaque marker should be placed over the anus or the most caudal extent of 
the tumor, whichever is most inferior. Small bowel contrast should be 
administered approximately one hour prior to simulation. 
 
Patients must be treated with radiotherapy equipment with photon energy of 6 
MV or greater for pelvic fields with minimum target/axis distance (TAD of 100 
cm). Supplementary inguinal node irradiation (see section 5.5.3) is to be given 
preferably by electrons (low energy photons are allowed at Investigator's 
discretion). 
 
Three-dimensional treatment planning is allowed. 
 
5.5.3 Standard Radiation Treatment Fields 
 Initial Pelvic Fields  
Patients will receive 30.6 Gy at 1.8 Gy/day with bladder distended. All fields 
should receive radiation daily. The pelvis, anus, perineum, and bilateral 
inguinal lymph nodes will be treated with AP-PA fields, 3-field or a 4-field 
technique. If a 3 or 4-field technique is used, the inguinal nodes should not be 
included in the lateral fields. 
 
The superior border of this initial pelvic field shall be the L5-S1 interspace. 
The inferior border shall include the anus with a minimum margin of 2.5 cm 
around the anus and inferior extent of the tumor. The lateral border of the 
AP/PA field shall include the lateral inguinal nodes as determined by bony 
landmarks or lymphangiogram. If the Investigator chooses not to include the 
lateral extent of the inguinal fossa in the PA field, then the inguinal nodes are 
to be boosted with electrons (section 5.5.3) and the lateral border of the PA 
field shall extend 2 cm lateral to the greater sciatic notch. If a 3-4 field 
technique is utilized, the target volume includes all areas at risk (pelvis, anus 
plus margin, inguinal nodes, external iliac nodes). A CT or lymphangiogram 


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should be used to construct nodal volumes. Inguinal nodes must not be 
underdosed (see Inguinal Field section below). 
 
Note: If the patient has a CD4 count less than 200, then the reduced pelvic 
field #2 or PTV 2 may be used for the entire treatment course. 
 
 Reduced Pelvic Field #1 
After 30.6 Gy has been given to the initial pelvic field, the superior border 
shall be dropped to the upper level of the greater sciatic notch (inferior border 
of SI joints). The reduced pelvic field shall be continued to 39.6 Gy at 1.8 Gy 
per day.  
 
For patients with CD4 counts of < 200, reduced pelvic field # 2 should be 
used after 30 Gy. 
 
 Reduced Pelvic Field #2 
After 39.6 Gy, boost fields shall be utilized to encompass the original primary 
tumor volume plus a 2.0 to 2.5 cm margin. Treatment field options include 
reduced multiple photon fields with the patient in supine position (i.e., 4-field 
or PA and laterals with wedges) or a direct photon or electron perineal field 
with the patient in the lithotomy position. All patients shall receive 5.4 Gy 
(total 45 Gy) with this boost. 
 
Patients with T3, T4, or N+ lesions, or T2 lesions with residual disease after 
45 Gy, may receive an additional 5.4-9 Gy (total 50.4-54 Gy) with this 
reduced field, per the treating radiation oncologist's discretion. Further 
radiation boosts are discouraged, and must be discussed with the protocol 
chairs. 
 
If pelvic nodes are grossly involved, they should be included in the final boost 
field if small bowel can be avoided. Of note, all small bowel should be 
excluded from the treatment field after 50.4 Gy. 
 
 Inguinal Fields 
All patients shall receive elective inguinal node irradiation. The initial AP 
pelvic field should be designed to include the entire inguinal region along with 
the pelvis; the PA field may or may not include the lateral inguinal region, (as 
per the discretion of the Investigator). 
 
Patients with N0 disease or patients with N1 disease (perirectal only 
involvement) will receive 30.6 Gy at a minimum depth of 3 cm from the 
anterior surface (use CT or lymphangiogram to calculate the depth). If lateral 
inguinal nodes are not covered by the PA photon field, supplementary RT will 
be delivered with anterior electron fields to the lateral inguinal region which 


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are matched with the exit PA field; the boost may be given with low energy 
photons if electron beam is not available. 
 
In patients with involved inguinal nodes not completely included within the 
idealized pelvic AP photon field, the treatment volume is to be extended as 
needed to provide a minimum 2-cm margin around all palpable and 
radiographic metastatic disease. 
 
For patients with inguinal metastases the entire metastatically involved 
inguinal region is to be included to 45 Gy. Further boost irradiation (5.4-9 Gy 
in 1.8 Gy fractions) may be administered to the tumor plus 2.0-2.5 cm margin 
for residual disease, or for lymph nodes greater than 3 cm, per the discretion 
of the treating radiation oncologist. 
 
Pelvic lymph node metastases will require photon therapy to include the 
primary tumor along with nodal disease. Inguinal lymph node metastases will 
require carefully planned electron fields (low energy photons may be used if 
electrons are not available). 
 
5.5.4 Standard Radiation Dose Specifications 
 Photon Beams 
a) For two opposed coaxial equally weighted beams: on the central ray at 
mid separation of beams.  
b) For an arrangement of two or more intersecting beams: at the intersection 
of the central rays of beams. 
c) For two opposing coaxial unequally weighted beams: on the central ray at 
the center of the target area. 
d) Other or complex treatment arrangements: at the center of the target area 
(Note: there may be several target areas). 
e) Off axis calculation at the level of the primary tumor is required. 
 
 Electron Beams: 
a) The target dose shall be prescribed at the depth of maximum dose. 
b) The energy and field size shall be chosen so that the target volume is 
encompassed within 90% of the prescribed dose. 
c) The maximum or minimum acceptable dose variation across the tumor 
volume is ± 10% of the maximum dose at central axis. 
 
 Inguinal Node Fields 
The daily dose, at the appropriate depth specified below, shall be 1.8 Gy. The 
total dose at this depth shall be 30.6 Gy for N0 patients or patients with N1 
disease (perirectal only involvement) or 45 Gy for N+ patients, and 50.4-54 
Gy for patients with residual inguinal metastases after 45 Gy or for lymph 


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nodes greater then 3 cm. In N0 or NI patients, the dose shall be specified at a 
minimum depth of 3-cm (use CT or lymphagiogram for exact depth). If 
electrons are used, energy is to be selected so that the dose at dmax is no more 
than 10% greater than the dose at prescription depth. In patients with 
metastatically involved inguinal lymph nodes, the dose shall be specified on 
the central axis at the deepest portion of metastatically involved tumor. If 
electrons are used, energy is to be selected so that the dose at dmax is no more 
than 10% greater than the dose at the specified prescription depth. 
 
5.5.5 IMRT and 3D Conformal Planning Guidelines 
Because of the potential advantages of IMRT, this protocol allows use of both 
standard and conformal planning techniques. For conformal techniques, approved 
benchmarks must be on file at QARC. Centers participating in this protocol using 
3D conformal techniques are required to complete the 3D Benchmark; those 
treating with IMRT must complete the IMRT Questionnaire and either the QARC 
Benchmark or irradiate the RPC’s IMRT head and neck phantom. The Benchmark 
material can be obtained from the Quality Assurance Review Center 
(www.QARC.org). Contact the RPC (http://rpc.mdanderson.org/rpc) for 
information regarding their IMRT phantoms. 
 
The radiation oncologist prior to induction chemotherapy will see all patients. The 
radiation therapy treatment planning will be based on pre-chemotherapy tumor 
volumes. Treatment breaks will only be allowed for toxicity. Dose adjustments 
for toxicity are discussed below. There will be no scheduled breaks. Treatment 
breaks of < 10-days will only be allowed for severe toxicity. Patients should 
receive their chemotherapy concurrently. If a patient is on a break for skin 
toxicity, the chemotherapy and cetuximab should be held until radiation therapy 
resumes. Patients should be seen and examined weekly to monitor tolerance to 
treatment, skin toxicity, and tumor response. Supportive care should be provided 
as appropriate. 
 
5.5.6 IMRT Equipment 
• 
Modality: Linear accelerator-based photons with a minimum energy of 6 MV 
will be used. Electrons may be used in the elective treatment of inguinal nodes 
at the discretion of the attending radiation oncologist. 
• 
Geometry: Teletherapy units with a source-to-axis distance greater than or 
equal to 80 cm. 
• 
Calibration: Teletherapy units used in this study shall have their calibration 
verified by the Radiological Physics Center (RPC). 
 
5.5.7 IMRT and 3D Conformal Planning Target Volume Definitions 
ICRU 50 and ICRU 62 prescription methods and nomenclature shall be utilized 
for this study. This will apply to both conformal and non-conformal techniques. 
The volumes are to be defined by planning CT techniques. There are two 
treatment volumes: an initial volume (PTV1) and a boost (PTV2). 


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 Gross Tumor Volume (GTV) 
This is defined as all known gross disease determined from the digital rectal 
examination, proctoscope and CT (and MRI or PET if performed), including 
the gross primary anal tumor volume and any enlarged (> 1cm on imaging) or 
biopsy positive peri-rectal, iliac or inguinal nodes. 
 
 Clinical Target Volume 1 (CTV 1) 
This is defined as the GTV with a 2-cm. margin, plus areas considered 
containing potential microscopic disease. The CTV for this study should 
include the pre-sacral space with the superior boundary at the sacral 
promontory, the mesorectum, the right and left inguinal fossa, the right and 
left internal iliacs, and the right and left external iliacs. The cephalad 
(superior) border of the treatment volume shall be at or above S2 but not 
beyond L5/S1. The caudad (inferior) border of the treatment volume shall 
attempt to exclude the lateral perineal skin. The elective nodal regions will be 
contoured based on the elective lymph node contouring guidelines of RTOG 
(http://www.rtog.org/anoratlas/main.html). For contouring of elective 
inguinal lymph node region, a 1.5 cm margin on contrast enhanced femoral 
vessels extending from the level of top of the femoral heads to bottom of the 
ischial tuberosity will be used. Care should be taken to ensure adequate 
coverage of the mesorectum and presacral area as outlined by the atlas, as well 
as manually trimming the CTV off nontarget muscle, bone and small bowel. 
 
 Planning Target Volume 1 (PTV 1) 
Initial Planning Target Volume (PTV1): For the purpose of this study, a 
margin for set up error and/or patient motion is to be added to the CTV. 
Depending upon the immobilization methods and patient cooperation, this 
may vary but must be at least 1 cm. Exact margins will be left to the discretion 
of the treating radiation oncologist and do not have to be uniform in all 
dimensions. A nodal PTV should not be allowed to overlap with the primary 
PTV, provided that their dose objectives are different, so that the maximum 
dose to the nodal PTV can be controlled in the optimization. 
 
 Clinical Target Volume 2 (CTV 2) 
This is defined as the GTV only with a 2 cm margin. 
 
 Planning Target Volume 2 (PTV 2) 
This is defined as the CTV 2 with at least a 1 cm margin. 
After 39.6 Gy in 1.8 Gy Monday through Friday daily fractions to the PTV 1, 
boost fields shall be utilized to treat the GTV alone (PTV 2). All patients shall 
receive 5.4 Gy (total 45 Gy) with this boost. 
 


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Patients with T3, T4, or N+ lesions, or T2 lesions with residual disease after 
45 Gy, may receive an additional 5.4-9 Gy (total 50.4-54 Gy) to PTV2, per the 
treating radiation oncologist's discretion. Further radiation boosts are 
discouraged, and must be discussed with the protocol chairs. If pelvic or 
inguinal nodes are grossly involved, they should be included in PTV2 if small 
bowel can be avoided. Of note, all small bowel should be excluded from the 
treatment field after 50.4 Gy. 
 
5.5.8 IMRT/3D Conformal Target Dose 
 Prescription Point 
The prescription point for each target volume is at or near the center of the 
target volume.  For 3D conformal planning and IMRT dose may be prescribed 
to an isodose surface provided that the dose uniformity requirements below 
are satisfied. 
 
 Dose Definition 
Dose is to be specified in cGy to muscle. 
 
 Tissue Heterogeneity 
Calculations that take into account tissue heterogeneities are required for all 
CT-based planning techniques. 
 
 Prescription Dose and Fractionation 
All patients are to receive a minimum dose of 4500 cGy to the GTV. The 
prescription is as follows: 
• 
PTV1: The total dose will be 3960 cGy in 22 fractions. 
• 
PTV2: The cumulative dose within the boost volume shall be 4500 cGy. 
 
For patients with T3, T4, or N+ lesions, or T2 lesions with residual disease 
after 45 Gy, an additional 5.4-9 Gy (total 50.4-54 Gy) may be delivered to 
PTV2, per the treating radiation oncologist's discretion. 
 
Note: If the patient has a CD4 count of less than 200, than the PTV 2 may be 
used for the entire treatment course. 
 
 Dose Uniformity 
The PTV should receive +10/-5% of the prescribed dose. For 3D conformal 
and IMRT planning this may be interpreted as requiring that at least 95% of 
the PTV or should be encompassed within the 95% isodose surface and no 
more than 5% of the PTV should receive greater than 110% of the 
prescription dose as evaluated by DVH. 
 


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5.5.9 IMRT Time-Dose Considerations 
 Daily Dose 
The daily dose to the prescription point of the original and boost volumes 
shall be 180 cGy. 
 
 Fractionation 
Treatment shall be given 5 days per week. All radiation fields shall be treated 
daily. 
 
5.5.9.1 IMRT Treatment Technique 
This study allows both standard and conformal planning techniques. 
Conformal planning techniques are encouraged. IMRT is allowed. 
 
 Simulation 
Patients should be planned using a CT simulator, or on a simulator, 
which exactly reproduces the geometry of the treatment machine and 
is capable of producing diagnostic quality radiographs. Conformal 
simulation will be done with the patient in the supine "arms up" or 
prone “arms up” position using a CT-simulator with a slice thickness 
≤ 5 mm. A custom immobilization device (such as Alpha Cradle for 
supine patients and an Alpha Cradle with bowel displacement device 
for prone patients) is suggested to minimize set-up variability.  Oral 
and IV CT contrast is recommended, as is air in the rectum. Of note, 
daily portal imaging is strongly encouraged for patients being treated 
in the prone position on a bowel displacement device. Additionally, 
consideration should be given to using the lightest couch top 
available to avoid unnecessary bolus effect. A radio-opaque marker, 
should be placed over the anus or the most caudal extent of the 
tumor, whichever is most inferior. Small bowel contrast should be 
administered approximately one hour prior to simulation. Target 
tumor volumes are delineated slice by slice on the treatment 
planning CT images. 
 
5.5.9.2 IMRT Normal Tissue Sparing 
 Critical Normal Structures 
The PTVs should spare non-target skin surfaces (manually or 
automatically trimmed to 3-5mm within the skin surface). In 
addition, surrounding critical normal structures, including the 
femoral heads (right and left), bladder, external genitalia, iliac crest, 
small bowel, large bowel outside the CTVs, and perianal skin should 
be outlined. The normal tissues will be contoured and considered as 
solid organs. The tissue within the skin surface and outside all other 
critical normal structures and PTVs is designated as unspecified 


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tissue. DVHs must be generated for all critical normal structures. 
Effort should be made to achieve the listed dose constraints to 
normal tissues below, as follows. NOTE: They are listed in order 
from most to least important. 
 
 Small Bowel 
• No more than 200 cc above 30 Gy 
• No more than 150 cc above 35 Gy 
• No more than 20 cc above 45 Gy 
• None above 50 Gy 
 
 Femoral Heads 
• No more than 50% above 30 Gy 
• No more than 35% above 40 Gy 
• No more than 5% above 44 Gy 
 
 Iliac Crests 
• No more than 50% above 30 Gy 
• No more than 35% above 40 Gy 
• No more than 5% above 50 Gy 
 
 External Genitalia 
• No more than 50% above 20 Gy 
• No more than 35% above 30 Gy 
• No more than 5% above 40 Gy 
 
 Bladder 
• No more than 50% above 35 Gy 
• No more than 35% above 40 Gy 
• No more than 10% above 50 Gy 
 
 Large Bowel 
• No more than 200 cc above 30 Gy 
• No more than 150 cc above 35 Gy 
• No more than 20 cc above 45 Gy 
 
5.5.9.3 IMRT/3D Conformal Planning Dose Calculation and Reporting 
 Monitor Unit Calculations 
Computer printouts used to determine monitor unit settings to deliver 
the prescribed dose shall be submitted.  If IMRT is used, the monitor 
units generated by the IMRT planning system must be independently 
checked prior to the patient’s first treatment. Measurements in a QA 


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phantom can suffice for a check as long as the plan’s fluence 
distributions can be recomputed for a phantom geometry. 
 
 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 DVHs. 
 
 Critical Organs 
The daily dose to the critical organs indicated in Section 5.5.9.2 shall 
be calculated whenever they are included in the radiation therapy 
treatment field. These doses must be recorded in the treatment 
records and submitted with the QA documentation. For patients 
treated with volume-based techniques, the appropriate dose volume 
histograms shall be submitted.  
 
 Isodose Distributions 
A 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 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. 
 
 Conformal Volume Contouring 
CT submission of GTV, CTV1, PTV1, CTV2, PTV2, Small Bowel, 
on all planning slices must be submitted in patients receiving 
conformal therapy. 
 
5.5.9.4 IMRT/3D Conformal Planning QA Documentation 
Please refer to the QARC Submission Schedule for Radiation Materials 
found on page 39 for an itemized list of submission materials and 
instructions regarding the timing of submissions.  
 
• 
These data should be forwarded to: 
Quality Assurance Review Center 
272 West Exchange Street, Suite 101 
Providence, Rhode Island 02903-1025 
Phone: 401-454-4301 
Fax: 401-454-4683 
 


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• 
Questions regarding the dose calculations or documentation should 
be directed to: 
Protocol Dosimetrist 
Quality Assurance Review Center 
272 West Exchange Street, Suite 101 
Providence, Rhode Island 02903-1025 
Phone: 401-454-4301 
Fax: 401-454-4683 
 
• 
Questions regarding the radiotherapy section of this protocol should 
be directed to: 
Madhur Garg, MD, Email: mgarg@montefiore.org or  
Lisa Kachnic, MD, Email: Lisa.Kachnic@bmc.org  
 
5.5.9.5 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% 
PTVs (primary or nodal) 
• 
Major Deviation: The dose to the prescription point differs from 
that in the protocol by more than 10% 
 
• 
Minor deviation: 150-300 cc above 35 Gy, or 20-30 cc above 45 
Gy 
Small Bowel 
• 
Major deviation: ≥ 300 cc above 35 Gy, or ≥ 30 cc above 45 Gy 
 
• 
Minor deviation:  5-10% above 44 Gy 
Femoral Heads 
• 
Major deviation:  ≥10% above 44 Gy 
 
• 
Minor Deviation: The variation of dose in one of the target 
volumes exceeds the limits specified in 
Dose Uniformity 
section 5.5.8. 
 
• 
Minor Deviation: Margins less than specified or fields 
excessively large as deemed by the study. 
Volume 
• 
Major Deviation: Transection of tumor (GTV) or potentially 
tumor bearing area (CTV). 
 


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5.5.9.6 Monitoring of Radiation 
• 
Patients are to be seen and status checked at least once weekly with 
notation of weight, primary tumor status, skin toxicity, and tolerance 
to treatment (see section 6.2). 
• 
Blood counts are to be checked weekly during radiation therapy. 
• 
Criteria for dose modifications/delays of radiation therapy are 
outlined in section 7.0. Questions regarding radiation therapy may be 
addressed to the radiation oncology protocol co-chair (Lisa S. 
Kachnic, MD, see Protocol Roster for contact information). 
• 
Radiation therapy quality control will be performed by the Quality 
Assurance Review Center (QARC). All radiotherapy quality 
assurance materials should be submitted to QARC using the 
schedule outlined below:  
 
QARC Submission Schedule for Radiation Materials 
Radiation Oncology Materials 
QARC Submission Schedule 
Copies of the planning CT and the diagnostic imaging 
utilized in defining the gross target volume.* 
Copies of simulator films and /or digitally reconstructed 
radiographs (DRRs) for each field. It is strongly 
encouraged that the GTV, CTV and PTV1, PTV2 be 
drawn on the simulator films.  
Prescription sheet for ENTIRE treatment.  
Partial Daily Treatment record.  
First day portal films (or hard copy of real time portal 
images) if achievable.  
Photographs of the patient in the treatment position 
with the fields marked.  
Completed RT-1 form or IMRT Dosimetry Summary 
Form (These can be found at www.qarc.org). 
Copies of Beam’s eye views with target and critical 
structures displayed (if 3D conformal planning is used). 
Documentation of an independent check of the 
calculated dose (if IMRT is used). 
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.  
Copies of worksheets and /or printouts used for 
calculations of monitor units.  
Copies of composite isodose distributions to 
demonstrate that the dose variation is within 
specification. The target volume and the prescription 
point must be clearly shown.** 
Dose volume histograms for the PTV and critical 
structures listed in section 5.5.9.2 for the composite 
Within 3 days of the beginning of Radiation Therapy, 
the following data shall be submitted. 
*Submission of Diagnostic Imaging data in digital 
format is preferred over films.  Digital files must be in 
Dicom format.  These files can be burned to a CD and 
mailed to QARC.  Multiple studies for the same patient 
may be submitted on one CD; however, please submit 
only one patient per CD. 
Planning CTs with structures can be submitted in 
RTOG or DicomRT format. For more information 
about digital data submissions, please visit 
www.qarc.org. 
**Black and white copies of color documentation are 
not acceptable. 


