Clinical trial NCT02485834
Conditions: Adenocarcinoma of the Gastroesophageal Junction Gastric Adenocarcinoma Gastric Cancer
Sponsor: Alliance for Clinical Trials in Oncology
Start date: 2015-11-12; Completion date: 2018-08-01
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies how well fludeoxyglucose F-18 (FDG)/positron emission tomography (PET) directed treatment improves response in patients with stomach or gastroesophageal junction cancer that has not spread past the stomach and is not responding to the usual treatment. PET scans are a different way to take pictures of cancer and can be used to look at how much energy (such as glucose) is being used by the cancer. Using PET scans early to monitor the success of treatment may allow doctors to measure response and change treatment accordingly.

Detailed description:
Pre-registered patients receive standard pre-operative chemotherapy comprising epirubicin intravenously 50mg/m\^2 (IV) on day 1; oxaliplatin 130 mg/m\^2 IV or cisplatin 60 mg/m\^2 IV on day 1; and capecitabine 625 mg/m\^2 orally (PO) twice daily (BID) or fluorouracil 200 mg/m\^2/day IV continuously on days 1-21; and undergo FDG-PET following course 1 (days 15-19). Patients defined as FDG-PET non-responders are registered and randomized to 1 of 2 treatment arms.

Primary objective

To assess and compare the overall survival (OS) of patients with locally advanced gastric cancer classified as FDG-PET non-responders after one cycle of pre-operative chemotherapy randomly assigned to receive either salvage chemotherapy before and after surgery or immediate surgery followed by fluorouracil sensitized radiotherapy.

Secondary objectives

1. To assess and compare progression-free survival (PFS) between the treatment arms (Arms A and B).
2. To assess and compare R0 resection rate between the treatment arms (Arms A and B).
3. To assess and compare pathologic complete response (pCR) rate between the treatment arms (Arms A and B).
4. To assess the adverse events (AE) profile and safety of each treatment arm (Arms A and B), including post-operative mortality rate, 30-day post-operative targeted adverse events (i.e., dehiscence, significant infection, and re-operation rate).
5. To examine the changes of FDG-PET SUV induced by pre-operative chemotherapy at different time points (from baseline to completion of one cycle of treatment before randomization, and 2 cycles of salvage treatment) in patients randomized to salvage treatment arm (Arm B).
6. To collect measurement of fatigue and overall perception of QOL at registration of the study (Alliance registration QOL assessment study).

Arms: arm 1: Patients undergo surgery within 42 days of completion of pre-registration chemotherapy. Beginning within 49 days of surgery, patients receive 5-FU IV continuously and capecitabine PO BID on days 1-7, and undergo 3D-CRT or IMRT QD on days 1-5. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. arm 2: Beginning within 28 days of day 1 of pre-registration chemotherapy, patients receive docetaxel IV and irinotecan IV on days 1 and 8. Treatment repeats every 3 weeks for 2 courses. Beginning within 42 days of completion of docetaxel and irinotecan, patients undergo surgery. Patients also undergo FDG-PET within 14 days of planned surgery. Beginning within 60 days after surgery, patients receive 3 additional courses of docetaxel and irinotecan hydrochloride courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: FDG-PET intervention 2: surgery intervention 3: 5-FU intervention 4: capecitabine intervention 5: docetaxel intervention 6: Irinotecan intervention 7: 3D-CRT intervention 8: IMRT
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: 200 mg/m\^2/day IV intervention 4: oral 800 mg/m\^2 BID intervention 5: 30 mg/m\^2 IV intervention 6: 50 mg/m\^2 IV intervention 7: None intervention 8: None

Protocol documents:
Prot_SAP_000.pdf: 






 
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IMPACT OF EARLY FDG-PET DIRECTED INTERVENTION ON PREOPERATIVE THERAPY FOR 
LOCALLY ADVANCED GASTRIC CANCER: A RANDOM ASSIGNMENT PHASE II STUDY 
Pre-Registration (Step 0) Eligibility Criteria (see Section 3.2) 
Required Initial Laboratory Values 
Histologically confirmed adenocarcinoma of the stomach or gastroesophageal 
junction (Siewert type II, III) 
Absolute neutrophil 
count (ANC) 
≥ 1500/mm3 
Pre-treatment clinical stage of T3-4NanyM0 or TanyNpositiveM0 as determined 
by laparoscopy, CT scan (or PET/CT), or endoscopic ultrasound (histologic 
confirmation of lymph involvement not required). 
Patients can have measurable or non-measurable disease.  
Platelet Count 
Creatinine 
Total Bilirubin 
Alkaline Phosphatase 
≥ 100,000/mm3 
< 1.5 x ULN 
≤ 1.5 x ULN 
≤ 2.5 x ULN 
Patients must be eligible for curative intent surgical resection. 
AST / ALT ≤ 2.5 x ULN 
Patients must have an FDG avid tumor(s), which are defined as a primary tumor with an increased uptake in the region of the 
tumor that has an SUV of > 5.0 or a tumor:liver ratio of > 1.5. 
No prior history of Congestive heart failure (NYHA class I to IV) or known DPD deficiency 
No current grade 2, 3, or 4 of neuropathy or known hypersensitivity to oxaliplatin and cisplatin, capecitabine and 5-flurouracil, 
docetaxel or irinotecan 
Not pregnant and not nursing. Women of childbearing potential only, a negative serum pregnancy test pregnancy test done ≤ 7 
days prior to pre-registration is required 
Age ≥ 18 years and ECOG Performance Status 0 or 1 
Registration (Step 1) Eligibility Criteria (see Section 3.3) 
Patient must continue to be eligible for curative intent surgical resection 
FDG avid malignancy that is classified as an FDG PET non-responder, which are defined as having < 35% reduction in the 
FDG uptake of the primary tumor when compared to baseline. 
Chronic concomitant treatment with strong inhibitors of CYP3A4 and strong CYP3A4 inducers is not allowed. Such drugs must 
be discontinued 14 days prior to the start of study treatment. See Sections 8.1.9 and 8.1.10 for more information. 
Patient must have received one cycle of the following regimens during the pre-registration time period Epirubicin 
(optional), Oxaliplatin (or Cisplatin), Capecitabine (or Fluorouracil) 
Toxicity recovery including the following: Grade ≤ 2 neuropathy; Grade ≤ 2 diarrhea; Grade ≤ 2 mucositis 
Pre-registration chemotherapy given within 42 days of initiation of randomized treatment  
Schema 
Baseline FDG-PET Scan (1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
1  
Baseline FDG-PET scan is to be performed within 28 days of Cycle 1 pre-op chemo 
2  
Pre-op chemo (Cycle 1 of standard chemo) = Epirubicin (optional) + Oxaliplatin (or Cisplatin) + Capecitabine (or 
Fluorouracil) 
3  
Second scan is to be performed between days 15-19 of Cycle 1 of pre-op chemo. 
4  
A FDG-Responder is classified as someone who had ≥ 35% decrease in SUVmax on central review of the second FDG-
PET scan; they will be classified as screen failures and will not continue to the registration step. 
5  
A FDG-Non-Responder is classified as someone who had < 35% decrease in SUVmax on central review of the second 
FDG-PET scan. 
6 
Third scan is to be performed within 14 days of planned resection (Arm B Only) 
Please refer to the full protocol text for a complete description of the eligibility criteria and treatment plan. 
Sites must be ICL credentialed prior to patient enrollment (See Section 15.0 for details). 
Pre-Registration 
Pre-Op Chemo (Cycle 1 of Standard Chemo) (2)  +  Second FDG-PET Scan (3) 
Treatment per Physician Discretion 
(ONLY if FDG-Responder) (4) 
Registration/Randomization 
(ONLY if FDG-Non-Responder) (5) 
Arm A 
Surgery + 
Post-op FU/RT (5-
fluorouracil or capecitabine) 
Arm B 
2 Cycles Pre-Op Salvage 
Chemo  FDG-PET Scan (6) 
Surgery  3 Cycles Post-
Op Salvage Chemo 


 
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Table of Contents 
Section 
Page 
1.0  BACKGROUND 
............................................................................................................................ 7 
1.1  Rationale for selected approach and trial design. 
................................
........................................... 7 
1.2  Trial importance 
................................
................................
............................................................. 8 
1.3  Use of PET-SUV to Predict Response ........................................................................................... 8 
1.4  Targeted Therapy ......................................................................................................................... 10 
1.5  Salvage Chemotherapy In Gastric Cancer 
................................................................................... 11 
1.6  Post-operative Chemoradiation 
................................
................................
.................................... 11 
1.7  Rationale for using 35% decrease in SUV as the cutoff in Gastric Cancer 
.................................. 11 
1.8  Rationale for Current Study Design 
................................
............................................................. 12 
1.9  Registration Quality of Life (QOL) Measurements ..................................................................... 12 
2.0  OBJECTIVES 
............................................................................................................................. 13 
2.1  Primary objective ......................................................................................................................... 13 
2.2  Secondary objectives 
.................................................................................................................. 13 
2.3  Other objective(s) 
................................
................................
......................................................... 13 
3.0  PATIENT SELECTION 
................................
................................
............................................... 13 
3.1  On-Study Guidelines 
................................
................................
.................................................... 13 
3.2  Pre-Registration (Step 0) Eligibility Criteria 
............................................................................... 14 
3.3  Registration (Step 1) Eligibility Criteria to Treatment Arms A or B 
........................................... 15 
4.0  PATIENT REGISTRATION ....................................................................................................... 16 
4.1  CTEP Investigator Registration Procedures 
................................................................................ 16 
4.2  CTEP Associate Registration Procedures / CTEP-IAM Account 
................................................ 16 
4.3  CTSU Site Registration Procedures 
................................
............................................................. 16 
4.4  Patient Pre-Registration Requirements 
........................................................................................ 18 
4.5  Patient Registration/Randomization Requirements 
..................................................................... 19 
4.6  Patient Pre-Registration and Registration/Randomization Procedures using OPEN 
................... 19 
4.7  Stratification Factors and Treatment Assignments 
...................................................................... 19 
5.0  STUDY CALENDAR 
................................
................................
.................................................... 20 
6.0  DATA AND SPECIMEN SUBMISSION 
.................................................................................... 22 
6.1  Data collection and submission 
................................
................................
.................................... 22 
6.2  Specimen collection and submission for banking 
................................
........................................ 23 
6.3  FDG-PET Imaging Requirements, Credentialing and Submission Instructions – Required for 
ALL patients 
......................................................................................................................................... 25 
7.0  TREATMENT PLAN/INTERVENTION 
................................
................................................... 28 
7.1  Chemotherapy (or Adjuvant, or Neo-adjuvant therapy, if applicable) 
......................................... 29 
7.2  Surgery (Arms A and B) .............................................................................................................. 30 
7.3  Post-Operative Chemoradiation (For patients randomized to Arm A) 
......................................... 31 
7.4  FDG-PET/CT Imaging Procedures, Interpretation, Analysis, and Quality Assurance ................ 39 
8.0  DOSE AND TREATMENT MODIFICATIONS........................................................................ 40 
8.1  Ancillary therapy, concomitant medications, and supportive care 
............................................... 40 
8.2  Dose Modifications 
................................
................................
...................................................... 42 
9.0  ADVERSE EVENTS 
................................
................................
..................................................... 46 
9.1  Routine adverse event reporting 
................................................................................................. 46 
9.2  CTCAE Routine Study Reporting Requirements 
........................................................................ 47 
9.3  Expedited adverse event reporting (CTEP-AERS) ...................................................................... 47 


 
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10.0 DRUG INFORMATION 
............................................................................................................. 52 
10.1 General Considerations: 
................................
................................
............................................... 52 
10.2 Epirubicin (Ellence®) .................................................................................................................. 52 
10.3 Oxaliplatin (Eloxatin®, OXAL) 
................................................................................................. 54  
10.4 Cisplatin (Platinol®, CDDP) 
...................................................................................................... 58 
10.5 Capecitabine (Xeloda) 
................................................................................................................ 60 
10.6 Fluorouracil (Adrucil®, 5FU) 
................................
................................
...................................... 62 
10.7 Docetaxel (Taxotere®, TATER) 
................................
................................
.................................. 64 
10.8 Irinotecan (Camptosar®, CPT11) ................................................................................................ 67 
11.0 MEASUREMENT OF EFFECT 
................................
................................
.................................. 69 
11.1 PET/CT Imaging Interpretation of Baseline and Post-Induction Chemotherapy PET Scans....... 69 
11.2 Semiquantitative PET/CT Analysis Using the SUV Approach 
.................................................... 70 
11.3  Quality Assurance of PET/CT data 
................................
............................................................. 71 
11.4 Progression of Disease ................................................................................................................. 71 
11.5 Pathological tumor response after surgery 
................................
................................................... 71 
11.6 Completeness of Surgical Resection 
................................
............................................................ 71 
11.7  Recurrence of disease: 
................................................................................................................ 72 
12.0 END OF TREATMENT/INTERVENTION 
................................
............................................... 72 
12.1 Duration of Treatment 
................................
................................
.................................................. 72 
12.2 Managing ineligible patients and registered patients who never receive protocol intervention 
... 72 
12.3 Extraordinary Medical Circumstances 
................................
......................................................... 73 
13.0 STATISTICAL CONSIDERATIONS 
................................
......................................................... 73 
13.1 Primary Endpoint ......................................................................................................................... 73 
13.2 Secondary Endpoints 
.................................................................................................................. 73 
13.3 Sample size 
................................................................................................................................ 74 
13.4 Power justification 
...................................................................................................................... 74 
13.5 Analysis Populations 
................................
................................
.................................................... 75 
13.6 Treatment Efficacy Decision Rules: 
............................................................................................ 75 
13.7 Analysis plan: 
................................
................................
...............................................................
 75 
13.8 Early stopping rules based on R1/2 resection rate:....................................................................... 76 
13.9  Adverse events stopping rule: ...................................................................................................... 76 
13.10  
Study monitoring and reporting ................................................................................................... 77 
13.11 Inclusion of Women and Minorities 
............................................................................................ 77 
14.0 CORRELATIVE AND COMPANION STUDIES 
................................
..................................... 78 
14.1 Tissue Specimens for Banking 
................................
................................
..................................... 78 
15.0 GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING 
...................... 80 
15.1 Institutional credentialing 
........................................................................................................... 80 
16.0 REFERENCES .............................................................................................................................. 81 
APPENDIX I - REGISTRATION FATIGUE/UNISCALE ASSESSMENTS..................................... 84 
APPENDIX II: OPTIONAL PATIENT CAPECITABINE MEDICATION DIARY 
........................ 85 
APPENDIX III: INFORMATION ON POSSIBLE DRUG INTERACTIONS 
.................................. 87 
APPENDIX IV: EXTENDED STUDY SCHEMA 
................................
................................................. 90 
 
 


 
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1.0   BACKGROUND 
Patients  with  locally  advanced  gastric  cancer  achieve  a  survival  advantage  with  the  addition  of 
adjuvant therapy to surgical resection.  As evidenced by several large phase III random assignment 
studies, standard treatment algorithms now include the use of peri-operative chemotherapy[1], post-
operative chemo-radiation[2, 3], or post-operative chemotherapy[4-6] as adjuvant treatment options.  
However, no matter the treatment paradigm, the benefit of therapy in addition to surgery is modest.  
Across all treatment strategies, patients with locally advanced gastric cancer are afforded a 10-15% 
absolute improvement in survival over surgery alone when additional treatment is prescribed. The 
limited benefit of adjuvant therapy is likely due to the persistence of microscopic disease that was 
not eradicated by the additional therapy.  Based on numerous studies, it is also established that a good 
FDG-PET response, which can be identified early following initiation of therapy, is associated with 
improved patient survival. However, it remains unresolved whether or not FDG-PET can be used as 
a  barometer  for  the  response  in  micrometastatic  disease.    Specifically,  does  a  good  FDG-PET 
response simply reflect a tumor with better underlying biology that was destined not to recur, or does 
a good FDG-PET response indicate a higher likelihood that micrometastases were killed. If the latter 
is true, then patients with a poor FDG-PET response to chemotherapy (i.e. associated with a higher 
chance  of  recurrence)  may  
then  be  salvaged  with  alternative  
treatment.  
  This  proposal  
tests  
this 
question directly.   
In patients who are classified as FDG-PET non-responders, we will examine the utility of salvage 
therapy  versus  standard  of  care.  
  If  we  demonstrate  an  
improvement  
in  FDG-PET  response  and 
survival in FDG-PET non-responding patients who receive salvage therapy, it would support two 
important concepts that would advance the field: (1) that FDG-PET may be used as a surrogate for 
response  in  micrometastatic  disease,  and  (2)  early  intervention  with  salvage  chemotherapy  is 
meaningful. Alternatively, if salvage therapy does not improve patient outcomes in FDG-PET non-
responders,  it  would  suggest  that  early  FDG-PET  response  may  be  only  a  prognostic  marker, 
identifying  
tumors  with  better  biology  
that  are  destined  
to  do  well,  or  
that our  salvage  
treatment 
options are presently inadequate. 
1.1   Rationale for selected approach and trial design.  
A standard treatment paradigm for patients with locally advanced gastric cancer is to administer 
pre-operative  chemotherapy  
followed  by  complete surgical  
resection,  
followed  by  additional 
post-operative chemotherapy[1].  Serial FDG-PET/CT scanning can identify response to pre-
operative chemotherapy by evaluation of the change from baseline in the standardized uptake 
value (SUV) of the administered FDG (18F-2-fluoro-2-deoxyglucose).  This response may be 
identified early in the pre-operative treatment plan, before completion of the first cycle [7-11].  
FDG-PET  non-responders,  which  comprise  approximately  50%  of  patients  who  
initiate  pre-
operative therapy, have significantly worse outcomes. Early assessment of response may afford 
the  opportunity  
to  modify  therapy  in  
those  patients  who  are  not  responding  in  an  effort  
to 
improve  patient  outcomes.  
In  essence, this  approach uses  
functional  FDG-PET imaging  as  a 
radiographic biomarker to personalize therapy – i.e. allows for a decision on appropriate therapy 
to be made early (within 2-3 weeks) following initiation of therapy.  Attempts to capitalize on 
the early identification of response to preoperative therapy have included stopping ineffective 
therapy and going directly to surgery[9], and adding radiation therapy to the same chemotherapy 
in  FDG-PET  non-responding  patients[12, 13].  Although  both  approaches  failed  to  improve 
patient outcomes in the FDG-PET non-responding group, it is notable that both approaches also 
involved changes to local-regional therapy – i.e. neither approach applied a change to systemic 
therapy.  Our proposal examines specifically the use of salvage systemic chemotherapy in FDG-
PET  non-responding  patients  
to  determine  
if  
the  early  application  of  alternative  
therapy  can 
improve the outcome of patients with locally advanced gastric cancer not responding to standard 
pre-operative therapy. 