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Radiation Oncology Materials 
QARC Submission Schedule 
plan (for CT-based planning). 
Dose volume histogram for “unspecified tissue,” which 
is defined as tissue contained within the skin, but which 
is not otherwise identified by containment within any 
other structure (for IMRT). 
Copies of additional simulation and verification (portal) 
films for any field modifications made subsequent to 
the initial reporting of data for on-treatment review.  
A copy of the patient’s radiotherapy completed daily 
treatment record.  
Copies of calculations and isodoses performed 
subsequent to the submission of the initial data. 
Completed RT-2 form (This can be found at 
www.qarc.org). 
Within one week of the completion of radiotherapy, the 
following data shall be submitted. 
 
 
5.6 
Concurrent Medications 
• 
Some of the agents used in this trial may have an overlapping toxicity profile with 
antiretroviral agents and other agents commonly used in the management of patients 
with advanced HIV infection (e.g., neurotoxicity due to cisplatin and nucleoside 
analogues). To the extent that is possible, care should be taken to avoid medications 
that have an overlapping toxicity profile with cisplatin, 5-FU, and cetuximab. 
• 
Antiviral Therapy: It is highly suggested but not required, that patients receive 
antiviral medications while on study. Antiviral regimens may be modified during the 
course of protocol treatment as necessitated by the occurrence of drug induced 
toxicity or based upon measurement of HIV viral load. If antiviral agents are to be 
initiated or changed between study enrollment and the start of study treatment, then a 
viral load measurement should be taken before and after the change. The choice of 
antiviral medications is to be left to the treating physician’s discretion as this is often 
a decision that requires individualization. However, it is recommended to avoid 
antiretovirals that cause peripheral neuropathy (stavudine, didanosine) because of the 
need for cisplatin therapy, those that are particularly myelosuppressive (such as 
zidovudine containing medications), and those that induce chronic diarrhea. 
• 
Pneumocystis Carinii Pneumonia (PCP) Prophylaxis: Patients should receive PCP 
prophylaxis if they meet established guidelines for PCP prophylaxis (eg, CD4 count < 
200/µL). 
• 
Acyclovir or other herpes medication is strongly suggested during the course of active 
treatment as reactivation of HSV within the radiation treatment area may contribute to 
local toxicity. 
• 
Pain Medications: It is suggested that all patients be prescribed and instructed on the 
use of narcotics. In general this will include a short acting agent (such as liquid 
morphine) in combination with a long acting agent. Titration of these agents should 
be addressed regularly and clinic notes should reflect pain levels and narcotic use. 
• 
Growth Factor Support: Myeloid and erythroid growth factor support is often 
required in this type of study population. Prophylactic use is encouraged but not 


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mandated. General guidelines are to begin GCSF on day 6 following each 
chemotherapy cycle and continue daily through the nadir until the ANC is above 
5,000. Thereafter GCSF may be used as needed. For instance, the dose may be 
adjusted to keep the ANC > 1000. 
• 
Antiemetics will be required before and after cisplatin according to NCCN 
(www.nccn.org) and/or local institutional guidelines. 
• 
Anti-diarrhea medications should be used at the first sign of 5-FU induced diarrhea, 
and may include Loperamide, Imodium, Tincture of Opium, and/or Octreotide. 
• 
Topical medications to the area of radiation therapy injury are to be avoided unless 
specifically discussed with the radiation oncologist. 
 
5.7 
Criteria for Treatment Discontinuation  
If therapy is discontinued early, patients should remain on study whenever possible. 
When this is not possible, see section 5.7 for Criteria for Study Discontinuation. Patients 
may discontinue therapy before the planned completion of the study treatment for the 
following reasons: 
• Study medication will be interrupted or permanently discontinued for treatment 
related toxicity as outlined in sections 7.1-7.3. 
• Disease progression. Further therapy will be at the discretion of the treating 
physician. 
• Patients study treatment must be discontinued for patients who require a break in 
study treatment for longer than 4 weeks. 
• 
• Patients who are non-compliant with respect to keeping appointments or completing 
required tests for the evaluation of drug safety and efficacy may be discontinued from 
study treatment voluntarily or by the discretion of the Investigator. 
For any delay in treatment > 1 week, the study chair should be informed by 
telephone or e-mail regarding the delay, including the following information: (1) 
patient number, (2) date of registration, (3) total dose of radiation therapy given, 
(4) number of cycles of cisplatin/5FU given, (5) total number of doses of 
cetuximab given, (6) component(s) of treatment delayed and reason for the 
delay. The purpose of this communication is to inform the study chair regarding 
clinically significant treatment delays, and to assist treating physicians in 
adhering to protocol guidelines. 
• Patients may decline to receive further therapy, or any part of the therapy, at any time. 
These patients will be encouraged to remain on study for follow up. 
• The Investigator has the right to discontinue any portion of the study treatment, or the 
entire therapy for clinical reasons that he/she believes could be deleterious to the 
subject, even if such reasons do not fall into the toxicity classifications and dose 
modifications described in sections 7.1-7.3. 
 
5.8 
Criteria for Study Discontinuation 
All patients should be followed after completion of study-specified therapy for survival 
and disease status (progressed, relapsed, or disease-free) for 5 years. After 5 years, 


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additional survival and disease status is no longer required. Patients may withdraw from 
the study at any time prior to 5 years. 
 


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6.0 
STUDY EVALUATIONS 
Note: ECOG sites are to follow all study requirements and will participate in all discipline reviews 
and sample submissions as outlined within the protocol. 
 
6.1 
Baseline/Pretreatment Evaluation 
The following will be obtained within the time frames specified in Appendix I: 
 
 Obtained within 6 months of registration 
• Cervical PAP for females with a cervix. 
 
 Obtained within 6 weeks of registration 
• HIV Plasma RNA: Viral load studies will be performed locally at the institution 
using an ultra sensitive assay with a limit of detection of at least 50 copies/mL. If 
the antiviral medications were changed after this was obtained and before 
registration, it should be repeated prior to registration. 
• T CELLS: CD4/CD8 counts and percentages will be included in baseline labs. 
• Electrocardiogram. 
 
 Obtained within 4 weeks of registration 
• CXR – PA and Lateral. 
• Chest CT scan if there is any suspicion of metastatic disease by history, physical, 
or by CXR. 
• Abdomen and pelvic CT scan (or MRI). 
• Endorectal ultrasound is encouraged if available at the institution to obtain an 
accurate estimate of tumor size. 
 
 Obtained within 2 weeks of registration 
• Complete history and physical examination, including information regarding: (1) 
Duration of HIV and AIDS diagnoses, (2) history of major opportunistic illnesses 
and prior cancer diagnoses, (3) date of initial diagnosis of anal cancer and a copy 
of the pathology report must be available, (4) prior history of anal dysplasia and 
prior treatment of any such dysplasia, if known, (5) Presence of any symptoms 
related to the anal cancer including a quantification of pain, (6) current 
medications and history of drug allergies. All antiviral medications taken within 
the past 28 days will be documented. Current pain medication usage will be 
quantified. 
• Complete physical examination, including: (1) Karnofsky performance status, (2) 
vital signs, weight, height, (3) anal examination must include a digital rectal exam 
to document the size and location of the tumor pre-treatment unless this cannot be 
tolerated due to pain. This may be supplemented by the surgeon’s exam during an 
exam under anesthesia performed at the time of diagnostic biopsy (which may be 
done more than 2 weeks prior to registration, (4) assessment of inguinal lymph 


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nodes. Palpable or otherwise abnormal inguinal lymph nodes (such as those that 
appear abnormal on radiographic imaging) should be subjected to fine needle 
biopsy whenever possible.  
• Routine Laboratory Testing: Baseline laboratory testing will include CBC 
(including WBC, differential, hemoglobin, hematocrit, platelet count), and 
CHEMISTRY PANEL (including creatinine, total and direct bilirubin, 
AST(SGOT), ALT(SGPT), alkaline phosphatase, albumin and serum electrolytes 
(sodium, potassium, chloride, bicarbonate) and serum magnesium. 
• Pregnancy Test: Pregnancy test (urine β-HCG) will be performed (and results 
obtained) within 14 days of treatment initiation when indicated (sexually active 
females of child bearing potential). 
 
 After consent but before treatment is initiated 
• The EORTC quality of life instruments, QLQ-C30 and QLQ-CR38, and the 
Memorial Sloan-Kettering Cancer Center anal function criteria (MSK-AF) (See 
Appendix V). This information will be collected and entered in AdvantageEDC 
via the QLC form. The QLQ form will be used to submit all Quality of Life data 
not faxed to the AMC Operations & Data Management Center as of August 22, 
2008. All previously submitted Quality of Life data will be captured in 
AdvantageEDC by the AMC Operations & Data Management Center. 
• Anal swab for HPV testing and cytology (see Appendix VI). 
• Optional tumor biopsy for research purposes (Appendix IX). 
• Optional resolution anoscopy: In sites that have the capacity to perform high 
resolution anoscopy, this exam will be performed at baseline and at month 6. The 
clinical exam will be described and a clinical assessment will be made as to the 
presence of dysplasia. At month 6, biopsies will not be required but may be 
performed if warranted by a high suspicion for cancer, as biopsies obtained from a 
previously irradiated field may lead to non-healing ulcers. Any decision to 
perform a subsequent Pap or high resolution anoscopy (HRA) over the next 4.5 
years while patients remain on study will be made on clinical grounds and not for 
study purposes. 
 
 After consent and registration, but within 28 days after registration 
Submission of the tissue block from the original biopsy (see Appendix VI) and frozen 
tissue from the optional biopsy (if performed) (see Appendix IX).  
 
Histologic confirmation of the anal cancer diagnosis is required for enrollment. 
Central Pathology Review of the primary tumor will be performed. A tissue block 
along with a copy of the surgical pathology report must be submitted (
Tissue Samples 
Appendix VI). 
If the block is not available, a representative H & E stained section and ten unstained 
slides should be submitted. All materials will be retained unless return is specifically 
requested. If an FNA with cytology was obtained for diagnostic purposes instead of a 
biopsy, this will suffice if a cell block was prepared. 
 


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Although it is optional, fresh frozen tissue obtained before the start of therapy is 
requested whenever possible for research purposes. This should be sent to the ACSR 
tissue bank for storage (Appendix IX) and REQUIRES a separate consent form. The 
tissue can be obtained at the time of the exam under anesthesia if a patient has signed 
an ACSR donation consent form or at the time of endoscopic ultrasound (US) of the 
rectum, again if this ACSR donation consent has been signed. As an alternative to 
obtaining a biopsy, a FNA sample could also be obtained for this purpose. The ideal 
location is from the primary tumor; however, if a biopsy or FNA is planned of a 
metastatic site such as the inguinal nodes, then collecting the research material can be 
done at the same time from that site. 
 
It is expected that tissue may be evaluated for HPV detection and typing, gene 
expression by microarray analysis and potentially other research assays as additional 
correlative science studies are developed. These evaluations will not be done in real 
time. 
 
 Quality of Life Survey 
The EORTC quality of life instruments, QLQ-C30 and QLQ-CR38, and the 
Memorial Sloan-Kettering Cancer Center anal function criteria (MSK-AF) will be 
completed (via the QLQ form in Advantage EDC) at baseline, at treatment 
completion, at week 12 (i.e., month 3), then at week 26 and months 12, 24 and 36. 
The QLQ form will be used to submit all Quality of Life data not faxed to the AMC 
Operations & Data Management Center as of August 22, 2008. All previously 
submitted Quality of Life data will be captured in AdvantageEDC by the AMC.  
 
 Patient Care in Preparation of Treatment 
A vascular access device, a home infusion company and home nursing agency may be 
needed to coordinate the 5-FU infusion, unless the patient is to be admitted for this 
therapy. 
 
6.2 
Evaluations During and Immediately after Treatment 
6.2.1 Week 1 (Day 1) 
• Initial chemotherapy and radiation therapy is to begin on this day.  
• At baseline, a focused H & P will include: 
o History and physical exam. 
o PREGNANCY TEST: Pregnancy test (urine β-HCG) will be performed 
whenever it is felt to be warranted by clinical judgment while on active 
therapy. 
 
6.2.2 Week 2 (Day 8 +/- 3 days) 
• A focused H & P is required weekly during active therapy and additionally as 
needed.   Include: 
o Concurrent medications, vital signs, KPS, weight. Changes in underlying 
HIV disease such as intercurrent illness or other changes in health status. 


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o Symptoms recorded. Quantify usage of pain medication and growth 
factors. 
o Toxicity documentation will include an anogenital inspection to document 
the local toxicity of radiation therapy. 
o Requirement for myeloid or erythroid growth factors, or transfusions will 
be documented. 
o Focused physical exam as indicated. Digital rectal exam may not likely be 
possible due to tumor symptoms or the presence of toxicity, but whenever 
possible, the tumor size should be documented on a weekly basis. 
 
• Laboratory Testing 
o CBC weekly (and additionally as needed) through the end of the active 
therapy. Abnormal results should be repeated in 3-4 days time (2 per 
week) when the ANC is < 1000 or Platelet count is < 50K. 
o CHEMISTRY PANEL and serum Mg++ should be performed at week 2, 
3, 4, 5, 6, 7, 8, and 9, and as needed. 
 
• Submission of radiation therapy port films, boost films, and treatment 
o Please refer to the QARC Submission Schedule for radiation materials 
found on page 39 for an itemized list of submission materials and 
instructions regarding the timing of submissions.  
o All submission materials should be sent to the address noted in section 
5.5.9.4. 
 
6.2.3 Week 3 (Day 15 +/- 3 days) 
• Focused H & P as above in section 6.2.2 (week 2) 
• Laboratory Testing 
o CBC, platelet count, differential (repeated in 3-4 days PRN as noted in 
6.2.2) 
o CHEMISTRY PANEL 
 
6.2.4 Week 4 (Day 22 +/- 3 days) 
• Focused H & P as above in section 6.2.2 (week 2) 
• Laboratory Testing 
o CBC and CHEMISTRY PANEL.  
o Electrolytes, BUN, Creatinine, Total Bilirubin, Direct Bilirubin, Alkaline 
Phosphatase, AST, ALT, Albumin. 
 
• Treatment Planning 
o Most patients will receive cycle 2 of their chemotherapy beginning on Day 
29 and arrangements should begin the week prior. 
 
6.2.5 Week 5 (Day 29 +/- 3 days) 
• Day 29 chemotherapy initiated. 
• Complete H & P (see section 6.1) 


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• Laboratory Testing 
o CBC and CHEMISTRY PANEL.  
o HIV viral load: Viral load study on Days 29 and 57 (will be performed 
locally at the institution). 
o T CELLS: CD4/CD8 counts and percentages on Days 29 and 57.  
o Quality of Life Instruments (EORTC QLQ-C30 and QLQ-CR38 and 
MSK-AF) via the QLQ form in AdvantageEDC. The QLQ form will be 
used to submit all Quality of Life data not faxed to the AMC Operations & 
Data Management Center as of August 22, 2008. All previously submitted 
Quality of Life data will be captured in AdvantageEDC by the AMC. 
 
6.2.6 Week 6 (Day 36 +/- 3 days) 
• Focused H & P as above in 6.2.2 (week 2). 
• Laboratory testing: 
o CBC and CHEMISTRY PANEL.  
 
6.2.7 Week 7 (Day 43 +/- 3 days) 
• Focused H & P as above in 6.2.2 (week 2). 
• Laboratory testing: 
o CBC and CHEMISTRY PANEL.  
 
6.2.8 Week 8 (Day 50 +/- 3 days) 
• Focused H & P as above in 6.2.2 (week 2). 
• Laboratory testing: 
o CBC and CHEMISTRY PANEL. 
 
6.2.9 Week 9 (Day 57 +/- 5 days) 
• Complete H & P (see sections 6.1). 
• Laboratory testing: 
o CBC and CHEMISTRY PANEL.  
o HIV viral load will be performed locally at the institution. 
o T CELLS: CD4/CD8 counts and percentages. 
 
6.2.10 Additional Weeks 
If therapy has been delayed, the same requirements of weekly focused 
examinations and laboratory studies will continue until at least 2 weeks after the 
completion of therapy. If residual grade 3 or greater toxicity persists, patients 
should be evaluated every 2 weeks with appropriate studies until the toxicity has 
dropped to grade 2 or lower.  
 


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6.3 
Evaluations after Completion of Therapy 
6.3.1 Week 12 (Day 78 +/- 14 days) 
• Complete H & P 
• Laboratory Testing 
o CBC and CHEMISTRY PANEL. 
Quality of Life Instruments (EORTC QLQ-C30 and QLQ-CR38 and 
MSK-AF) via the QLQ form in AdvantageEDC. The QLQ form will be 
used to submit all Quality of Life data not faxed to the AMC Operations & 
Data Management Center as of August 22, 2008. All previously submitted 
Quality of Life data will be captured in AdvantageEDC by the AMC. 
 
- Radiographic Studies 
CXR and abdominal and pelvic CT scan. 
These studies will be performed once therapy is complete and acute 
inflammation has resolved. This may be delayed if therapy was late 
finishing due to lengthy treatment breaks for example, as scans will be 
difficult to perform and interpret if significant pelvic inflammation is 
still present. Alternatively, these may be performed early if residual or 
recurrent disease is suspected and results are required on clinical 
grounds. 
 
- Biopsy 
Whenever residual or progressive disease is suspected, radiographic 
imaging or biopsy may be performed as indicated. One caveat is that a 
full thickness biopsy within the radiation field can be complicated by 
the development of a non-healing ulcer. An FNA could be used as an 
alternative to a full thickness biopsy. Because a potentially curative 
procedure such as an APR for uncontrolled local disease may be 
warranted, concern about the risk of a biopsy should not delay an 
appropriate evaluation for residual disease. 
 
- Submission of Radiation Therapy Boost Films and Treatment Record 
Please refer to the QARC Submission Schedule for Radiation Material 
found on page 39 for an itemized list of submission materials and 
instructions regarding the timing of submissions.  
All submission materials should be sent to the address noted in section 
5.5.9.4. 
 
6.3.2 Week 18 (+/- 14 days) 
• Focused H & P including but not limited to: 
o Concurrent medications and vital signs, weight, KPS 
o Pain medication usage quantified 


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o Residual toxicity such as neuropathy, need for myeloid or erythroid grow 
factor support 
o Assess for tumor relapse, changes in underlying HIV disease such as 
intercurrent illness or other changes in health status (evaluation by PE is 
acceptable) 
o Radiographic and laboratory studies as indicated 
 
6.3.3 Week 26 (+/- 14 days) 
• Complete H & P including but not limited to: 
o Concurrent medications and vital signs, weight, KPS 
o Pain medication usage quantified 
o Assess for tumor relapse (including an exam of the anus and inguinal 
lymph nodes), residual toxicity, changes in underlying HIV disease such 
as intercurrent illness or other changes in health status 
o Laboratory testing:  
o CBC and CHEMISTRY PANEL 
o HIV viral load will be performed locally 
o CD4/CD8 counts and percentages 
o Radiographic Studies if indicated by H & P 
o Quality of Life Instruments (EORTC QLQ-C30 and QLQ-CR38 and 
MSK-AF) Via the QLQ form in AdvantageEDC. The QLQ form will be 
used to submit all Quality of Life data not faxed to the AMC Operations & 
Data Management Center as of August 22, 2008. All previously submitted 
Quality of Life data will be captured in AdvantageEDC by the AMC 
o Repeat anal swab for HPV, anal cytology (Appendix VI) 
o High resolution anoscopy (if available): In sites that have the capacity to 
perform high resolution anoscopy, this exam will be performed at baseline 
and at month 6. The clinical exam will be described and a clinical 
assessment will be made as to the presence of dysplasia. At month 6, 
biopsies will not be required but may be performed if warranted by a high 
suspicion for cancer, as biopsies obtained from a previously irradiated 
field may lead to non-healing ulcers. Any decision to perform a 
subsequent Pap or high resolution (HR) anoscopy over the next 4.5 years 
while patients remain on study will be made on clinical grounds and not 
for study purposes. 
 
6.3.4 Month 9 (+/- 14 days) 
• Complete H & P as above (see week 26) 
• Laboratory testing:  
o CBC and CHEMISTRY panel 
o Radiographic Studies if indicated by H & P 
 
6.3.5 Month 12 (+/- 14 days) 
• Complete H & P as above (see week 26). 
• Laboratory testing:  
 


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o CBC and CHEMISTRY panel. 
o HIV viral load will be performed locally, CD4/CD8 counts and 
percentages 
o Radiographic Studies if indicated by H & P. 
o Quality of Life Instruments (EORTC QLQ-C30 and QLQ-CR38 and 
MSK-AF) via the QLQ form in AdvantageEDC. The QLQ form will be 
used to submit all Quality of Life data not faxed to the AMC Operations & 
Data Management Center as of August 22, 2008. All previously submitted 
Quality of Life data will be captured in AdvantageEDC by the AMC. 
 
6.3.6 Months 18, 24 and 30 (+/- 1 month) 
• Complete H & P as above (see week 26) 
• Laboratory testing: 
o CBC and CHEMISTRY panel. 
o Quality of Life Instruments (EORTC QLQ-C30 and QLQ-CR38 and 
MSK-AF) via the QLQ form in AdvantageEDC for month 24 follow-up 
only. 
o Radiographic Studies if indicated by H & P. 
 
6.3.7 Month 36 (3 Years +/- 1 month) 
• Complete H & P including an exam of the anus and inguinal lymph nodes. 
• Laboratory testing: 
o CBC and CHEMISTRY panel. 
o Additional laboratory testing will be performed as indicated. 
o HIV viral load will be performed locally, CD4/CD8 counts and 
percentages. 
o Radiographic Studies if indicated by H & P. 
o Quality of Life Instruments (EORTC QLQ-C30 and QLQ-CR38 and 
MSK-AF) via the QLQ form in AdvantageEDC 
 
6.3.8 Month 48 (4 Years +/- 1 month) 
• Same as in 6.3.6 above. 
 
6.3.9 Month 60 (5 Years +/- 1 month) 
• Complete H & P including an assessment of tumor status. 
• Laboratory testing:  
o CBC and CHEMISTRY panel. 
o Additional laboratory testing will be performed as indicated. 
o HIV viral load will be performed locally, CD4/CD8 counts and 
percentages. 
o Patients are taken off study at this time point. 
 


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6.4 
Off Study Evaluation 
For patients that withdraw from the study prematurely, the following evaluations will be 
performed whenever possible, preferably at the time of or up to 1 month after withdrawal 
from the study: 
1. History and physical: A full history and physical exam. 
2. Anogenital exam: A digital rectal exam to document local control. If there is an 
abnormality that suggests tumor, an FNA or biopsy should be performed. Tumor size 
should be documented. The anogenital region will also be evaluated for toxicity. 
3. Anal swab for HPV testing (Appendix VI). 
4. Routine laboratory testing: CBC and CHEMISTRY panel. 
• 
HIV viral load will be performed locally. 
5. HIV viral load 
6. T Cells: CD4/CD8 counts and percentages. 
7. Quality of life survey: The final quality of life assessment will be performed unless 
the subject is more than 36 months into the study and has completed the 36 M QOL 
surveys. This will be completed via the QLQ form in AdvantageEDC. 


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7.0 
DOSE MODIFICATION/TOXICITY MANAGEMENT 
This study will utilize the NCI’s Common Terminology Criteria for Adverse Events and 
the RTOG/EORTC Late Morbidity Scoring Scheme (Appendix IV). A copy of the 
CTCAE can be downloaded from the CTEP home page (http://ctep.info.nih.gov). 
 
Dose adjustments may be necessary due to toxicity. The decision regarding treatment 
adjustment or discontinuation from drug therapy or radiation therapy for suspected 
treatment associated toxicity must follow the protocol guidelines but ultimately rests 
with the investigator. The investigator must use the available data and exercise clinical 
judgment.  
 
Attribution of toxicity to one therapy may be difficult when there are three concurrent 
agents with overlapping toxicities being given as components of the CMT. Dose 
modifications or dose delays may be due to multiple causes. Judgment is needed in 
deciding if more than one agent is to be held or modified.  
 
If radiation therapy is being held because of local toxicity, chemotherapy and 
cetuximab will also be held until the radiation therapy is resumed. It is possible that 
radiation therapy will be permanently discontinued yet the treating physician may still 
wish to give a second cycle of chemotherapy. That will be permitted if the following 
criteria have been met. 
 
If there are conflicting rules regarding dose reduction (i.e., a 25% dose reduction is 
specified based on the nadir blood counts following cycle 1, but a 50% dose 
reduction is specified due to delayed and/or incomplete count recovery) then the 
greater reduction, i.e. the more conservative guideline, will be followed.  
 
 
Concurrent illness such as a severe opportunistic infection may interrupt therapy. A 
break of greater than 8 weeks should result in treatment discontinuation. If therapy 
is to be resumed, this decision should be discussed first with one of the study chairs.  
7.1 
Hematologic Toxicity 
7.1.1 Dose Delay of Cycle 2 of chemotherapy (and cetuximab)  
Cycle 2 chemotherapy (and continued weekly cetuximab) will be delayed if there 
has been a break required in radiation therapy. The goal is to continue to provide 
concurrent cetuximab plus chemo- and radiotherapy. See section 5.0 for details. 
 
Cycle 2 chemotherapy should not be resumed until there has been adequate 
recovery from any hematologic toxicity induced by cycle 1. The ANC should be ≥ 
1200 and platelet count ≥ 100,000. In this case, concurrent cetuximab may 
continue if radiation therapy is continuing. In order to continue to provide 
concurrent therapy, cycle 2 of chemotherapy should be given before the last week 
of radiation therapy begins. See section 7.2.3 regarding radiation therapy breaks 
for hematologic toxicity. If after one week of delay, the ANC is > 1200 and 


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platelets are > 100,000 full dose therapy will be administered. If the ANC has not 
returned to > 1,200 or platelets are not > 100,000 after the one week delay, the 
drug doses will be modified as follows: 
 
ABSOLUTE NEUTROPHIL COUNT 
COUNT 
> 1,200 / mm3 
750 - 1,199/ mm3 
< 750 / mm3 
> 100 K 
Full Dose 
50% 5-FU, 50% Cisplatin 
Hold Cisplatin/5-FU 
75-99 K 
50% 5-FU, 50% Cisplatin 
50% 5-FU, 50% Cisplatin 
Hold Cisplatin/5-FU 
< 75 K 
Hold Cisplatin/5-FU 
Hold Cisplatin/5-FU 
Hold Cisplatin/5-FU 
 
If by these guidelines, treatment is to be held, then radiation therapy may need to 
be held in addition. A treatment hold becomes a treatment discontinuation as 
defined in section 5.7. 
 
When there is a conflict in these instructions, it is advised that the issue be 
discussed with one of the study chairs. 
 
7.1.2 Dose Modification of Cycle 2 Chemotherapy Based on Nadir 
Dose Modification for Cycle 2 Chemotherapy based on Hematologic Nadir with 
Cycle 1: 
ABSOLUTE NEUTROPHIL COUNT NADIR 
PLATELET 
  NAIDR** 
   > 500 / mm3 
< 500 / mm3 for < 4    
days 
< 500 / mm3 confirmed 
          for > 4 days 
>  40 K 
Full Dose 
75% 5-FU, 75% Cisplatin 
50% 5-FU, 
50% Cisplatin 
20-39 K 
75% 5-FU 
75% Cisplatin 
75% 5-FU, 75% Cisplatin 
50% 5-FU, 
50% Cisplatin 
< 20 K 
50% 5-FU 
50% Cisplatin 
50% 5-FU, 50% Cisplatin 
25-50% 5-FU, 
25-50% Cisplatin 
 
Notes: 
75% 5-FU or 75% CDDP = chemotherapy dose to be delivered, representing a 
25% dose reduction 
 
The 50-75% dose reduction for severe neutropenia and thrombocytopenia 
covers a range to allow for discretion of the treating physician.  
 
7.2 
Non-Hematologic Chemotherapy-Associated, Radiation-Associated, and 
Cetuximab-Associated Toxicity 
7.2.1 5-FU Dose Modification  
Severe GI Toxicity is likely the result of extreme sensitivity to 5-FU. Before 
initiation of 5-FU, patients will be instructed to begin therapy such as Lomotil and 


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oral hydration if they should develop diarrhea. If the diarrhea is unresponsive to 
Lomotil, if 8 or more Lomotil tablets per 24 hours are required to control the 
diarrhea, or if cramping, abdominal pain or bleeding are present, the patient 
should report this immediately to his physician. Appropriate therapy (such as 
Tincture of Opium or Octreotide, hydration, pain control, electrolyte replacement) 
and evaluation (examination, laboratory monitoring of electrolytes) should be 
initiated as clinically appropriate. 
 
The development of grade 3-4, 5-FU induced diarrhea before the end of the 
96-hour infusion, should lead to immediate discontinuation of the infusion. 
 
Dose Modifications for Cycle 2 Chemotherapy Based on Diarrhea or Stomatitis 
Toxicity 
Parameters 
Agent 
Modification 
for Cycle 2 
Diarrhea 
Grade 3 
Increase of ≥ 7 stools/day or incontinence; or need for 
parenteral support for dehydration 
5-FU 
75% 5-FU 
Diarrhea 
Grade 4 
Physiologic consequences requiring intensive care; or 
hemodynamic collapse 
5-FU 
50% 5-FU 
Stomatitis 
Grade 3 
Painful erythema, edema, or ulcers requiring IV hydration 
5-FU 
75% 5-FU 
Stomatitis 
Grade 4 
Severe ulceration or requires parenteral nutritional support  
5-FU 
50% 5-FU 
 
7.2.2 CDDP Dose Modification 
 Renal Insufficiency, NeuroToxicity, Ototoxicity: 
A serum creatinine of 1.5-2.0 X ULN on Day 29 (or the planned day of cycle 
2 cisplatin dose) will result in a 50% reduction in the dose of cisplatin for 
cycle 2. The second dose of cisplatin will be withheld if the serum creatinine 
is greater than 2.0 X ULN on Day 29 (or the planned day of cycle 2 cisplatin). 
At the discretion of the investigator mitomycin (at a dose of 10 mg/m2 or 20 
mg maximum) may be substituted in cycle 2 for toxicity that is felt to be 
CDDP dependent and specific. 
 
If the serum creatinine rose significantly following cycle 1 but has recovered 
to < 1.5 X ULN when cycle 2 is due, then several options are suggested. 
Either a 25% dose reduction or improved post CDDP hydration (such as daily 
IV hydration for several days) or both are potential interventions. 
 
Tinnitus, hearing loss, or grade 3 peripheral neuropathy will result in a 50% 
reduction in the dose of cisplatin. Grade 4 neuropathy will result in no further 
CDDP being given. Investigator discretion will allow the use of mitomycin (at 
a dose of 10 mg/m2 or 20 mg maximum) to be substituted for cycle 2 if the 


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toxicity is felt to be CDDP dependent. The table also describes dose 
modifications for CDDP induced ototoxicity.  
 
Dose Modifications for Cycle 2 Chemotherapy Based on Cycle 1 Toxicity 
Toxicity 
Parameters 
Agent 
Modification 
Creatinine 
1.5 - 2.0 X ULN 
CDDP 
50% CDDP 
Creatinine 
> 2.0 X ULN 
CDDP 
Hold  
Consider mitomycin 
Ototoxicity 
(Inner ear/hearing) 
Grade 2 Tinnitus or hearing loss, not 
requiring hearing aid or treatment. 
CDDP 
50% CDDP 
 
Ototoxicity 
(Inner ear/hearing) 
Grade 3 Tinnitus or hearing loss,  
correctable with an aid or treatment. 
CDDP 
50% CDDP 
Consider mitomycin 
Neuro:   
(Sensory, Motor) 
Grade 2 Motor or Grade 3 Sensory 
loss or paresthesia interfering with  
activities of daily living. 
CDDP 
50% CDDP 
Consider mitomycin 
Neuro:  
(Sensory, Motor) 
Grade 3 Motor or any Grade 4  
Peripheral neuropathy 
CDDP 
Hold CDDP 
Consider 
mitomycin 
 
7.2.3 Radiation Therapy Modification for Non-hematologic Toxicity 
Contact the radiation oncology protocol co-chair (Lisa S. Kachnic, MD, see page 
5 for contact information) by telephone or email for the indications outlined 
below. Please include the following information in your communication: (1) 
patient ID number, (2) treating physician name, (3) date of question, (4) date 
radiation therapy started, (5) number of radiation doses given to date, (6) 
cumulate radiation dose given to date, (7) question/problem. The radiation 
oncology co-chair will document any deviations in the protocol: 
• The treating physician wishes to interrupt radiation during the first 28 days of 
the treatment program. Permission must be obtained from the radiation 
oncology co-chair.  
• If RT is suspended for > 10 days, contact the study chair all study chair before 
proceeding. 
• Any deviation from the radiation therapy program not specified in the 
protocol. 
 
Radiation therapy may be held interrupted for the following indications: 
• ANC < 500/mm3 and/or platelets < 40,000: RT will resume when ANC > 500 
and PLT > 40,000. If chemotherapy is being held in order to allow for count 
recovery, radiation therapy can be held as well, based on treating physician 
discretion. If radiation is held due to cytopenia, laboratory monitoring should 
increase to include twice per week CBC, differential, and platelet count until 
recovery to an ANC.  


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• Grade 3 or greater diarrhea (> 6 stools/day above baseline): resume when RT 
is < 6 stools/day above baseline.  
• Grade 4 vomiting (parenteral nutrition, intensive care, or hemodynamic 
collapse): resume when vomiting is < grade 3.  
• Grade 4 skin ulceration: resume when the skin reaction is grade 2 or less. If 
localized or generalized infection develops secondary to an area of confluent 
moist desquamation, radiation therapy will be suspended. In this setting, 
radiation therapy will be resumed after there has been complete resolution of 
sepsis and re-epithelialization in the area of desquamation. The presence of 
moist desquamation in the absence of infection shall not constitute grounds 
for unplanned suspension of radiation therapy. 
 
7.2.4 Cetuximab-Associated Toxicity and Dose Modifications 
Cetuximab should be held if radiation therapy is held for toxicity, or if both 
chemotherapy and radiation therapy are held for toxicity. A minimum of 6 and 
maximum of 8 doses of cetuximab should be administered
 
. 
7.2.4.1 Infusion Reactions 
Severe infusion reactions require the immediate interruption of 
cetuximab therapy and permanent discontinuation from further 
treatment. 
Appropriate 
medical 
therapy 
including 
epinephrine, 
corticosteroids, IV antihistamines, bronchodilators, and oxygen should 
be available for use in the treatment of such reactions. Patients should be 
carefully observed until the complete resolution of all signs and 
symptoms. 
 
In clinical trials, mild to moderate infusion reactions were managed by 
slowing the infusion rate of cetuximab and by continued use of 
antihistamine pre-medications (e.g., diphenhydramine) in subsequent 
doses. If the patient experiences a mild or moderate (grade 1 or 2) 
infusion reaction, the infusion rate should be permanently reduced by 
50%. For grade 1 or 2 reactions manifesting only as delayed drug fever, 
see below in section 7.2.4.2. 
 
Cetuximab should be immediately and permanently discontinued in 
patients who experience severe (grade 3 or 4) infusion reactions. 
 
7.2.4.2 Drug Fever 
In the event of isolated drug fever, the investigator must use clinical 
judgment to determine if the fever is related to the study drug or to an 
infectious etiology. If a patient experiences isolated drug fever, for the 
next dose, pre treat with acetaminophen or non-steroidal anti-
inflammatory agent (investigator discretion), repeat antipyretic dose 6 
and 12 hours after cetuximab infusion. The infusion rate will remain 
unchanged for future doses. If a patient experiences recurrent isolated 


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drug fever following premedication and post-dosing with an appropriate 
antipyretic, the infusion rate for subsequent dosing should be 50% of 
previous rate. If fever recurs following infusion rate change, the 
investigator should assess the patient’s level of discomfort with the 
event and use clinical judgment to determine if the patient should 
receive further cetuximab. 
 
7.2.4.3 Pulmonary Toxicity 
In the event of acute onset (grade ≥ 2) or worsening pulmonary 
symptoms which are not thought to be related to underlying cancer, 
cetuximab therapy should be interrupted and a prompt investigation of 
these symptoms should occur. Cetuximab retreatment should not occur 
until these symptoms have resolved to grade 1. If interstitial lung disease 
is confirmed, cetuximab should be discontinued and the patient should 
be treated appropriately. 
 
7.2.4.4 Dermatologic Toxicity 
Patients developing dermatologic toxicities while receiving cetuximab 
should be monitored for the development of inflammatory or infectious 
sequelae, and appropriate treatment of these symptoms initiated. Dose 
modifications of any future cetuximab infusions should be instituted in 
case of severe acneform rash. Treatment with topical and/or oral 
tetracyclines should be considered; topical corticosteroids are not 
recommended. 
 
Dry skin will be noted in most patients receiving cetuximab. This should 
be treated with an emollient twice daily. 
 
With prolonged use of cetuximab, some patients may develop 
paronychial inflammation of the fingers and toes or fissuring of the 
fingertips. In general, good hygiene with appropriate local measures 
such as soaks in aluminum acetate (Burow’s) solution BID-QID will 
prevent secondary infection. Symptom relief may be achieved with 
standard bandages or with the application of liquid bandages 
(cyanoacrylate preparations such as Band-Aid Liquid Bandage). 
 
If a patient experiences severe acneform rash, cetuximab treatment 
adjustments should be made according to the following table. In patients 
with mild and moderate skin toxicity, treatment should continue without 
dose modification. 
 


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Cetuximab Dose Modification Guidelines 
Grade 3 Acneiform 
Rash 
Cetuximab 
Outcome 
Cetuximab Dose 
Modification 
1st occurrence 
Delay infusion 1 to 2 weeks 
Improvement 
Continue at 250 mg/m2 
 
 
No Improvement 
Discontinue cetuximab 
2nd occurrence 
Delay infusion 1 to 2 weeks  
Improvement 
Reduce dose to 200 mg/m2 
 
 
No Improvement 
Discontinue cetuximab 
3rd occurrence 
Delay infusion 1 to 2 weeks 
Improvement 
Reduce dose to 150 mg/m2 
 
 
No Improvement 
Discontinue cetuximab 
4th occurrence 
Discontinue cetuximab 
 
 
 
Dose levels for cetuximab are as follows: 
Cetuximab Dose Levels 
 
Weekly Cetuximab 
Dose 
Starting dose 
250 mg/m2 
Dose Level –1 
200 mg/m2 
Dose Level –2 
150 mg/m2 
 
7.2.4.5 Cardiac Toxicity 
Cardiac ischemia/infarction and acute cardiomyopathy are known side 
effects of infusional 5-FU based chemotherapy. There have been several 
reports of such events in patients receiving cetuximab with infusional 5-
FU regimens. The following guidelines apply for patients who develop 
cardiac toxicity: 
• 
Grade 4 cardiac event: Discontinue cetuximab permanently. The 
decision to resume chemotherapy should be carefully made based on 
the physician’s discretion and discussion with the patient. If 
retreatment with chemotherapy is considered, it should be delayed 
for a minimum of 2-3 weeks from the last dose of cetuximab AND 
after full recovery from the cardiac event. In addition, the dose of 
chemotherapy should be reduced by one dose level. Patients should 
be monitored carefully, as cardiac events may recur upon 
rechallenge.  
• 
Grade 3 cardiac event: The treating physician may discontinue 
cetuximab, or contact the study chair to discuss the event and 
determine if rechallenge with cetuximab is appropriate.  
 
7.2.4.6 Management of Hypomagnesemia 
Hypomagnesemia has been reported with cetuximab when administered 
as a single agent and in combination with multiple different 


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chemotherapeutic regimens. The incidence of hypomagnesemia (both 
overall and severe [NCI TC grades 3 and 4]) is increased in patients 
receiving chemotherapy and cetuximab as compared with those 
receiving chemotherapy alone based on controlled clinical trials. Patients 
receiving cetuximab therapy should be monitored for hypomagnesemia. 
Magnesium repletion may be necessary based on clinical judgment. 


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8.0 
ADVERSE EVENTS 
This study will utilize the NCI’s Common Terminology Criteria for Adverse Events and 
the RTOG/EORTC Late Morbidity Scoring Scheme (Appendix IV). CTCAE version 3.0 
will be utilized for AE reporting until June 30, 2011. CTCAE version 4.0 will be utilized 
beginning July 1, 2011. All appropriate treatment areas should have access to a copy of 
the CTCAE version 3.0 and 4.0. A copy of the CTCAE version 3.0 and 4.0 can be 
downloaded from the CTEP home page (http://ctep.cancer.gov/reporting/ctc.html). 
The document “CTEP, NCI Guidelines: Adverse Event Reporting Requirements for NCI 
Investigational Agents” (sections 2 and 3) clearly outlines reporting criteria. 
 
8.1 
Classification of Adverse Events by Severity and Relationship to Study Drug 
• 
Adverse Event: Any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a 
medical treatment of procedure regardless of whether it is considered related to the 
medical treatment or procedure (attribution of unrelated, unlikely, possible, probable, 
or definite). 
• 
Life-threatening Adverse Event: Any adverse drug experience that places the patient 
or subject, in the view of the investigator, at immediate risk of death from the reaction 
as it occurred, i.e., it does not include a reaction that, had it occurred in a more severe 
form, might have caused death. 
• 
Serious Adverse Event (SAE): Any adverse drug experience occurring at any dose 
that results in any of the following outcomes: death, a life-threatening adverse drug 
experience, inpatient hospitalization, or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
• 
Please note for hospitalization: All hospitalizations (or prolongation of existing 
hospitalization) for medical events equivalent to CTCAE grade 3, 4, 5 must be 
reported regardless of the requirements for Phase of study, expected or unexpected, 
and attribution. For example, do not report an admission for pharmacokinetic 
sampling, but do report an admission for a myocardial infarction. For this study, 
hospitalization for expedited AE reporting purposes is defined as an inpatient hospital 
stay equal to or greater than 24 hours. A hospital visit where a patient is admitted for 
observation or minor treatment (e.g., hydration) and released in less than 24 hours 
would not meet the requirements for hospitalization. 
• 
Toxicity: Toxicity is a term NOT clearly defined by regulatory organizations. 
Toxicity has been described as an AE that has an attribution of possibly, probably or 
definitely related to investigational treatment.  To minimize confusion the NCI would 
recommend that the term toxicity NOT be utilized for AE reporting purposes. 