 
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1.2   Trial importance  
The demonstration of the benefit of additional treatment following surgical resection in gastric 
cancer was initially reported in 2001 by the INT-0116 investigators who reported their results 
of the US phase III study of post-operative chemoradiation versus surgery alone[2].  Since this 
landmark  study,  there  have  been  several  phase  III  studies  across  the  globe  that  have 
demonstrated a similar benefit of additional treatment to surgery alone in patients with locally 
advanced  gastric  cancer.  
  There  
is  widespread  acknowledgement  
that  
the  benefit  of  current 
treatment paradigms is marginal (approximately 10-15% improvement in survival) and there is 
an ongoing intensive research effort to improve patient outcomes in this setting.   
The  recent  US  Intergroup  study  (CALGB  80101)  attempted  to  improve  efficacy  by 
intensification of post-operative chemotherapy with the addition of epirubicin and cisplatin in 
addition to post-operative fluorouracil sensitized radiation.  This negative study suggests that 
intensification of chemotherapy in unselected patients is not useful[14]. 
 An alternative approach 
is to add radiation to patients who are not responding to pre-operative chemotherapy for patients 
with locally advanced disease[12]. However, the addition of local-regional radiotherapy in non-
responding patients was also not beneficial when compared with a historical control.   
An  untested  approach  is  to  examine the  potential  role  of  alternative,  or  salvage,  systemic 
chemotherapy, in patients who are not responding to initial pre-operative therapy. 
 This approach 
leverages  
the  
fact  
that  gastric  cancer  
is  a  chemotherapy  sensitive  disease,  with  many  active 
chemotherapy agents[15].   Indeed, salvage chemotherapy has already demonstrated improved 
survival in the advanced, metastatic disease setting, and is now a standard treatment option [16, 
17].  Specifically, we propose to examine the efficacy of salvage chemotherapy in FDG-PET 
non-responders in the pre-operative setting.  Several studies now have demonstrated that FDG-
PET/CT can be used to identify non-responding patients early in their treatment course.  This 
protocol tests the paradigm that early switching to alternative systemic treatment early in the 
treatment will improve patient outcomes.  A positive result, i.e. that early identification of non-
response  
is  clinically  
relevant and actionable,  will  change  current therapeutic paradigms  and 
would  have  a  potential  profound  effect  on  the  management  of  patients  with  local-regional 
malignancies, not  only  gastric  cancer,  but  across  many  solid  
tumor  malignancies  where  pre-
operative therapy is indicated.   
1.3  Use of PET-SUV to Predict Response 
Several  studies  have  examined  whether  the  change  in  SUV  of  the  primary  tumor  with 
chemotherapy  
is  useful  
in  determining  
the  
response  
to  
the  
intervening  
therapy.  Notably,  
the 
studies evaluated different treatment regimens, with similar results, suggesting that FDG-PET 
metabolic  response  may  be  a  universal  property  of  cancer  therapeutics.  Most  studies  used 
pathological  
response  as  
the  gold  standard  for  evaluation  of  chemotherapy  efficacy.  This  
is 
commonly  measured using the Mandard system[18] or a simple modification of this system, 
where  pathological  response  is  classified  according  to  the  percentage  of  viable  tumor  cells 
remaining, with non-responders having >10% tumor cells remaining, partial response 0–10%, 
and complete responders 0% viable tumor cells.  
A first prospective study in 2001 by Weber et al of 40 patients with adenocarcinoma of the GE 
junction and gastric cardia demonstrated a median reduction in SUV of responders of more than 
three times that of non-responders and was significantly correlated with pathological response 
(P < 0.001). Response was also significantly associated with survival. Those with no response 
had a 2-year survival of 37% versus 60% in PET responders. A prospective trial by Ott et al 
used a predetermined level of reduction in SUV to determine the cut-off point for metabolic 
responder versus non-responder. This had been previously determined to be a reduction of 35% 
from baseline[19], which had been demonstrated to have a sensitivity and specificity of 93% 


 
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and 95%, respectively, for the detection of a pathological response[8, 19]. Sixty five patients 
with  locally advanced  GE  junction  tumors  undergoing  preoperative  chemotherapy  were 
enrolled. Baseline tumor FDG uptake was 8.1 ± 3.4 SUV for assessable patients. SUV uptake 
significantly  decreased  to  5.4  ±  2.0  (~33%)  in  the  follow-up  scan.  Eighteen  patients  were 
classified  as  metabolic  responders  and  38  as  metabolic  nonresponders.  The  pathological 
response was highly significantly correlated with the metabolic response (P < 0.001); 44% of 
patients with a metabolic response had a pathological response, compared to 5% of metabolic 
non-responders.  Median  overall  survival  for  non-responders  was  18  months,  significantly 
shorter  than  overall  survival  for  the  group  as  a  whole  at  32  months.  Median  survival  for 
metabolic responders had not yet been reached at the time of publication.  A similar study was 
performed at Memorial Sloan Kettering Cancer Center as a validation study[11]. In this study, 
patients  with  locally  advanced  but  resectable  gastric/GE  junction  adenocarcinoma  received 
preoperative chemotherapy with irinotecan and cisplatin for two cycles. An FDG-PET CT scan 
was performed at baseline and again at day 15 and day 35. This study confirmed the results 
initially reported by Weber et al, demonstrating that a significant drop in SUV from baseline 
was associated with the pathologic response to therapy as well as with patient survival[11]. 
The primary utility of a change in FDG-PET SUV from baseline as a marker for response to 
chemotherapy  and  subsequently  survival  is  that  this  information  is  available  early  in  the 
treatment plan, and thus could potentially be used in order to guide future management. This 
approach was taken by Lordick et al in the MUNICON trial [9]. This study recruited 119 patients 
with  locally  advanced  tumors  of  the  GE  junction  undergoing  preoperative  chemotherapy. 
Patients  who  did  not  meet  a  predefined  metabolic  response  level  on  FDG-PET  of  a  35% 
reduction from baseline SUVmax 2 weeks after commencing treatment did not continue with 
chemotherapy but proceeded directly to surgery. Metabolic responders completed the course of 
preoperative  chemotherapy  and  
then  proceeded  
to  surgery;  49%  of  patients  were  metabolic 
responders  and  51%  were  metabolic  non–responders.  Of  the  metabolic  responders,  58% 
achieved a major histological response, with 0% in the non-responders. R0 surgical resection 
was  possible  
in  96%  of  metabolic  
responders  and  
in  74%  of  metabolic  non-responders.  On 
pathologic assessment, metabolic responders demonstrated earlier stage tumors than metabolic 
non-responders.  Metabolic  non-responders  had  a  median  event-free  survival of  14.1  months 
compared to 29.7 months in metabolic responders. It was noted that metabolic responders who 
did not have a pathological response had survival comparable to those who were metabolic non-
responders, implying that a metabolic response was necessary but not sufficient for improved 
survival [9].  
In a cross trial comparison between the original study by Ott et al, where chemotherapy was 
continued despite a metabolic non-response, and MUNICON where non-responders proceeded 
directly to surgery, amongst those patients that went on to complete surgical resection, survival 
between non-responders in both groups was similar. This suggests that, amongst metabolic non-
responding patients,  patient  survival  was  unaffected  (either  adversely  or  positively)  by 
continuing  with  ineffective  chemotherapy  or  by  stopping  ineffective  chemotherapy  and 
proceeding early to surgery. These results have led to a clinical trial in which failure to respond 
to initial induction chemotherapy with a reduction in SUV on PET is followed by introduction 
of  a  salvage  regimen  of  non-cross  resistant  chemotherapy  in  an  effort  to  improve  outcome 
(NCT00737438  on  clinicaltrials.gov;  Memorial  Sloan  Kettering  study, IRB  08-081).  PET 
responders (≥35% decline in SUV) continued standard ECX for 2 more cycles prior to surgery, 
whereas, PET  non-responders  switched  to  2  cycles  of  salvage  irinotecan/docetaxel  based 
therapy[20].  Though this study closed prematurely, in the first 20 patients enrolled, 11/20 were 
classified  as  FDG-PET  responders.    Ten  out  of  11  (91%)  underwent  R0  resection:  1/10 
pathologic  CR,  3/10  pathologic  PR.  
  Nine  out  of  20 patients  were  PET  non-responders,  and 
switched to salvage therapy. 
 Seven out of 9 non-responders had R0 resection, and none achieved 


 
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a pathological response. The DFS for PET responders was 27.8 months (95% CI 10.3-27.8) and 
DFS in salvage group has not been reached.  These data support the proposed study of an early 
cross over to improve patient outcomes with salvage therapy.  
1.4  Targeted Therapy 
Recently, several targeted therapies have been examined in gastric cancer, with few positive 
results.  Since the success of trastuzumab in the ToGA trial for metastatic gastric cancer there is 
interest in multi-targeted inhibition of pathways. In the ToGA study, trastuzumab, a humanized 
anti-HER2 monoclonal antibody was evaluated in addition to fluropyridimidine and platinum 
combination chemotherapy. The median OS was improved significantly in the trastuzumab arm 
compared with the chemotherapy-alone arm (13.5 months vs. 11.1 months, p = 0.0048; hazard 
ratio [HR], 0.74; 95% confidence interval, 0.60 to 0.91) and benefit was most evident in patients 
with  HER2  overexpressing  
tumors  
(OS  16  months  vs.  11.8  months[21].  Lapatinib  
is  a  dual 
inhibitor of the tyrosine  kinase  domains  of  HER1  and  HER2.  Two  
international  
randomized 
studies have completed accrual testing lapatinib in addition to systemic chemotherapy. In the 
TYTAN trial, lapatinib in addition to paclitaxel was compared to paclitaxel alone in patients 
progressing on platinum-based first line therapy. Median overall survival was 11.0 months for 
the combination compared with 8.9 months with paclitaxel alone but did not reach statistical 
significance (hazard ratio [HR]: 0.84; p = 0.2088). In a preplanned subgroup analysis median 
OS among patients in the HER2 IHC 3+ subgroup was 14.0 months vs 7.6 months in favor of 
the addition of lapatinib (HR: 0.59; p = 0.0176)[22]. The LOGiC 
trial compares first line therapy 
with capecitabine and oxaliplatin with or without lapatinib. Accrual was complete as of March 
2013  and  results  are  awaited.  In  the  localized  setting,  the  addition  of  trastuzumab  to  pre-
operative chemoradiation is being examined in esophageal cancer (RTOG 1010).  The proposal 
to  evaluate  trastuzumab  in  patients  with  locally  advanced  gastric  cancer  through  the  US 
Cooperative groups was met with limited enthusiasm because of concerns for patient accrual. 
Inhibition  of  the  EGFR  pathway  has  been  examined  in  two  recent  phase  III  studies,  the 
EXPAND  and  
the  REAL-3  
trials  which  explored the  addition  of two  monoclonal  antibodies 
against  EGFR-  cetuximab  and  panitumumab  respectively-  in  combination  with 
platinum/fluoropyrimidine chemotherapy [23, 24]. Both trials failed to show OS benefit [9.4 vs 
10.7 months, p= 0.9547 in the EXPAND trial] and actually suggested inferior survival with the 
addition of anti-EGFR therapy [OS, 8.8 months vs. 11.3 months, p = 0.013, REAL-3].  Further 
development of EGFR inhibition in gastric cancer is unlikely at this point.  
Antiangiogenic therapy has been examined in advanced gastric cancer as well.  The AVAGAST 
study  
failed  
to  show  any  
improvement  
in  OS  with  
the  addition  of  bevacizumab  
to  standard 
platinum/fluoropyrimidine therapy in first-line unselected metastatic gastric cancer patients[25]. 
In  subset  analyses  
it  was  observed  
that  patients  with  high  baseline  plasma  VEGF-A  levels 
showed a trend toward improved  OS (HR  0.72;  95%  CI,  0.57  
to  0.93)  vs.  patients  with  
low 
VEGF-A levels (HR, 1.01; 95% CI, 0.77 to 1.31; interaction P = 0.07)[26]. Ramucirumab (IMC-
1121B) is a fully human IgG1 monoclonal antibody targeting VEGF-receptor 2. The REGARD 
study,  a  placebo-controlled,  double-blind,  phase  III  
international  
trial,  was  conducted  
in  
the 
second line setting in patients with metastatic gastric or GEJ adenocarcinoma. Median OS was 
5.2 months for ramucirumab and 3.8 months for placebo [HR 0.776 (95% CI, 0.603-0.998; p = 
0.0473)][27].  The role of antiangiogenic therapy remains investigational in the preoperative 
setting.  There is an ongoing phase III study evaluating standard chemotherapy with or without 
bevacizumab  in  the  preoperative  setting  run  in  England  by  the  MRC  (MAGIC-B, 
NCT00450203). 


 
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1.5   Salvage Chemotherapy In Gastric Cancer 
Gastric cancer is a chemotherapy-sensitive disease, with multiple standard first-line therapies 
associated  with  
response  
rates  of  ~35-50%,  and  second-line  
response  
rates  of  ~15-35%[15].  
There have been 2 recent studies that demonstrate a clear advantage of salvage chemotherapy 
(2nd line) following progression on first line therapy for metastatic disease.  Taxanes are active 
in gastric cancer, and there is considerable data of taxane-based combination therapies in the 
salvage setting. 
Summarizing data from phase II 2nd line studies following progression on cisplatin/fluorouracil 
based  first  line  therapy  reveals  a  response  rate  range  of  11-35%,  median  time  to  tumor 
progression range of 2.7-4.4 months, and median 2nd line overall survival of 6.0-9.1 months 
with  taxane  based  therapy.    The  choice  of  docetaxel/irinotecan  was  chosen  as  the  salvage 
regimen based on the fact that the drugs are not cross-reactive with the first line therapy, and 
there is adequate salvage data in this setting. The specific non cross-resistant regimen we are 
proposing, weekly irinotecan and docetaxel, was examined in the salvage setting in metastatic 
gastric  cancer[28].  
  The  investigators  observed  a  salvage  response  rate  of  33%,  with  most 
common  
toxicity  being  
febrile  neutropenia (8%),  nausea  and  vomiting,  and diarrhea (both  < 
5%). 
1.6   Post-operative Chemoradiation 
The potential benefit of the addition of post-operative chemoradiation following preoperative 
chemotherapy  and  adequate  surgery  is  currently  being  tested  in  a  phase  III Dutch  study 
(CRITICS, NCT00407186), with expected results in 2016.  The use of salvage chemo/RT in 
PET non-responders has been examined previously. The MUNICON-II study examined the role 
of salvage chemoradiation in PET non-responders in patients with distal esophageal and GEJ 
tumors,  and  found  that  the  addition  of  chemoradiation  following  poor  PET  response  to 
chemotherapy was not associated with improvement in pathologic response rates and did not 
improve  survival  when  compared  
to  historical  controls[12]. However, despite  
these  data, in 
which  patients  are  demonstrated  to  have  lack  of  response  to  standard  preoperative 
chemotherapy,  post-operative  chemoradiation  is  commonly  administered,  extrapolating  the 
results  of  
INT-0116.  
  We will  
therefore  
include  post-operative chemoradiation as  a standard 
option for patients in the salvage group who are randomly assigned to direct surgical resection. 
1.7   Rationale for using 35% decrease in SUV as the cutoff in Gastric Cancer 
Two  studies  evaluating  FDG  PET  scans  in  the  preoperative  setting  in  gastric  cancer  were 
performed  at  MSKCC  (MSK  IRB  03-032[11] and  IRB  08-081[29],  both  manuscripts  in 
preparation),  together  treating  62  patients  with  gastric  cancer.  In  addition,  Ott  and 
colleagues[30] reported  
their  experience  
in  44  patients  with  gastric  cancer,  providing  a  
total 
experience of 106 patients with localized gastric cancer having been evaluated with an early 
PET scan to predict treatment response. Ott and colleagues used the 35% cutoff as currently 
proposed  and  found  a  significant  correlation  with  patient  survival.  The  MSK  03-032  study 
similarly  found  a  significant  correlation  with  PET  response  and  survival,  despite  using  a 
different preoperative chemotherapy regimen of irinotecan and cisplatin. Specifically, the 03-
032 study examined the decrease in SUVmax serially at the end of cycle 1 (day 15) and at the 
end of cycle 2 (day 35) of preoperative chemotherapy. We found that the median decrease in 
SUVmax was 35% at day 15, which is identical to the median decrease identified by Weber and 
colleagues initially taken at day 14 with cisplatin and fluorouracil.[19] This cutoff of 35% has 
been used subsequently as the threshold value to distinguish response in gastroesophageal cancer 
using many different preoperative chemotherapy regimens, where the PET scan for response 
assessment is performed early in the treatment plan. This suggests that a decrease in FDG PET 
uptake may be a surrogate for cytotoxic therapy response, independent of the actual treatment 


 
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regimen used. In the MSK 03-032 study, we also found that the median SUVmax decrease by 
day 35 was 42%, and also significantly correlated with survival.[11] This finding has also been 
previously reported, suggesting that SUV uptake continues to decrease as patients who respond 
to treatment continue on therapy.[7, 31] Our current proposal examines a PET scan after cycle 
1 (day 16-19), and uses a 35% cutoff, which is consistent with previous studies, and which has 
the most validated data across both gastric and esophageal malignancies.  Notably, this is also 
the cutoff used in protocol 08-081, which has provided preliminary consistent positive results 
already.[29] 
Together, we believe these data support utilizing the 35% threshold as a biomarker for response 
in advanced gastric cancer. 
1.8   Rationale for Current Study Design 
As mentioned above, there is one published study examining the role of salvage chemoradiation 
in patients with a poor PET response to chemotherapy (MUNICON-II)[12].  These data might 
suggest  
that  patients  with  a  poor  metabolic  
response  
to  
initial  chemotherapy  have  
refractory 
underlying  
tumor biology because in  
this  study,  salvage  chemoradiotherapy  did  not  
improve 
survival.  However, patients who received salvage chemoradiation on this study received either 
cisplatin or fluorouracil as chemotherapy radiosensitizers – the same chemotherapy agents that 
they received prior to the PET scan.  Our hypothesis is that systemic chemotherapy that has not 
been  previously  given  
to  
the  patient  at full  systemic doses  may  better  eradicate  microscopic 
metastatic  disease  
than additional local-regional therapy.  We  propose  
to  examine the  
role  of 
alternative, salvage systemic chemotherapy in PET non-responding patients.  This is supported 
by two lines of evidence – first, that gastric cancer is a chemotherapy–sensitive disease with 
many agents having modest activity, and second that salvage strategies have proven beneficial 
in  the  metastatic  setting  with  documented  improvement  in  overall  survival  in  randomized 
studies,  and  is  now  standard  of  care.    This  second  point  suggests  that  patients  who  have 
progression on initial therapy still have the opportunity to achieve a survival benefit with salvage 
treatment.  Our  study  design  addresses  
the  value  of  early  switching  
to  salvage  chemotherapy 
prospectively,  examining  the  hypothesis  that  full  doses  of  systemic  non-overlapping 
chemotherapy improve patient survival, thereby directly addressing the underlying question of 
whether or not an early assessment of response (by an early PET scan) is actionable. 
Further, we have preliminary evidence that ‘second line’ chemotherapy can indeed salvage non-
responding  patients  in  the  neoadjuvant  setting  as  well.  Specifically,  we  initiated  a  single 
institution study to examine the role of salvage chemotherapy in the peri-operative setting, and 
found that in PET non-responding patients, salvage chemotherapy appeared to improve survival 
to that of responding patients[29].  Specifically, with a median follow up of 38.2 months, 2-year 
disease free survival was 55% (95% CI 30-85%) in PET responders and 56% (95% CI 20-80%) 
in PET non-responders who received salvage irinotecan/docetaxel[29]. Also notably, we used 
the identical construct of EOX chemotherapy, with a PET scan at the end of cycle 1, and then 
docetaxel/irinotecan to salvage PET non-responding patients. These data to support the concept 
of salvage chemotherapy in gastric cancer in the peri-operative setting. 
1.9  Registration Quality of Life (QOL) Measurements 
QOL measurements of fatigue and overall perception of QOL are routinely included in Alliance 
studies and will be assessed upon registration in this study.  Evidence has arisen indicating that 
baseline single-item assessments of fatigue and overall QOL are strong prognostic indicators for 
survival in cancer patients, independent of performance status. This evidence was derived from 
two  separate  meta-analyses  
recently  presented  at  ASCO,  
the  
first  
involving  23  NCCTG  and 
Mayo  Clinic  Cancer  Center  oncology  clinical  
trials,  
the  second  
involving  43  clinical  
trials. 
Routine  inclusion  of  these  measures  should  be  considered  similar  to  that  of  including 


 
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performance  status,  either  as  stratification  or  prognostic  covariates.[32, 33] It  will  take 
approximately one minute to complete this measure. 
2.0   OBJECTIVES  
2.1   Primary objective 
To assess and compare the overall survival (OS) of patients with locally advanced gastric cancer 
classified as FDG-PET non-responders after one cycle of pre-operative chemotherapy randomly 
assigned to receive either salvage chemotherapy before and after surgery or immediate surgery 
followed by fluorouracil sensitized radiotherapy. 
2.2  Secondary objectives 
2.2.1 To assess and compare progression-free survival (PFS) between the treatment arms (Arms 
A and B). 
2.2.2 To assess and compare R0 resection rate between the treatment arms (Arms A and B). 
2.2.3 To assess and compare pathologic complete response (pCR) rate between the treatment arms 
(Arms A and B). 
2.2.4 To assess the adverse events (AE) profile and safety of each treatment arm (Arms A and B), 
including post-operative mortality rate, 30-day post-operative targeted adverse events (i.e., 
dehiscence, significant infection, and re-operation rate). 
2.2.5 To  examine  the  changes  of  FDG-PET  SUV  induced  by  pre-operative  chemotherapy  at 
different  time  points  (from  baseline  to  completion  of  one  cycle  of  treatment  before 
randomization,  and  2  cycles  of  salvage  treatment)  in  patients  randomized  to  salvage 
treatment arm (Arm B). 
2.2.6  To collect measurement of fatigue and overall perception of QOL at registration of the study. 
(Alliance registration QOL assessment study) 
2.3  Other objective(s) 
Results of the primary analysis will be examined for consistency, while taking into account the 
stratification factors and/or covariates of baseline QOL and fatigue. 
3.0   PATIENT SELECTION 
For questions regarding eligibility criteria, see the Study Resources page. Please note that the Study 
Chair cannot grant waivers to eligibility requirements.  
3.1  On-Study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. 
All  relevant  medical  and  other  considerations  should  be  taken  into  account  when  deciding 
whether this protocol is appropriate for a particular patient. Physicians should consider the risks 
and  benefits  of  any  therapy,  and  therefore  only  enroll  patients  for  whom  this  treatment  is 
appropriate.  
Although they will not be considered formal eligibility (exclusion) criteria, physicians should 
recognize that the following may seriously increase the risk to the patient entering this protocol: 
•  Psychiatric illness which would prevent the patient from giving informed consent. 


 
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•  Medical  condition  such  as  uncontrolled  
infection  
(including  HIV),  uncontrolled  diabetes 
mellitus or cardiac disease which, in the opinion of the treating physician, would make this 
protocol unreasonably hazardous for the patient. 
•  Patients  with  a  “currently  active”  second  malignancy  other  than  non-melanoma  skin 
cancers. Patients are not considered to have a “currently active” malignancy if they have 
completed therapy and are free of disease for ≥ 3 years. 
•  Patients who cannot swallow oral formulations of the agent(s). 
In addition: 
•  Women and men of reproductive potential should agree to use an appropriate method of 
birth control throughout their participation in this study due to the teratogenic potential of 
the therapy utilized in this trial. Appropriate methods of birth control include abstinence, 
oral  contraceptives,  implantable  hormonal  contraceptives  or  double  barrier  method 
(diaphragm plus condom). 
3.2  Pre-Registration (Step 0) Eligibility Criteria  
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. 
It is not required to complete or submit the following page(s). 
When  calculating  days  of  
tests  and  measurements,  
the  day  a  
test  or  measurement  
is  done  
is 
considered Day 0. Therefore, if a test were done on a Monday, the Monday four weeks later 
would be considered Day 28. 
A female of childbearing potential is a sexually mature female who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 
12 consecutive  months  (i.e.,  has  had  menses  at  any  time  in  the  preceding 12 consecutive 
months). 
___   3.2.1   Documentation of Disease 
  ___  
Histologically confirmed  Adenocarcinoma  of  
the  stomach  or  gastroesophageal  
junction 
(Siewert type II, III) 
  ___  
Pre-treatment  clinical  stage  of T3-4NanyM0 or  TanyNpositiveM0  as  determined  by 
laparoscopy, CT scan (or PET/CT that includes diagnostic CT), or endoscopic ultrasound 
(histologic confirmation of lymph involvement is not required). Therefore, patients can 
have measurable or non-measurable disease. 
    
Patients with T1-2N0M0 tumors or patients with metastatic disease are NOT eligible. 
   3.2.2  Patients must be eligible for curative intent surgical resection. 
___   3.2.3  FDG Avid malignancy  
Patients must have an FDG avid tumor(s). 
FDG avid tumors are defined as a primary tumor with an increased uptake in the region 
of the tumor that has an SUV of > 5.0 or a tumor:liver SUV ratio of > 1.5. 
   3.2.4   No prior history of: 
  ___   
Congestive heart failure (NYHA class I to IV) 
  ___   
Known DPD deficiency 
   3.2.5   No current grade 2, 3, or 4 of neuropathy. 


 
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___   3.2.6  No  known  hypersensitivity  to any  of  the  following  agents: oxaliplatin, cisplatin, 
capecitabine, 5-flurouracil, docetaxel, or irinotecan. 
___   3.2.7  Not pregnant  and  not  nursing, because  
this  study  
involves  an  agent  
that  has  known 
genotoxic, mutagenic and teratogenic effects. 
Therefore, for women of childbearing potential only, a negative serum pregnancy test 
pregnancy test done ≤ 7 days prior to pre-registration is required. 
___   3.2.8   Age ≥ 18 years  
   ___   3.2.9  ECOG Performance Status 0 or 1 
   ___   3.2.10 Required Initial Laboratory Values:  
Absolute Neutrophil Count (ANC)  ≥ 1,500/mm3 
Platelet Count  ≥ 100,000/mm3 
Creatinine*  ≤ 1.5 x upper limit of normal (ULN) 
Total Bilirubin**  ≤ 1.5 x upper limit of normal (ULN) 
AST and ALT   ≤ 2.5 x upper limit of normal (ULN) 
Alkaline Phosphatase  ≤ 2.5 x upper limit of normal (ULN) 
*  
Either lab result or calculated clearance 
**  
Except in patients with Gilbert’s disease 
3.3  Registration (Step 1) Eligibility Criteria to Treatment Arms A or B 
___   3.3.1  Patient must continue to be eligible for curative intent surgical resection 
___   3.3.2  Disease  Progression: FDG  avid  malignancy  that  is  classified  as  an  FDG PET  non-
responder. 
PET  non-responders  are  defined  as  having  <  35%  
reduction  
in  
the  FDG  uptake  of  
the 
primary tumor when compared to baseline. 
___   3.3.3   Concomitant Medications 
Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this 
trial. Patients on strong CYP3A4 inhibitors must discontinue the drug 14 days prior to the 
start of study treatment. See Section 8.1.9 for more information. 
Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must 
discontinue the drug 14 days prior to the start of study treatment. See Section 8.1.10 for 
more information. 
___   3.3.4  Patient must have received only one cycle of the following regimens (with or without 
epirubicin) during the pre-registration time period and no other therapy for gastric 
or gastroesophageal junction cancer: 
-  Oxaliplatin, and Capecitabine 
-  Oxaliplatin, and Fluorouracil 
-  Cisplatin, and Capecitabine 
-  Cisplatin, and Fluorouracil 
 
 




 
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IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol  and  submit  IRB  approval  and  supporting  documentation  to  the  CTSU  Regulatory 
Office before they can be approved to enroll patients.  Assignment of site registration status in 
the CTSU Regulatory Support System (RSS) uses extensive data to make a determination of 
whether a site has fulfilled all regulatory criteria including but not limited to: an active Federal 
Wide  Assurance  (FWA)  number,  an  active  roster  affiliation  with  the  Lead  Network  or  a 
participating  organization,  a  valid  IRB  approval,  and  compliance  with  all  protocol  specific 
requirements. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process. Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
4.3.1 Downloading Site Registration Documents 
Site registration forms may be downloaded from the A021302 protocol page located on the 
CTSU members’ website. Permission to view and download this protocol and its supporting 
documents  
is  
restricted  and  
is  based  on  person  and  site  
roster  assignment  housed  
in  
the 
CTSU RSS. 
•  Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
•  Click on the Protocols tab in the upper left of your screen 
•  Either enter the protocol # in the search field at the top of the protocol tree, or 
•  Click on the By Lead Organization folder to expand 
•  Click on the NCTN – ALLIANCE link to expand, then select trial protocol 
#A021302 
•  Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided 
4.3.2 Requirements for A021302 Site Registration 
•  CTSU Transmittal Sheet (optional)  
•  IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, 
an  IRB-signed  CTSU  Certification  Form,  Protocol  of  Human  Subjects  Assurance 
Identification/IRB  Certification/Declaration  of  Exemption  Form,  or  combination  is 
accepted) 
•  Imaging Core Lab (ICL) at IROC Ohio confirmation 
•  CTSU RT Facilities Inventory Form  
NOTE: Per NCI policy all institutions that participate on protocols with a radiation therapy 
component  must  participate  in  the Image  and  Radiation  Oncology  Core  (IROC) 
monitoring program. If this form has been previously submitted to CTSU it does not 
need to be resubmitted unless updates have occurred at the RT facility 






 
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5.0   STUDY CALENDAR 
Laboratory and clinical parameters during treatment are to be followed using individual institutional 
guidelines and the best clinical judgment of the responsible physician. It is expected that patients on 
this study will be cared for by physicians experienced in the treatment and supportive care of patients 
on this trial.  
The tests and procedures outlined in the study calendar have been reviewed by a Medicare coverage 
analyst. 
Pre-Study Testing Intervals  
•  To  be  completed ≤ 16  DAYS before pre-registration  and registration:  All  
laboratory  studies, 
history and physical. 
•   To be completed ≤ 28 DAYS before pre-registration and/or registration: Any X-ray, scan of any 
type or ultrasound which is utilized for tumor measurement per protocol. 
•  To  be  completed ≤ 42  DAYS  before pre-registration and/or registration:  Any  baseline exams 
used for screening, or any X-ray, scan of any type or ultrasound of uninvolved organs which is 
not utilized for tumor measurement. 
 
Prior to 
Pre-
Registr-
ation* 
 
Prior to 
Registr-
ation 
Arm A: Day 1 
of Weeks 1 
and 4 of 
ChemoRT 
 
Arm B: 
Day 1 of 
Each Cycle 
(Pre and 
Post 
Surgery)** 
 
Prior to 
Surgery 
Post 
treatment 
follow 
up*** 
At PD, 
withdra
wal, or 
removal
*** 
Tests & Observations 
 
History and physical, 
weight, PS† 
X  
  
X  
X  
X  
X  
X 
Height 
X  
  
 
  
  
  
 
Pulse, Blood Pressure  
X  
  
X 
C  
X  
X  
 
Echo or MUGA 
(Recommended not 
required) 
X  
  
 
  
 
  
 
Adverse Event Assessment#  X  
X  
X  
X  
D  
  
 
Registration Fatigue/ 
Uniscale Assessment 
  
X(1)  
 
  
  
  
 
Laboratory Studies 
 
Complete Blood Count, 
Differential, Platelets 
X  
  
X  
C  
X  
X  
 
Serum Creatinine,  
X  
  
X  
X  
X  
X  
 
AST, ALT, Alk. Phos., Bili  
X  
  
X 
X  
X  
X  
 
Serum HCG 
X(2)  
  
 
  
  
  
 
Staging 
 
FDG-PET Scan (A)  
X (3)  
R  
 
  
D  
  
 
CT chest/abd/pelvis (B)  
X (3)  
  
 
  
  
X  
 
Correlative studies: For patients who consent to participate 
Tissue and Blood samples  See Section 6.0 for Specimen Submission Requirements for Consenting Patients 
*   Labs completed prior to pre-registration may be used for day 1 of cycle 1 tests if obtained ≤ 16 
days prior to treatment.  
**  Treatment on Arm A (surgery) must begin within 42 days completion of the pre-registration 
chemotherapy. Treatment on Arm B (chemotherapy) must begin within 28 days of day 1 of pre-


 
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registration  chemotherapy.  All  
tests,  observations,  and  
labs  
for  Arms  A  and  B  have  a  5  day 
window. 
***  Physical examination, adverse event assessment and labs are required 21 to 35 days after the 
end of treatment. All patients are required 
to complete a physical exam, labs, and scans 6 months 
(+/- 4 weeks) following surgery. Thereafter, physical exam and labs are every 12 weeks (+/- 4 
weeks) and scans are every 24 weeks (+/- 4 weeks) until disease progression or for 3 years after 
registration, whichever comes first. Thereafter, survival information is required every 6 months 
until 5 years following registration. Patients who do not receive adjuvant therapy (in both arms 
A and B for a reason other than ineligibility) are required to complete a physical exam and labs 
3 months (+/- 4 weeks) following surgery. See also Section 12.0.  
†   Drug dosages need not be changed unless the calculated dose changes by ≥ 10%. 
#   Solicited AEs are to be collected starting at baseline. Routine AEs are to be collected starting 
after registration. See Section 9.3 for expedited reporting of SAEs. 
1  To be completed after registration and ≤ 7 days prior to treatment, see Section 1.9 and Appendix 
I. 
2  For  women  of  childbearing  potential  
(see Section  3.3).  Must  be  done ≤ 7  days  prior to  pre-
registration. 
3  Baseline scans can include either: 1) a CT chest/abd/pelvis and FDG-PET scan or 2) an FDG-
PET/CT scan with diagnostic quality CT. The CT in either case must be of diagnostic quality, 
performed with both IV and oral contrast, and acquired with 5 mm or less slice thickness. If 
option  2  
is  used,  a  separate  CT  need  not  be  performed.  Supporting  documentation  
is  
to  be 
submitted, per Section 6.1.1. Baseline FDG-PET scan should be performed within 28 days of 
starting platinum/FU based cycle 1 chemotherapy, and the diagnostic CT should be performed 
within 42 days of starting platinum/FU based cycle 1 pre-registration chemotherapy. 
A  FDG-PET Scan imaging is from base of skull to mid-thigh. PET scan is to be performed prior 
to and during cycle 1 of pre-registration chemotherapy (day 15-19) in all patients. In Arm B, 
PET scan is to be performed after 2 cycles of salvage chemotherapy, within 14 days of planned 
surgical resection. 
B  CT scan is to be performed prior to pre-registration chemotherapy. After completion of protocol 
therapy, see footnote *** for scan frequency 
C   Also to be performed on Day 8 of Cycles 1 and 2 of Pre-Op Salvage Chemotherapy 
D   Required for patients on Arm B only 
R  Research Funded. Scan should be performed on or between days 15 through 19. Fluorouracil or 
capecitabine should be held for 48 hours prior to PET scan. 








 
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6.2.3  Whole Blood submission for banking 
For patients who consent to participate, whole blood samples will be banked for potential 
studies described in Section 14.1. This sample should be collected prior to surgery. 
Collect 10 mL of peripheral venous blood in an EDTA (lavender) tube. The tube should be 
inverted  several  
times  
to  mix  
the  EDTA  and  
refrigerated  until  shipped  on  cool  pack  by 
overnight mail to the ABOSU.  
Label the sample with the following identification: 
1)   Procurement date 
2)   Alliance patient number 
3)   Alliance study number (i.e., A021302) 
4)   Whole Blood 
The samples should be shipped the same day that the blood is drawn per Section 6.2.1.  
6.3  FDG-PET Imaging Requirements, Credentialing and Submission Instructions – Required 
for ALL patients 
6.3.1 PET/CT Imaging Credentialing Procedure 
Prior to registering patients, all participating sites should review the imaging protocol and 
required forms with the CRA as well as individuals from the imaging facility who will be 
acquiring the PET/CT images. Data and form submission guidelines will be reviewed and 
contact information will be verified via correspondence with the ICL at IROC Ohio. 
6.3.2 Requirements for Participation 
1) The  participating  center  must  have,  or  have  access  to,  a  facility  with  an  
integrated 
positron-emission tomography and computed tomography (PET/CT) scanner. 
 
2) The  participating  center  must  have  the  ability  to  submit  PET  and  CT  studies 
electronically  to  the  ICL  in  digital  DICOM  format  (other  formats:  BITMAP,  JPG, 
hardcopy or scanned files are not acceptable). 
 
3) Participating  sites  must  be  credentialed  by  the  ICL  so  that  the  performance 
characteristics and infrastructure requirements are met, as follows: 
o If a site has been credentialed by the ICL for participating in CALGB 50303, 
CALGB  50604,  CALGB  50801,  CALGB  50904,  and/or CALGB  80803 
PET/CT  imaging  studies,  a  protocol  refresher  only  will  be  needed  for 
participating in Alliance A021302. 
o If a site has not been credentialed by the ICL, however the site participated or 
is participating in any other legacy Alliance PET/CT imaging trials, a protocol 
refresher (and a Virtual Site Visit, if necessary) is required for participating in 
Alliance A021302. 
o If a site has neither been credentialed by the ICL nor participated in any legacy 
Alliance  PET/CT  or  CT  
imaging  
trials,  
the  Alliance ICL  (IROC  Ohio)  will 
adhere  to  the  ACRIN  criteria  for  PET/CT  imaging  approval  procedures. 
Consistency  
in  
the  acquisition  protocol  both  
from  a  
time  and  an  acquisition 
mode is required. In addition, data management must be done in a standardized 
process.   
 
 


 
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In order for an institution to be approved to participate in this study, they will be required to 
review  
the  data  acquisition  and  quality  management  process  during  
the  virtual  site  visit 
coordinated  by  
the  
ICL  at  
IROC  Ohio,  which  will  be  scheduled  after  submission  of  
the 
following: 
a.  
Two test patients (FOR ALL PET/CT instruments utilized). Images of two 
unidentified  patients  shall  consist  of  
three  volume  or  multislice  
files  as 
follows: a) Whole body CT from PET/CT scanner; b) Whole body (torso) 
emission  with  attenuation  correction  
(A/C);  and  c)  Whole  body  
(torso) 
emission without A/C. 
 
b.  
Uniform phantom data with SUV measurement of the phantom (FOR ALL 
PET/CT  instruments  utilized).  Water-fillable  uniform  phantom:  The 
phantom must be filled with water, and a known amount of F-18 (either as 
fluoride  or  as  FDG)  should  be  
injected  
into  
the  phantom.  The  activity 
injected should be determined by measurement of the syringe before and 
after  
the  
injection  
in  a  properly  calibrated  dose  calibrator.  The  
injected 
activity should be chosen to result in an activity concentration similar to 
that encountered in clinical FDG imaging (i.e., 1 – 1.5 mCi of F-18 should 
be added to the 6,283 mL phantom: 2 mCi for the 9.293 mL phantom). 
After thoroughly mixing the phantom, the phantom must be scanned with 
the same protocol used for the patient imaging. The images also must be 
reconstructed with the same algorithm and filters sued for patient imaging. 
A  circular  or  elliptical  region  of  interest  (ROI)  covering  most  of  the 
interior of the phantom must be drawn over all slices, and the average SUV 
and  standard  deviation  must  be  measured  and  reported  
in  
the  PET/CT 
Instrument  Technical  Specifications  Form.  The  expected  SUV  for  the 
uniform phantom is 1.0 and the acceptable range is 0.9 to 1.1. 
 
c.  
Alternatively,  Ge-68/Ga-68  calibration  phantom:  This  phantom  can 
readily be scanned with the same protocol used for patient imaging. The 
assay  date  and  activity  from  
the  calibration  certificate  of  
this  phantom 
must  be  reported  on  the  PET/CT  Instrument  Technical  Specifications 
Form.  The  
images  must  be  reconstructed  with  
the  same  algorithm  and 
filters used for patient imaging. A circular or elliptical ROI covering most 
of  the  interior  of  the  phantom  must  be  drawn  over  all  slices,  and  the 
average SUV and standard deviation must be measured and reported in the 
PET Instrument Technical Specifications Form. The expected SUV for the 
uniform phantom is 1.0 and the acceptable range is 0.9 to 1.1 
 
d.  
PET/CT Instrument Technical Specifications Form (FOR ALL  PET/CT 
instruments utilized). 
 
e.  
Imaging Site Personnel Form  
 
If  an  
institution’s  PET/CT  scanner  has  already  undergone  
legacy  ACRIN  credentialing, 
documentation of this certification may be provided to the ICL at IROC Ohio in lieu of the 
requirements above.  The ICL at IROC Ohio regularly performs team telephone calls as well 
as virtual site visits, and serves as consultant to help the local sites resolve questions with 
regard to adherence to the acquisition and reconstruction protocol. 
 
See Section 7.4 for FDG-PET scan requirements. 
 






 
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Patients defined as FDG-PET non-responders will be registered and randomized to go directly 
to surgery (Arm A) or to salvage chemotherapy (Arm B). Patients MUST begin treatment on Arm 
A  (treatment  meaning  surgery)  within  42  days  from  completing  platinum based  cycle  of 
chemotherapy given during pre-registration. Patients assigned to Arm B should begin treatment on 
Arm B (treatment meaning 1st cycle docetaxel irinotecan) within 28 days from day 1 of platinum 
based cycle of chemotherapy during pre-registration. 
Arm A patients (assigned  
to  
surgery  
first) will also receive post-operative FU/RT, which should 
begin  within  49  days  of  surgery. Post-operative  FU/RT  may  consist  of  either  5-fluorouracil  or 
capecitabine. Patients who are unable to initiate post-operative FU/RT within 56 days of surgery will 
not be required to have it. 
Arm B patients are treated with 2 cycles docetaxel + irinotecan.  Following completion of docetaxel 
+ irinotecan, a PET scan should be performed within 14 days of planned resection. The purpose of 
this PET scan is to ensure patient does not have metastatic disease and is still a surgical candidate. 
Then patients should undergo surgery, which should occur within 42 days of completing docetaxel + 
irinotecan. After surgery, patients should receive 3 further cycles of docetaxel + irinotecan, which 
should begin within 60 days of surgery.  
7.1  Chemotherapy (or Adjuvant, or Neo-adjuvant therapy, if applicable) 
7.1.1   Pre-registration Chemotherapy 
Agent  
Dose  
Route  
IV Duration  
Days 
Epirubicin 
(optional) (1) 
50 mg/m
2  
IV 
Per Institutional 
Standard 
Day 1 
Oxaliplatin (2) 
 
OR 
 
Cisplatin (3,4) 
130 mg/m
2 
 
 
60 mg/m
2 
IV 
 
 
IV 
Per Institutional 
Standard 
 
 
Per Institutional 
Standard 
Day 1 
Capecitabine * 
OR 
Fluorouracil* 
625 mg/m
2 bid 
 
200 mg/m
2/day 
Oral 
 
IVCI 
 
N/A 
 
Days 1-21 
 
Days 1-21 
(1) Epirubicin  is  optional – patients  may  proceed  with  therapy  without  epirubicin. Patients 
receiving  epirubicin may  receive  reduced  doses of  epirubicin  of  40mg/m
2 at  treating 
physician’s discretion 
(2) Patients may receive reduced dose of oxaliplatin at 115mg/m2 at treating physician’s discretion 
(3) Patients may receive reduced dose of cisplatin at 50mg/m2 at treating physician’s discretion 
(4) Choice of oxaliplatin or cisplatin is at treating physician’s discretion  
* Medication should be held for 48 hours prior to on treatment FDG-PET scan performed on target 
day 15-19. Medication can resume after the FDG-PET scan through, but not beyond, day 21 
(total # of days of capecitabine/fluorouracil received is 19 days). 


 
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7.1.2   Arm B Chemotherapy 
Agent  
Dose  
Route 
IV 
Duration 
Days 
Cycle 
Frequency 
Docetaxel  30 mg/m
2  
IV 
Per 
Institutional 
Standard 
Days 1 and 
8 
every 3 
weeks 
Irinotecan  50 mg/m
2  
IV 
Per 
Institutional 
Standard 
Days 1 and 
8 
every 3 
weeks 
7.2  Surgery (Arms A and B) 
At the time of surgical resection, as outlined by the protocol, the surgeons will follow standard 
surgical  procedures  
for  
the  
resection  of  a  gastric  cancer  specimen  as  outlined  by  
the  NCCN 
guidelines  for  gastric  cancer.  This  includes  adequate  resection  of  the  involved  area  of  the 
stomach  to  achieve  negative  microscopic  margins  utilizing  a  distal  gastrectomy,  subtotal 
gastrectomy  or  
total  gastrectomy,  as  needed.  T4  resection  may  require  en  bloc  resection  of 
involved structures. Wedge resections of the stomach are not considered appropriate resections 
for gastric adenocarcinoma and will be excluded.  
Gastric resection should include the regional lymphatics including perigastric lymph nodes and 
those along the named vessels of the celiac axis with a goal of examining at least 15 or greater 
lymph  nodes.  Due  
to  natural  variations  
in  
lymph  node  counts  
from  
individual  
to  
individual, 
patients  with lymph  node  counts  
less  
than  10 may  undergo  an  amended  final  analysis.  All 
patients should submit follow-up data. 
Reconstruction via a Bilroth I, Bilroth II or Roux-en-Y reconstruction is recommended.  
7.2.1 Surgical Quality Assurance  
General Guidelines 
The surgical quality will be assessed by the Surgical Study Chair. Surgical data from this 
study will be reviewed at regular meetings of the Surgical Quality Assurance Committee 
(SQAC)  of  the  Alliance.  This  committee  meets  quarterly  to  review  ongoing  Alliance 
protocols with surgical components.  
Any deviations in surgical quality identified by the SQAC will be addressed by the surgical 
Co-Chair of this trial, Dr. Vivian Strong.  
All  adverse  events  
in  
the  post-operative  period  will  be  documented  
to  determine  
risk  of 
complications related to neoadjuvant therapy followed by surgery. 
7.2.2  Definitions of Deviations in Protocol Performance  
Major Deviations 
The following will be considered major protocol deviations: 
•  Wedge resection for a gastric cancer  
•  Failure to perform a perigastric lymph node dissection 
Minor Deviations 
The following will be considered minor protocol deviations: 
•  Less than 10 lymph nodes harvested during operation 
•  Microscopically positive margin for cancer 


 
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•  Failure to perform a frozen section of the proximal margin at the time of 
surgery 
•  Incomplete documentation of anastomotic complication 
Summary Quality Assurance Evaluation and Scoring 
If a point score below 20 is determined, the Surgical Co-Chair will review the site 
and determine if remediation, retraining or exclusion from the protocol is required. 
Such  action  will  be  determined  within  30  days  of  finishing  the  QA  score 
assessment. 
7.3  Post-Operative Chemoradiation (For patients randomized to Arm A) 
Post-operative chemoradiation is to begin within 49 days of surgery. 
7.3.1 Chemotherapy 
Agent  
Dose  
Route  
Days  
Cycle Length 
Fluorouracil  
200 mg/m
2/day  
IV  
Continuous  
5 weeks 
OR 
Capecitabine  
800 mg/m
2 bid  
Oral 
Daily During 
Radiation 
5 weeks 
Chemotherapy is administered concurrently with radiation. Fluorouracil is administered as 
an IV continuous infusion for 7 days every week during RT. Capecitabine is administered 
only Monday through Friday during radiation. An optional patient capecitabine medication 
diary is provided in Appendix II for patient convenience. It does not need to be submitted 
to the Alliance Statistics and Data Center. 
7.3.2 Radiotherapy 
Radiation therapy will be started on the first day of combined chemoradiation. The total 
dose of RT will be 45 Gy in 1.8 Gy fractions. A volumetric treatment planning CT study 
will  be  required  for  
this  study.  Each  patient  will  be  positioned  and  
immobilized  as  per 
institutional  standards  
in  
the  
treatment  position  on  a  flat  
table. Treatment  plans  will  be 
submitted for review within 3 days of the start of radiation therapy. 
Please see Section 15.1.3 for credentialing requirements. 
7.3.2.1  Technical Factors 
Linear accelerators with a minimum energy of 6 MV will be used. A multiple field 3-
D conformal technique or IMRT will be used. All fields will be treated each day. The 
patient will be treated in the supine position. Radiation will be delivered 5 days/week, 
once per day. 
Digital submission of treatment plans is required for this portion of the study. See 
Section 7.3.2.13. 
7.3.2.2  Target Volume Definitions 
ICRU-50  and  62  prescription  methods  and  nomenclature  shall  be  utilized  for  
this 
study. This will apply for conformal and non-conformal techniques. These volumes 
shall be based on the following information: preoperative imaging including barium 
swallow  (if  available)  and  CT/MRI  findings,  surgical  findings  including  size  and 
location of the primary lesion and pathologically involved lymph nodes, and location 
of surgical margins. Normal tissue tolerance limits are defined in Section 7.3.2.9. 