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• 
Unexpected Adverse Event: Any AE that is not listed in the NCI Agent Specific 
Expected Adverse Event List. This list is updated electronically in real time. 
• 
Attribution: The determination of whether an AE is related to a medical treatment or 
procedure. Attribution categories: 
o Definite – The AE is clearly related to the investigational agent(s). 
o Probable – The AE is likely related to the investigational agent(s). 
o Possible – The AE may be related to the investigational agent(s). 
o Unlikely – The AE is doubtfully related to the investigational agent(s). 
o Unrelated – The AE is clearly NOT related to the investigational agent(s). 
 
8.2 
Reporting of AEs  
Commercial agents (Cisplatin, 5-FU) are those agents not provided under an IND but 
obtained instead from a commercial source. In some cases an agent obtained 
commercially may be used for indications not included in the package label. The NCI 
may on some occasions distribute commercial supplies for a trial. Even in these cases, the 
agent is still considered to be a commercial agent and, unless specified otherwise in the 
protocol, the following procedures should be followed. 
 
Refer to the pharmaceutical section of the protocol document to determine if an agent is 
investigational or commercial. Also see sections 2.10 and 2.11 of the “NCI Guidelines: 
Expedited Adverse Event Reporting Requirements” for definitions. 
 
All AEs, regardless of severity, and whether or not ascribed to the study drug 
administration, will be recorded in the appropriate section of the CRF. Patients 
withdrawn from the study due to AEs will be followed by the Investigator until the 
outcome is determined and, when appropriate, additional written reports and 
documentation will be provided. 
 
8.3 
Expedited AE Reporting 
Expedited AE reporting for this study will occur via the CTEP Adverse Event Reporting 
System (CTEP-AERS) accessed via the CTEP home page. (http://ctep.cancer.gov). 
Expedited reporting requirements are outlined in the table in section 8.3.1. CTEP-AERS 
is programmed for automatic electronic distribution of reports to the following 
individuals: Protocol Study Chair, Principal Investigator at the local AMC treating 
institution, and AMC Operations Center. CTEP-AERS provides a copy feature for other 
e-mail recipients. All reported SAEs will be reviewed by the Protocol Study Chair to 
determine if further action is necessary. 
 
A 24-hour notification is to be made to the AMC ODMC by telephone at 301-251-1161, 
only when Internet connectivity is disrupted. Once Internet connectivity is restored, a 24-
hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 


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8.3.1 Expedited Reporting Requirements for AEs that occur within 30 Days of Last 
Protocol Treatment  
 
1 
2 
2 
3 
3 
4 & 5 
4 & 52 
Unexpected 
and  
Expected 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
Expected 
With  
Hospitalization 
Without 
Hospitalization 
With 
Hospitalization 
Without 
Hospitalization 
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 
1Adverse events with attribution of possible, probable, or definite that occur greater
• 
24-hour notification followed by complete report within 5 calendar days for: 
 than 30 days after the last dose of treatment  require reporting as 
follows: 
─ Grade 4 and Grade 5 unexpected events 
• 
Complete SAE report within 10 calendar days: 
─ Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
─ Grade 5 expected events 
2Although 24-hour notification is not required for death clearly related to progressive disease, a full report is required as outlined in the table.  
Cardiac: Any grade 3-5 cardiac event must be reported via CTEP-AERS regardless of the attribution and designation as expected or unexpected.   
Note: If the event is a grade 4-5 unexpected event with an attribution of possible, probable, or definite, the investigator must initially report the AE via CTEP-
AERS within 24 hours of learning of the event followed by a complete CTEP-AERS report within 5 calendar days of the initial 24-hour report.  Otherwise, the 
investigator must report the AE via CTEP-AERS within 10 calendar days. 
 
December 15, 2004 
 
• Expedited AE reporting timelines defined: 
o “24 hours; 5 calendar days” – The investigator must initially report the AE 
via CTEP-AERS according to the procedures outlined in section 8.3.1 
within 24 hours of learning of the event followed by a complete AE report 
submitted via CTEP-AERS within 5 calendar days
o “10 calendar days” – A complete CTEP-AERS report on the AE must be 
submitted within 
 of the initial 24-hour 
report. 
10 calendar days
• 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 AE reporting 
exclusions. 
 of the investigator learning of the event. 
• Any event that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS 
according to the guidelines as described above.  
• All type III AEs as defined in section 8.4 must be reported within 5 calendar 
days via the “Type III Adverse Event Reporting Form”. All Type I and II AEs 
meet the criteria for CTEP-AERS reporting.  
 


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8.4 
Safety and Treatment Monitoring 
The following AEs will be classified as type I, II, or III for the purposes of safety 
analysis: (a) Type I AEs -- any grade 5 event possibly, probably, or definitely attributed 
to treatment, or grade 4 cardiac toxicity, (b) Type II AE - grade 4 radiation associated 
skin or diarrhea, (c) Type III AE - (1) any interruption in radiation therapy lasting more 
that 7 days, (2) failure to complete at least 6 courses of cetuximab and 2 cycles of 
cisplatin and 5-FU due to toxicity, and (3) failure to complete the prescribed course of 
irradiation due to toxicity. Patients who develop type I, II, and III events concurrently 
should be reported at the same time. Patients who develop type I, II, and III events at 
different times should have each episode reported separately. Type I and II AEs are 
captured by the AMC AE Form and must also be reported via CTEP-AERS. Type III 
AEs will be captured by the “Type III Adverse Event Reporting Form” developed for this 
protocol. 
 
8.5 
Reporting Secondary Malignancies 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to 
describe the event: 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML]) 
• Myelodysplastic syndrome (MDS) 
• Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol. 
 
8.6 
Adverse Event Reporting for ECOG Investigators 
All ECOG Investigators are responsible for reporting adverse events according to the 
NCI guidelines. ECOG investigators should assess adverse events according to the 
instructions and tables in Section 8.0 of the protocol. All reporting should be conducted 
within the time frames specified in Section 8.0 of the protocol.  Both 24 hour and 
written/electronic adverse event reports should be made directly to the AMC and other 
appropriate regulatory agencies according to the instructions in that section. 
 
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. 
 
All cases of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and 
acute lymphocytic leukemia (ALL) that occur in patients on NCI-sponsored trials 


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following their chemotherapy for cancer must be reported to the AMC and ECOG in 
accordance with Section 8.5. 
 


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9.0 
END POINT DEFINITIONS AND RESPONSE CRITERIA 
9.1 
Toxicity Criteria and Definitions 
All eligible patients receiving at least one dose (i.e., 1 day) of therapy will be evaluable 
for toxicity and efficacy. All toxicity will be graded and summarized by severity grade. 
All toxicity will be monitored, categorized and graded by severity using the NCI’s 
Common Terminology Criteria for Adverse Events. A copy of the CTCAE can be 
downloaded from the CTEP home page (http://ctep.info.nih.gov). The RTOG late 
Toxicity Criteria are included in Appendix IV. 
 
If a colostomy is required, a designation of the reason (i.e., for control of disease, 
management of toxicity or both) will be obtained. 
 
Toxicity will be categorized as acute or late. Acute toxicity is defined as that seen during 
CMT and during the 90 days following the last dose of therapy. Late complications are 
classified according to the RTOG grading system (Appendix IV). 
 
Toxicity will be categorized as local or systemic. Local toxicity will likely be limited to 
radiation induced skin and mucosal injury in the radiation field and can be acute or 
chronic.  
 
The requirement for, duration of, and reason for hospitalization and or treatment breaks 
will also be recorded. 
 
The median and range of baseline CD4 count and HIV viral load will be reported. These 
values will be compared to similar values at week 12, month 6 and month 12.  
 
The proportion of patients progressing to AIDS will be reported.  
 
9.2 
Response Criteria 
Responses will be determined by use of the new NIH guidelines for tumor response: 
Response Evaluation Criteria in Solid Tumors (RECIST Criteria). 
 
All patients will be evaluated for clinical response or progression by physical 
examinations, by imaging studies at baseline and at the conclusion of therapy following 
resolution of serious toxicity, and when appropriate, histology.  
 
9.2.1 Measurability of Tumor Lesions at Baseline 
At baseline, tumor lesions will be categorized as follows: measurable or non-
measurable. The term "evaluable" is not recommended. All baseline evaluations 
should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of treatment.  
 
At baseline, tumor lesions will be categorized as follows:  


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• 
Measurable: Lesions that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as 20 mm with conventional 
techniques or as 10 mm with spiral CT scan or MRI. Clinically detected 
lesions will be considered measurable when they are superficial (e.g., skin or 
mucosal nodules and palpable lymph nodes). Documentation by a ruler or 
calipers to estimate the size of the lesion is recommended. 
• 
Nonmeasurable: All other lesions, including small lesions (longest diameter 
<20 mm with conventional techniques or <10 mm with spiral CT scan or 
MRI) and truly nonmeasurable lesions.  
 
Patients that have had an excisional biopsy of their anal cancer at the time of 
diagnosis may have no measurable disease. Because response rate is a secondary 
endpoint, patients with no measurable disease are eligible for study entry if they 
met the other eligibility criteria. 
• 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung. However, CT 
is preferable and will be required when the chest x-ray is abnormal at baseline. 
• 
CT and MRI: Conventional CT and MRI should be performed with 
contiguous cuts of 10 mm or less in slice thickness. Spiral CT should be 
performed by use of a 5-mm contiguous reconstruction algorithm. 
• 
Ultrasound: Endoscopic ultrasound, supplemented by clinical examination 
may be useful in selected cases for assessment of tumor in the anal canal 
either at baseline or to confirm the complete disappearance of these lesions. 
This is not required but it is suggested. 
• 
Cytology and histology: Histologic confirmation of disease is required prior to 
enrollment is required. 
 
9.2.2 Response Evaluation Criteria in Solid Tumors (RECIST Criteria) 
 Baseline Evaluation: Assessment of Overall Tumor Burden and Measurable 
Disease 
To assess objective response, it is necessary to estimate the overall tumor 
burden at baseline. A sum of the longest diameter for all target lesions 
(primary tumor, abnormal and measurable lymph nodes) will be calculated 
and reported as the baseline sum longest diameter. This measurement will be 
used as the reference by which subsequent measurements will be compared to 
characterize the objective tumor response. 
 
 Response Criteria: Subsequent Evaluation of Target Lesions 
Response criteria take into account the measurement of the longest diameter 
only for all target lesions. Complete response: the disappearance of all target 
lesions. Partial response: at least a 30% decrease in the sum of the longest 
diameter of target lesions, taking as reference the baseline sum longest 
diameter. Progressive disease: at least a 20% increase in the sum of the 
longest diameter of target lesions, taking as reference the smallest sum longest 


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diameter recorded since the treatment started, or the appearance of one or 
more new lesions. Stable disease: neither sufficient shrinkage to qualify for 
partial response nor sufficient increase to qualify for progressive disease, 
taking as reference the smallest sum longest diameter since the treatment 
started. 
 
 Evaluation of Best Overall Response 
Those who have non-measurable disease will not be evaluable for response. 
This includes patients who have had a full resection of their primary tumor via 
an excisional biopsy. Patients who never began study treatment will also not 
be included in the assessment of response. Those who receive a minimum of 
one week of the planned treatment will be included in the analysis of 
response. Every effort should be made to document disease progression, even 
after early discontinuation of treatment. Because of issues such as non-
measurable disease at baseline or lack of histologically confirmed complete 
responses, progression free survival is an additional study endpoint for all 
patients. 
 
The best overall response is the best response recorded from the start of 
treatment until disease progression or recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started). Because response rate is a secondary endpoint, and because the 
clinical examination is often more revealing than scans, confirmation of 
objective response by a repeat scan in a short interval following the 
documentation of an objective response will not be required. 
 
In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue. Because of a concern regarding the potential for poor wound 
healing in the radiated field, a biopsy will only be done if clinically warranted. 
The need to determine the difference between a partial and complete response, 
purely for study documentation, will not be adequate justification for a biopsy. 
If a biopsy result would alter a clinical decision, it should be considered. 
 
9.3 
Quality Of Life Assessments 
The EORTC QLQ-C30 and QLQ-CR38 will be used (Appendix V). Data will be entered 
into the QLQ form in AdvantageEDC. Permission has been granted by the EORTC for 
use of these instruments for the purpose described in this study.  
 
In addition, anal sphincter function will be evaluated according to the Memorial Sloan-
Kettering Cancer Center anal function criteria (MSK-AF) (Appendix V). Data will be 
entered into the QLQ form in AdvantageEDC. The score Excellent (or 1) corresponds to 
1-2 bowel movements per day and no soilage. Good (or 2) corresponds to 3-4 bowel 
movements per day and/or soilage. Fair (or 3) corresponds to episodic > 4 bowel 
movements per day and or moderate soilage. Poor (or 4) corresponds to incontinence. 
 


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9.4 
HPV and Anal Cytology 
Polymerase chain reaction (PCR) will be used to detect type specific HPV from anal 
swab specimens. Type specific PCR will be used to detect HPV in biopsy specimens. The 
Bethesda criteria will be utilized to classify anal cytology (anal Pap results) as normal, 
atypical, low or high grade dysplasia or cancer. 


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10.0 
STATISTICAL CONSIDERATIONS 
10.1 
Rate of Accrual 
It is estimated that accrual to this study will proceed at the rate of 2 eligible and evaluable 
patients enrolled per month. The study should require approximately 24 months to 
complete accrual of the 45 eligible and evaluable patients. 
 
10.2 
Patient Characteristics  
Summary statistics will be used to describe the demographic and baseline characteristics 
of the study population. 
 
10.3 
Sample Size Estimation 
The primary clinical endpoint is local failure rate at 3 years. This trial is designed to 
detect whether the addition of cetuximab to standard chemoradiation reduces the local 
failure rate by at least 50%. It is assumed that the local failure rate is approximately 35% 
at 3 years. To detect a 50% reduction in the local failure rate with a one-sided 0.10 
significance level and power of 0.90, 45 eligible patients will be required. Assuming a 
10% ineligibility rate, 50 patients will be enrolled. Local failure is defined as persistence 
or recurrence of disease in the anal canal and/or regional organs and/or regional lymph 
nodes after completion of protocol therapy (or progression during therapy). 
 
10.4 
Safety and Additional Toxicity Analysis 
Safety Analysis and Early Stopping Rule: Type I, II, or III AEs will be reported in an 
expedited manner (as defined and described in section 8.4).  The study will be interrupted 
if the incidence of type I events exceed 5%, the incidence of type II events exceeds 20%, 
or the incidence of type III events exceeds 20% (with a type I error of 0.05). In R9811, 
the incidence of grade 4 toxicity in the cisplatin/5-FU arm was as follows (as of June 
2004): (a) worst overall toxicity 22% (b) worst non-hematologic 9%, (c) worst skin 9%, 
gastrointestinal 9%, cardiovascular 1%; there were no treatment related deaths recorded. 
This trial will be stopped if the number of any type of event equals or excels the number 
outlined in the table below, which would be indicative that true risk of a type I event is at 
least 5%, or the true risk of a type II or type III event is at least 20% (with a type I error 
rate of 0.05). The research team will analyze the toxicity data, and the study may reopen 
after an amendment in the trial designed to reduce toxicity is formulated and submitted to 
CTEP for review and approval. Toxicity will be analyzed separately in the standard RT 
group and IMRT group. 
 
No. Patients 
Treated 
No. Patients with 
Type I Events 
No. Patients with 
Type II Events 
No. Patients with Type 
III Events 
1-10 
> 3 
> 5 
> 5 
11-20 
> 4 
> 8 
> 8 
21-30 
> 5 
> 11 
> 11 
 


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Efficacy Analysis and Early Stopping Rule: The objective response rate reported in 
previous phase II trials of cisplatin/5-FU/RT in immunocompetent patients was 95%. In 
this trial, if an objective response rate of 85% or less is seen in the first 22 evaluable 
patients, the study investigators will discuss with CTEP whether to continue the study. 
 
Additional Toxicity Analyses: A descriptive report of toxicity of AEs will be performed. 
Additional analyses of toxicity will be performed looking at the group as a whole in order 
to document the entire scope of toxicity in this patient population. Toxicity will be 
evaluated by use of the following markers: 
• Colostomy rate 
• The duration and frequency of any treatment breaks or hospitalizations 
• The change in HIV viral load and CD4 levels with therapy or progression to AIDS 
• The occurrence of grade 3 or higher late treatment complications 
• The occurrence of grade 3 or higher systemic toxicity 
 
A logistic regression analysis will be done to determine if the rate of grade 3 or higher 
acute toxicity within 90 days of completing protocol therapy is related to baseline CD4 
count (>/< 200), HIV viral load (detectable or not), nadir CD4 level, use of HAART 
while on CMT, or radiation dose. 
 
Analysis of variance for repeated measures will be used to evaluate the group for changes 
from baseline to weeks 12, 26 and 52 with respect to viral load and CD4 as continuous 
variables.  
 
10.5 
Efficacy Analysis 
The primary endpoint of the trial is local failure rate at 3 years. Objective response at the 
completion of treatment is a secondary endpoint. Patients will be classified into two 
groups for purposes of primary endpoint analysis: failure or no failure at 3 years (in the 
primary analysis, patients lost to follow-up prior to 3 years will be considered failures). 
For the secondary endpoint of objective response, patients will be classified as responders 
(complete or partial responders) and non-responders. The binomial proportion and its 
95% confidence interval will be used to estimate the 3-year local failure rate, complete 
response rate, and overall response rate. Logistic regression analysis will be used to 
evaluate the effect of baseline characteristics and other covariates with failure rate and 
response. The efficacy analysis will include patients treated with both conventional RT 
and IMRT. An exploratory analysis of the primary endpoint (local failure) will be 
conducted based on the type of radiation received (RT and IMRT); local failure will be 
monitored continuously for both treatment strata (conventional RT vs. IMRT) throughout 
the course of the study. The trial may be amended to exclude IMRT if it becomes 
apparent that IMRT results in inferior disease control or worse toxicity. 
 
The Kaplan-Meier method will be used to evaluate the distribution of response duration, 
progression-free survival, relapse-free survival, colostomy-free survival, and overall 
survival. The Cox proportional hazards model will be used to evaluate baseline 
characteristics and other covariates with respect to these time to event measures. These 


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analyses will be performed after the study has reached its accrual goal, and the data have 
sufficiently matured to permit a definitive analysis regarding the primary objective. The 
following definitions will be used for these analyses: (1) response duration: date objective 
response first documented until date of progression or relapse [patients who died of 
causes other than anal cancer are censored at the time of death] (2) progression-free 
survival: date of registration until date of progression, relapse, or death from any cause, 
(3) relapse-free survival: date objective response first documented until date of 
progression, relapse, or death from any cause, (4) colostomy free survival: date of 
registration (for those without colostomy at registration) until date that colostomy is 
required, (5) overall survival: date of registration until date of death from any cause. 
 
If there is more than one HIV viral load measurement taken between the time the cancer 
was detected and treatment was initiated, the first viral load measurement will be used for 
the purposes of correlating presenting or baseline factors with efficacy outcomes. The 
final viral load obtained just prior to the initiation of therapy will be used for the purposes 
of correlating treatment tolerance relative to viral load. This distinction is made as some 
patients may have a change in antiviral therapy made before CMT for anal cancer is 
begun. The Wilcoxon signed rank test will be used to evaluate changes from baseline in 
HIV viral load and CD4 counts. The incidence of opportunistic infections will be 
estimated using the binomial proportion and its 95% confidence interval. The 
multivariate analysis will be done to determine if lack of tumor control is related to 
baseline CD4 count, HIV viral load, tumor stage, use of HAART, or other factors. 
 
10.6 
HPV Response and Anal Cytology 
Descriptive statistics will be used to describe the types of HPV found in baseline anal 
swabs and tissue biopsies, the proportion of cases with each type, and the proportion that 
remain positive for the same type(s) at week 26 (month 6). See Appendix VI for details 
of the HPV detection methods. Similarly, descriptive statistics will be used to describe 
the proportion of patients with HSIL, LSIL, and normal anal cytology. 
 
10.7 
Quality of Life Analysis 
The EORTC QLQ-C30 and QLQ-CR38 are validated instruments. The scoring of the 
instruments is described in Appendix V. All scores obtained are linearly transformed 
such that all scales range from 0 to 100. Missing values will be calculated such that if at 
least half the items from the scale are completed, it will be assumed that the missing 
items would have been equal to the average of the completed items. Analysis of variance 
(ANOVA) methods will be used to evaluate changes in quality of life measures with 
time. Multivariate analysis of variance (MANOVA) will be used to evaluate changes 
across quality of life measures for the entire group and for each arm. General linear 
models will be used to evaluate the associations between quality of life measures and the 
following factors: baseline CD4 (< 200 or > 200), viral load (detectable or not), prior 
AIDS diagnosis (yes, no), baseline performance status (> 80, < 80), nadir CD4 (< 200 or 
> 200), or radiation dose (> 55 Gy). A difference with a P-value of < 0.05 will be 
considered as significant.  
 


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10.8 
AMC Policy for Monitoring of Phase II Trials 
This protocol will follow the AMC’s policy for data monitoring (see Appendix X). 


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11.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
11.1 
Publication of Research Findings 
Publication of the results of this trial will be governed by AMC policies. 
 
11.2 
Discipline Review 
All pathology and cytology will be evaluated by a single pathologist at a central location 
(Appendix VI). This will not be done in real time. This will include a review of the pre-
treatment biopsy and anal Pap tests. Radiation therapy quality control will be performed 
by QARC (as outlined in section 5.5): 
Quality Assurance Review Center 
272 West Exchange Street, Suite 101 
Providence, RI  02903-1025 
Phone: (401) 454-4301/Fax: (401) 454-4683  
URL: www.qarc.org 
 
11.3 
Institutional Review Board (IRB) Review and Informed Consent 
This protocol and the informed consent document (Appendix VII) and any subsequent 
modifications will be reviewed and approved by the IRB or Ethics Committee 
responsible for oversight of the study. Written informed consent will be obtained from 
the subject. The subject must be able to understand the nature, significance and risks 
associated with the study. The informed consent will describe the purpose of the study, 
the procedures to be followed and the risks and benefits of participation.  A copy of the 
consent form will be given to the subject. 
 
11.4 
Subject Confidentiality 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number only. Clinical information will not be 
released without written permission of the subject, except as necessary for monitoring by 
the FDA, the AMC or the NCI. 
 
11.5 
Study Discontinuation 
This study may be discontinued at any time by the NCI or the AMC. 
 
11.6 
Biohazard Containment 
The transmission of HIV and other blood borne pathogens can occur through contact with 
contaminated needles, blood and blood products. Appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study as currently recommended by the Centers for 
Disease Control. 


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All infectious specimens will be sent using the II-1 SAF-T-PAK mandated by the 
International Air Transport Association Dangerous Goods Regulations - Packing 
Instruction 602. Please refer to individual carrier guidelines (e.g., FedEx, Airborne) for 
specific instructions. 
 
11.7 
Women and Minorities 
This is a study being conducted by the NCI sponsored AIDS Malignancy Consortium 
(AMC). As part of their contractual obligations, each participating site within the AMC 
and the AMC as a whole are required to assure that the participation of women and 
minority patients reflects the percentage representation of these populations in their 
geographic region and, for the AMC, the United States as a whole. As such, it is expected 
that the representation of patients on this trial will reflect the constitution of the 
respective populations. 


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12.0 
COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) 
Not applicable.  


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13.0 
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21. Chadha, M., et al., Squamous-cell carcinoma of the anus in HIV-positive patients. Dis Colon 
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22. Peddada, A.V., et al., Chemotherapy and low-dose radiotherapy in the treatment of HIV-
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23. Hocht, S., et al., Low acute toxicity of radiotherapy and radiochemotherapy in patients with 
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24. Place, R.J., et al., Outcome analysis of HIV-positive patients with anal squamous cell 
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26. Cleator, S., et al., Treatment of HIV-associated invasive anal cancer with combined 
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27. Cunningham, D., et al., Cetuximab monotherapy and cetuximab plus irinotecan in 
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31. Forastiere, A.A., Is there a new role for induction chemotherapy in the treatment of head and 
neck cancer? J Natl Cancer Inst, 2004. 96(22): p. 1647-9. 
32. Bonin, S.R., et al., Overexpression of p53 protein and outcome of patients treated with 
chemoradiation for carcinoma of the anal canal: a report of randomized trial RTOG 87-
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33. Palefsky, J.M., et al., Detection of human papillomavirus DNA in anal intraepithelial 
neoplasia and anal cancer. Cancer Res, 1991. 51(3): p. 1014-9. 
34. Cerovac, Z., et al., Detection of human papillomavirus (HPV) type 6, 16 and 18 in head and 
neck squamous cell carcinomas by in situ hybridization. Neoplasma, 1996. 43(3): p. 185-
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35. Badaracco, G., et al., Overexpression of p53 and bcl-2 proteins and the presence of HPV 
infection are independent events in head and neck cancer. J Oral Pathol Med, 2000. 
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36. Gupta, A.K., et al., Local recurrence in head and neck cancer: relationship to radiation 
resistance and signal transduction. Clin Cancer Res, 2002. 8(3): p. 885-92. 
37. Palefsky, J.M., et al., Prevalence and risk factors for human papillomavirus infection of the 
anal canal in human immunodeficiency virus (HIV)-positive and HIV-negative 
homosexual men. J Infect Dis, 1998. 177(2): p. 361-7. 
38. Gagne SE, J.R., Polvi A Da Costa M, Ginzinger D, Efird JT Holly EA, Darragh T, Palefsky 
JM., High-resolution analysis of genomic alterations and human papillomavirus 
integration in anal intraepithelial neoplasia. J Acq Immun Defic Syndr, 2005, in press. 
39. Bibikova, M., et al., Quantitative gene expression profiling in formalin-fixed, paraffin-
embedded tissues using universal bead arrays. Am J Pathol, 2004. 165(5): p. 1799-807. 
40. Nutting C, Dearnaley DP, Webb S. Intensity modulated radiation therapy; a clinical review. 
Br J Radiol 2000; 73:459– 469. 
41. Butler EB, The BS, Grant WH, et al. Smart (simultaneous modulated accelerated radiation 
therapy) boost: a new accelerated fractionation schedule for the treatment of head-and 
neck cancer with intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 1999; 
45:21–32. 
42. Eisbruch A, Ship JA, Martel MK, et al. Parotid gland sparing in patients undergoing bilateral 
head-and-neck irradiation: techniques and early results. Int J Radiat Oncol Biol Phys 
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43. Eisbruch A, Ten Haken RK, Kim HM, et al. Dose, volume, and function relationships in 
parotid salivary glands following conformal and intensity-modulated irradiation of head-
and neck cancer. Int J Radiat Oncol Biol Phys 1999; 45:577–587. 
44.  Zelefsky MJ, Fuks Z, Leibel SA. Intensity-modulated radiation therapy for prostate cancer. 
Semin Radiat Oncol 2002; 12: 229–237. 
 45.  
Milano MT, Jani AB, Farrey KJ et al. Intensity-Modulated Radiation Therapy (IMRT) In 
The Treatment Of Anal Cancer: Toxicity And Clinical Outcome. J Radiat Oncol Biol 
Phys2005; 63: 354-361 


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46. Chen YJ, Liu A, Tsai PT etal. Organ Sparing By Conformal Avoidance Intensity-Modulated 
Radiation Therapy For Anal Cancer: Dosimetric Evaluation 
47. Tsai HK, Hong TS, Willins J, Kung JH, Feng JK, Shih HA and Kachnic LA:  Dosimetric 
Comparison of Dose-painted Intensity Modulated Radiation Therapy vs. Conventional 
Radiation Therapy for Anal Cancer.  Poster Presentation
 
 at the American Society of 
Clinical Oncology Gastrointestinal Cancer Symposium, San Francisco, CA, January 26-
28, 2006. 
 


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APPENDIX I: SCHEDULE OF EVALUATIONS 
 
Test/Evaluation 
Within 
6 weeks 
Within  
4 weeks 
Within 
2 weeks 
W 
1 
W 
2 
W 
3 
W 
4 
W 
5 
W 
6 
W 
7 
W 
8 
W 
9 
W 
12 
W 
18 
W 
26 
M 
9 
M 
12 
M 
18, 
24, 
30 
M 
36 
M 
48 
M 
60 
Clinical 
Medical History 
 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication Review 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Measurement/Assessment (8) 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cervical PAP smear (9) 
X  
(6 mo.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Studies 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential, platelets (11) 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
PT and PTT 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry Panel (2) and Mg++ 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
CD4/CD8 Lymphocyte Count 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
HIV-1 Plasma RNA 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Anal swab for HPV, cytology (3) 
 
 
X (3) 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Optional frozen tumor specimen (12) 
X (12) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor specimen submission (4) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (5) 
 
 
X  
PR
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Staging 
Chest x-ray (or chest CT if indicated) 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Abdominal/Pelvic CT (or MRI) 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Endorectal ultrasound (10) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QOL Survey (3,6) 
 
 
X (3) 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
(24 
mo.) 
X 
 
 
ACSR Donation (3, 7) 
 
 
X (3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Abbreviations: Within 6, 4, 2 weeks (of registration); W – week; M – months;; mo. - months 
See section 6.4 for off-study testing for patients who withdraw from treatment or from study prior to completion (if they are agreeable to testing). 
1. HIV seropositivity may have been documented at any time prior to registration. 
2. Chemistry panel includes: BUN, creatinine, total and direct bilirubin, AST(SGOT), ALT(SGPT), alkaline phosphatase,  albumin, electrolytes (sodium, potassium, chloride, 
bicarbonate) and serum magnesium.  
3. These tests should be performed after consent is obtained because they would not otherwise be performed as part of routine clinical care. 
4. See Appendix VI for submission of baseline diagnostic biopsy specimen confirming diagnosis of anal carcinoma (preferably obtained within 6 weeks of registration).  The specimen 
should be submitted within 4 weeks of registration. 
5. A negative serum or urine pregnancy test is required within 14 days prior to registration, and may be repeated PRN by the treating physician if clinically indicated after this time.  
6. The EORTC quality of life instruments.  (See Appendix V). 
7. After patient has provided a separate consent for ACSR donation. 
8. Tumor measurement/assessment by physical examination should be performed within two weeks of registration and at the indicated times in order to monitor response to therapy; 
biopsy may be indicated after completion of treatment or at a future date if persistent disease or relapse is suspected. 
9. A cervical PAP smear should be performed within 6 months of registration for women with a cervix.  
10. Suggested but not required to assess disease if available at local institution. 
11. If radiation is held due to cytopenia, laboratory monitoring should increase to include twice per week CBC, differential, and platelet count until recovery to an ANC. 
12. For patients who consent to optional tumor biopsy for submission of fresh frozen tumor tissue to ACSR (see Appendix IX). 
 
 


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APPENDIX II: ANAL CANCER STAGING CRITERIA 
 
From the AJCC Cancer Staging Manual Fifth Edition 
 
Primary Tumor (T) 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ 
T1 
Tumor 2 cm or less in greatest dimension. This includes microscopically invasive 
tumor confirmed histologically but not apparent clinically 
T2 
Tumor more than 2 cm but not more than 5 cm in greatest dimension 
T3 
Tumor more than 5 cm in greatest dimension 
T4 
Tumor of any size invades adjacent organ(s), e.g., vagina, urethra, bladder. 
Involvement of the sphincter muscle(s) alone is not classified as T4.  
 
 
Regional Lymph Nodes (N) 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Metastasis in perirectal lymph nodes(s) 
N2 
Metastasis in unilateral internal iliac and/or inguinal lymph node(s) 
N3 
Metastasis in perirectal and inguinal lymph nodes and/or bilateral internal iliac 
and/or inguinal lymph nodes 
 
 
Distant Metastasis (M) 
MX 
Distant metastasis cannot be assessed 
M0 
No distant metastasis 
M1 
Distant metastasis 
 
 
Stage Grouping 
Stage 0 
 
Tis 
 
N0 
 
M0 
Stage 1 
 
T1 
 
N0 
 
M0 
Stage II 
 
T2 
 
N0 
M0 
 
 
 
T3 
 
N0 
 
M0 
Stage IIIA 
 
T1 
 
N1 
 
M0 
 
 
 
T2 
 
N1 
 
M0 
T3 
 
N1 
 
M0 
T4 
 
N0 
 
M0 
Stage IIIB 
 
T4 
 
N1 
 
M0 
 
 
 
Any T  
N2 
 
M0 
 
 
 
Any T  
N3 
 
M0 
Stage IV 
 
Any T  
Any N  
M1 


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APPENDIX III: KARNOFSKY PERFORMANCE SCALE 
 
Able to carry on normal activity; no 
special care is needed 
100 
Normal; no complaints; no evidence of 
disease 
 
 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease 
 
 
80 
Normal activity with effort; some signs 
of symptoms of disease 
 
Unable to work, able to live at home and 
care for most personal needs; a varying 
amount of assistance is needed 
 
70 
Cares for self; unable to carry on normal 
activity or to do active work 
 
60 
Requires occasional assistance but is able 
to care for most of his needs 
 
 
50 
Requires considerable assistance and 
frequent medical care 
 
Unable 
to 
care 
for 
self; 
requires 
equivalent of institutional or hospital 
care; disease may be progressing rapidly 
 
40 
Disabled; requires special care and 
assistance 
 
30 
Severely disabled; hospitalization is 
indicated although death is not imminent 
 
 
20 
Very sick; hospitalization necessary; 
active supportive treatment is necessary 
 
 
10 
Moribund; fatal processes progressing 
rapidly 
 
 
0 
Dead 
 
 


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APPENDIX IV:  RTOG/EORTC LATE RADIATION MORBIDITY SCORING SCHEME 
 
Use for Adverse Event Occurring Greater Than 90 Days After Radiation Therapy 
 
Grade 
Adverse Event 
0 
1 
2 
3 
4 
Bladder-  
Late RT Morbidity 
Scoring 
No change from 
baseline 
Slight epithelial 
atrophy/minor 
telangiectasia 
(microscopic 
hematuria) 
Moderate 
frequency/ 
generalized 
telangiectasia/ 
intermittent 
macroscopic 
hematuria 
Severe frequency 
and dysuria/severe 
generalized 
telangiectasia 
(often with 
petechiae); 
frequent 
hematuria; 
reduction in 
bladder capacity 
(<150 mL) 
Necrosis/ 
contracted bladder 
(capacity <100 
mL)/severe 
hemorrhagic 
cystitis 
Bone- 
Late RT Morbidity 
Scoring 
No change from 
baseline 
Asymptomatic; no 
growth retardation; 
reduced bone 
density 
Moderate pain 
or tenderness; 
growth 
retardation; 
irregular bone 
sclerosis 
Severe pain or 
tenderness; 
complete arrest of 
bone growth; 
dense bone 
sclerosis 
Necrosis/ 
spontaneous 
fracture 
Brain- 
Late RT Morbidity 
Scoring 
No change from 
baseline 
Mild headache; 
slight lethargy 
Moderate 
headache; great 
lethargy 
Severe headaches; 
severe CNS 
dysfunction 
(partial loss of 
power or 
dyskinesia) 
Seizures or 
paralysis; coma 
Esophagus- 
Late RT Morbidity 
Scoring 
No change from 
baseline 
Mild fibrosis; slight 
difficulty in 
swallowing solids; 
no pain on 
swallowing 
Unable to take 
solid food 
normally; 
swallowing 
semi-solid food; 
dilation may be 
indicated 
Severe fibrosis; 
able to swallow 
only liquids; may 
have pain on 
swallowing; 
dilation required 
Necrosis/ 
perforation; fistula 
Eye- 
Late RT Morbidity 
Scoring 
No change from 
baseline 
Asymptomatic 
cataract; minor 
corneal ulceration or 
keratitis 
Symptomatic 
cataract; 
moderate 
corneal 
ulceration; 
minor 
retinopathy or 
glaucoma 
Severe keratitis; 
severe retinopathy 
or detachment; 
severe glaucoma 
Panophthalmitis; 
blindness 


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Grade 
Adverse Event 
0 
1 
2 
3 
4 
Heart- 
Late RT Morbidity 
Scoring 
No change from 
baseline 
Asymptomatic or 
mild symptoms; 
transient T wave 
inversion and ST 
changes; sinus 
tachycardia >110 (at 
rest) 
Moderate 
angina on 
effort; mild 
pericarditis; 
normal heart 
size; persistent 
abnormal T 
wave and ST 
changes; low 
QRS 
Severe angina; 
pericardial 
effusion; 
constrictive 
pericarditis; 
moderate heart 
failure; cardiac 
enlargement; EKG 
abnormalities 
Tamponade/ 
severe heart 
failure/severe 
constrictive 
pericarditis 
Joint- 
Late RT Morbidity 
Scoring 
No change from 
baseline 
Mild joint stiffness; 
slight limitation of 
movement 
Moderate 
stiffness; 
intermittent or 
moderate joint 
pain; moderate 
limitation of 
movement 
Severe joint 
stiffness; pain 
with severe 
limitation of 
movement 
Necrosis/ 
complete fixation 
Kidney- 
Late RT Morbidity 
Scoring 
No change from 
baseline 
Transient 
albuminuria; no 
hypertension; mild 
impairment of renal 
function; urea 25 - 
35 mg%; creatinine 
1.5 - 2.0 mg%; 
creatinine clearance 
>75% 
Persistent 
moderate 
albuminuria 
(2+); mild 
hypertension; 
no related 
anemia; 
moderate 
impairment of 
renal function; 
urea >36 - 60 
mg%; creatinine 
clearance >50 - 
74% 
Severe 
albuminuria; 
severe 
hypertension; 
persistent anemia 
(<10 g%); severe 
renal failure; urea 
>60 mg%; 
creatinine >4 
mg%; creatinine 
clearance  
<50% 
Malignant 
hypertension; 
uremic coma/urea 
>100% 
Larynx- 
Late RT Morbidity 
Scoring 
No change from 
baseline 
Hoarseness; slight 
arytenoid edema 
Moderate 
arytenoid 
edema; 
chondritis 
Severe edema; 
severe chondritis 
Necrosis 
Liver- 
Late RT Morbidity 
Scoring 
No change from 
baseline 
Mild lassitude; 
nausea; dyspepsia; 
slightly abnormal 
liver function 
Moderate 
symptoms; 
some abnormal 
liver function 
tests; serum 
albumin normal 
Disabling hepatic 
insufficiency; 
liver function tests 
grossly abnormal; 
low albumin; 
edema or ascites 
Necrosis/hepatic 
coma or 
encephalopathy 


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Grade 
Adverse Event 
0 
1 
2 
3 
4 
Lung- 
Late RT Morbidity 
Scoring 
No change from 
baseline 
Asymptomatic or 
mild symptoms (dry 
cough); slight 
radiographic 
appearances 
Moderate 
symptomatic 
fibrosis or 
pneumonitis 
(severe cough); 
low grade fever; 
patchy 
radiographic 
appearances 
Severe 
symptomatic 
fibrosis or 
pneumonitis; 
dense 
radiographic 
changes 
Severe respiratory 
insufficiency/ 
continuous 
O2/assisted 
ventilation 
Mucous membrane- 
Late RT Morbidity 
Scoring 
No change from 
baseline 
Slight atrophy and 
dryness 
Moderate 
atrophy and 
telangiectasia; 
little mucus 
Marked atrophy 
with complete 
dryness; severe 
telangiectasia 
Ulceration 
Salivary glands- 
Late RT Morbidity 
Scoring 
No change from 
baseline 
Slight dryness of 
mouth; good 
response on 
stimulation 
Moderate 
dryness of 
mouth; poor 
response on 
stimulation 
Complete dryness 
of mouth; no 
response on 
stimulation 
Fibrosis 
Skin- 
Late RT Morbidity 
Scoring 
No change from 
baseline 
Slight atrophy; 
pigmentation 
change; some hair 
loss 
Patchy atrophy; 
moderate 
telangiectasia; 
total hair loss 
Marked atrophy; 
gross 
telangiectasia 
Ulceration 
Small/Large 
intestine- 
Late RT Morbidity 
Scoring 
No change from 
baseline 
Mild diarrhea; mild 
cramping; bowel 
movement 5 x daily; 
slight rectal 
discharge or 
bleeding 
Moderate 
diarrhea and 
colic; bowel 
movement >5 x 
daily; excessive 
rectal mucus or 
intermittent 
bleeding 
Obstruction or 
bleeding, 
requiring surgery 
Necrosis/ 
perforation fistula 
Spinal cord- 
Late RT Morbidity 
Scoring 
No change from 
baseline 
Mild Lhermitte’s 
syndrome 
Severe 
Lhermitte’s 
syndrome 
Objective 
neurological 
findings at or 
below cord level 
treatment 
Mono-, para-, 
quadriplegia 
Subcutaneous tissue- 
Late RT Morbidity 
Scoring 
No change from 
baseline 
Slight induration 
(fibrosis) and loss of 
subcutaneous fat 
Moderate 
fibrosis but 
asymptomatic; 
slight field 
contracture; 
<10% linear 
reduction 
Severe induration 
and loss of 
subcutaneous 
tissue; field 
contracture >10% 
linear 
measurement 
Necrosis 
Radiation - Other 
(Specify, 
__________) 
None 
Mild 
Moderate 
Severe 
Life-threatening 
or disabling 
 
 


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APPENDIX V: QUALITY OF LIFE INSTRUMENTS 
 
The following pages include: 
1) The EORTC Instruments (QLQ-C30 and QLQ-CR38) 
2) Supplemental Quality of Life Questions, including The Memorial Sloan Kettering Anal 
Function Scale (MSK-AF) 
3) Scoring procedures for the EORTC Instruments 
 
 
EORTC QLQ-C30 (version 3)  
 
We are interested in some things about you and your health.  Please answer all of the questions 
yourself by circling the number that best applies to you.  There are no "right" or "wrong" 
answers.  The information that you provide will remain strictly confidential. 
 