 
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Gross  Tumor  Volume  (GTV): As  
these  patients  are  being  
treated  
in  
the  adjuvant 
setting there is no GTV. However, the area of the entire mass defined by preoperative 
imaging and pathological findings at the time of resection of the primary lesion should 
be  defined.  Areas  of  involved  adenopathy  should  be  carefully  depicted  and  their 
geographic  relationship  to  the  primary  lesion  be  accurately  defined  on  planning 
images. 
Clinical Target Volume (CTV): The CTV in general is defined in this study according 
to the description and tables below. These volumes are defined according to location 
of the primary tumor, as well as T and N stage 
Planning Target Volume (PTV): For the purpose of this study, a margin for motion 
and set-up  variability  is  
to  be  added  to  
the  clinical  
target  volume.  Depending  on 
immobilization methods and patient cooperation, this may vary but must be at least 1 
cm. Exact margins will be left up to the treating radiation oncologist and do not need 
to be uniform in all directions. If the treating radiation oncologist needs to decrease 
the  PTV  for normal  tissue  concerns  defined  in Section  7.3.2.9,  please  obtain 
permission from the RT Study Coordinator. 
7.3.2.3  General  Guidelines  of  Impact  of  T  and  N  Stage  on  Inclusion  of  Remaining 
Stomach, Tumor Bed, Nodal Sites within Irradiation Fields 
In general, for patients with node positive disease, there should be wide coverage of 
tumor bed, residual stomach, resection margins, and nodal drainage regions. Fields 
need to be modified to assure that tolerance of kidneys, spinal cord, liver, heart and 
lungs  are  respected.  For  node  negative  disease,  if  there  is  a  good  surgical  nodal 
resection  (evaluation  of  15+  nodes),  and  there  are  wide  surgical  margins  on  the 
primary tumor (at least 5 cm), treatment of the nodal beds is not necessary. Treatment 
of the residual stomach should depend on a balance between the likely normal tissue 
morbidity and the perceived risk of relapse in the residual stomach. 
The tables below define the sites that should be treated for various locations and T 
and N stages of the primary lesion (AJCC 7
th Edition). If a tumor involves more than 
one site, then the coverage should correspond to the at risk areas for both of the sites. 
7.3.2.4  General Guidelines for Gastroesophageal Junction Tumors 
For tumors of the gastroesophageal (GE) junction, the fields should be as below. In 
addition, the fields need to be extended into the chest to cover adequately any tumor 
bed  located  in  the  chest  with  margin.  The  extent  of  thoracic  coverage  will  be 
dependent on the known involvement, but should generally extend approximately 5 
cm proximal to the area of known esophageal involvement. Care should be taken to 
treat the peri-esophageal tissues at the level of the tumor fully. 


 
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Site of 
Primary 
and T, N 
Stage 
Inclusion into Irradiation Fields
#: 
Tolerance 
Organs or 
Structures to 
be Considered 
Stomach  
Remaining Volumes  
Tumor Bed 
Nodal Volumes 
Gastro-
esophageal 
Junction 
If can exclude 2/3 
one kidney (usually 
right) 
T stage dependent  N stage dependent  Heart, lung, 
spinal cord, 
kidneys, liver 
T3N0  
Variable dependent 
on surg-path 
findings* 
Medial left hemi-
diaphragm; adjacent 
body of pancreas 
None or peri-gastric, 
peri-esophageal; 
Optional^: 
mediastinal, celiac 
 
T4N0  
Preferable, but 
dependent on surg-
path findings* 
As for T3N0 plus 
site(s) of adherence 
with 3-5 cm margin 
Nodes related to site 
of adherence, +/- 
peri-gastric, peri-
esophageal, 
mediastinal, celiac 
 
T1-2 N+  
Preferable  
Not indicated for T1; 
for T2 Medial left 
hemi-diaphragm; 
adjacent body of 
pancreas 
Peri-esophageal, 
mediastinal, 
proximal peri-
gastric, celiac 
 
T3-4 N+  
Preferable  
As for T3, T4 N0  As for T1-2N+ and 
T4N0 
 
*  For  tumors  with  wide  (>5  cm)  surgical  margins  confirmed  pathologically,  treatment  of  residual 
stomach is optional if this would result in substantial increased normal tissue morbidity.  
# Use pre-op imaging, surgical clips and post op imaging. 
^ Optional node may be excluded for T3N0 lesions, if 15+ nodes have been pathologically examined. 
7.3.2.5  General Guidelines for Cardia/Proximal Third of the Stomach Tumors 
Site of Primary 
and T, N Stage 
Inclusion into Irradiation Fields
#: 
Tolerance 
Organs or 
Structures 
to be 
Considered 
Stomach  
Remaining 
Volumes 
Tumor Bed 
Nodal Volumes 
Cardia/proximal 
third of stomach 
Preferred, but 
spare 2/3 of 
one kidney 
(usually right) 
T stage dependent  
N stage dependent  
Kidneys, 
spinal cord, 
liver, heart, 
left lung 
T3N0  
Variable 
dependent on 
surg-path 
findings* 
Medial left hemi-
diaphragm, 
adjacent body of 
pancreas (+/- tail) 
None or peri-gastric; 
Optional ^: peri-
esophageal, mediastinal, 
celiac 
 
T4N0  
Preferable, but 
dependent on 
surg-path 
findings* 
As for T3N0 plus 
site(s) of adherence 
with 3-5 cm margin 
Nodes related to site of 
adherence, +/- peri-gastric, 
celiac, peri-esophageal, 
mediastinal** 
 
T1-2N+  
Preferable  
Not indicated for 
T1; for T2 Medial 
left hemi-
diaphragm, 
adjacent body of 
pancreas (+/- tail) 
Peri-gastric, celiac, 
splenic, supra-panc, +/- 
peri-esophageal, 
pancreato-duodenal, porta-
hepatis, mediastinal, ** 
 
T3-4 N+  
Preferable  
As for T3,T4N0  As for T1-2N+ and T4N0  
 
* For  tumors  with  wide  (>5  cm)  surgical  margins  confirmed  pathologically,  treatment  of  residual 
stomach is optional, if this would result in substantial increased normal tissue morbidity.  
# Use pre-op imaging, surgical clips and post op imaging. 
** Pancreatico-duodenal and porta-hepatis nodes are at minimal risk if nodal positivity is minimal (i.e., 
if  only  1-2  nodes  are  positive  and  15+  nodes  have  been  examined,  
these  sites  do  not  need  
to  be 
irradiated).  Peri-esophageal  and  mediastinal  nodes  are  at  
risk,  and  should  be  
included,  
if  
there  
is 
esophageal extension 
^  Optional node may be excluded for T3N0 lesions if 15+ nodes have been pathologically examined. 


 
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7.3.2.6  General Guidelines for Body/Middle Third of Stomach Tumors 
Site of 
Primary and  
T, N Stage 
Inclusion into Irradiation Fields
#: 
Tolerance 
Organs or 
Structures to 
be 
Considered 
Stomach  
Remaining 
Volumes 
Tumor Bed 
Nodal Volumes 
Body/middle 
third of 
stomach 
es – but spare 2/3 
of 1 kidney 
(usually right) 
T stage dependent N stage dependent- spare 2/3 of 
right kidney 
Kidneys, 
spinal cord, 
liver 
T3N0  
Yes  
Body of pancreas 
(+/- tail) 
None or peri-gastric; Optional^: 
celiac, splenic, supra-pancreatic, 
pancreato-duodenal, porta-hepatis 
 
T4N0  
Yes  
As for T3N0 plus 
site(s) of 
adherence with 3-5 
cm margin 
Nodes related to site of adherence 
+/- peri-gastric, celiac, supra-
pancreatic, splenic, pancreato-
duodenal, porta-hepatis 
 
T1-2 N+  
Yes  
Not indicated for 
T1; for T2 Body of 
pancreas (+/- tail) 
Peri-gastric, celiac, supra-
pancreatic, splenic, pancreato-
duodenal, porta-hepatis; optional- 
splenic hilum 
 
T3-4N+ 
 
Yes  
As for T3,T4N0  
As for T1-2N+ and T4N0  
 
*Use pre-op imaging, surgical clips and post op imaging 
^ Optional node may be excluded for T3N0 lesions if 15+ nodes have been examined pathologically 
7.3.2.7    General Guidelines for Antrum/Pylorus/Distal Third of the Stomach Tumors 
Site of Primary 
and T, N Stage 
Inclusion into Irradiation Fields
#: 
Tolerance 
Organs or 
Structures to 
be 
Considered 
Stomach  
Remaining 
Volumes 
Tumor Bed 
Nodal Volumes 
Antrum/Pylorus/
distal third 
stomach 
Yes – but spare 2/3 of 
1 kidney (usually 
left) 
T stage dependent  
N stage dependent  
Kidneys, 
liver, spinal 
cord 
T3N0  Variable dependent on 
surg-path findings* 
Head of pancreas, 
(+/- body), 1
st and 
2nd part duodenum 
None or peri-gastric; 
Optional^: pancreato-
duodenal, porta-hepatis, 
celiac, supra-pancreatic 
 
T4N0  
Preferable, but 
dependent on surg-
path findings* 
As for T3N0 plus 
site(s) of adherence 
with 3-5 cm margin 
Nodes related to site(s) of 
adherence +/- peri-gastric, 
pancreato-duodenal, porta-
hepatis, celiac, supra-
pancreatic 
 
T1-2N+  
Preferable  
Not indicated for T1; 
for T2 Head of 
pancreas, (+/- body), 
1st and 2
nd part 
duodenum 
Peri-gastric, pancreato-
duodenal, porta-hepatis, 
celiac, supra-pancreatic; 
Optional^ – splenic hilum^ 
 
T3-4N+  
Preferable  
As for T3,T4N0  As for T1-2N+ and T4N0  
 
* For  tumors  with  wide  (>5  cm)  surgical  margins  confirmed  pathologically,  treatment  of  residual 
stomach is optional if this would result in substantial increased normal tissue morbidity.  
# Use pre-op imaging, surgical clips and post op imaging 
^  Optional node may be excluded if 15+ nodes examined pathologically and 0-2 nodes positive 


 
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7.3.2.8  Target Dose Constraints 
Prescribed dose: Dose will be prescribed to an isodose line that encompasses the PTV 
and that satisfies the dose uniformity requirements below. 
Dose Definition: Dose is specified in Gy to muscle 
Tissue  Heterogeneity: Calculation  shall  take  into  account  the  effects  of  tissue 
heterogeneities.  Planning  must  be  performed  using  an  approved  dose  calculation 
algorithm. Approved algorithms include: convolution superposition, collapsed cone 
convolution,  and  Monte  Carlo. An  extended  list  of  approved  and  unapproved 
algorithms,  as  well  as  contact  
information  for  further  questions, may  be  found  at 
http://rpc.mdanderson.org/rpc/Services/Anthropomorphic_%20Phantoms/TPS%20-
%20algorithm%20list%20updated.pdf. 
Fractionation: The total dose will be 45 Gy given in 25 fractions. Dose per fraction 
will be 1.8 Gy.  The patient will be treated with one fraction per day with all fields 
treated per day. 
Dose Uniformity: The dose to 99% of the PTV must be at least 93% of the prescribed 
dose, and no more than 2cc within the PTV may receive a dose greater than 120% of 
the prescribed dose. 
Rests: There are no planned rests on this study. Please contact the study coordinator 
for treatment interruptions greater than three days. 
7.3.2.9  Normal tissue Dose Constraints 
The  normal  structures  
to  be  contoured  will  depend  on  
the  
level  of  
the  esophagus 
involved, but can include left and right lungs, heart, esophagus, brachial plexus, left 
and right kidneys, liver, 
stomach, small intestine, and spinal canal. The dose to normal 
tissues must be kept within the parameters described below. 
Normal Tissue Constraints: 
1. Lungs 
a. V20Gy ≤ 20% 
b. and V
30Gy ≤ 15% 
c. and V
40Gy ≤ 10% 
d. V10Gy ≤ 40%  
2. Cord 
a. Max ≤ 45 Gy  
3. Bowel 
a. Max bowel dose < Max PTV dose  
b. D05 ≤ 45 Gy  
4. Heart 
a. V25Gy ≤ 75% (GE junction tumors) 
b. Mean < 30 Gy (non-GE junction tumors) 
5. Left Kidney, Right Kidney (evaluate each one separately and combined): 
a. V20Gy ≤ 32% (combined) 
6. Liver 
a. V30Gy ≤ 30% 


 
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b. Mean < 32 Gy  
7. Residual Stomach 
a. Mean < 30 Gy (if not within PTV) 
b. Max dose < 54Gy  
7.3.2.10 Treatment Planning  
Simulation: Patients will be positioned supine with arms above the head immobilized 
as per institutional standards for immobilization. A CT simulation will be performed 
using oral and IV contrast, when possible, using ≤3 mm slice thickness. In patients 
for  whom  treatment  will  be  delivered  using  respiratory  gating  or  tracking,  the 
planning  CT  scan  should  be  performed  with  the  patient  in  a  breath-hold  in  end-
expiration. 
Motion  Management: Respiratory  and  abdominal  motion  can  be  significant.  
  
  We 
recommend  an  assessment  of  motion  at  the  time  of  simulation  and  utilization  of 
delivery  and  immobilization  techniques  according  to  institutional  practice.      A 
surrogate such as the diaphragm may be 
used to assess the degree of motion for gastric 
body in patients who have had less than a total gastrectomy.  To determine the extent 
of respiratory motion for gastroesophageal junction tumors, a respiratory correlated 
CT  scan  may  be  obtained  at  
the  
time of  simulation.  This  scan  will  be  performed 
throughout the breathing cycle (i.e., 4-dimensional CT) so that separate CT data sets 
associated  with  each  phase  of  respiration  can  later  be  reconstructed.  Treatment 
delivery  can  be  done  using  the  motion  management  technique  available  at  the 
institution  and  can  
include  treatment  during  free-breathing  as  long  as  the  motion 
determined from the 4DCT has been included in the PTV. The Motion Management 
Reporting  Form  shall  be  submitted  to  document  the  method  used  (see Section 
7.3.2.13). 
Beam Arrangements: Beams shall be chosen for optimal coverage of the PTV while 
satisfying the dose constraints for normal tissues in Section 7.3.2.9. 
7.3.2.11 Field Verification 
As a minimum requirement, institutions are required to obtain verification images at 
the start of treatment and each week thereafter. Prior to the first treatment images that 
verify  
the  position  of  
the  
isocenter  placement  must  be  obtained.  For  3D-CRT  
this 
imaging can include individual portal views. Weekly imaging can consist of portal 
views for 3D-CRT and isocenter verification images. For IMRT orthogonal images 
verifying isocenter position are required. More frequent (daily) imaging is encouraged 
particularly  for  patients  treated  with  motion  management  techniques,  but  is  not 
required. 
7.3.2.12  Definitions of Deviations in Protocol Performance 
Prescription Dose 
•  Per Protocol: ≥ 99% of the PTV receives ≥ 93% of the prescribed dose, and a 
contiguous volume of no more than 2cc inside the PTV receives a dose greater 
than 120% of the prescribed dose. 
•  Variation Acceptable: Between 95% and 99% of the PTV receives 93% of the 
prescribed dose, or a volume of 2cc within the PTV receives a dose between 120% 
and 125% of the prescribed dose. 








 
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phantoms imaged with both systems are very similar (i.e., < 10% difference). This 
verification will be made via coordination between the site and the Imaging Core Lab. 
7.4.1  Baseline PET/CT Scan Interpretation 
Semiquantitative  analysis will be used to determine  
the change in FDG uptake using the 
SUVmax approach for PET/CT  scans  obtained at baseline  and 15-19 days  
into  
therapy. 
SUV  analysis  will  be performed  using  the  maximum  voxel  SUV  (SUVmax)  to assess 
response  to  therapy.  A  35% or  greater decrease in  SUV  will constitute  response  to 
therapy.  Regions  of interest  (ROIs)  will  be manually  placed around  
the entire extent of 
any abnormality and around the most intense portion of this abnormality to determine the 
average and maximum tissue activity within the ROI, respectively  
(SUVmax), and decay 
corrected  
to time of injection. 
7.4.2 Interpretation of Concomitant and Post Induction Chemotherapy PET/CT Scans 
Semiquantitative analysis will also be used to determine the change in 18FDG uptake from 
pretherapy  baseline  PET/CT  using  
the  SUVmax  approach  
(i.e.,  change  
in SUVmax,  see 
below) during or following induction chemotherapy. This will be correlated with clinical 
and histopathological response to therapy as well as disease-free and overall survival. For 
assessment of new lesions that may appear during or following induction chemotherapy, 
visual  
interpretation, as  described above,  will  be  used  
to determine  
if  
the  new  
lesion  
is 
positive  or  negative  for  tumor  in  conjunction  with  available  clinical  and radiological 
findings.    A  new  site  seen  by  PET/CT  will only  be considered  disease  progression  if 
corroborated  by  biopsy  or  other  established  imaging  methods.  Patients  with  disease 
progression,  considered  M1  disease, documented  by  PET/CT imaging  and  confirmed  by 
biopsy or imaging should be removed from protocol therapy. An increase in the SUVmax 
(see  below)  of  >  20%  at  any  
time during  or  post  
induction  chemotherapy  will  only  be 
considered  as  possible  “indication”  of  disease  progression,  unless  correlated  by  disease 
progression documented by biopsy or other imaging modalities such as barium esophagram 
or CT, in which case disease progression will be established. 
8.0   DOSE AND TREATMENT MODIFICATIONS 
8.1  Ancillary therapy, concomitant medications, and supportive care 
8.1.1 Patients should not receive any other agent which would be considered treatment for 
the primary neoplasm or impact the primary endpoint. 
8.1.2 Patients  should  receive  
full  supportive  care while  on  
this  study.  
  This  
includes  blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or concurrent 
medical conditions.  All blood products and concomitant medications such as antidiarrheals, 
analgesics, and/or antiemetics received from the first day of study treatment administration 
until 30 days after the final dose will be recorded in the medical records. 
8.1.3 Treatment  with  hormones or  other  chemotherapeutic  agents  may  not  be  administered 
except for steroids given for adrenal failure; hormones administered for non-disease-related 
conditions  (e.g.,  insulin  for  diabetes);  and  intermittent  use  of  dexamethasone  as  an 
antiemetic. 
8.1.4 Antiemetics should be used at the discretion of the attending physician. 
Suggested regimens during the pre-registration chemotherapy are steroids, 5HT3 
antagonists, and/or aprepitant, and during the post-registration chemotherapy are steroids 
and 5HT3 antagonists. 


 
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8.1.5  Diarrhea: This could be managed conservatively with loperamide. The recommended dose 
of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free 
(maximum 16 mg/day). Escalation (i.e. to lomotil and/or tincture of opium) should be at the 
discretion of the attending physician. 
The following supportive measures are allowed:  hydration, octreotide, and antidiarrheals. 
8.1.6 Hypersensitivity Reaction: Manage as per institutional standard. 
8.1.7 Edema: Steroid  premedication  
for  docetaxel  
infusion  
is  at  
the  discretion  of  
the  
treating 
physician. If edema occurs, manage with diuretics at treating physician discretion. 
8.1.8 Alliance Policy Concerning the Use of Growth Factors 
Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies  and  recommendations. The  use  of  growth  factors  should  follow 
published  guidelines  of  the  American  Society  of  Clinical  Oncology  2010  Update  of 
Recommendations on the Use of Epoetin and Darbepoetin in Adult Patients With Cancer. J 
Clin Oncol 28(33): 4996-5010, 2010. 
Epoetin (EPO): Use of epoetin in this protocol is permitted at the discretion of the treating 
physician. 
Filgrastim (G-CSF) and sargramostim (GM-CSF) 
1.  Filgrastim (G-CSF)/pegfilgrastim and sargramostim (GM-CSF) is discouraged. 
a.  For the treatment of febrile neutropenia the use of CSFs should not be routinely 
instituted as an adjunct to appropriate antibiotic therapy. However, the use of CSFs 
may  be indicated  
in  patients  who  have  prognostic  factors  
that  are  predictive  of 
clinical  deterioration  such  as  pneumonia,  hypotension,  multi-organ  dysfunction 
(sepsis syndrome) or fungal infection, as per the ASCO guidelines.  Investigators 
should therefore use their own discretion in using the CSFs in this setting.  The use 
of  CSF  (filgrastim/pegfilgrastim  or  sargramostim)  must  be  documented  and 
reported.  
b.  If filgrastim/pegfilgrastim or sargramostim are used, they must be obtained from 
commercial sources.     
8.1.9 CYP3A4 Inhibitors  
Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this trial 
during  post-registration  chemotherapy  on  Arm  B.  The  
follow  drugs  are  EXAMPLES  of 
strong inhibitors of CYP3A4 and are not allowed during treatment with docetaxel:  
•    Indinavir  
•   Clarithromycin  
•    Ketoconazole.  
Because lists of these agents are constantly changing, please consult and review any drugs 
for their potential to inhibit CYP3A4. Examples of resources that may be utilized include 
the product information for the individual concomitant drug in question, medical reference 
texts such as the Physicians’ Desk Reference, the FDA and/or IUPUI websites, or your local 
institution’s pharmacist. 
An information handout and wallet-size card providing information for patients and their 
caregivers regarding potential drug interactions have been made available in Appendix III. 


 
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8.1.10 CYP3A4 Inducers 
Chronic concomitant treatment with strong inducers of CYP3A4 is not allowed during on 
this  trial  during  post-registration  chemotherapy  on  Arm  B.  The  following  drugs  are 
EXAMPLES  of  strong  
inducers  of  CYP3A4  and  are  not  allowed  during  
treatment  with 
docetaxel. 
•  Rifampin 
•  Carbamazepine 
Because lists of these agents are constantly changing, please consult and review any drugs 
for their potential to induce CYP3A4. Examples of resources that may be utilized include 
the product information for the individual concomitant drug in question, medical reference 
texts such as the Physicians’ Desk Reference, the FDA and/or IUPUI websites, or your local 
institution’s pharmacist. 
An information handout and wallet-size card providing information for patients and their 
caregivers regarding potential drug interactions have been made available in Appendix III. 
8.2  Dose Modifications 
•  If multiple adverse events are seen, administer dose based on greatest reduction required for 
any single adverse event observed.  Reductions or increases apply to treatment given in the 
preceding cycle and are based on adverse events observed since the prior dose. 
•  Neither docetaxel nor irinotecan will be re-escalated once reduced. 
•  If  both  irinotecan  and  docetaxel are held  for  3  weeks  or  more during  pre-operative 
chemotherapy,  chemotherapy  will  be  discontinued  and  the  patient will  be  referred  for 
resection.  
•  If  both  irinotecan  and  docetaxel  are  held  for  3  weeks  or  more  during  post-operative 
chemotherapy, chemotherapy will be discontinued 
•  If dose reductions beyond level -2 are required, then the agent will be discontinued. 
•  Depending  on  
the  specific  
toxicity,  a  single  chemotherapy  drug  
(i.e.  either  
irinotecan  or 
docetaxel) may be modified without alteration of the other drug. 
CTEP-AERS reporting may be required for some adverse events (See Section 9.0) 
8.2.1 Dose Levels of Arm B (Docetaxel and Irinotecan) 
Dose 
Level  Drug Name 
Dose (mg/m
2) 
 0*  Docetaxel 
30 
-1  Docetaxel 
25 
-2  Docetaxel 
20 
*Dose level 0 refers to the starting dose. 
 
Dose 
Level  Drug Name 
Dose (mg/m2) 
 0* 
Irinotecan 
50 
-1 
Irinotecan 
40 
-2 
Irinotecan 
30 
*Dose level 0 refers to the starting dose. 


 
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8.2.2 Dose Modifications for Arm B: 
8.2.2.1  Hematologic Toxicities  
For grade  3  neutrophil  count  decreased  on  day  1  or  8,  delay  docetaxel  and 
irinotecan  until  grade  ≤  2,  then resume  docetaxel  at  1  dose  level  decreased, and 
irinotecan at same dose  
For grade 4 neutrophil count decreased or grade 3 or 4 febrile neutropenia, delay 
docetaxel and irinotecan until grade ≤ 2, then resume docetaxel and irinotecan with 
one dose level decreased  
For grade 2 platelet count decreased, delay docetaxel and irinotecan until grade ≤ 
1, then resume docetaxel at one dose level decreased, and irinotecan at same dose  
For grade 3 or 4 platelet count decreased, delay docetaxel and irinotecan until grade 
≤ 1, then resume docetaxel and irinotecan with one dose level decreased 
8.2.2.2  Neurotoxicity  
For grade  2 neuropathy,  continue  docetaxel  at  one  dose  level  decreased,  and 
irinotecan at the same dose 
For grade 3 or 4 neuropathy, discontinue docetaxel  
8.2.2.3  Gastrointestinal Toxicity  
For grade 3 nausea or vomiting, delay docetaxel and irinotecan until grade ≤ 2, then 
restart irinotecan at 1 dose level decreased, and docetaxel at the same dose 
For grade  4  vomiting,  delay  docetaxel  until  grade  ≤  2,  
then  
restart docetaxel  and 
irinotecan with one dose decreased 
For grade  2  diarrhea,  delay  docetaxel  and  
irinotecan  until  grade ≤ 1,  
then restart 
docetaxel and irinotecan at same dose 
For grade  3  diarrhea,  delay  docetaxel  and  
irinotecan  until  grade ≤ 1,  
then restart 
docetaxel at same dose and irinotecan at 1 dose level reduced 
For grade  4  diarrhea,  delay  docetaxel  and  
irinotecan  until  grade ≤ 1,  
then  
restart 
docetaxel and irinotecan at one dose decreased  
For grade  3  anorexia,  delay  docetaxel  and  
irinotecan  until  grade ≤ 2,  
then restart 
docetaxel and irinotecan at 1 dose level reduced and irinotecan at same dose 
For grade  4  anorexia,  delay  docetaxel and  
irinotecan  until  grade ≤ 2,  
then  
restart 
docetaxel and irinotecan at 1 dose level reduced 
For grade 2 stomatitis, treat with docetaxel at 1 dose level reduced and irinotecan at 
same dose level 
For grade  3  or  4  stomatitis,  delay  docetaxel  and  
irinotecan  until  grade  ≤  1,  
then 
restart docetaxel and irinotecan at 1 dose level reduced 
8.2.2.4  Hepatobiliary Toxicity  
For grade 2 or 3 AST or ALT elevated, delay docetaxel and irinotecan until grade 
≤ 1, then restart docetaxel and irinotecan at one dose level decreased  
For grade 4 AST or ALT elevated, discontinue docetaxel and irinotecan 
For grade 2 bilirubin elevated, delay docetaxel and irinotecan until grade ≤ 1, then 
restart docetaxel and irinotecan at 1 dose level decreased 
For grade 3 or 4 bilirubin elevated, discontinue docetaxel and irinotecan  


 
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8.2.2.5  Renal Insufficiency: 
For grade 3 or 4 creatinine increased and NOT attributed to study treatment, delay 
irinotecan until grade ≤ 1 then restart irinotecan at same dose 
8.2.2.6  Opthalmalogic Toxicities: 
For grade 3 watering eyes, delay docetaxel until grade ≤ 1, then restart docetaxel at 
1 dose level decreased 
For any grade cystoid macular edema, discontinue docetaxel 
8.2.2.7  General disorders  
For grade 3 or 4 edema, omit docetaxel until grade < 2, then resume docetaxel at one 
dose level decreased  
For grade 3 or 4 fatigue, delay docetaxel and irinotecan until grade ≤ 2, then resume 
docetaxel at 1 dose level decreased and irinotecan at same dose level 
For grade 4 hypersensitivity reaction, discontinue offending study agent.  
8.2.2.8  Non-hematologic Toxicities 
For  all  other grade  3  or  4  non-hematologic  
toxicities likely  
related  
to  docetaxel 
and/or irinotecan, omit docetaxel and/or irinotecan until resolved to < grade 1, then 
resume docetaxel and/or irinotecan at one dose decreased 
8.2.2.9  Dose Modifications for Obese Patients 
There is no clearly documented adverse impact of treatment of obese patients when 
dosing is performed according to actual body weight. Therefore, all dosing is to be 
determined  solely  by  actual  weight  without  any  modification  unless  explicitly 
described  
in  
the  protocol.  This  will  eliminate  
the  
risk  of  calculation  error  and  
the 
possible introduction of variability in dose administration. Failure to use actual body 
weight  in  the  calculation  of drug  dosages  will  be  considered  a  major  protocol 
deviation. Physicians who are uncomfortable with calculating doses based on actual 
body  weight  should  
recognize  
that  doing  otherwise would  be  a  protocol  violation. 
Physicians may consult the published guidelines of the American Society of Clinical 
Oncology Appropriate Chemotherapy Dosing for Obese Adult Patients with Cancer: 
American  Society  of  Clinical  Oncology  Clinical  Practice  Guideline.  J  Clin  Oncol 
30(13): 1553-1561, 2012. 
8.2.3 Dose Levels during chemoradiation in Arm A: 
Dose 
Level  Drug Name 
Dose (mg/m2/day) 
 0*  5FU 
200 
-1  5FU 
150 
-2  5FU 
100 
  
*Dose level 0 refers to the starting dose. 
Dose 
Level  Drug Name 
Dose (mg/m2) bid M-F during RT 
 0*  capecitabine 
800 
-1  capecitabine 
600 
-2  capecitabine 
400 
  
*Dose level 0 refers to the starting dose. 


 
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8.2.4 Dose Modifications during chemoradiation in Arm A: 
8.2.4.1  5FU Dose Modifications: 
5FU should be delayed at any point that radiotherapy is delayed, regardless of whether 
there is 5FU related toxicity present 
Hematologic Toxicity: 
For grade 2 platelet count decreased, delay 5FU until grade ≤ 1 then resume at same 
dose  
For grade 3 or 4 platelet count decreased, delay 5FU until grade ≤ 1 then resume at 
1 dose level decreased 
Gastrointestinal Toxicity: 
For grade 3 or 4 diarrhea, delay 5FU until grade ≤ 1 then resume at 1 dose level 
reduced. 
For grade 3 or 4 mucositis, delay 5FU until grade ≤ 1 then resume at 1 dose level 
reduced. 
Hepatic Insufficiency: 
For grade 3 or 4 bilirubin increased and NOT related to study treatment, delay 5FU 
until grade ≤ 2, then resume at same dose level 
Skin Toxicity: 
For grade 2 or 3 palmar-plantar erythrodysesthesia syndrome, delay 5FU until 
grade ≤ 1, then resume at 1 dose level reduced. 
8.2.4.2  Capecitabine Dose Modifications: 
Hematologic Toxicity: 
For grade 2 platelet count decreased, delay capecitabine until grade ≤ 1 then resume 
at same dose  
For grade 3 or 4 platelet count decreased, delay capecitabine until grade ≤ 1 then 
resume at 1 dose level decreased 
Gastrointestinal Toxicity: 
For grade 3 or 4 diarrhea, delay capecitabine until grade ≤ 1 then resume at 1 dose 
level reduced. 
For grade 3 or 4 mucositis, delay capecitabine until grade ≤ 1 then resume at 1 dose 
level reduced. 
Renal Insufficiency 
For grade 2, 3, or 4 creatinine increased and NOT attributed to study treatment, 
delay capecitabine until grade ≤ 1, then restart capecitabine at same dose level. 
Skin Toxicity: 
For grade 2 or 3 palmar-plantar erythrodysesthesia syndrome, delay capecitabine 
until grade ≤ 1, then resume at 1 dose level reduced. 
8.2.4.3  Non-hematologic Toxicities 
For  all  other grade  3  or  4  non-hematologic  toxicities likely  related  to  5FU  or 
capecitabine, omit 5FU or capecitabine until resolved to < grade 1, then resume 5FU 
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8.2.4.4  Radiotherapy Dose Modifications 
The  dose  of  
radiation  will  be  45GY  
in  25  
fractions  as  standard  
for  post-operative 
therapy for gastric cancer. Dose modifications are not anticipated, but may arise based 
on treatment related toxicity. 
Radiotherapy should be held for any of the following treatment related toxicities: 
•  
Grade 3 or 4 platelet count decreased 
•  
Grade 3 or 4 neutropenia, or for febrile neutropenia 
•  
Grade 2, 3 or 4 renal insufficiency 
•  
Grade 3 nausea, or grade 3 or 4 vomiting.  
•  
Grade 3 or 4 dehydration 
Radiotherapy  may  resume  once  any  of  the  above  toxicities  improve,  generally 
returning to < grade 1. Additional breaks in therapy can be performed at the discretion 
of the treating radiation oncologist. If patients are held for more than 2 consecutive 
weeks, or if radiotherapy is interrupted for a cumulative duration of 4 weeks or more 
during the course of radiotherapy, further radiotherapy will be discontinued.  
8.2.6 Dose Modifications for Obese Patients 
There is no clearly documented adverse impact of treatment of obese patients when dosing 
is  performed  according  
to  actual  body  weight.  Therefore,  all  dosing  
is  
to  be  determined 
solely by actual weight without any modification unless explicitly described in the protocol. 
This will eliminate the risk of calculation error and the possible introduction of variability 
in dose administration. Failure to use actual body weight in the calculation of drug dosages 
will  be  considered  a  major  protocol  deviation.  Physicians  who  are  uncomfortable  with 
calculating doses based on actual body weight should recognize that doing otherwise would 
be a protocol violation. Physicians may consult the published guidelines of the American 
Society of Clinical Oncology Appropriate Chemotherapy Dosing for Obese Adult Patients 
with Cancer: American Society of Clinical Oncology Clinical Practice Guideline.  J Clin 
Oncol 30(13): 1553-1561, 2012. 
9.0   ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Adverse events must be described and graded using the 
terminology and grading categories defined in the NCI’s Common Terminology Criteria for Adverse 
Events   (CTCAE),   Version  
4.0.   The  CTCAE   is   available   at 
ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  Attribution  to  protocol 
treatment for each adverse event must be determined by the investigator and reported on the required 
forms, using the codes provided. 
9.1  Routine adverse event reporting 
Adverse event data collection and reporting, which are required as part of every clinical trial are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times according to the study calendar in Section 5.0. For this trial, the Adverse Events: Solicited 
and Adverse Events: Other forms are used for routine AE reporting in Rave. 
Solicited Adverse Events: The following adverse events are considered "expected" and their 
presence/absence  should  be  solicited,  and  severity  graded,  at  baseline  and  
for  each  cycle  of 
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CTCAE v4.0 Term 
CTCAE  v4.0  System  Organ  Class 
(SOC) 
Anorexia 
Metabolism and nutrition disorders 
Weight Loss 
Investigations 
Fatigue 
General disorders 
Diarrhea 
Gastrointestinal disorders 
Peripheral motor neuropathy 
Nervous systems disorders 
Peripheral sensory neuropathy 
Nervous systems disorders 
Febrile neutropenia 
Blood and lymphatic system disorders 
Anemia 
Blood and lymphatic system disorders 
9.2  CTCAE Routine Study Reporting Requirements 
In addition to the solicited adverse events listed in Section 9.1, the following table outlines the 
combinations of time points, grades and attributions of AEs that require routine reporting to the 
Alliance Statistics and Data Center. Questions about routine reporting should be directed to the 
Data Manager. 
*Combinations  of  CTCAE  Grade  &  Attribution  Required  for  Routine  AE  Data 
Submission on Case Report Forms (CRFs) 
 
Attribution  
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Grade 5 
Unrelated  
 
 
a 
a 
a 
Unlikely  
 
 
a 
a 
a 
Possible  
 
a  
a, b  
a, b  
a, b 
Probable  
 
a  
a, b  
a, b  
a, b 
Definite  
 
a  
a, b  
a, b  
a, b 
a) Adverse  Events:  Other  CRF - Applies  to  AEs  occurring  between  registration  and 
within 30 days of the patient’s last treatment date, or as part of the Clinical Follow-Up 
Phase. 
b) Adverse Events: Late CRF - Applies to AEs occurring greater than 30 days after the 
patient’s last treatment date. 
9.3  Expedited adverse event reporting (CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined in 
the table below. Alliance investigators are required to notify the Investigational Drug Branch 
(IDB), the Alliance Central Protocol Operations Program, the Study Chair, and their Institutional 
Review Board if a patient has a reportable serious adverse event. The descriptions and grading 
scales found in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4 
will be utilized for AE reporting.  The CTCAE is identified and located on the CTEP website 
at:  ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  All  appropriate 
treatment areas should have access to a copy of the CTCAE. All reactions determined to be 
“reportable”  
in  an  expedited  manner  must  be  
reported  using  
the Cancer  Therapy  Evaluation 
Program  Adverse  Event  Reporting  System  (CTEP-AERS) accessed  via  https://eapps-
ctep.nci.nih.gov/ctepaers/. 


 
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Note:  
  All  deaths  on  study  require  both  routine  and  expedited  reporting  regardless  of 
causality.  Attribution to treatment or other cause should be provided. 
9.3.1 CIP Commercial Agent Studies:  Expedited Reporting Requirements for Adverse Events 
that  Occur  in  a  CIP  Non-IND/IDE  trial  ≤ 30  Days  of  the  Last  Administration  of  a 
Commercial Imaging Agent 
1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious 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. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
•  Grade 1 
Timeframes 
•  Grade 2 
Timeframes 
•  Grade 3 
Timeframes 
  Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour; 
5 Calendar Days 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required 
10 Calendar 
Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS ≤ 24 hours 
of learning of the AE, followed by a complete expedited report ≤ 5 calendar days of the 
initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted ≤ 10 
calendar days of learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report ≤ 5 calendar days for: 


 
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•  All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
•  Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
•  Grade 3 adverse events 
2  For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half lives, rounded UP to the nearest whole day, after the agent/intervention was last administered.  
Footnote “1” above applies after this reporting period. 
NOTE: Deaths clearly due to progressive disease should NOT be reported via CTEP-AERS but 
rather should be reported via routine reporting methods (e.g., CDUS and/or CTMS). 
 
•   Expedited AE reporting timelines defined: 
 “24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-AERS 
≤ 24 hours of learning of the event followed by a complete CTEP-AERS report ≤ 5 calendar 
days of the initial 24-hour report. 
 “10 calendar days” - A complete CTEP-AERS report on the AE must be submitted ≤ 10 
calendar days of the investigator learning of the event.  
•  Any  medical  event  equivalent to  CTCAE  grade  3,  4, or  5  
that  precipitates  hospitalization (or 
prolongation  of  existing  hospitalization)  must  be  reported  regardless  of  attribution  and 
designation as expected or unexpected with the exception of any events identified as protocol-
specific expedited adverse event reporting exclusions (see below). 
•  Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, 
or birth defects must be reported via CTEP-AERS if the event occurs following treatment with 
an agent under a CTEP IND. 
•  Use  the  NCI  protocol  number  and  the  protocol-specific  patient  ID  provided  during  trial 
registration on all reports. 
Additional Instructions or Exclusions to CTEP-AERS reporting: 
•  All adverse events reported via AERS (i.e., serious adverse events) should also be forwarded to 
your local IRB, according to local IRB policies. 
•  Grade  1-3  nausea  or  vomiting  and  hospitalization  resulting  from  such  do  not  require  AERS 
reporting, but should be reported via routine AE reporting.  
•  Grade 3 nausea or vomiting does not require AERS reporting, but should be reported via routine 
AE reporting 
•  Grade 1-3 diarrhea and hospitalization resulting from such does not require AERS reporting, but 
should be reported via routine AE reporting 
•  Grade  3  diarrhea  does  not  require  AERS  reporting,  but  should  be  reported  via  routine  AE 
reporting 
•  Grade 1-3 mucositis and hospitalization resulting from such does not require AERS reporting, 
but should be reported via routine AE reporting 
•  Grade  3  mucositis  does  not  require  AERS  reporting,  but  should  be  reported  via  routine  AE 
reporting 
•  Grade 1-3 neuropathy and hospitalization resulting from such does not require AERS reporting, 
but should be reported via routine AE reporting.  


 
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•  Grade 3  neuropathy  does not require  AERS  
reporting,  but  should  be reported via  
routine  AE 
reporting 
•  Grade 1-3 hand foot syndrome and hospitalization resulting from such does not require AERS 
reporting, but should be reported via routine AE reporting 
•  Grade 3 hand foot syndrome does not require AERS reporting, but should be reported via routine 
AE reporting 
•  Grade  1-4 hypersensitivity  reaction  and  hospitalization  resulting  from  such  does  not  require 
AERS reporting, but should be reported via routine AE reporting.  
•  Grade 3 or 4 hypersensitivity reaction does not require AERS reporting, but should be reported 
via routine AE reporting 
•  Grade 1-3 edema and hospitalization resulting from such does not require AERS reporting, but 
should be reported via routine AE reporting.  
•  Grade 3 or 4 edema does not require AERS reporting, but should be reported via routine AE 
reporting 
•  Grade 1-3 dehydration and hospitalization resulting from such does not require AERS reporting, 
but should be reported via routine AE reporting 
•  Grade 3 dehydration does not require AERS reporting, but should be reported via routine AE 
reporting 
•  Grade 1-3 fatigue and hospitalization resulting from such does not require AERS reporting, but 
should be reported via routine AE reporting.  
•  Grade 3 fatigue does not require AERS reporting, but should be reported via routine AE reporting 
•  Grade  1-3  hematosuppression  (leukopenia,  neutropenia,  lymphopenia,  anemia,  and 
thrombocytopenia) with hospitalization resulting from such do not require AERs reporting, but 
should be reported via routine AE reporting 
•  Grade  3  or  4  hematosuppression  (leukopenia,  neutropenia,  lymphopenia,  anemia,  and 
thrombocytopenia)  does  not  require  AERs  reporting,  but  should  be  reported  via  routine  AE 
reporting 
•  All new malignancies must be reported through CTEP-AERS whether or not they are thought to 
be related to either previous or current treatment. All new malignancies should be reported, i.e. 
solid  tumors  (including  non-melanoma  skin  malignancies),  hematologic  malignancies, 
myelodysplastic syndrome/acute myelogenous leukemia, and in situ tumors. In CTCAE version 
4.0, the new malignancies (both second and secondary) may be reported as one of the following: 
(1)  Leukemia  secondary  to  oncology  chemotherapy,  (2)  Myelodysplastic  syndrome,  (3) 
Treatment-related secondary malignancy, or (4) Neoplasms benign, malignant and unspecified-
other. Whenever possible, the CTEP-AERS reports for new malignancies should include tumor 
pathology,  history  or  prior  tumors,  prior  treatment/current  treatment  including  duration,  any 
associated  risk  factors  or  evidence  regarding  how  long  the  new  malignancy  may  have  been 
present,  when and  how  the  new  malignancy  was  detected,  molecular  characterization  or 
cytogenetics  of  
the  original  
tumor  
(if  available)  and  of  any  new  
tumor,  and  new  malignancy 
treatment and outcome, if available. 
•  All pregnancies and suspected pregnancies occurring in female during therapy or within 28 days 
after completion of treatment on A021302 must be reported via CTEP-AERS. In CTCAE version 
4.0, use the event term, “pregnancy, puerperium, and perinatal condition-other, pregnancy (grade 
3)”.  