Please fill in your initials: 
 
_______________ 
Your birthdate (Month, Day, Year): ____/____/______ 
Today's date (Month, Day, Year):  ____/____/______ 
 
 
NOT AT 
ALL 
A 
LITTLE 
QUITE 
A BIT 
VERY 
MUCH 
1. 
Do you have any trouble doing strenuous activities, like 
carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. 
Do you have any trouble taking a long
1 
 walk? 
2 
3 
4 
3. 
Do you have any trouble taking a short
1 
 walk outside of the 
house? 
2 
3 
4 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. 
Do you need help with eating, dressing, washing yourself 
or using the toilet? 
1 
2 
3 
4 
During the past week: 
 
 
 
 
6. 
Were you limited in doing either your work or other daily 
activities? 
1 
2 
3 
4 
7. 
Were you limited in pursuing your hobbies or other leisure 
time activities? 
1 
2 
3 
4 


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NOT AT 
ALL 
A 
LITTLE 
QUITE 
A BIT 
VERY 
MUCH 
 
8. 
Were you short of breath? 
1 
2 
3 
4 
9. 
Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
During the past week: 
 
 
 
 
14.    Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 
17. Have you had diarrhea? 
1 
2 
3 
4 
18. Were you tired? 
1 
2 
3 
4 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on things, like 
reading a newspaper or watching television? 
1 
2 
3 
4 
21. Did you feel tense? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
24. Did you feel depressed? 
1 
2 
3 
4 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment interfered 
with your family
1 
 life? 
2 
3 
4 


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NOT AT 
ALL 
A 
LITTLE 
QUITE 
A BIT 
VERY 
MUCH 
27. Has your physical condition or medical treatment interfered 
with your social
1 
 activities? 
2 
3 
4 
28. Has your physical condition or medical treatment caused 
you financial difficulties? 
1 
2 
3 
4 
For the following questions please circle the number 
between 1 and 7 that best applies to you 
 
 
 
 
29. How would you rate your overall health
 
 during the past 
week? 
 
 
 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent 
 
30. How would you rate your overall quality of life
 
 during the past 
week? 
 
 
 
 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent 


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EORTC QLQ – CR38  
 
Patients sometimes report that they have the following symptoms or problems.  Please indicate 
the extent to which you have experienced these symptoms or problems during the past week.  
Please answer by circling the number that best applies to you. 
 
 
NOT AT 
ALL 
A 
LITTLE 
QUITE
A BIT 
VERY
MUCH 
During the past week: 
 
 
 
 
31. Did you urinate frequently during the day? 
1 
2 
3 
4 
32. Did you urinate frequently during the night? 
1 
2 
3 
4 
33. Did you have pain when you urinated? 
1 
2 
3 
4 
34. Did you have a bloated feeling in your abdomen? 
1 
2 
3 
4 
35. Did you have abdominal pain? 
1 
2 
3 
4 
36. Did you have pain in your buttocks? 
1 
2 
3 
4 
37. Were you bothered by gas (flatulence)? 
1 
2 
3 
4 
38. Did you belch? 
1 
2 
3 
4 
39. Have you lost weight? 
1 
2 
3 
4 
40. Did you have a dry mouth? 
1 
2 
3 
4 
41. Have you had thin or lifeless hair as a result of your disease 
or treatment? 
1 
2 
3 
4 
42. Did food and drink taste different from usual? 
1 
2 
3 
4 
43. Have you felt physically less attractive as a result of your 
disease or treatment? 
1 
2 
3 
4 
44. Have you been feeling less feminine/masculine as a result 
of your disease or treatment? 
1 
2 
3 
4 
45. Have you been dissatisfied with your body? 
1 
2 
3 
4 


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NOT AT 
ALL 
A 
LITTLE 
QUITE
A BIT 
VERY
MUCH 
46. Were you worried about your health in the future? 
1 
2 
3 
4 
During the past four
 
 weeks: 
 
 
 
47. To what extent were you interested in sex? 
1 
2 
3 
4 
48. To what extent were you sexually active (with or without 
intercourse)? 
1 
2 
3 
4 
49. Answer this question only if you have been sexually active: 
To what extent was sex enjoyable for you? 
1 
2 
3 
4 
During the past week: 
 
 
 
 
For men only: 
 
 
 
 
50. Did you have difficulty getting or maintaining an erection? 
1 
2 
3 
4 
51. Did you have problems with ejaculation? (i. e., a so called 
dry ejaculate?) 
1 
2 
3 
4 
Only for women who have had intercourse: 
 
 
 
 
52. Did you have a dry vagina during intercourse? 
1 
2 
3 
4 
53. Did you have pain during intercourse? 
1 
2 
3 
4 
During the past week: 
 
 
 
 
Only for patients WITHOUT a stoma (colostomy bag): 
 
 
 
 
55. Did you have frequent bowel movements during the day? 
1 
2 
3 
4 
56.  Did you have frequent bowel movements during the night? 
1 
2 
3 
4 
57.  Did you feel the urge to move your bowels without 
actually producing any stools? 
1 
2 
3 
4 
58.  Have you had any unintentional release of stools? 
1 
2 
3 
4 
59.  Have you had blood with your stools? 
1 
2 
3 
4 
60.  Have you had difficulty in moving your bowels? 
1 
2 
3 
4 


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NOT AT 
ALL 
A 
LITTLE 
QUITE
A BIT 
VERY
MUCH 
61.  Have your bowel movements been painful? 
1 
2 
3 
4 
Only for patients WITH a stoma (colostomy bag): 
 
 
 
 
62. Were you afraid that other people would be able to hear 
your stoma? 
1 
2 
3 
4 
63. Were you afraid that other people would be able to smell 
your stools? 
1 
2 
3 
4 
64. Were you worried about possible leakage from the stoma 
bags? 
1 
2 
3 
4 
65. Did you have problems with caring for your stoma? 
1 
2 
3 
4 
66. Was your skin around the stoma irritated? 
1 
2 
3 
4 
67. Did you feel embarrassed because of your stoma? 
1 
2 
3 
4 
68. Did you feel less complete because of your stoma? 
1 
2 
3 
4 
 


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Supplemental Quality of Life Questions 
 
1. How satisfied are you with your current degree of anal or anal / rectal function, on a scale 
of 1-10 with 1 being totally dissatisfied to 10 totally satisfied? 
 
     1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
     Totally Dissatisfied 
 
Totally Satisfied 
 
 
2.   MEMORIAL SLOAN KETTERING ANAL FUNCTION SCALE 
How well does your anus function? 
1 = Excellent; Typically 1-2 bowel movements per day and no soilage. 
2 = Good; Typically 3-4 bowel movements per day and / or mild soilage. 
3 = Fair; > 4 bowel movements a day at least at times and / or moderate soilage. 
4 = Poor; Incontinence. 
 
 


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SCORING PROCEDURES FOR  
THE EORTC COLORECTAL CANCER MODULE (EORTC QLQ-CR38) 
 
I. 
Functional scales 
The questionnaire includes 4 functional scales/single items: 
• Body image (BI) 
• Sexual functioning (SX) 
• Sexual enjoyment (SE) 
• Future perspective (FU) 
 
These 4 scales are all constructed in a similar manner: (1) the raw scores for the 
individual items within a scale are first summed, and then divided by the number of items 
in the scale; and (2) these scale scores are then linearly transformed such that all scales 
range from 0 to 100, with a higher scale score representing a higher
 
 level of functioning.  
The following are the scoring algorithms for the 4 functional scales, including the SPSS 
computational language. 
 
Body Image
1. Compute an additive scale (BI) by adding the questionnaire items 43-45 and dividing 
this sum by the number of items (3): 
 (Questionnaire items 43-45) 
 
COMPUTE BI = (Q43+Q44+Q45)/3 
 
2. Carry out a linear transformation to convert the scale (BI) to a 0-100 scale (XBI): 
 
COMPUTE XBI = 100 - ((BI-1)*100/3) 
 
Future Perspective
COMPUTE FU = Q46 
 (Questionnaire item 46) 
COMPUTE XFU = 100- ((FU-1)*100/3) 
 
Sexual Functioning
1. Compute an additive scale (SX) by adding the questionnaire items 47 and 48 and 
dividing this sum by the number of items (2): 
 (Questionnaire items 47 and 48) 
 
COMPUTE SX = (Q47+Q48)/2 
 
2. Carry out a linear transformation to convert the scale (SX) to a 0-100 scale (XSX): 
 
COMPUTE  XSX = (SX-1)*100/3 
 
Sexual Enjoyment
COMPUTE SE = Q49 
 (Questionnaire item 49) 
COMPUTE XSE = (SE-1)*100/3 
 


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II. 
Symptom Scales/Items 
The questionnaire includes a number of multi-item scales and single items assessing a 
range of symptoms common among patients with colorectal cancer. These scales and 
single items are linearly transformed such that all scales/items range from 0-100, with a 
higher score representing a higher
• Micturition problems (MI) 
 level of symptomatology.  
• Chemotherapy side effects (CT) 
• Symptoms in the area of the gastro-intestinal tract (GI) 
• Male sexual problems (MSX) 
• Female sexual problems (FSX) 
• Defaecation problems (DF) 
• Stoma-related problems (STO) 
• Weight loss (WL) 
 
Micturition Problems
1. Compute an additive scale (MI) by adding the questionnaire items 31-33 and dividing 
this sum by the number of items (3): 
 (Questionnaire items 31-33) 
 
COMPUTE MI = (Q31+Q32+Q33)/3 
 
2. Carry out a linear transformation to convert the scale (MI) to a  0-100 scale (XMI): 
 
COMPUTE  XMI = (MI-1)*100/3) 
 
Chemotherapy Side-effects
1. Compute an additive scale (CT) by adding the questionnaire items 40-42 and dividing 
this sum by the number of items (3): 
 (Questionnaire items 40-42) 
 
COMPUTE CT = (Q40+Q41+Q42)/3 
 
2. Carry out a linear transformation to convert the scale (CT) to a 0-100 scale (XCT): 
 
COMPUTE  XCT = (CT-1)*100/3) 
 
Symptoms in the Area of the Gastro-intestinal Tract
1. Compute an additive scale (GI) by adding the questionnaire items 34-38 and dividing 
this sum by the number of items (5): 
 (Questionnaire items 34-38) 
 
COMPUTE GI = (Q34+Q35+Q36+Q37+Q38)/5 
 
2. Carry out a linear transformation to convert the scale (GI) to a 0-100 scale (XGI): 
 
COMPUTE  XGI = (GI-1)*100/3) 
 
Male Sexual Problems
1. Compute an additive scale (MSX) by adding the questionnaire items 50 and 51 and 
dividing this sum by the number of items (2): 
 (Questionnaire items 50 and 51) 
 
COMPUTE MSX = (Q50+Q51)/2 


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2. Carry out a linear transformation to convert the scale (MSX) to a 0-100 scale 
(XMSX): 
 
COMPUTE  XMSX = (MSX-1)*100/3) 
 
Female Sexual Problems
1.  Compute an additive scale (FSX) by adding the questionnaire items 52 and 53 and 
dividing this sum by the number of items (2): 
 (Questionnaire items 52 and 53) 
 
COMPUTE FSX = (Q52+Q53)/2 
 
2. Carry out a linear transformation to convert the scale (FSX) to a 0-100 scale (XFSX): 
 
COMPUTE  XFSX = (FSX-1)*100/3) 
 
1. Compute an additive scale (DF) by adding the questionnaire items 55-61 and dividing 
this sum by the number of items (7): 
Defecation Problems (Questionnaire items 55 -61) 
 
COMPUTE DF = (Q55+Q56+Q57+Q58+Q59+Q60+Q61))/7 
 
2. Carry out a linear transformation to convert the scale (DF) to a 0-100 scale (XDF): 
 
COMPUTE  XDF = (DF-1)*100/3) 
 
1. Compute an additive scale (STO) by adding the questionnaire items 62-68 and 
dividing this sum by the number of items (7): 
Stoma-related Problems (Questionnaire items 62-68) 
 
COMPUTE STO = (Q62+Q63+Q64+Q65+Q66+Q67+Q68))/7 
 
2. Carry out a linear transformation to convert the scale (STO) to a 0-100 scale (XSTO): 
 
COMPUTE  XSTO = (STO-1)*100/3) 
 
COMPUTE WL = Q39 
Weight loss (Questionnaire item 39) 
COMPUTE XWL = (WL-1)*100/3 
 
Further inquiries regarding the scoring algorithms for the EORTC QLQ-C38 can be 
directed to: Dr. Mirjam Sprangers, Department of Medical Psychology, Academic 
Medical Hospital, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The 
Netherlands. Telephone: +31-20-5664641; Telefax: +31-20-5669104. 
 
 © Copyright 1994 EORTC Study Group on Quality of Life. All rights reserved. 


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SCORING PROCEDURES FOR 
EORTC QLQ-C30 version 3.0 
 
Table 1:  Scoring the QLQ-C30 version 3.0 
 
Scale 
Number 
of Items 
Item 
Range* 
Version 3.0 
Item Numbers 
Function 
Scales 
Global Health Status / QOL 
 
 
 
 
 
  Global health status/QOL (revised)† 
QL2 
2 
6 
29, 30 
 
Functional Scales 
 
 
 
 
 
  Physical functioning (revised)† 
PF2 
5 
3 
1 to 5 
F 
  Role functioning (revised)† 
RF2 
2 
3 
6, 7 
F 
  Emotional functioning 
EF 
4 
3 
21 to 24 
F 
  Cognitive functioning 
CF 
2 
3 
20, 25 
F 
  Social functioning 
SF 
2 
3 
26, 27 
F 
Symptom Scales / Items 
 
 
 
 
 
  Fatigue 
FA 
3 
3 
10, 12, 18 
 
  Nausea and vomiting 
NV 
2 
3 
14, 15 
 
  Pain 
PA 
2 
3 
9, 19 
 
  Dyspnoea 
DY 
1 
3 
8 
 
  Insomnia 
SL 
1 
3 
11 
 
  Appetite loss 
AP 
1 
3 
13 
 
  Constipation 
CO 
1 
3 
16 
 
  Diarrhoea 
DI 
1 
3 
17 
 
  Financial difficulties 
FI 
1 
3 
28 
 
* Item range is the difference between the possible maximum and the minimum response to individual items; most 
 items take values from 1 to 4, giving range = 3. 
† (revised) scales are those that have been changed since version 1.0, and their short names are indicated in this 
 manual by a suffix “2” – for example, PF2. 
 
For all scales, the RawScore, RS, is the mean of the component items: 
 
 
(
) n
I
I
I
RS
RawScore
n
+
+
+
=
=
...
2
1
 
 
Then, for Functional scales: 
 
(
)
100
1
1
×






−
−
=
range
RS
Score
 
 
and for Symptom scales / items and Global health status / QOL: 
 
 
 
 
 
 
 
 
 
(
)
{
} 100
1
×
−
=
range
RS
Score
  
Examples: 
 
Emotional Functioning  
 
(
)
{
} 100
3
1
1
 
EF
4
)
(
24
23
22
21
×
−
−
=
+
+
+
=
RawScore
Score
Q
Q
Q
Q
RawScore
 
Fatigue  
 
(
)
{
} 100
3
1
FA 
3
)
(
18
12
10
×
−
=
+
+
=
RawScore
Score
Q
Q
Q
RawScore
 


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APPENDIX VI: HPV, CYTOLOGY & PATHOLOGY SPECIMENS 
 
AMC-045: Phase II Trial of Combined Modality Therapy plus Cetuximab 
in HIV-Associated Anal Carcinoma 
 
SPECIMEN REQUIREMENTS 
 
All specimens will be reviewed at UCSF and must be submitted within 30 days of study 
enrollment.  The tissue block along with a copy of the surgical pathology report should be sent. 
If the block is not available, a representative H & E stained section and ten unstained slides 
should be submitted.  All materials will be retained unless return is specifically requested.  
Tissue will be evaluated for histology as demonstrated by H & E staining, HPV detection and 
typing, and microarray DNA expression.  Other studies might be added at a later point in time as 
additional correlative science studies are developed.  These evaluations will not be done in real 
time. The collaborating pathologist will be Dr. Teresa M. Darragh, M.D., Professor of Clinical 
Pathology, UCSF/ Mt. Zion Medical Center, Depts. of Pathology and OB/Gyn, Box 1785, 1600 
Divisadero Street, Room B221, San Francisco, CA 94115, phone:  415.353.7861, Fax:  
415.353.7676, Email: darragh@itsa.ucsf.edu.  
 
At baseline, an anogenital examination will be performed for HPV testing and anal cytology.  
To obtain the cytology specimen, a swab will be placed in the anus (another obtained from the 
cervix if applicable) for several seconds, withdrawn, immediately immersed in the Cytyc 
Thinprep bottle and agitated vigorously to remove the cells. Discard the swab, close the bottle 
tightly and send it to the UCSF Pathology Department.  This will be evaluated for cytology and 
an aliquot will be removed for PCR studies of the HPV types(s) present.   
 
SAMPLE LABELING 
 
Protocol #: AMC 045 
AMC Patient ID #  
Study period as described by week number 
Date and time of specimen collection. 
Specimen type: “Anal swab” or “Tissue block” 
Specimen purpose: “Cytology” or “Pathology” 
 
PRECAUTIONS 
 
All specimens are to be considered biohazard material, as they originate from HIV infected 
patients.  This should be designated by use of a “Universal Precautions” label.  
 


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SPECIMEN DELIVERY 
 
These samples should be shipped using the AMC Operations Center FedEx 
 
 
 
All specimens should be sent at room temperature immediately to: 
Dr. Joel Palefsky’s Laboratory 
c/o Maria Da Costa  
University of California, San Francisco 
513 Parnassus Ave., Room S-420 
San Francisco, CA  94143 
Tel: 415-476-8885 
 
RECORD OF SPECIMENS 
 
This study will track specimens via GlobalTraceSM, a component of the AMC AdvantageEDCSM 
system. The GlobalTraceSM shipment manifest must accompany all specimen shipments. 
 


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APPENDIX VII:  INFORMED CONSENT 
 
AMC-045: Phase II Trial of Combined Modality Therapy plus Cetuximab 
in HIV-Associated Anal Carcinoma 
 
This is a clinical trial (a type of research study). Clinical trials include only patients who choose 
to take part. Please take your time to make your decision. Discuss it with your friends and 
family. 
 
You are being asked to take part in this study because you have recently been diagnosed with 
cancer of the anus for which radiation and chemotherapy together have been recommended to 
you, in an attempt to cure this cancer. You must also be an adult infected with the AIDS virus, 
HIV, but otherwise be in fairly good health with adequate bone marrow, kidney and liver 
function. 
 
WHY IS THIS STUDY BEING DONE? 
 
The main purpose of this study is to determine the effectiveness of standard chemotherapy and 
radiation when combined with cetuximab for anal cancer. Although there is much information 
regarding the specific treatment used for anal cancer used in this study, there is less information 
regarding how patients with anal cancer and HIV infection respond to the treatment and what 
side effects they have as a result of the treatment. A standard treatment for patients with anal 
carcinoma not associated with HIV infection includes treatment with chemotherapy plus 
radiation therapy.  The chemotherapy drugs typically used with radiation therapy include 
mitomycin-C and 5-fluorouracil (5-FU), although recent studies have suggested that cisplatin and 
5-FU may be as effective and associated with fewer side effects.  In this study, cisplatin and 5-
FU will be the chemotherapy regimen used. In addition, we will utilize a drug called cetuximab, 
which is approved for the treatment of colon cancer. Cetuximab is a mononclonal antibody, or 
protein, that is directed against a target on the surface of the cancer cell. The target is called 
"epidermal growth factor receptor", or EGFR. Cetuximab has been shown to enhance the 
effectiveness of cisplatin and radiation therapy in other types of cancer.  
 
During this study, you will be followed closely during and after therapy to see how well your 
cancer is controlled by the radiation and chemotherapy treatment, how the treatment affects your 
HIV illness, what side effects you have, and how you tolerate the treatment.  
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY 
 
About 46 people will take part in this study. 
 
WHAT IS INVOLVED IN THE STUDY? 
 
You have already been diagnosed with anal cancer and are already known to be HIV-positive or 
have just found this out. Radiation and chemotherapy given together (combined modality therapy 
or “CMT”) has been recommended as the best treatment for your condition. A standard treatment 


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for patients with anal carcinoma not associated with HIV infection includes treatment with 
chemotherapy plus radiation therapy. The chemotherapy drugs typically used with radiation 
therapy include mitomycin-C and 5-flourorucil (5-FU), although recent studies have suggested 
that cisplatin and 5-FU may be as effective and associated with fewer side effects. In this study, 
cisplatin and 5-FU will be the chemotherapy regimen used. 
 
Before being enrolled in this study, you went through a physical examination and other routine 
tests to determine the size and extent of your cancer. The studies probably included a CT scan or 
MRI of your pelvis, a CT scan of your abdomen to check the liver, and a chest Xray or CT scan 
of the chest. If anything suggested that the cancer has spread outside of the pelvis, a biopsy of the 
area may be needed. If you have cancer that has spread outside of the pelvis, you will not be 
eligible for this study. You also had a history and physical examination and blood work to see if 
you are, in general, healthy enough to receive this type of treatment. These are all standard 
procedures that are routinely done even if you were not going to enter the study. However, the 
study will need for all of these tests to be done within a defined time, so that the results are all up 
to date. If too much time has gone by since these were done before the treatment was started, 
some of these tests and procedures may need to be repeated. You also must enroll in this study 
before you have received any of the radiation or chemotherapy.  
 
Once you have entered the study, many of the treatments and tests that you need to do are 
standard. That is, you would be asked to do many of these things even if you were not in this 
study. Other treatments or tests and procedures are additional and will be done specifically 
because you are taking part in this study.  
 