 
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o CTEP-AERS  
reports should be  amended  upon  completion  of the  pregnancy  
to  
report 
pregnancy outcome (e.g. normal, spontaneous abortion, therapeutic abortion, fetal death, 
congenital abnormalities). Fetal death should be reported as pregnancy, puerperium and 
perinatal conditions- other pregnancy loss (grade 4). 
o The CTEP-AERS report should be amended for any neonatal deaths occurring within 28 
days of birth considered at least possibly related to treatment. Use the event term “general 
disorders and administration site conditions-other, neo-natal loss” (grade 4). 
•  The  reporting  of  adverse  events  described  
in  
the  table  above  is  in  addition  to  and  does  not 
supplant the reporting of adverse events as part of the report of the results of the clinical trial, e.g. 
cooperative group data reporting. 


 
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10.0  DRUG INFORMATION 
10.1  General Considerations: 
•  The total administered dose of chemotherapy may be rounded up or down within a range of 
5% of the actual calculated dose. 
•  It is not necessary to change the doses of all study agents due to changes in weight unless 
the calculated dose changes by ≥10%. 
10.2  Epirubicin (Ellence®) 
Procurement 
Commercial  supplies.  
  Pharmacies  or  clinics  shall  obtain  supplies  from  normal  commercial 
supply chain or wholesaler. 
Formulation 
Commercially available for injection 2 mg/ml (25 ml and 100 ml)  
Preparation, Storage and Stability 
Refer to package insert for complete preparation and dispensing instructions. 
Solution: Store intact vials refrigerated at 2°C to 8°C (36°F to 46°F); do not freeze. Product may 
“gel” at refrigerated temperatures; will return to slightly viscous solution after 2-4 hours at room 
temperature (15°C to 30°C). Discard unused solution from single dose vials within 24 hours of 
entry.  
Administration 
Refer to the treatment section for specific administration instructions. 
 Infuse over 15-20 minutes 
or slow I.V. push; if lower doses due to dose reduction are administered, may reduce infusion 
time  proportionally.  Do  not  
infuse over  <3  minutes.  
Infuse  
into  a free-flowing I.V. solution. 
Avoid  
the  use  of  veins  over  
joints  or  
in  extremities  with  compromised  venous  or  
lymphatic 
drainage.  
Vesicant; avoid extravasation. 
Prophylactic antiemetics should be administered per institutional standard. 
Drug Interactions 
Concomitant use of Epirubicin with other cardioactive compounds that could cause heart failure 
(e.g.  calcium  channel  blockers)  requires  close  monitoring  of  cardiac  function  throughout 
treatment. 
It is likely that the use of epirubicin with radiotherapy  may sensitize tissues to the cytotoxic 
actions of irradiaton.  Administration of epirubicin after previous radiation therapy may induce 
an inflammatory recall reaction at the site of irradiation. 
Epirubicin  
is  extensively  metabolized  by  
the  
liver.  
  Changes  
in  hepatic  
function  
induced  by 
concomitant therapies may affect epirubicn metabolism. 
Cimetidine increased the AUC of epirubicin by 50%.  Cimetidine treatment should be stopped 
during treatment with epirubicin. 
Pharmacokinetics 
Distribution: Vss: 21-27 L/kg 
Protein binding: ~77% to albumin 
Metabolism: Extensively via hepatic and extrahepatic (including RBCs) routes 
Half-life elimination: Triphasic; Mean terminal: 33 hours 


 
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Excretion: Feces (34% to 35%); urine (20% to 27%) 
Adverse Events 
Common known potential toxicities, >10%:          
  Central nervous system: Lethargy  
Dermatologic: Alopecia 
Endocrine & metabolic: Amenorrhea, hot flashes  
Gastrointestinal: Nausea/vomiting, mucositis, diarrhea  
Hematologic: Leukopenia, neutropenia, anemia, thrombocytopenia 
Local: Injection site reactions  
Ocular: Conjunctivitis 
Miscellaneous: Infection 
   Less common known potential toxicities, 1% to 10%: 
Cardiovascular: LVEF decreased, HF  
Central nervous system: Fever  
Dermatologic: Rash, skin changes  
Gastrointestinal: Anorexia  
Hematologic: Neutropenic fever  
   Rare known potential toxicities, <1% (Limited to important or life-threatening): 
Abdominal pain, acute lymphoid leukemia (ALL), acute myelogenous leukemia (AML),   
anaphylaxis,  arrhythmia,  arterial  embolism,  ascites,  atrioventricular  block,  bradycardia, 
bundle-branch block, cardiomyopathy, chills, dehydration, dyspnea, ECG abnormalities, 
erythema, esophagitis, flushing, GI burning sensation, GI erosions/ulcerations, GI pain, GI 
bleeding,  hepatomegaly,  hyperpigmentation  
(oral  mucosa,  nails,  skin),  hypersensitivity, 
hyperuricemia,  myelodysplastic  syndrome,  myocarditis,  neutropenic  
typhlitis,  phlebitis, 
photosensitivity,  pneumonia,  premature  menopause,  premature  ventricular  contractions, 
pulmonary edema, pulmonary embolism, radiation recall, sepsis, shock, sinus tachycardia, 
stomatitis,  ST-T  wave  changes  (nonspecific),  tachyarrhythmias,  thromboembolism, 
thrombophlebitis,  toxic  megacolon,  transaminases  increased,  urine  discoloration  (red), 
urticaria, ventricular tachycardia 
Nursing Guidelines 
Assess patient carefully for any previous history of heart disease.  Cardiotoxicity is a known risk 
and may manifest by early or late events.  Early cardiotoxicity consists of sinus tachycardia, ST-
T wave changes, AV block, ventricular tachycardia.  Delayed cardiotoxicity (cardiomyopathy) 
is manifested by LV CHF.  The risk of CHF increases with cumulative doses.  Cardiotoxicities 
may be life threatening.  Monitor cardiac function assessments regularly. 
Assess heart and lung sounds.  Monitor vital signs (resting pulse).  Be alert to early signs of 
cardiotoxicity,  i.e.,  dyspnea,  steady  weight  gain,  nonproductive  cough,  arrhythmias, 
tachycardia, and pulmonary rales. 
Epirubicin  is  mutagenic.  
  Discuss  birth  control  
issues  with  patient.  
  Advise  patient  against 
pregnancy during and for 6 months after treatment. 
Advise female patients that epirubicin may induce irreversible amenorrhea in pre-menopausal 
women. 


 
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Epirubicin is a vesicant.  Venous sclerosis may result from injection into a small 
vein or repeated 
injections into the same vein.  Check IV patency before and frequently during administration.  
If  extravasation  occurs,  
refer  
to  your  extravasation  policy.  
  Extravasation  may  cause  severe 
tissue necrosis, pain, and lesions. 
 Central venous access may be necessary for patients with poor 
peripheral access.  Discuss options with treating physician. 
Epirubicin  causes  
rapid  cellular  destruction.  
  Assess  
for  signs  of  
tumor  
lysis  syndrome,  
i.e., 
hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia.  Clinical signs would be 
arrhythmias,  neuromuscular  irritability,  weakness,  nausea/vomiting/diarrhea,  paresthesias, 
decreased heart rate, and flaccid paralysis.  Instruct patient to report muscle cramps or twitching 
to health care team immediately. 
Assess baseline renal function for comparison, then watch electrolytes and physical signs for 
compromised  renal  function,  i.e.,  nausea/vomiting/diarrhea,  lethargy,  flank  pain,  edema, 
hematuria, azotemia, oliguria, and anuria.  Encourage hydration and diuresis.  Monitor I&O and 
weight.  Observe for distended neck veins, edema, SOB, and pulmonary rales. 
Epirubicin causes nausea and vomiting in about 90% of patients, especially when given with 
other  emetogenic  agents.    Administer  antiemetics  prophylactically  and  monitor  for  their 
effectiveness. 
Drug may cause stomatitis.  Emphasize the need for good oral hygiene. 
“Radiation  recall”  
is  a  possibility.  
  Assess  patient  for  previous  or  current  sites  of  radiation 
therapy.  Monitor skin in those areas carefully. 
Myelosuppression is common. Monitor CBC closely and advise patient to report any signs or 
symptoms of infection, unusually bruising, and/or bleeding to the health care team immediately. 
Advise patient of alopecia. 
Advise patient that urine may turn pink for 1-2 days after drug administration. 
Patients with impaired liver function must have dose reduction.  Monitor liver function tests 
closely.
 
10.3  Oxaliplatin (Eloxatin®, OXAL) 
Procurement 
Commercial  supplies.  Pharmacies  or  clinics  shall  obtain  supplies  from  normal  commercial 
supply chain or wholesaler. 
Formulation 
Commercially available for injection as: Solution [preservative free]: 5 mg/mL (10 mL, 20 mL, 
40 mL) 
Preparation, Storage and Stability 
Refer to package insert for complete preparation and dispensing instructions. Store 
intact vials in original outer carton at room temperature and; do not freeze. According to 
the manufacturer, solutions diluted for infusion are stable up to 6 hours at room 
temperature or up to 24 hours under refrigeration. Oxaliplatin solution diluted with D
5W 
to a final concentration of 0.7 mg/mL (polyolefin container) has been shown to retain 
>90% of its original concentration for up to 30 days when stored at room temperature or 
refrigerated; artificial light did not affect the concentration (Andre, 2007). As this study 
did not examine sterility, refrigeration would be preferred to limit microbial growth. Do 
not prepare using a chloride-containing solution (e.g., NaCl). Dilution with D
5W (250 or 
500 mL) is required prior to administration. Infusion solutions do not require protection 
from light. 


 
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Administration 
Refer to the treatment section for specific administration instructions. Administer as I.V. 
infusion over 2-6 hours. Flush infusion line with D5W prior to administration of any 
concomitant medication. Patients should receive an antiemetic premedication regimen. Cold 
temperature may exacerbate acute neuropathy. Avoid mucositis prophylaxis with ice chips 
during oxaliplatin infusion. 
Drug Interactions 
Increased Effect/Toxicity: Nephrotoxic agents may increase Oxaliplatin toxicity.  
When administered as sequential infusions, observational studies indicate a potential for 
increased toxicity when platinum derivatives (carboplatin, cisplatin, oxaliplatin) are 
administered before taxane derivatives (docetaxel, paclitaxel). 
Decreased Effect: Oxaliplatin may decrease plasma levels of digoxin 
Pharmacokinetics 
Distribution: V
d: 440 L 
Protein binding: >90% primarily albumin and gamma globulin (irreversible binding to 
platinum) 
Metabolism: Nonenzymatic (rapid and extensive), forms active and inactive derivatives 
phase: 16.8 hours 
Excretion: Primarily urine (~54%); feces (~2%) 
Adverse Events 
Consult the package insert for the most current and complete information. Percentages 
reported with Monotherapy. 
Common known potential toxicities, > 10%:   
Central nervous system: Fatigue, fever, pain, headache, insomnia 
Gastrointestinal: Nausea, diarrhea, vomiting, abdominal pain, constipation, 
anorexia, stomatitis  
Hematologic: Anemia, thrombocytopenia, leukopenia 
Hepatic: Liver enzymes increased 
Neuromuscular & skeletal: Back pain, peripheral neuropathy (may be dose 
limiting). The most commonly observed oxaliplatin toxicity is acute and 
cumulative neurotoxicity, observed in patients treated at doses above 100 
mg/m2/cycle.  This neurotoxicity has included paresthesias and dysesthesias of the 
hands, feet, and perioral region as well as unusual laryngopharyngeal dysesthesias 
characterized by a loss of sensation of breathing without any objective evidence of 
respiratory distress (hypoxia, laryngospasm, or bronchospasm).  OXAL 
neurotoxicity appears to be exacerbated by exposure to cold.  Patients on this study 
will be counseled to avoid cold drinks and exposure to cold water or air.  Should a 
patient develop laryngopharyngeal dysesthesia, their oxygen saturation should be 
evaluated via a pulse oximeter; if normal, an anxiolytic agent should be given and 
the patient observed in the clinic until the episode has resolved.  Because this 
syndrome may be associated with the rapidity of OXAL infusion, subsequent 
doses of OXAL should be administered as a 6-hour infusion (instead of the normal 
2-hour infusion). 
Acute and cumulative neurotoxicities are dose limiting for OXAL.  The acute 
neurotoxicity is characterized by paresthesias and dysesthesias that may be 
triggered or exacerbated by exposure to cold.  These symptoms occur within hours 
of exposure and are usually reversible over the following hours or days.  
Cumulative doses of OXAL above 680 mg/m2 may produce functional impairment 


 
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characterized by difficulty performing activities requiring fine sensory-motor 
coordination; impairment is caused by sensory rather than motor changes.  
The likelihood of experiencing neurotoxicity is directly related to the total 
cumulative dose of OXAL administered.  The relative risk of developing 
neurotoxicity was 10%, 50%, and 75% in patients who received total cumulative 
OXAL doses of 780 mg/m2, 1,170 mg/m
2, and 1,560 mg/m
2, respectively.  Both 
acute and cumulative neurotoxicities due to OXAL have lessened in 82% of 
patients within 4 to 6 months, and have completely disappeared by 6 to 8 months 
in 41% of patients.  In addition, the likelihood that neurologic symptoms will 
regress has been shown to correlate inversely with cumulative dose.  
Respiratory: Dyspnea, cough 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Edema, chest pain, peripheral edema, flushing, thromboembolism 
Central nervous system: Dizziness 
Dermatologic: Rash, alopecia, hand-foot syndrome 
Endocrine & metabolic: Dehydration, hypokalemia 
Gastrointestinal: Dyspepsia, taste perversion, flatulence, mucositis, 
gastroesophageal reflux, dysphagia 
Genitourinary: Dysuria 
Hematologic: Neutropenia 
Local: Injection site reaction 
Neuromuscular & skeletal: Rigors, arthralgia 
Ocular: Abnormal lacrimation 
Renal: Serum creatinine increased 
Respiratory: URI, rhinitis, epistaxis, pharyngitis, pharyngolaryngeal dysesthesia 
Miscellaneous: Allergic reactions, hypersensitivity (includes urticaria, pruritus, 
facial flushing, shortness of breath, bronchospasm, diaphoresis, hypotension, 
syncope, hiccup 
Rare known potential toxicities, <1% (Limited to important or life-threatening):  
Gastrointestinal: Life threatening enteric sepsis secondary to neutropenia and 
diarrhea. 
Hepatic: Veno-occlusive disease of the liver is a rare serious adverse event that has 
occurred in association with administration of oxaliplatin and fluorouracil.  
Otic: Clinical ototoxicity occurs in less than 1% of patients following oxaliplatin 
administration, and sever ototoxicity has not been reported 
Nursing Guidelines 
GI toxicity similar to cisplatin occurs with doses above 30 mg/m2.  It can be almost constant and 
frequently  severe,  but  not  always  dose-limiting.  
  Monitor  
for  nausea  and  vomiting  and treat 
accordingly. 
Dose-limiting side effect can be paresthesias of hands, fingers, toes, pharynx, and occasionally 
cramps which develops with a dose-related frequency (>90 mg/m
2).  Duration of symptoms tend 
to be brief (less than a week) with the first course, but longer with subsequent courses.  Phase I 
patients  have  
reported  exacerbation  of  paresthesias  by  
touching  cold  surfaces  or  exposure to 
cold.  Advise patient of these possibilities and instruct patient to report these symptoms to the 
health  care  team.    Also  advise  patient  to  refrain  from  operating  dangerous  machinery  that 
requires fine sensory-motor coordination, if symptoms appear. 
OXAL is incompatible with NS.  Flush lines with D5W prior to and following OXAL infusion. 
Low back pain is a common side effect, perhaps a form of hypersensitivity reaction.  Instruct 
patient in good body mechanics, advise light massage, heat, etc. 


 
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Laryngopharyngeal dysesthesia (LPD) occurs in about 15% of patients and is acute, sporadic, 
and  self-limited.    It  usually  occurs  within  hours  of  infusion,  is  induced  or  exacerbated  by 
exposure to cold, and presents with dyspnea and dysphagia.  The incidence and severity appear 
to be reduced by prolonging infusion time.  Instruct patient to avoid ice and cold drinks the day 
of  
infusion.  
  
If ≥Grade  2  
laryngopharyngeal  dysesthesia  occurs  during  
the  administration  of 
OXAL, do the following: 
•  Stop OXAL infusion 
•  • Administer benzodiazepine and give patient reassurance 
•  • Test oxygen saturation via a pulse oximeter 
•  • At the discretion of the investigator, the infusion can be restarted at 1/3 the original 
rate of infusion. 
•  • Rapid resolution is typical within minutes to a few hours.  Can recur with retreatment. 
Comparison of the Symptoms and Treatment of Laryngopharyngeal 
Dysesthesias and Platinum Hypersensitivity Reactions 
 
Clinical 
Symptoms 
Laryngopharyngeal 
Dysesthesias 
Platinum 
Hypersensitivity 
dyspnea 
present 
present 
bronchospasm 
absent 
present 
laryngospasm 
absent 
present 
anxiety 
present 
present 
O2 saturation 
normal 
decreased 
difficulty 
swallowing 
present 
(loss of sensation) 
absent 
pruritus 
absent 
present 
urticaria/rash 
absent 
present 
cold-induced 
symptoms 
yes 
no 
BP 
normal or increased  
normal or decreased 
Treatment 
anxiolytics, 
observation in a 
controlled clinical 
setting until 
symptoms abate or at 
the physicians’ 
discretion 
oxygen, steroids, 
epinephrine, 
bronchodilators; fluids 
and vasopressors, if 
appropriate 
Alopecia is rare with OXAL alone, but is seen with 5-FU-OXAL combination.  Advise patient. 
Mild-moderate diarrhea has been seen -- usually of short duration.  Treat accordingly. 
Respiratory  problems  (i.e.,  pulmonary  fibrosis,  cough,  dyspnea,  rales,  pulmonary  
infiltrates, 
hypoxia, air hunger and tachypnea) have been observed in patients administered OXAL.  In rare 
cases, death has occurred due to pulmonary fibrosis.  Please monitor and instruct the patient to 
report any respiratory difficulties and hold OXAL until interstitial lung disease is ruled out for 
cases of Grade ≥3.  If patient is experiencing shortness of breath, a chest x-ray and assessment 
of oxygenation via either finger oximetry or arterial blood gas evaluation are required to confirm 
the  absence  or  presence  of  pulmonary  infiltrates  and/or  hypoxia  (treat  accordingly:    no 
intervention, steroids, diuretics, oxygen, or assisted ventilation). 


 
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Veno-occlusive  disease  (VOD)  
is  a  rare  but  serious  complication  
that  has  been  reported  
in 
patients  receiving  oxaliplatin  in  combination  with  5-FU.    This  condition  can  lead  to 
hepatomegaly, splenomegaly, portal hypertension and/or esophageal varices.  Instruct patients 
to report any jaundice, ascites, or hematemesis to the MD immediately as these could be a sign 
of VOD or other serious condition. 
Acute vein irritation can occur with infusion.  Apply heat to arm of infusion if you are using a 
peripheral line.  However, extravasation of drug can cause severe pain, redness, soreness, and 
exfoliation of the skin in the affected area with loss of affected vein for a long period.  If a patient 
has  a  problem  with  pain  or  sclerosis  when  chemotherapy  
is  given  by  a  peripheral  
line,  
then 
placement of a central line should be considered. 
Patients  may  experience  sleep  disturbances,  specifically  insomnia.    Encourage  good  sleep 
hygiene,  and  
instruct  patient  
to  
report  any  problems  with  sleep  
to  
the  MD,  
to  assess  
for  
the 
potential use of sleeping aids. 
Cold-induced  transient  visual  abnormalities  can  be  experienced  by  patients  while  receiving 
OXAL, although the relationship to OXAL has not been completely determined. 
 Instruct patient 
to report any problems with vision to the MD. 
Extrapyramidal  side  effects  and/or  involuntary  limb  movement  has  been  seen  with  OXAL 
administration.  Patients may also experience restlessness.  Instruct patient to report any of these 
side effects to the MD. 
10.4  Cisplatin (Platinol®, CDDP) 
Procurement 
Commercial  supplies.  Pharmacies  or  clinics  shall  obtain  supplies  from  normal  commercial 
supply chain or wholesaler. 
Formulation 
Commercially available for injection as:  
Solution [preservative free]: 1 mg/mL (50 mL, 100 mL, 200 mL) 
Preparation, Storage and Stability 
Refer to package insert for complete preparation and dispensing instructions. Store 
intact vials at room temperature and protect from light. Do not refrigerate solution, a 
precipitate may form. Further dilution stability is dependent on the chloride ion 
concentration and should be mixed in solutions of sodium chloride concentrations at 
least 0.3% NaCl. Further dilutions in 0.9% NaCl, D
5/0.45% NaCl, or D
5/0.9% NaCl to a 
concentration of 0.05-2 mg/mL are stable for 72 hours at 4ºC to 25ºC. The infusion 
solution should have a final sodium chloride concentration equal to or greater than 0.2% 
NaCl. 
Administration 
Refer to the treatment section for specific administration instructions. When administered as 
sequential infusions, observational studies indicate a potential for increased toxicity when 
platinum derivatives (carboplatin, cisplatin) are administered before taxane derivatives 
(docetaxel, paclitaxel). Pretreatment hydration with 1-2 L of fluid is recommended prior to 
cisplatin administration; adequate hydration and urinary output (> 100 mL/hour) should be 
maintained for 24 hours after administration. Hydration may be accomplished by adding the 
appropriate dose of cisplatin to 750 mL 0.5 D5/0.45% NaCl with 25 grams of Mannitol 
(approximating 1000 mL final volume) and infused over 2 hours. The IV rate of administration 
has varied from a 15- to 120-minute infusion, 1 mg/minute infusion, 6- to 8-hour infusion, 24-
hour infusion, or per protocol; maximum rate of infusion of 1 mg/minute in patients with CHF. 


 
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Drug Interactions 
Increased  Effect/Toxicity: Delayed  bleomycin  elimination  with  decreased  Glomerular 
filtration  rate.  When  administered  as  sequential  infusions,  observational  studies  indicate  a 
potential  for  increased toxicity  when  platinum  derivatives  (carboplatin,  cisplatin)  are 
administered before taxane derivatives (docetaxel, paclitaxel). 
Decreased Effect: Sodium thiosulfate and amifostine theoretically inactivate drug systemically; 
have been used clinically to reduce systemic toxicity with administration of cisplatin. 
Herb/Nutraceutical  Interactions:  Avoid  black  cohosh,  dong  quai  in  estrogen-dependent 
tumors.  
Pharmacokinetics 
Distribution: Rapidly  
into  
tissue;  high  concentrations  
in  kidneys,  
liver,  ovaries,  uterus,  and 
lungs 
Protein binding: >90% 
Metabolism: Nonenzymatic; inactivated (in both cell and bloodstream) by sulfhydryl groups; 
covalently binds to glutathione and thiosulfate 
Half-life  elimination: Initial:  20-30  minutes;  Beta:  60  minutes;  Terminal:  ~  24 hours; 
Secondary half-life: 44-73 hours 
Excretion: Urine (>90%); feces (10%) 
Adverse Events 
Consult the package insert for the most current and complete information.  
Common known potential toxicities, > 10%:   
Central nervous system: Neurotoxicity: Peripheral neuropathy is dose- and duration-
dependent 
Dermatologic: Mild alopecia 
Gastrointestinal: Nausea and vomiting  
Hematologic: Myelosuppression (mild with moderate doses, mild to moderate with 
high-dose therapy) 
Hepatic: Liver enzymes increased 
Renal: Nephrotoxicity (acute renal failure and chronic renal insufficiency) 
Otic: Ototoxicity, manifested as high frequency hearing loss; ototoxicity is especially 
pronounced in children 
Less common known potential toxicities, 1% - 10%:  
Local: Tissue irritation 
Rare known potential toxicities, <1% (Limited to important or life-threatening):  
Anaphylactic reaction, arrhythmias, blurred vision, Bradycardia, cerebral blindness, 
hemolytic anemia, liver enzymes increased, mild alopecia, mouth sores, optic neuritis, 
and papilledema 
Nursing Guidelines 
May react with aluminum IV set, forming a black precipitate and losing its potency. 
Assess laboratory values prior to drug administration, especially CBC, platelets, creatinine. 
Patient should be hydrated before administration. Stress post infusion hydration maintenance to 
reduce risk of nephrotoxicity. 
Administer aggressive antiemetic therapy pre- and post-treatment. 
Monitor  for  signs  of  neurotoxicity  and  ototoxicity.  Instruct  patient  
to  report  any  numbness, 
burning, or tingling in hands and feet to health care team. Also instruct patient to report any 
changes in hearing or ringing in the ears to health care team. 


 
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Monitor magnesium and potassium levels, and for signs and symptoms of hypomagnesemia and 
hypokalemia, supplements may be needed. 
Instruct patient about alopecia. 
Use cautiously with loop diuretics as these may increase the risk of ototoxicity. 
Monitor  for  signs  and  symptoms  of  allergic  reactions.  Treat  according  to  your  
institution’s 
protocol. 
Monitor renal function tests. 
10.5  Capecitabine (Xeloda) 
Procurement 
Commercial  supplies.  Pharmacies  or  clinics  shall  obtain  supplies  from  normal  commercial 
supply chain or wholesaler. 
Formulation 
Commercially available in 150 mg and 500 mg tablets for oral administration. 
Preparation, Storage and Stability 
Refer to package insert for complete preparation and dispensing instructions. 
Store at room temperature of 25ºC, with excursions between 15ºC and 30ºC permitted. 
Administration 
Refer to the treatment section for specific administration instructions. Usually administered in 
2 divided doses taken 12 hours apart. Doses should be taken with water within 30 minutes 
after a meal (Because current safety and efficacy data are based upon administration with food, 
it is recommended that capecitabine be administered with food. In all clinical trials, patients 
are instructed to take with water within 30 minutes after a meal). 
Drug Interactions 
Increased Effect/Toxicity: Phenytoin and warfarin levels or effects may be increased. [U.S. 
Boxed Warning] Capecitabine may increase the anticoagulant effects of warfarin; monitor 
closely. 
Nutrition Interactions: Food reduced the rate and extent of absorption of capecitabine. 
Pharmacokinetics 
Absorption: Rapid and extensive 
Protein Binding: <60%; ~35% to albumin 
Metabolism:  
Hepatic: Inactive metabolites  
Tissue, Active metabolite, Fluorouracil 
Distribution: V
d: 46 mL/kg 
Half-life elimination: 0.5-1 hour 
Time to peak: 1.5 hours; Fluorouracil, 2 hours 
Excretion: Urine (96%), Feces (<3%) 
Adverse Events 
Consult the package insert for the most current and complete information. Frequency 
listed derived from Monotherapy trials. 
Common known potential toxicities, > 10%:   
Cardiovascular: Edema 
Central nervous system: Fatigue, fever, pain 


 
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Dermatologic: Palmar-plantar erythrodysethesia (hand-and-foot syndrome), 
dermatitis. 
Gastrointestinal: Diarrhea may be dose limiting, nausea, vomiting, abdominal pain, 
stomatitis, appetite decreased, anorexia, constipation. 
Hematologic: Lymphopenia, anemia, neutropenia, thrombocytopenia. 
Hepatic: Bilirubin increased. 
Neuromuscular & skeletal: Paresthesia. 
Ocular: Eye irritation. 
Respiratory: Dyspnea. 
Less common known potential toxicities, 5% - 10%:  
Cardiovascular: Venous thrombosis, chest pain. 
Central Nervous System: Headache, lethargy, dizziness, insomnia, mood 
alteration, depression. 
Dermatologic: Nail disorder, rash, skin discoloration, alopecia, Erythema. 
Endocrine& metabolic: Dehydration. 
Gastrointestinal: Motility disorder, oral discomfort, dyspepsia, upper GI 
inflammatory disorders, hemorrhage, ileus, taste perversion. 
Neuromuscular & skeletal: Back pain, weakness, neuropathy, myalgia, arthralgia, 
limb pain 
Ocular: Abnormal vision, conjunctivitis. 
Respiratory: Cough. 
Miscellaneous: Viral infection. 
Rare known potential toxicities, <5% (Limited to important or life-threatening):  
Angina, ascites, asthma, atrial fibrillation, Bradycardia, bronchitis, 
bronchopneumonia, bronchospasm, cachexia, cardiac arrest, cardiac failure, 
cardiomyopathy, cerebral vascular accident, cholestasis, coagulation disorder, 
colitis, deep vein thrombosis, diaphoresis, duodenitis, dysphagia, dysrhythmia, 
ECG changes, encephalopathy, epistaxis, fungal infection, gastric ulcer, 
gastroenteritis, hematemesis, hemoptysis, hepatic failure, hepatic fibrosis, 
hepatitis, Hypokalemia, hypomagnesemia, hyper-/hypotension, hypersensitivity, 
hypertriglyceridemia, idiopathic thrombocytopenia purpura, ileus, infection, 
intestinal obstruction, keratoconjunctivitis, lacrimal duct stenosis, leukopenia, loss 
of consciousness, lymphedema, MI, multifocal leukoencephalopathy, myocardial 
ischemia, myocarditis, necrotizing enterocolitis (typhlitis), oral candidiasis, 
pericardial effusion, thrombocytopenic purpura, pancytopenia, photosensitivity 
reaction, pneumonia, pruritus, pulmonary embolism, radiation recall syndrome, 
renal impairment, respiratory distress, sedation, sepsis, skin ulceration, 
tachycardia, thrombophlebitis, toxic megacolon, tremor, ventricular extrasystoles. 
Nursing Guidelines 
Instruct patients to take the tablets within 30 minutes of a meal (breakfast and dinner). Tablets 
should be swallowed with 6 8 oz. of water. 
Instruct patient to avoid taking a missed dose, to never double up on a dose, and to notify the 
health care team if a dose has been missed. 
Diarrhea  can  be  severe  and  dose-limiting.  
  Instruct  patient  to  contact  
the  health  care  team 
immediately if they experience >4 BMs/day and/or nocturnal diarrhea above baseline.  Monitor 
carefully for dehydration and need for fluid and electrolyte replacement.  Standard antidiarrheal 
treatment, e.g., loperamide is recommended. 


 
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Nausea  and  vomiting  can be  severe  and  dose-limiting.  
  
Instruct  patient  
to  
report  nausea  and 
vomiting to the health care team if they experience >2 episodes of emesis in a 24-hour period.  
Initiate symptomatic treatment. 
Hand  and  Foot  Syndrome  
is  common  and  dose-limiting  
(redness,  swelling,  pain,  numbness, 
tingling,  blistering,  and  moist  desquamation).    Instruct  patient  to  notify  health  care  team 
immediately if symptoms appear.  Chemotherapy may have to be discontinued until symptoms 
subside with future dose reduction initiated.  The syndrome may recur with a rechallenge.  
•  
Advise patient to apply cool compress for comfort. 
•   
Advise patient to avoid harsh soaps and to use alcohol-free emollients. 
•  
Administer analgesics as prescribed. 
•  
Administer systemic steroids and pyridoxine as prescribed. 
Treat stomatitis symptomatically -- may try dabbing vitamin E oil on lesions.  Do not swallow 
oil. Advise frequent and careful oral hygiene. 
Assess for warfarin use.  Patients taking coumadin-derivative anticoagulants concomitantly with 
capecitabine should be monitored regularly for alterations in their coagulation parameters (PT 
or INR). 
Carefully  assess  patient’s  understanding  and  need  of  instruction  in  adequate  birth  control 
measures.  Discuss importance of avoiding pregnancy.  Periodically re-assess. 
Renal impairment: Check creatinine values weekly and calculate creatinine clearance weekly 
for signs of renal impairment (if this is part of test schedule!!).  Follow dose modifications. 
The  use  of  Sorivudine  or  
its  analogue,  Birivudine,  
is  contraindicated  
for  
this  study  due  
to  a 
possible,  even  fatal,  drug  reaction.    Assess  patient’s  drug  use.    Impress  on  patients  the 
importance of avoiding these drugs while on study. 
Cardiotoxicity  (including  MI,  angina,  dysrhythmias,  and  cardiac  arrest)  has  been  seen  with 
capecitabine.  Observe patients closely for signs of cardiac dysfunction. Instruct patient to report 
any chest pain or palpitations to the health care team immediately or seek emergency medical 
attention. 
Monitor patient closely who are taking concomitant phenytoin therapy. There have been reports 
of increased levels of phenytoin in patients who are also taking capecitabine.  These patients 
may  require  more  frequent  monitoring  of  their  phenytoin  levels  and  dose  adjustments  as 
necessary. 
Cimetidine may alter the clearance of capecitabine and cause toxic levels. Cimetidine should be 
avoided while taking capecitabine. 
10.6  Fluorouracil (Adrucil®, 5FU) 
Procurement 
Commercial  supplies.  Pharmacies  or  clinics  shall  obtain  supplies  from  normal  commercial 
supply chain or wholesaler. 
Formulation 
Commercially available for injection 50 mg/mL (10 mL, 20 mL, 50 mL, and 100 mL). 
Preparation, Storage and Stability 
Refer to package insert for complete preparation and dispensing instructions. 
Store intact vials at room temperature and protect from light. A slight discoloration may 
occur with storage but usually does not denote decomposition. Dilute in 50 – 1000 mL 


 
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of 0.9% NaCl or D5W. If exposed to cold, a precipitate may form; gentle heating to 
60ºC will dissolve the precipitate without impairing the potency. Solutions in 50 – 1000 
mL 0.9% NaCl or D5W or undiluted solutions in syringes are stable for 72 hours at 
room temperature. . 
Administration 
Refer to the treatment section for specific administration instuctions. 
Fluorouracil  may  be  given  IV  push,  
IV  
infusion.  Refer  
to  
the  
treatment  section  
for  specific 
administration instructions.  Avoid extravasation, may be an irritant. 
Drug Interactions 
Fluorouracil may increase effects of warfarin. Avoid ethanol (due to GI irritation). 
Avoid black cohosh. 
Pharmacokinetics 
Distribution: V
d ~ 22% of total body water; penetrates extracellular fluid, CSF, and 
third space fluids (e.g., pleural effusions and ascitic fluid), marrow, intestinal mucosa, 
liver and other tissues 
Metabolism: Hepatic (90%); via a dehydrogenase enzyme; Fluorouracil must be 
metabolized to be active. 
Half-life elimination: Biphasic: Initial: 8-20 minutes; two metabolites, FdUMP and 
FUMP, have prolonged half-lives depending on the type of tissue. 
Excretion: Lung (large amounts as CO
2); urine (5% as unchanged drug) in 6 hours. 
Adverse Events 
Consult the package insert for the most current and complete information. 
Common known potential toxicities, > 10%:   
Dermatologic: Dermatitis, pruritic maculopapular rash, alopecia. 
Gastrointestinal (route and schedule dependent): Heartburn, nausea, vomiting, anorexia, 
stomatitis, esophagitis, anorexia, diarrhea. GI toxicity (anorexia, nausea, and vomiting) is 
generally more severe with continuous-infusion schedules. 
Emetic potential: <1000 mg: Moderately low (10% to 30%) ≥ 1000 mg: Moderate (30% to 
60%) 
Hematologic:  Leukopenia;  Myelosuppressive  
(tends  
to  be  more  pronounced in  patients 
receiving bolus dosing of FU). Decreased white blood cell count with increased risk of 
infection; decreased platelet count with increased risk of bleeding. 
Local: Irritant chemotherapy.  
Less common known potential toxicities, 1% - 10%:  
Dermatologic: Dry skin 
Gastrointestinal: GI ulceration 
Rare known potential toxicities, <1% (Limited to important or life-threatening):  
Cardiac enzyme abnormalities, chest pain, coagulopathy, dyspnea, ECG changes 
similar to ischemic changes, hepatotoxicity; hyperpigmentation of nail beds, face, 
hands, and veins used in infusion; hypotension, palmar-plantar syndrome (hand-
foot syndrome), photosensitization. Cerebellar ataxia, headache, somnolence, 
ataxia are seen primarily in intracarotid arterial infusions for head and neck 
tumors. 
Nursing Guidelines 
Monitor complete blood count and platelet count.  Instruct patient to report signs and symptoms 
of infection, unusual bruising or bleeding to the physician. 
Administer antiemetics as indicated. 


 
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Diarrhea may be dose–limiting; encourage fluids and treat symptomatically. 
Assess for stomatitis; oral care measures as indicated. May try vitamin E oil dabbed on sore, six 
times daily.  Cryotherapy recommended with IV push administration. 
Monitor for neurologic symptoms (headache, ataxia). 
Inform patient of potential alopecia. 
Those  patients  on  continuous  infusion  may  need  instruction  regarding  central  intravenous 
catheters and portable intravenous or IA infusion devices. 
 
5FU–induced conjunctivitis is a common problem.  Advise patient to report any eye soreness or 
redness to the healthcare team. 
Photosensitivity may occur.  Instruct patients to wear sun block when outdoors. 
10.7  Docetaxel (Taxotere®, TATER) 
Procurement 
Commercial  supplies.  Pharmacies  or  clinics  shall  obtain  supplies  from  normal  commercial 
supply chain or wholesaler. 
Formulation 
Note: Docetaxel is now available as a one-vial formulation in two concentrations: 10 mg/mL 
and 20 mg/mL. The older formulation included 2 vials which consisted of a concentrated 
docetaxel vial and a diluent vial, resulting in a reconstituted concentration of 10 mg/mL. 
Admixture errors could occur due to the concentration difference between the new 
formulations of 10 mg/mL and 20 mg/mL and the old formulation (10 mg/mL). Do not use the 
two-vial formulation with the one-vial formulation for the same admixture product. 
Preparation, Storage and Stability 
Refer to package insert for complete preparation and dispensing instructions. Storage conditions:
  
Store the packaged docetaxel between 2 and 25°C (36 and 77°F).  Retain in the original package 
to protect from bright light. Freezing does not adversely affect the product. 
 
One-vial  formulation: Note:  One-vial  formulation  is  available  in  two  concentrations:  10 
mg/mL and 20  mg/mL. Further reconstitution with diluent is not required. Further dilute for 
infusion in 250-500 mL of NS or D
5W in a non-DEHP container (e.g., glass, polypropylene, 
polyolefin)  to  a  final  concentration  of  0.3-0.74  mg/mL.  Gently  rotate  to  mix  thoroughly. 
Solutions prepared from the one-vial formulation and diluted for infusion should be used within 
4 hours of preparation (infusion should be completed within 4 hours). 
 
Two-vial formulation: Vials should be diluted with 13% (w/w) ethanol/water (provided with 
the drug) to a final concentration of 10 mg/mL. Do not shake. Further dilute for infusion in 250-
500 mL of NS or D5W in a non-DEHP container (e.g., glass, polypropylene, polyolefin) to a 
final concentration of 0.3-0.74 mg/mL. Gently rotate to mix thoroughly. Diluted solutions of the 
two-vial formulation are stable in the vial for 8 hours at room temperature or under refrigeration. 
Solutions  prepared  with  
the  
two-vial  
formulation  and  diluted  
for infusion in  D
5W  or  NS  are 
stable for up to 4 weeks (Thiesen, 1999) at room temperature of 15ºC to 25ºC (59ºF to 77ºF) in 
polyolefin  containers;  however,  
the  manufacturer  recommends  use  within  4  hours  (infusion 
should be completed within 4 hours). 
 
 


 
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Administration 
Refer to the treatment section for specific administration instructions. Administer IV infusion 
over 1-hour through nonsorbing polyethylene lined (non-DEHP) tubing; in-line filter is not 
necessary.  Do not administer to patients with a history of hypersensitivity to docetaxel or 
polysorbate 80.  Docetaxel is an irritant with vesicant-like properties.   Note: Premedication 
with dexamethasone 8 – 10 mg orally twice daily for 3-5 days, beginning the day before 
docetaxel administration is recommended to decrease the incidence and severity of fluid 
retention and prevent hypersensitivity reactions and pulmonary/peripheral edema.  When 
administered as sequential infusions, taxane derivatives should be administered before 
platinum derivatives (cisplatin, carboplatin) to limit myelosuppression and to enhance 
efficacy. 
Drug Interactions 
Cytochrome P450 Effect: Substrate (major) of CYP3A4; Inhibits CYP3A4 (weak).  
Increased Effect/Toxicity: CYP3A4 inhibitors may increase the levels/effects of 
docetaxel. Concomitant use of docetaxel with a potent CYP3A4 inhibitor should be 
avoided. Refer to the package insert or LexiComp
1 for example inhibitors. When 
administered as sequential infusions, observational studies indicate a potential for 
increased toxicity when platinum derivatives (carboplatin, cisplatin) are administered 
before taxane derivatives (docetaxel, paclitaxel). Taxane derivatives may enhance the 
adverse/toxic effect of anthracyclines. 
Decreased Effect: CYP3A4 inducers may decrease the levels/effects of docetaxel. 
Refer to the package insert or LexiComp1 for example inducers. 
Ethanol/Herb/Nutraceutical Interactions: Avoid ethanol (due to GI irritation). Avoid 
St John’s wort (may decrease docetaxel levels). 
Pharmacokinetics 
Docetaxel exhibits linear pharmacokinetics at the recommended dosage range. 
Distribution: Extensive extravascular distribution and/or tissue binding; Vd: 80-90 
L/m2, Vdss: 113 L (mean steady state) 
Protein binding: ~94% to 97% 
Metabolism: Hepatic; oxidation via CYP3A4 to metabolites 
Half-life elimination: Terminal: ~11 hours 
Excretion: Feces (~75%, <8% as unchanged drug); Urine (<5%)  
Adverse Events 
Consult the package insert for the most current and complete information. Percentages 
reported for docetaxel Monotherapy; frequency may vary depending on diagnosis, dose, 
liver function, prior treatment, and premedication. The incidence of adverse events was 
usually higher in patients with elevated liver function tests. 
Common known potential toxicities, > 10%:   
Cardiovascular: Fluid retention 
Central nervous system: Neurosensory events including neuropathy, fever, 
neuromotor events. 
Dermatologic: Alopecia, cutaneous events, nail disorder 
Gastrointestinal: Stomatitis, diarrhea, nausea, vomiting 
Hematologic: Neutropenia, leukopenia, anemia, thrombocytopenia, febrile 
neutropenia 
Hepatic: Transaminases increased 
Neuromuscular & skeletal: Weakness, myalgia 
Respiratory: Pulmonary events 
Miscellaneous: Infection, hypersensitivity 


 
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Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Left ventricular ejection fraction decreased, hypotension 
Dermatologic: Rash/erythema 
Gastrointestinal: Taste perversion 
Hepatic: Bilirubin increased, alkaline phosphatase increased 
Local: Infusion-site reactions including hyperpigmentation, inflammation, redness, 
dryness, phlebitis, extravasation, swelling of the vein 
Neuromuscular and skeletal: Arthralgia 
Ocular: Epiphora associated with canalicular stenosis 
Rare known potential toxicities, <1% (Limited to important or life-threatening):  
Acute myeloid leukemia, acute respiratory distress syndrome, anaphylactic shock, 
angina, ascites, atrial fibrillation, atrial flutter, bleeding episodes, bronchospasm, 
cardiac tamponade, chest pain, chest tightness, colitis, conjunctivitis, constipation, 
cutaneous lupus erythematosus, deep vein thrombosis, dehydration, disseminated 
intravascular coagulation, drug fever, duodenal ulcer, Dyspnea, dysrhythmia, ECG 
abnormalities, erythema multiforme, esophagitis, gastrointestinal hemorrhage, 
gastrointestinal obstruction, gastrointestinal perforation, hand and foot syndrome, 
hearing loss, heart failure, hepatitis, hypertension, ileus, intestinal pneumonia, 
ischemic colitis, lacrimal duct obstruction, loss of consciousness (transient), MI, 
multiorgan failure, Myelodysplastic syndrome, neutropenic enterocolitis, 
ototoxicity, pleural effusion, pruritus, pulmonary edema, pulmonary embolism, 
pulmonary fibrosis, radiation pneumonitis, radiation recall, renal insufficiency, 
seizure, sepsis, sinus tachycardia, Stevens-Johnson syndrome, syncope, toxic 
epidermal necrolysis, tachycardia, thrombophlebitis, unstable angina, visual 
disturbances (transient) 
Nursing Guidelines 
Monitor  CBC  closely,  as  neutropenia,  and  thrombocytopenia  are  common  and  may  be  life 
threatening, and dose limiting.  Instruct patient to report any signs or symptoms of infection, any 
unusual bruising, or bleeding. 
Administer antiemetics as ordered. Evaluate for their effectiveness. 
Monitor  for  signs/symptoms  of  hypersensitivity reactions  that  may  include  chills,  rigors, 
dyspnea,  bronchospasms,  etc.  
  Stop  
infusion  
immediately  and  administer  proper  emergency 
treatment. 
Because of the risk of anaphylaxis and development of edema, instruct patient that is imperative 
to take steroid premedications as ordered. 
Instruct patient on proper oral care, as mucositis may occur. 
Advise patient about alopecia. 
Monitor liver function tests. 
Drug is a vesicant.  Monitor infusion site frequently for signs of irritation or infiltration.  Drug 
extravasation causes acute streaking, burning pain, and discoloration at the site.  Skin may be 
reddened for several weeks and occasionally blister and/or peel. 
 Reactions are usually reversible 
over time.   Because of this central venous access may be necessary.  Discuss with MD if patient 
has  poor  peripheral  venous  access.  
  If  docetaxel  concentrate  or  diluted  solution  comes  
into 
contact with skin, wash with soapy water immediately.  If it comes into contact with mucosa, 
wash with warm water immediately. 
Instruct  patient  to  report  any  signs  of  peripheral  neuropathy  to  the  health  care  team  (pain, 
numbness, tingling). 