If you take part in this study, you will receive the following standard treatments: 
 
• CHEMOTHERAPY: You will be under the care of a medical oncologist while receiving 
chemotherapy. Two chemotherapy drugs will be used. 5-Flourouricil (5-FU) will be infused 
continuously over 4 days (96 hours), starting on the day one of treatment (days 1-4). You will 
also receive a second course of 5-FU, to be started at the fourth week of treatment (days 29-
32). Some patients are admitted to the hospital to receive their 5-FU, but it is more 
commonly given at home with the assistance of home care nursing agency and/or home 
infusion company. The second chemotherapy drug that you will receive is cisplatin. This is 
given in the clinic as an IV infusion over 60 minutes on the first of each 5-FU infusion (day 1 
and day 29). Additional fluids and medicines (to prevent nausea) will be given on this day, so 
this will require several hours of time. A large amount of intravenous fluid (3 liters) must be 
given intravenously, including about 2 liters before cisplatin and about 1 liter after cisplatin. 
This will take about 6-8 hours to administer. You may receive the treatment in the treatment 
in the clinic or the hospital in-patient unit, depending upon the standard procedures used by 
your doctor at his/her particular hospital/clinic. You will also receive a dose of radiation on 
the day that cisplatin is given. Medications will be given intravenously and/or orally in order 
to reduce the chance of developing nausea and/or vomiting.  
 
In order to receive this 5-FU at home, a catheter is placed into one of your veins. This is not 
just a typical IV (intravenous) line but is one that can be left in for a much longer time. There 
are several choices of catheters that you can discuss with your doctor. Depending on the type 


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of catheter placed, you may have to take care of it. The two most common choices include a 
PIC line placed (usually) in your arm or a Porta-Cath placed internally (under the skin) in 
your chest.  
 
• CETUXIMAB: Cetuximab IV will be given 1 week before the cycle 1 chemotherapy begins. 
Cetuximab will then be given weekly as an IV infusion for 6 consecutive weeks (Days 1, 8, 
15, 22, 29, 36, and 43) during the period of chemotherapy and radiation therapy. Therefore, a 
minimum of 6 and maximum of 8 doses of cetuximab will be given. Cetuximab is usually 
given over 60-90 minutes, depending upon the dose given. Diphendyramine (50 mg) is given 
IV before cetuximab is given to prevent allergic reactions. Diphenhydramine (also called 
Benadryl) may cause drowsiness. Cetuximab will be held if the radiation therapy is held; this 
is because it is believed that cetuximab must be given at the same time that radiation therapy 
is given to improve control of the disease.   
 
• RADIATION THERAPY: Treatment will be given every weekday (Monday through 
Friday), over approximately five to seven weeks in the outpatient setting. Brief treatment 
breaks are sometimes needed because of side effects, so this can even take a little longer to 
finish for some patients. The total number of doses that you are prescribed will depend on the 
size and extent of your tumor at the start of treatment. You will receive this care from a 
Radiation Oncologist who will work closely with your Medical Oncologist to coordinate the 
radiation therapy with the chemotherapy. The minimum number of treatments required will 
be about 28 (which will take a minimum of about 5 weeks to deliver) and the maximum 
number of treatments required will be about 35 (which will take a minimum of about 7 weeks 
to deliver). The treatment itself takes only a few minutes to administer. You will have to lie 
flat on a table for about 5-10 minutes each time that you receive the treatment. The radiation 
may be held or interrupted by your doctor if you have significant side effects (eg, skin rash, 
diarrhea, or other side effects)  
 
There are several ways of administering radiation therapy, including the standard technique 
and a new technique called IMRT (which stands for Intensity Modulated Radiation Therapy). 
IMRT is an advanced radiation therapy delivery technique that reduces the amount of 
radiation given to normal tissues, and may therefore reduce unwanted side effects.  IMRT 
tries to lower the amount of radiation that normal tissues receive, while still delivering the 
desired amount of radiation to your cancer and to the areas that your doctor thinks may have 
cancer cells, such as lymph nodes.  IMRT does this by using multiple, computer-controlled 
radiation beams aimed at your cancer, while still delivering a radiation dose comparable to 
standard radiation. There is little information regarding the effectiveness of IMRT in anal 
cancer, although some radiation oncologists are beginning to gain experience in using it for 
this condition. It is not known at this time whether IMRT will result in similar control of the 
cancer.  The choice of whether you will receive standard radiation therapy or IMRT will be 
at the discretion of your treating physicians, and they will discuss whether conventional RT 
or IMRT is being recommended in your case. 
 
• SUPPORTIVE CARE: You will receive the standard supportive care to control side effects 
as best as possible. Medicines to control or treat infection, pain, nausea, vomiting, diarrhea, 
dehydration, and low blood counts will be prescribed as needed. You may need blood 


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transfusions if you become too anemic, intravenous fluids if you become dehydrated, 
antibiotics if you develop an infection, narcotics to control pain, and other routine, standard 
treatments. You may need to be hospitalized if you develop serious side effects.  
 
If you take part in this study, you will have the following standard tests and procedures: 
 
• Before beginning treatment, you will have a complete history and physical examination. 
Additional tests that will be required in blood tests (including T cell count and HIV viral 
load, and pregnancy test for women), and electrocardiogram, a chest x-ray, and CT scans 
and/or MRI to adequately stage the disease. In some cases, a bone scan may be needed if you 
have symptoms suggesting that the cancer has spread to the bone (bone pain). Your doctor 
may also recommend an endorectal ultrasound in order to determine whether there is 
extension of the tumor beyond the anus; this procedure involves insertion of a small probe in 
the anal canal. All of these tests are considered part of routine medical care for someone with 
your diagnosis.  
• During the course of treatment, you will be seen at your doctor’s office once per week for a 
brief check of how you are doing, what medicines you are taking, and what side effects you 
are having. Blood tests will also be done regularly.  
• At about three months after the start of treatment, you will have a CXR, and CT scan of the 
abdomen and pelvis, or comparable tests to see how your cancer responded to treatment.  
• Once treatment is finished, you will be seen and have blood taken approximately every six 
weeks, then every three months, then eventually every six to twelve months for a total of five 
years.  
• Additional tests will be repeated as necessary if your cancer is ever suspected of returning. 
 
If you take part in this study, there will be extra tests and procedures, in addition to the standard 
tests and procedures: 
 
• The tissue that was obtained at the time that the anal cancer was diagnosed (the biopsy) will 
be stored for research tests. If there is not enough tissue available from this biopsy, another 
biopsy may be requested before treatment begins. However, this is optional and may only be 
a needle biopsy.  It should not require surgery. 
• Before treatment begins, a swab will be inserted briefly into your anus. This is sent to a 
research laboratory to be tested for HPV (human papillomavirus), the most common cause of 
anal cancer. The specific type of HPV will be identified. A second swab will be obtained for 
a Pap smear. This also will be sent to the research laboratory. The Pap smear test will look to 
see if you have any dysplastic cells. These are not cancer cells but can sometimes be a 
precursor to cancer. This procedure will be repeated at 6 months. You will not be billed for 
the HPV test or Pap test. 
• If your treatment center has the ability to perform an examination of your anus using high 
resolution anoscopy (which provides a magnification view of the anal surface), this will be 
done to more clearly examine the anal canal before treatment begins and at 6 months.   
• Quality of life surveys will be performed at several time points. This survey will include a 
series of questions about how you feel using multiple choice questions and answers. The 
survey will be given before treatment, and at 3, 6, 12, 24, and 36 months after beginning 
treatment. 


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HOW LONG WILL I BE IN THE STUDY? 
 
The treatment program outlined in this trial will take approximately three months to complete. 
After you complete the chemotherapy and irradiation, your doctor will continue to follow you 
and request additional tests at 3, 6, 9, 12, 18, 24, 30, 36, 48, and 60 months after treatment is 
initiated.  
 
You can withdraw your consent at any time. If you request that the treatment be discontinue 
because of side effects or another reason, your doctor would still need to evaluate you at periodic 
intervals to monitor the status of the cancer and any early or late side effects you may have. 
However, you also have the right to withdraw consent for monitoring the status of your cancer at 
any time. 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
While on the study, you are at risk for the following side effects. You should discuss these with 
the researcher and/or your regular doctor. There also may be other side effects that are not 
predicted and other very rare side effects that are known but not included in this list. Other drugs 
will be given to lessen side effects and discomfort. Many side effects go away shortly after the 
treatment is stopped, but in some cases side effects can be serious or long lasting or permanent. 
 
Chemotherapy (5-FU and Cisplatin) 
 
Common (likely) side effects of 5-FU or cisplatin include: 
• Hair loss 
• Mouth sores and/or soreness of the throat 
• Diarrhea with cramping and/or bleeding 
• Nausea and vomiting, reduced appetite, weight loss and a change in taste 
• Low blood cell counts including white cells, red cells (anemia) and platelets 
• Decreased magnesium in the blood – this may also be caused by cisplatin: it may result in 
muscle weakness and cramps 
• Loss of energy 
• Kidney injury especially if the kidney function is already poor before treatment or if you 
become dehydrated during therapy. This typically resolves but can be long lasting. It can be 
worsened by repeated doses of cisplatin.  
• Nerve injury which most often is a peripheral neuropathy causing numbness or discomfort in 
the hands and feet. This generally improves with time but at times can be permanent.  
• Hearing loss or ringing in the ears. As above, this generally improves with time but can at 
times be permanent.  
• Reproductive risks: Since 5-FU and cisplatin, and radiation therapy, can affect an unborn 
baby, you should not become pregnant or father a baby while receiving this therapy. You 
should not nurse your baby while receiving this therapy. Ask about counseling and more 
information about preventing pregnancy.  
• This therapy can also cause infertility (sterility) so chances for a future pregnancy will be 
reduced. Ask about more information about ways to preserve fertility 


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Unlikely side effects of 5-FU or cisplatin include: 
• Sensitivity to sunlight 
• Skin rash, other nail and skin changes, hair loss 
• Tightening of the tear ducts 
• Darkening of the vein used for infusion 
• Allergic reactions  
 
Very unlikely but serious side effects of 5-FU or cisplatin include: 
• Chest pain, heart attack or other heart abnormalities 
• Confusion or other neurologic problems including seizures 
• Severe diarrhea due to damage of the bowel which can, in rare cases, can lead to death 
• Severe drops in the blood counts, which if associated with an infection, could lead to death 
• Eye damage 
• Loss of muscle or nerve function 
Cetuximab 
 
Likely: 
• Diarrhea 
• Nausea or the urge to vomit 
• Fatigue or tiredness 
• Fever 
• Headache or head pain 
• Dry skin 
• Acne 
• Skin rash with the presence of macules (flat discolored area) and papules (raised bump) 
 
Less Likely: 
• Lack of enough red blood cells (anemia) 
• Inflammation (swelling and redness) of the skin of outer ear and canal 
• Noise in the ears, such as ringing, buzzing, roaring, clicking 
• Inflammation (swelling and redness) of the conjunctiva (the outermost layer of the eye and 
the inner surface of the eyelids).  Commonly called "pink eye". 
• Dry eye 
• Inflammation (swelling and redness) of the middle layer of the eye (uvea) 
• Excessive tearing in the eyes 
• Belly pain 
• Inflammation (swelling and redness) of the lip 
• Constipation 
• Dry mouth 
• Heartburn 
• Irritation or sores in the lining of the mouth 
• Vomiting 
• Chills 


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• Swelling of the arms and/or legs  
• Flu-type symptoms (including body aches, fever, chills, tiredness, loss of appetite, cough) 
• Reaction that can occur during or following infusion of the drug.  The reaction may include 
fever, chills, rash, low blood pressure, and difficulty breathing. 
• Chest pain not heart-related 
• Allergic reaction by your body to the drug product that can occur immediately or may be 
delayed.  The reaction may include hives, low blood pressure, wheezing, swelling of the 
throat, and difficulty breathing. 
• Infection 
• Decreased number of a type of white blood cell (neutrophil/granulocyte) 
• Weight loss 
• Decrease in the total number of white blood cells (leukocytes) 
• Loss of appetite 
• Dehydration (when your body does not have as much water and fluid as it should) 
• Decreased blood level of calcium 
• Decreased blood level of magnesium 
• Joint pain 
• Back pain 
• Muscle pain 
• Fainting 
• Stuffy or runny nose, sneezing 
• Sudden constriction of the small airways of the lung that can cause wheezing and shortness 
of breath 
• Cough 
• Shortness of breath 
• Hoarseness 
• Hair loss 
• Loss of some or all of the finger or toenails 
• Increased skin sensitivity to sunlight  
• Itching 
• Area of bleeding within the skin causing a reddish purple discoloration 
• Sore or destruction of skin 
• Hives 
• Low blood pressure 
• Formation of a blood clot that plugs the blood vessel; blood clots may break loose and travel 
to another place, such as the lung 
 
Rare but Serious: 
• Serious, life-threatening allergic reaction requiring immediate medical treatment by your 
doctor.  The reaction may include extremely low blood pressure, swelling of the throat, 
difficulty breathing, and loss of consciousness. 
• Inflammation of the lining of the brain and spinal cord  
• Inflammation of the lungs that may cause difficulty breathing and can be life-threatening  
• Fluid build-up in the lungs that is not due to a heart problem that can be life-threatening  


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• Swelling and redness of the skin on the palms of the hands and soles of the feet 
 
• Rare incidents of heart problems such as chest pain, decreased heart function, and injury to 
the heart muscle have been observed in clinical trials with cetuximab in combination with 5-
FU containing chemotherapies.  Cardiac site effects are known to occur with 5-FU; however, 
we do not know at this time whether the addition of cetuximab to 5-FU increases the risk of 
these events. 
Also Reported on Clinical Trials of Cetuximab: 
• Heart failure due to heart attack and abnormal heart rhythm, and sudden death has occurred 
in patients who received cetuximab in combination with radiation therapy. 
 
It is recommended that you wear sunscreen and hats and limit sun exposure while receiving 
cetuximab as sunlight can worsen any skin reactions that may occur. 
 
Reproductive Risks and Breast Feeding: 
Because the drugs in this study can affect an unborn baby, you should not become pregnant or 
father a baby while on this study, or up to 60 days after the last dose of cetuximab.  You should 
not nurse your baby while on this study, or up to 60 days after the last dose of cetuximab.  You 
may ask your doctor about counseling and more information about preventing pregnancy. 
 
Radiation therapy given to the pelvis and anus 
 
Common (likely) side effects of radiation include: 
• A mild skin burn will always develop but sometimes this can progress to blisters, peeling of 
the skin, and oozing of the tissues. This will affect the anus, the skin around the anus and 
possible the skin over the groin, scrotum and penis. This is uncomfortable and can be quite 
painful when sores develop. 
• Diarrhea  
• Low white blood cell count, anemia 
• Fatigue 
• Loss of hair in the groin which may be permanent  
• Even after the visible damage of radiation has healed, tissue healing may be slow or 
incomplete in this area. This means that injury to this area (a biopsy procedure for instance) 
can be slow to heal even years later. 
• Some patients do not return to normal sexual function. Radiation therapy to this area of the 
body may lead to problems with an erection, ejaculation, or may reduce your ability to have 
intercourse.  
 
Unlikely but serious side effects of radiation include: 
• Long lasting injury to the anus resulting in chronic pain, non-healing open ulcers, or 
difficulty controlling bowel movements. Sometimes a temporary colostomy (surgical 
diversion of the bowel through the wall of the abdomen, emptying into a bag) is needed or 
even a permanent colostomy with the surgical removal of the anus is required.  
 


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For more information about risks and side effects, ask the researcher or contact 
__________________ at _____________. 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
 
If you agree to take part in this study, there is no certainty of a direct medical benefit for you. We 
hope that adding cetuximab to standard therapy will improve our ability to control the disease. 
We hope the information learned from this study will benefit other patients with anal cancer in 
the future.  
 
WHAT OTHER OPTIONS ARE THERE? 
 
Instead of being in this study, you have these options: 
• 
You may receive radiation therapy and chemotherapy (combined modality therapy) even if 
you do not take part in this study.  
• 
You may receive no therapy at this time with standard of care to help you feel more 
comfortable. 
• 
You may receive surgery to remove the anal cancer, without chemotherapy and radiation or 
with reduced doses of chemotherapy and radiation.  
 
Please talk to your regular doctor about these and other options. 
 
WHAT ABOUT CONFIDENTIALITY? 
 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. 
 
Organizations that may inspect and/or copy your research records for quality assurance and data 
analysis include groups such as the AMC Operations Center, National Cancer Institute, Food and 
Drug Administration (FDA), the company that will provide cetuximab (Bristol-Myers). 
 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the 
National Institutes of Health. With this Certificate, the researchers cannot be forced to disclose 
information that may identify you, even by a court subpoena, in any federal, state, or local civil, 
criminal, administrative, legislative, or other proceedings. The researchers will use the 
Certificate to resist any demands for information that would identify you, except as explained 
below. 
 
The Certificate cannot be used to resist a demand for information from personnel of the United 
States Government that is used for auditing or evaluation of federally-funded projects or for 
information that must be disclosed in order to meet the requirements of the FDA. 
 
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 


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research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers may not use the Certificate to withhold that information. 
 
WHAT ARE THE COSTS? 
 
Taking part in this study may lead to added costs to you or your insurance company. Most of the 
care (radiation therapy and chemotherapy) will be charged to your insurance company because 
this care is considered standard care. The drug cetuximab will be provided to you at no cost 
unless, during the study, cetuximab becomes commercially available for this condition. In that 
case you may have to pay for the amount of drug needed to complete the study. Please ask about 
any expected added costs or insurance problems 
 
In the case of injury or illness resulting from this study, emergency medical treatment is 
available but will be provided at the usual charge. No funds have been set aside to compensate 
you in the event of injury. 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. 
 
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 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. 
 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about the study or a research-related injury, contact the researcher 
_____________________________ at __________________. 
 
For questions about your rights as a research participant, contact the __________________ 
Institutional Review Board (which is a group of people who review the research to protect your 
rights) at __________________. 
 
CONSENT FOR THE USE OF TISSUE SPECIMENS 
 
About Using Tissue for Research: 
You have had a biopsy (or surgery) in order to confirm your cancer diagnosis. This tissue is 
normally stored in a local pathology laboratory.  We would like to keep some of the tissue that 
is left over for future research. If you agree, this tissue will be kept and may be used in research 
to learn more about cancer and other diseases. This tissue will only be given to researchers 


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approved by the AIDS Malignancy Consortium (AMC). Any research done on the tissue must 
also be approved by the researcher's Institutional Review Board (IRB). 
 
The research that may be done with your 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 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 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 AMC study.  
If you decide now that your 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 
tissue. Then the tissue will no longer be used for research. 
 
In the future, people who do research may need to know more about your health. When the 
AMC gives them reports about your health, it will not give them your name, address, or phone 
number. 
 
Sometimes tissue is used for genetic research (about diseases that are passed on in families). 
Even if your tissue is used for this kind of research, the results will not be put in your health 
records. 
 
Your tissue will be used only for research and will not be sold. You will not be paid for 
allowing your leftover tissue to be used in research even though the research done with your 
tissue may help to develop new products in the future.  
 
Benefits: 
The benefits of research using 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. The greatest risk is the release of information from your health 
records. The AMC 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. 
 
In addition to the research you are consenting to under this study, other researchers at this or 
other institutions may wish to study the samples in future research. These samples, taken from 
your body, would be able to be linked back to you for the purpose of the study only. At this 
time, the researcher does not know what the future studies will be. Your specimens may also be 
submitted to a tissue/cell/DNA bank. The specimens may be kept for a long time, possibly up to 
50 years. Information about you may be shared with other researchers who will keep the 
information confidential, as stated in this consent. 
 


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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 tissue 
research studies. If you have any questions, please talk to your doctor or nurse, or call our 
research review board at _________________________________. 
 
I agree to have the following specimens sent for future studies: 
 
Specimen from diagnostic biopsy (this has already been performed and requires no additional 
procedures) 
Yes ___No 
 
____ 
Anal swab specimen (this requires putting an anal swab in the anal canal)  
Yes ___No 
 
____ 
An additional tumor biopsy in order to freeze and store the tissue (this requires another biopsy 
to be done) 
Yes ___No 
 
____ 
If you have checked YES in response to any of the following questions, please also answer the 
following questions: 
 
1. Your tissue may be kept for use in research to learn about, prevent, treat, or cure cancer. 
Yes ___No 
 
____ 
2. Your tissue may be kept for research about other health problems (for example: causes of 
diabetes, Alzheimer's disease, and heart disease). 
Yes ___No 
 
____ 
3. Your doctor (or someone from the AMC) may contact you in the future to ask you to take 
part in more research. 
Yes ___No 
 
____ 
You have read all of the above, asked questions and received answers concerning areas that you 
did not understand. You willingly agree or disagree to allow your blood and/or tissue to be 
stored for future research. 
 
WHERE CAN I GET MORE INFORMATION? 
 
You may call the NCI's Cancer Information Service at 
 
1 800 4 CANCER (1 800 422 6237) or TTY: 1 800 332 8615 
Visit the NCI's Web sites 
 
*CancerTrials: comprehensive clinical trials information http://cancertrials.nci.nih.gov. 


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*CancerNet: accurate cancer information including PDQ http://cancernet.nci.nih.gov. 
 
You will get a copy of this form. You may also request a copy of the protocol (full study plan). 
 
 
SIGNATURE 
 
I agree to take part in this study. 
 
Participant ________________________________  
 
 
Date_____________________________________ 
 


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APPENDIX VIII: ACSR INFORMED CONSENT 
 
AIDS Cancer Specimen Resource (ACSR) 
 
INTRODUCTION 
 
You are being asked to donate tissue for research.  Before you decide to be a part of this research 
study, you need to understand the risks and benefits so that you can make an informed decision.  
This is known as informed consent. 
 
This consent form provides information about the study, which has been explained, to you.  Once 
you understand the study and the tests it requires, you will be asked to sign this form if you want 
to take part in the study.  Your decision to take part in the study is voluntary.  This means that 
you are free to choose if you will take part in the study. 
 
PURPOSE AND BACKGROUND 
 
The National Cancer Institute (NCI) has set up a Bank for tissues and biological fluids from 
HIV-positive and HIV-negative individuals in order to have specimens available for scientists 
studying malignancies associated with HIV disease.  The specific studies for which specimens 
will be used are unknown at this point and will vary depending on investigators’ requests.  Only 
investigators whose studies are reviewed and approved by a committee assembled by the NCI 
from the scientific community will have access to specimens.  Specimens will only be used for 
the approved study and a progress report will be required.  Publications using AIDS Cancer 
Specimen Resource (ACSR) specimens will also be sent to the NCI.  
 
Individuals who have had biopsies to determine a malignancy are being asked for permission to 
have some of the tissue taken for the Bank.  Only tissue in excess of that required for decision-
making will be given to the Bank.  If it is determined that my physician needs more of my tissue 
for additional studies, the Bank will release all of my tissue back to my doctor.  No additional 
tissue will be taken from my body for the Bank.  In addition, I am being requested to donate 
some of my blood to the Bank so that scientists will also be able to look for any deviation that 
may explain the malignancy.  Once these specimens are deposited in the bank, they become the 
sole property of the Bank and I will no longer have any rights to the specimens.  
 
PROCEDURES 
 
If I agree to be in this study, the following will happen: 
 
1. Some of the material from my biopsy for a malignancy will be placed in the Bank. 
2. The swabs taken from my anus before the start of treatment and then at six months will be 
sent to the Bank. 
3.  My medical chart will be reviewed now and every six months for an indefinite period of time 
and clinical information will be obtained that could be useful to research investigators.  The 
report of the information retrieved from my medical record that is given to research 


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investigators will not have my name, or include any information that could personally 
identify me. 
4. Blood will be collected for the Bank.  Approximately twenty (20) milliliters of blood (about 
4 teaspoons) will be drawn at my next visit to my physician and placed in the Bank. 
5. If, during the course of treatment by my physician, it is necessary to perform additional 
biopsy procedures for diagnostic reasons, I will be asked at that time to consent to having a 
portion of that specimen sent to the Bank.  No additional blood will be drawn at that time. 
 
Participation in this study will not require me to make any additional visits to my doctor or have 
any additional biopsy specimens taken just for the Bank.  The Bank will only receive part of my 
specimen, and only what is in excess. 
 
POSSIBLE RISKS/DISCOMFORTS 
 
There is a possibility of a bruise and slight pain at the time the blood samples are taken.  There 
is also the possibility of fainting, and infection at the site of the blood draw.   
 
Treatment and Compensation for Injury:  If you are injured as a result of being in this study, 
treatment will be available.  If you require immediate medical care, you should go to an 
emergency room.  Otherwise, the doctor in charge of the study will take care of you or help you 
get the care you need.  You will be sent a bill for whatever medical care you receive.  All or part 
of your bill may be paid by the sponsor of the research study (according to its agreement with 
the AIDS Malignancy Clinical Trials Consortium), or by your health insurance.  (Institution) 
does not normally provide any form of compensation for injury that might occur from taking 
part in this research study. 
 
POSSIBLE BENEFITS 
 
It may be that there will be no direct benefit to you by participating in this study.  However, 
there may be possible benefit to medical knowledge and it is hoped that the information gained 
from the study will help in the treatment of HIV- infected individuals in the future. 
 
ALTERNATIVES 
 
My alternative is not to participate in this study. 
 
COSTS 
 
There will not be any additional cost to me for consenting to participate in this HIV-related 
malignancy tissue/biological fluids Bank. 
 


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PRIVACY 
 
Your hospital medical records will be confidentially reviewed to obtain clinical information that 
could be useful to research investigators.  However, the report of this information will be coded 
and my name and/or social security number will not appear anywhere on the report sent to the 
Bank, so I will not be easily identified.  The results of this research will be given to the sponsor, 
the National Cancer Institute, and may be asked for by the Department of Health and Human 
Services.  In addition, the Committee on Human Research of (Institution) may see your records.  
Except for these people, records from this study will be kept private unless you authorize their 
release or release is required by law (i.e. court subpoena).  Your name or any information, 
which could personally identify you, will not be used in any published reports about this study.   
 
QUESTIONS 
 
If I have any questions about the research study, you may contact Dr. (___________) at (Phone 
Number) day or night, or the person in charge of the study, the study coordinator at (Phone 
Number). If you have any questions about your rights as a research subject, you should call 
(IRB Representative), in (Institution) Office of Human Research at (Phone Number). (IRB 
Representative) is your representative and is not employed by the individuals conducting the 
study. 
 
CONSENT 
 
By signing this consent form you are agreeing that the study has been explained to you and that 
you understand the study, and your questions have been answered. 
 
PARTICIPATION IN RESEARCH IS VOLUNTARY.  You may decline to participate or to 
withdraw at any point in this study without jeopardy to any present or future medical care you 
may require. You are signing that you agree to take part in the study.  You will be given a copy 
of this consent form. By signing this form, you will not give up any of your legal rights. 
 
I agree to participate in this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject’s signature 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physician 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Witness 
 
 
 
 
 
 
 
Date 


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APPENDIX IX:  ACSR SPECIMEN PREPARATION & SHIPPING INSTRUCTIONS 
 
COLLECTION 
 
Consent patient for ACSR donation.  Collect 20 cc of whole blood in acid citrate dextrose (ACD) 
tubes.   
 
SHIPPING 
 
To ship, place the tubes into a canister of a STP-100 SAF-T-PAK shipper wrapping each tube in 
bubble wrap and using the absorbent paper at the bottom of the canister. Each sample tube 
should be labeled using a sharpie pen (permanent marker) with the following information: 
• Protocol #: AMC 045 
• AMC Patient ID# 
• Date and time of collection  
• Specimen type, i.e., WB=Whole Blood, P=Plasma, S=Serum 
• Specimen purpose: Donation 
 
Place the lid on the canister and place it inside of the ambient SAF-T-PAK shipper. Fold and 
pack ACSR form inside shipping box. Seal the ambient shipper with cellophane shipping tape. 
Label the ambient shipper with the "UN 3373" diamond shaped label. On one side, in black 
marker write, your name or name of responsible person, date of collection and phone number of 
the person responsible for the package.  
 
Specimen Shipment: Specimens are accepted MONDAY through THURSDAY. Specimens are 
not accepted on Friday. 
 
All BLOOD (whole blood, plasma, serum) specimens should be shipped by overnight express 
at room temperature to: 
ACSR Blood Receiving Laboratory 
Johns Hopkins University 
1650 Orleans Street, CRB-384 
Baltimore, MD  21231-1000 
TEL: (410) 955-8721 
FAX: (443) 287-3217 
 
All TISSUE specimens should be shipped by overnight express to: 
Dr. Sylvia Silver 
George Washington University Medical Center 
2300 I Street, NW 
Room 507 
Washington, DC  20037 
Phone: (202) 994-1444 
Fax: (202) 994-5056 
 


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Please use the AMC Operations Center FedEx account 
 
 
Instructions for specimens collected on Friday: 
 
PREPARATION OF PLASMA AND MONONUCLEAR CELLS 
 
It is preferable that separation occurs as soon as possible. If necessary, whole blood in acid 
citrate dextrose (yellow top tube) can be held at room temperature for no more than 24 hours. 
 
Materials:
• 
Lymphocyte Separation Medium (LSM Solution, Ficoll-Hypaque - sterile) 
  
• 
15 ml conical centrifuge tubes (sterile) 
• 
PBS (sterile) 
• 
1, 5 ml and 10 ml serologic pipettes (sterile) 
• 
NUNC tubes 
• 
Alcohol-saturated, control rate freezer container 
• 
DMSO freezing media: 
o 50% Cryoprotective Medium, Cambrex (catalog no.:12-132A) 
o 50% Heat Inactivated Fetal Bovine Serum 
1. Preparation of Plasma Samples  
a. The 7 ml tube of whole blood in acid citrate dextrose should be rotated gently 2 or 
3 times before being centrifuged. Do not transfer before centrifugation.  
b. The cells are separated by centrifugation at 500 g for 10 minutes.  
c. 0.5 ml aliquots of plasma are removed and put into 1.5 ml screw top tubes and 
transferred to liquid nitrogen storage.  
 
2. Peripheral Blood Mononuclear Cell Separation and Freezing  
a. The cells and plasma remaining from the previous step are transferred into a 15 
ml conical tube, capped and re-suspended by gently tapping the bottom of the 
tube.  
b. Sterile PBS should be added to the suspended cells until the final volume is 8 ml; 
invert to mix.  
c. The 8 ml whole blood-PBS mixture should be carefully overlaid onto 4 ml of 
room temperature LSM or Ficoll-Hypaque solution in a sterile 15 ml conical tube. 
A sharp interface should exist between the LSM and the whole blood mixture. (If 
the layer of LSM gets mixed with the blood-PBS, the tube should be gently 
rotated to mix the blood, PBS, and LSM, and transfer to a 50 ml sterile conical 
tube. An equal volume of PBS is added, and the cells are separated at 600 g for 15 
minutes. After removal of LSM-PBS supernatant, return to Step b).  
d. The 15 ml conical tube for 30 minutes at 900 g at room temperature. The 
mononuclear leukocytes (principally lymphocytes and monocytes) will band at 
plasma/LSM interface.  
e. The fluffy white layer just below the plasma layer should be aspirated off, along 
with approximately half of the LSM layer under it, and transferred to an 
appropriately labeled 15 ml sterile conical centrifuge tube. Mix by gentle rotation.  
f. Washed twice in sterile PBS - centrifuge at 500 g for 10 minutes.  


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g. Cell pellet should be mixed well with a gentle finger-tapping action.  
h. Using a 1 ml pipette, the *DMSO freezing mixture should be added drop wise to 
the cell pellet suspension. Gently finger-tap between drops. If the cell pellet is 
small, only 0.5 ml of freezing media is added (and only one aliquot of cells is 
frozen). If the cell pellet is large, up to 2 ml of freezing media can be added in a 
drop wise fashion. (Cell densities of 1 - 10 million PBMC/ml are best for 
cryopreservation. If a hemocytometer is available, the optimal concentration is 5 
million PBMC/ml).  
 
*Important-Do not put the DMSO containing media on the cell button all at 
once.
 
  
3. Freeze the cell suspension in 0.5 ml aliquots in sterile NUNC vials by placing the 
NUNC tubes in a room temperature, alcohol saturated, control rate freezer container 
and store in the -80°C freezer overnight. Transfer the cell suspension into the liquid 
nitrogen temperature freezer for long-term storage the next working day.  
 
 
***PLEASE DOUBLE CHECK PACKAGING OF SHIPPER AND DO NOT 
DEVIATE FROM REQUESTED LABELING. Shipping frozen aliquots requires the 
use of packaging acceptable for dry ice and Class 9 label with weight of dry ice 
written on package. 
 
 
Please Note: The shipper will be mailed back to the AMC site.  
 
 
 
The STP-210 SAF-T-PAK shipper is a complete kit w/ all trappings, bubble wrap, 
absorbent paper, labels, everything (but to reuse the shipper, you will need new 
labels, wrap, etc).   
 
RECORD OF SPECIMENS 
 
This study will track specimens via GlobalTraceSM, a component of the AMC AdvantageEDCSM 
system. The GlobalTraceSM shipment manifest must accompany all specimen shipments. 
 


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APPENDIX X:  AMC DATA SAFETY MONITORING PLAN 
(Version 5.0 · January 28, 2014) 
 
Monitoring the Progress of Trials and the Safety of Participants 
 
All AMC protocols that collect safety data follow the National Cancer Institute (NCI), Cancer 
Therapy Evaluation Program (CTEP) Guidelines: Adverse Event Reporting Requirements 
(http://ctep.cancer.gov/guidelines/index.html).  All adverse events that meet the NCI’s 
expedited reporting requirements are reported to the Investigational Drug Branch (IDB) of the 
NCI via the CTEP Adverse Event Reporting System (CTEP-AERS) web application.  All 
expedited adverse event reports are also required to be submitted to the local Institutional 
Review Board (IRB) of the reporting institution.  If NCI holds the IND or no IND is required for 
a study, the AMC site reports serious adverse events directly to the AMC Operations and Data 
Management Center (ODMC) via CTEP-AERS.  In some instances, the AMC sites may report 
serious adverse events directly to a commercial sponsor holding the IND, who will then report 
the event to the AMC ODMC.  Most AMC protocols require sites to report all serious adverse 
events via CTEP-AERS and the AMC ODMC to forward a copy of the report to the sponsor.  
The AMC ODMC also distributes all IND safety reports to all investigators upon receipt, and 
makes these reports available on the password-protected section of the AMC Operations web 
site.  Unless an AMC protocol specifies an alternate plan for the review and submission of 
serious adverse events, all serious adverse events received by the AMC ODMC will be reviewed 
by the AMC Medical Monitor at the AMC ODMC prior to submission to NCI and the sponsor.  
For protocols for which the IDB does not have an assigned drug monitor to review serious 
adverse event reports, in the event of disagreement between the reporting physician and the 
AMC Medical Monitor regarding the attribution of the event to the investigational agent(s) (i.e., 
determination of whether the relationship is unrelated, unlikely, possible, probable, or definite), 
the AMC Medical Monitor will provide the final determination of the relationship. 
 
The AMC ODMC provides listings of all reported adverse events and serious adverse events to 
the Protocol Chair and Co-chair(s) for review on a regular basis.  The AMC ODMC compiles 
these events in a tabular format and posts them on the password-protected section of the AMC 
web site where these reports are updated nightly.  The AMC web site is accessible to all AMC 
investigators, co-investigators, and their staff.  Email notification that this information is 
available on the web site will be sent to all site PIs.  It is the responsibility of each site to 
provide this information to their respective IRBs, if required by their IRB.  For blinded studies, 
the serious adverse events are reviewed and tabulated without treatment assignment.  The AMC 
Medical Monitor will review listings of all reported adverse events on a quarterly basis for 
safety concerns. 
 
Accrual summaries for each AMC trial are updated nightly on the password-protected section of 
the AMC web site.  The progress of each AMC trial is reviewed regularly by the Protocol Chair 
and also by the appropriate disease-oriented Working Group during scheduled conference calls.  
For phase I dose escalation trials, dose escalation (or dose de-escalation) is based on the rules in 
the protocol and the Protocol Chair, AMC Medical Monitor, and Group Statistician determine 
whether these criteria have been met.  For phase II trials, stopping the trial for toxicity or 
efficacy, or suspending enrollment pending observation of responses in a multi-stage phase II 


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trial, is based on meeting criteria stated in the protocol, and the Protocol Chair, AMC Medical 
Monitor, and Group Statistician determine whether these criteria have been met. 
 
For phase III trials, the AMC has formed an independent Data Safety and Monitoring Board 
(DSMB).  Voting members of the DSMB are physicians, a statistician, and a patient advocate.  
All voting members are from outside the AMC.  Nonvoting members are the AMC Group 
Statistician, the Statistician listed on the protocol, an AMC Operations Center staff member, two 
representatives (normally a clinician or statistician) from the Office of HIV AIDS Malignancy 
(OHAM) or from the Cancer Therapy Evaluation Program, Division of Cancer Treatment and 
Diagnosis, of the National Cancer Institute (NCI).   The AMC Data Safety and Monitoring 
Board reviews AMC phase III studies in accordance with the National Cancer Institute’s Policy 
for Data Safety and Monitoring.  Confidential reports of all phase III trials are prepared by the 
AMC Group Statistician with support from the AMC ODMC. A written report containing the 
current status of each trial monitored, and when appropriate, any toxicity and outcome data, are 
sent to DSMB members by the AMC ODMC within the timelines specified by the AMC DSMB 
Charter.  This report addresses specific toxicity concerns as well as concerns about the conduct 
of the trial.  The report may contain recommendations for consideration by the DSMB 
concerning whether to close the trial, report the results, or continue accrual or follow-up. 
 
The results of each DSMB meeting are summarized in a formal report sent by the DSMB Chair 
to the Group Chair and AMC ODMC. The DSMB report contains recommendations on whether 
to close each study reviewed, whether to report the results, and whether to continue accrual or 
follow-up. A primary recommendation (e.g., continue with no change; recommended or 
required modification; stop) must be included in the document. The Group Chair is then 
responsible for notifying the Protocol Chair and relevant Disease-oriented Working Group Chair 
before the recommendations of the DSMB are carried out. In the unlikely event that the Protocol 
Chair does not concur with the DSMB, then the NCI Division Director or designee must be 
informed of the reason for the disagreement.  The Study Chair, relevant Disease-oriented 
Working Group Chair, Group Chair, DSMB Chair, and NCI Division Director or designee will 
be responsible for reaching a mutually acceptable decision about the study.  CTEP approval of a 
formal amendment will be required prior to any implementation of a change to the study. 
 
Following a DSMB meeting, a summary of the serious adverse events reported to the DSMB is 
posted to the AMC web site.  It is each site’s responsibility for conveying this information to its 
IRB. 
 
Plans for Assuring Compliance with Requirements Regarding the Reporting of Adverse 
Events (AE) 
 
For trials monitored by the NCI’s Clinical Data Update System (CDUS), adverse event 
information is transmitted electronically to NCI on a quarterly basis.  For trials monitored by 
NCI’s Clinical Trials Monitoring Service (CTMS), adverse event information is transmitted 
electronically to NCI every two weeks. 
 
The Protocol Chair, AMC Group Chair, and the AMC ODMC share responsibility in assuring 
that participating investigators comply with the protocol requirements for adverse event 


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reporting.  All AMC investigators certify compliance with NCI and FDA requirements for 
adverse event reporting by signing the AMC Adherence Statement for site membership, the 
protocol signature page for each protocol active at the site, and Form FDA-1572 for CTEP 
investigator registration and IND studies sponsored by AMC investigators.  Investigators are 
responsible for identifying and reporting all adverse events to the AMC ODMC, CTEP-AERS, 
and/or sponsors according to the protocol requirements, and assuring compliance with reporting 
to the local IRB.  Protocol compliance with adverse event reporting requirements is assessed by 
the AMC ODMC during routine site monitoring visits by reviewing the site’s source 
documentation.   
 
The data entry system used for AMC studies, AdvantageEDCSM (a web-based data entry and 
enrollment system), is programmed to notify the site investigator, protocol chair, and AMC 
ODMC via email in the event that a site reports an adverse event that meets expedited reporting 
criteria to NCI and/or FDA.  If the site does not follow with a CTEP-AERS report, the AMC 
ODMC contacts sites to request an expedited report.  Additionally, the protocol chair, AMC 
ODMC, and the AMC Medical Monitor review reported adverse events on a routine basis to 
identify adverse events reported by sites that require expedited reporting via CTEP-AERS.  The 
Protocol Chair, AMC Group Chair, and IND sponsors have general oversight for assuring that 
routine and expedited adverse reporting requirements are met by the responsible parties. 
 
Plans for Assuring that any Action Resulting in a Temporary or Permanent Suspension of 
an NCI-Funded Clinical Trial is Reported to the NCI Grant Program Director 
Responsible for the Grant 
 
In the event that termination of the trial or major modification to the protocol is under 
consideration, the Protocol Chair will convene the AMC Data Coordinator and Disease-oriented 
Working Group Chair by conference call to discuss the options.  For phase I and II trials, the 
Protocol Chair also has the option of asking the AMC DSMB to review the study.  The AMC 
ODMC will inform the CTEP Protocol Information Office (PIO) when studies are temporarily 
or permanently closed.  The Cancer Treatment and Evaluation Program (CTEP) of the National 
Cancer Institute (NCI) must approve all protocol amendments prior to distributing to the AMC 
sites. 
 
Plans for Assuring Data Accuracy and Protocol Compliance 
 
All study data for AMC clinical trials are entered directly by AMC site staff into 
AdvantageEDCSM.  During data entry, the system performs validation checks on many fields 
and performs consistency checks between select fields.  Range checks are placed on each field 
to eliminate entry of out-of-range values.  Edit check programs are run on the database on a set 
schedule to identify and resolve inconsistencies between forms or data collected at different 
points in time.  AMC ODMC staff routinely interacts with site staff to resolve any data 
problems. 
 
In accordance with NCI guidelines, the AMC ODMC conducts monitoring visits at the AMC 
sites to evaluate compliance with regulatory issues, and to review data for specific cases by 
checking source documents.  These reports are sent to the site Principal Investigator and to the 


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NCI.  In the event that major violations are identified, sites are asked to provide a plan to correct 
deficiencies within 30 days.  If needed, a repeat site visit is conducted.  In the event that a site 
does not correct deficiencies in a pre-determined time frame, the AMC Executive Committee 
has the option of taking action against the site.  Possible actions include, but are not limited to, 
suspending enrollment of new patients to AMC trials until deficiencies are corrected; 
recommending a decrease in funding to the site; and requiring specific training for site 
investigators or staff members.