 
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Monitor for signs and symptoms of fluid retention, weight gain, ascites and CHF. 
Instruct patient about possible facial flushing, rash, and skin and nail changes.  Monitor for signs 
and symptoms of hand/foot syndrome. However premedication with steroids can minimize this 
side effect.  Discuss with MD possible ways to manage itching and skin changes that may occur 
up to a week after docetaxel administration.  Advise patients that nails may crack, peel, or fall 
off all together. This may be a chronic toxicity.  Instruct patient to keep nails clean, short and to 
avoid wearing nail polish or artificial nails. 
10.8  Irinotecan (Camptosar®, CPT11) 
Procurement 
Commercial  supplies.  Pharmacies  or  clinics  shall  obtain  supplies  from  normal  commercial 
supply chain or wholesaler. 
Formulation 
Commercially  available  
for  
injection  20  mg/mL  
(2  mL,  5  mL,  15  mL)  
[contains  sorbitol  45 
mg/mL; do not use in patients with hereditary fructose intolerance]. 
Preparation, Storage and Stability 
Refer to package insert for complete preparation and dispensing instructions. Store 
intact vials at room temperature and protect from light. Doses should be diluted in 250-
500 mL D
5W or 0.9% NaCl to a final concentration of 0.12-2.8 mg/mL. Due to the 
relatively acidic pH, Irinotecan appears to be more stable in D
5W than 0.9% NaCl. 
Solutions diluted in D5W are stable for 24 hours at room temperature or 48 hours under 
refrigeration at 2ºC to 8ºC. Solutions diluted in 0.9% NaCl may precipitate if 
refrigerated. Do not freeze. 
Administration 
Refer to the treatment section for specific administration instructions. 
Administer by I.V. infusion, usually over 90 minutes. 
Drug Interactions 
Cytochrome P450 Effect: Substrate (major) of CYP2B6, 3A4 
Increased Effect/Toxicity: CYP2B6 and CYP3A4 inhibitors may increase the 
levels/effects of irinotecan. Bevacizumab may increase the adverse effects of Irinotecan 
(e.g., diarrhea, neutropenia). Ketoconazole increases the levels/effects of Irinotecan and 
active metabolite; discontinue ketoconzaole 1 week prior to Irinotecan therapy; 
concurrent use is contraindicated. 
Decreased Effect: CYP2B6 and CYP3A4 inducers may decrease the levels/effects of 
irinotecan.  
Ethanol/Nutrition/Herb Interactions Herb/Nutraceutical: St John’s wort decreases 
therapeutic effect of irinotecan; discontinue ≥  2 weeks prior to irinotecan therapy; 
concurrent use is contraindicated. 
Pharmacokinetics 
Distribution: V
d: 33-150 L/m
2 
Protein binding, plasma: Predominantly albumin; Parent drug: 30% to 68%, SN-38 
(active metabolite): ~95% 
Metabolism: Primarily hepatic to SN-38 (active metabolite) by carboxylesterase 
enzymes; SN-38 undergoes conjugation by UDP- glucuronosyl transferase 1A1 
(UGT1A1) to form a glucuronide metabolite. Conversion of Irinotecan to SN-38 is 
decreased and glucoronidation of SN-38 is increased in patients who smoke cigarettes, 
resulting in lower levels of the metabolite and overall decreased systemic exposure. SN-


 
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38 is increased by UGT1A1*28 polymorphism (10% of North Americans are 
homozygous for UGT1A1*28 allele). Patients homozygous for the UGT1A1*28 allele 
are at increased risk of neutropenia; initial one-level dose reduction should be 
considered for both single-agent and combination regimens. The lactones of both 
Irinotecan and SN-38 undergo hydrolysis to inactive hydroxyl acid forms. 
Half-life elimination: SN-38: Mean terminal: 10-20 hours 
Time to peak: SN-38: Following 90-minute infusion: ~1 hour 
Excretion: Within 24 hours: urine: Irinotecan (11% to 20%), metabolites (SN-38 <1%, 
SN-38 glucuronide, 3%) 
Adverse Events 
Consult the package insert for the most current and complete information including U.S. 
Boxed Warnings pertaining to severe diarrhea and severe myelosuppression. 
 
Common known potential toxicities, > 10%:   
Cardiovascular: Vasodilation 
Central nervous system: Cholinergic toxicity (includes rhinitis, increased 
salivation, miosis, lacrimation, diaphoresis, flushing and intestinal 
hyperperistalsis); fever, pain, dizziness, insomnia, headache, chills 
Dermatologic: Alopecia, rash 
Endocrine & metabolic: Dehydration 
Gastrointestinal: Late onset diarrhea, early onset diarrhea, nausea, abdominal pain, 
vomiting, cramps, anorexia, constipation, mucositis, weight loss, flatulence, 
stomatitis 
Hematologic: Anemia, leukopenia, thrombocytopenia, neutropenia 
Hepatic: Bilirubin increased, alkaline phosphatase increased  
Neuromuscular & skeletal: Weakness, back pain 
Respiratory: Dyspnea, cough, rhinitis 
Miscellaneous: Diaphoresis, infection 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Edema, hypotension, thromboembolic events 
Central nervous system: Somnolence, confusion 
Gastrointestinal: Abdominal fullness, dyspepsia 
Hematologic: Neutropenic fever, hemorrhage, neutropenic infection 
Hepatic: AST increased, ascites and/or jaundice 
Respiratory: Pneumonia 
Rare known potential toxicities, <1% (Limited to important or life-threatening):  
ALT increased, amylase increased, anaphylactoid reaction, anaphylaxis, angina, 
arterial thrombosis, bleeding, Bradycardia, cardiac arrest, cerebral infarct, 
cerebrovascular accident, circulatory failure, colitis, deep thrombophlebitis, 
dysarthria, dysrhythmia, embolus, gastrointestinal bleeding, gastrointestinal 
obstruction, hepatomegaly, hiccups, hyperglycemia, hypersensitivity, 
hyponatremia, ileus, interstitial lung disease, intestinal perforation, ischemic 
colitis, lipase increased, lymphocytopenia, megacolon, MI, muscle cramps, 
myocardial ischemia, pancreatitis, paresthesia, peripheral vascular disorder, 
pulmonary embolus, pulmonary toxicity (dyspnea, fever, reticulnodular infiltrates 
on chest x-ray), renal failure (acute), renal impairment, syncope, thrombophlebitis, 
thrombosis, typhlitis, ulceration, ulcerative colitis, vertigo 
 
 


 
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Nursing Guidelines 
If possible, check for any history of hypersensitivity reaction to any previous drug formulated 
with polysorbate 80. 
Cholinergic symptoms of lacrimation, nasal congestion, diaphoresis, flushing, ABD cramping, 
and diarrhea can occur at the beginning, during, or immediately after the CPT-11 infusion.  It is 
suggested that the patient remain in the treatment area for a minimum of one hour following the 
completion of the very first CPT-11 infusion.  If diarrhea occurs within one hour of infusion 
follow institution’s policy regarding administration of Atropine. 
11.0  MEASUREMENT OF EFFECT 
11.1  PET/CT Imaging Interpretation of Baseline and Post-Induction Chemotherapy PET Scans 
11.1.1 Schedule of Evaluations 
For the purposes of this study, patients randomized onto salvage chemotherapy plus surgery 
arm should be reevaluated by FDG PET/CT < 2 weeks prior to surgical resection for clinical 
tumor response. Supporting documentation of response should be submitted, per Section 
6.1.1.  
11.1.2 Baseline PET/CT Scan Interpretation 
The  baseline  PET/CT  scan  (performed  prior  to  pre-op  chemotherapy,  scan  #1) will  be 
interpreted by an experienced nuclear medicine physician at each participating site who will 
be responsible for image interpretation and clinical reporting for the local site. The images 
will be interpreted together with pertinent clinical findings and findings of other imaging 
modalities such as standard (i.e., contrast-enhanced) CT or MRI, or endoscopic ultrasound 
if  performed.  Interpreting  the  PET/CT  scans  in  this  fashion  mimics  the  usual  clinical 
situation, in which this information is incorporated into the interpretation, especially in the 
case of an equivocal scan finding that may be easily explained by the CT/MRI scan result 
(e.g.,  anatomic  variation  of  
the  bowel  or  bladder)  or clinical  
information  
(e.g., increased 
uptake at a site of recent surgery or biopsy). Sites will be responsible for submitting PET/CT 
imaging datasets (per Section 6.3) and an adjunctive data form. If the baseline PET/CT scan 
is deemed not to be evaluable, the ICL at IROC Ohio staff will use the opportunity to educate 
the  personnel  at  the  local  site  to  ensure  that  future  studies  are performed  according  to 
protocol, and may request a repeat baseline PET/CT scan. 
Visual assessment will be used to interpret the PET/CT findings as positive or negative at 
baseline. Abnormal (positive) 18FDG tumor uptake using visual assessment will be defined 
as “any focal or diffuse FDG uptake above background that is incompatible with normal 
anatomy.” Visual interpretation will be the primary criterion used for positivity/negativity 
of baseline findings, since this is currently the only validated approach for gastric cancer. 
However, to objectively assess the degree of 18FDG uptake, a semi-quantitative approach 
using the SUV (standardized uptake value) will also be employed. The primary reasons for 
determining the SUV’s on the baseline PET/CT studies are to: 
1) Provide a baseline parameter for calculating the change in maximum SUV (SUVmax) of 
the  primary  gastric  
tumor  and  any  established/confirmed  
tumor  metastases  
following 
induction chemotherapy. 
2) Determine whether the patient will be eligible to undergo subsequent PET/CT scans for 
monitoring  of  
treatment  
response  under  
this  protocol  by  establishing  
that  at  
least  
the 
primary gastric tumor is 18FDG -avid by visual interpretation with an SUV max of at 
least 5.0 or a tumor:liver ratio of at least 1.5. Visually the gastric mass must have 
18FDG 
uptake significantly above background (qualitative).  


 
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11.1.3 Interpretation of Concomitant Cycle 1 of Pre-Op Chemotherapy PET/CT Scans 
The concomitant cycle 1 of pre-op chemotherapy PET or PET/CT scans will be interpreted 
preferably by the same PET/CT reader at each participating site who will be responsible for 
image  
interpretation.  Here  again,  
the  
images  will  be  
interpreted  
together  with  pertinent 
clinical findings and any available findings from other imaging modalities such as standard 
CT or MRI, as well as other imaging modalities performed at the discretion of the treating 
physician.  Both  
lesions  present  at  baseline  as  well  as  
the  appearance  of  new  
lesions  on 
follow-up PET/CT will be incorporated in the interpretation. Both visual assessment and 
semiquantitative  assessment  using  the  SUVmax  approach  will  be  used  to  interpret  the 
follow-up PET/CT findings. Semiquantitative analysis will also be used to determine the 
change in FDG uptake using the SUVmax approach (i.e., change in SUVmax, see below) 
following cycle 1 chemotherapy for registration eligibility. For assessment of new lesions 
that  may  appear  following  cycle  1  pre-surgery  chemotherapy,  visual  interpretation,  as 
described above, will be used to determine if the new lesion is positive or negative for tumor 
in conjunction with available clinical and radiological findings. A new site seen by PET/CT 
will only be considered disease progression if corroborated by biopsy or other established 
imaging  methods.  Patients  with  disease  progression that  constitutes  metastatic  disease 
documented by PET/CT imaging and confirmed by biopsy or imaging should be removed 
from protocol therapy. An increase in the SUVmax (see below) of > 20% in the primary 
gastric  tumor  following  cycle 1 chemotherapy  will  only  be  considered  as  possible 
“indication”  of local disease  progression,  unless  correlated  by  disease  progression 
documented by biopsy or other imaging modalities such as barium esophagram or CT, in 
which case disease progression will be established. 
Patients  will  be  categorized  as  responders  or  non-responders  based  on  SUVmax  of  the 
primary gastric tumor.  A response will be defined as a SUVmax decrease of ≥ 35% when 
compared to baseline.  Non-responders (those patients whose primary tumor SUVmax does 
not  decrease  by  at  least  35%)  will  be  randomized  to  surgery  or  salvage  chemotherapy 
followed by surgery.   Patients randomized to the salvage chemotherapy plus surgery arm 
must be reevaluated by FDG PET/CT < 2 weeks prior to surgical resection for clinical tumor 
response. 
11.2  Semiquantitative PET/CT Analysis Using the SUV Approach 
Semiquantitative  analysis  using  
the  SUVmax  approach  will  be  used  
to  assess  
the  change  
in 
18FDG uptake of established/confirmed baseline lesions between baseline and the subsequent 
time point in Arm A patients and two subsequent timepoints in Arm B patients. SUV is the ratio 
of activity in a tissue (in μCi/ml) divided by the decay-corrected activity injected into the patient 
(in μCi/g). The resultant number is almost unitless (actually g/ml) and is a crude measure of 
degree of uptake of 
18FDG into any tissue. The decision to utilize the SUVmax method is based 
on the fact that it is the most commonly used quantitative method in clinical 18FDG imaging, 
because of its practicality and its ease of calculation. The required information is the weight of 
the  patient,  
the  administered  dose  of 
18FDG,  
the  elapsed  
time  
from  
injection  
to  midpoint  of 
18FDG  image,  and  the  activity  in  a  tissue  of  interest  determined  from  the  PET/CT image. 
Importantly, this method does not require blood sampling. This parameter has also been found 
to be highly reproducible (mean difference between two measurements performed within a 1-
week interval was about 10%), further supporting its use in serial semiquantitative analysis in 
PET/CT [35]. SUVmax will be determined from the PET/CT images. It must be ensured that 
the images at all sites are reconstructed according to the algorithms described below, and with 
the same spatial resolutions. Regions of interest (ROIs) will be manually placed around the entire 
extent of any abnormality to include the most intense portion of this abnormality to determine 
the maximum tissue activity within the ROI (SUVmax) and decay corrected to time of injection. 


 
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The  
tomographs  will  be  calibrated  at  
least  monthly  by  
imaging  known  activity  
that  
is  also 
measured in a dose calibrator. Injected activity will be measured in a dose calibrator, corrected 
for residual activity in the syringe after injection, and decay corrected to time of injection.  
SUVmax will be calculated as ROI max μCi/ml divided by injected activity μCi/g body weight. 
The  change  in  SUVmax  between  the  baseline  and  target  day  15-19  of  cycle  1  pre-op 
chemotherapy PET/CT studies will be calculated for all established/confirmed lesions seen by 
baseline  PET/CT  with  an  SUVmax  of  ≥  5.0  or  a  
tumor:liver  ratio  of  >  1.5.  The  change  
in 
SUVmax of these lesions following therapy will be expressed as % decrease (or increase) in 
SUVmax from baseline to the day 15-19 of cycle 1 of pre-op chemotherapy PET/CT scan. The 
change in SUVmax for the primary gastric tumor identified at baseline will be calculated as well 
as the mean change in SUVmax for all established/confirmed lesions. These changes will be 
correlated with clinical and histopathological response to therapy as well as disease-free and 
overall survival. For lesions that have completely resolved by PET/CT (i.e., uptake in the area 
of previous disease is indistinguishable from background uptake), the SUV of the lesion will be 
considered as 0 (no tumor, uptake is not higher than background) and % decrease from baseline 
calculated as 100%. 
11.3   Quality Assurance of PET/CT data 
Every effort will be made to ensure that the collected PET/CT studies performed at the various 
sites are acquired and processed according to the protocol guidelines (Sections 6.3 and 11.1). 
This will be coordinated by the Imaging Co-Chair, Nathan Hall, M.D., PhD. 
11.4  Progression of Disease  
For  both  study  arms,  progression  of  disease  on  PET/CT  scan alone  
(new  sites  of  metastatic 
disease) prior to surgery should be corroborated by biopsy of distant metastatic disease sites, as 
clinically  indicated.  If  a  confirmatory  biopsy  of  metastatic  disease  is  not  performed,  it  is 
recommended that a second imaging study be performed using a different imaging modality. 
11.5  Pathological tumor response after surgery 
Definitive assessment of pathologic tumor response will be established on the basis of surgical 
outcome. All patients that are candidates for surgical resection at the completion of pre-operative 
chemotherapy will be classified with respect to their pathologic tumor response.  
11.5.1 Pathologic Tumor Response Criteria 
Pathologic Complete Response (PCR): No gross or microscopic tumor identified with the 
surgical specimen. All lymph nodes should be free of tumor to document a PCR. If no gross 
tumor is visible, section around the area of inflammation (nodularity) should be made every 
2-3 cm and specimens examined.  
Pathologic Persistent Disease (PPD): Residual viable tumor in the resected specimen. This 
will then be subclassified as macroscopic (evident at the time of surgery) or microscopic 
(evident only at the time of pathology review) residual disease 
11.6  Completeness of Surgical Resection  
All operative and pathology reports from patients in the study must be submitted. Reports must 
contain information about gross and microscopic contamination of surgical resection margins.  
 
 


 
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11.6.1 Curative Resection Definition 
Resections are defined as “curative” (i.e., complete resection; R0 resection) when all gross 
disease has been removed, and microscopic examination reveals all surgical margins free of 
tumor (i.e., pathological stage T1-3, NX, MO resected). Resections will still be considered 
curative if pathologic examination reveals positive lymph nodes as long as the nodes were 
completely resected.  
11.6.2 Palliative Resection Definition 
“Palliative  
resection”  
(i.e.,  
incomplete  
resection)  will  be  considered  
to  have  
taken  place 
when gross disease has been left behind (R2 resection), or when microscopic examination 
reveals surgical margins which are not free of tumor (R1 resection). Positive margins are 
defined as tumor at or less than 1 mm from the lateral (“deep”), proximal, or distal margins.  
11.6.3 No resection 
The primary tumor could not be removed.  
11.7  Recurrence of disease: 
11.7.1 NED 
No evidence of disease (NED). 
11.7.2 Recurrence of disease (REC).  
Recurrence of disease (REC) must be confirmed by imaging and/or biopsy, with supporting 
materials submitted. Distant metastatic disease on CT or PET/CT imaging or evidence of 
locally recurrent disease constitutes recurrence of disease (REC), and should be documented 
by endoscopy, CT or PET/CT imaging. Elevated CEA levels only or physical findings only 
does not meet criteria for recurrence of disease. 
12.0  END OF TREATMENT/I
NTERVENTION 
12.1  Duration of Treatment  
12.1.1 Disease Progression: Remove from protocol therapy any patient with disease progression 
before surgery (Arm B patients) or recurrence after surgery (either Arm A or B patients). 
Document details, including tumor measurements for pre-operative disease progressions of 
Arm B patients, on data forms. 
After disease progression, patients should be followed for survival per the study calendar 
(Section 5.0). 
12.2  Managing  ineligible  patients and registered patients who  never  receive  protocol 
intervention  
Definition of ineligible patients: A study participant who is registered to the trial but does not 
meet all of the eligibility criteria is deemed to be ineligible. Patients who are deemed ineligible 
may  continue protocol  
treatment,  provided the treating  physician,  study  chair,  and  executive 
officer agree there are no safety concerns if the patient continues protocol treatment. All scans, 
tests, and data submission are to continue as if the patient were eligible. Notification of the local 
IRB may be necessary per local IRB policies. In the case of either the patient is off protocol 
treatment or continue protocol treatment, patients should be followed for survival per the study 
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Study  participants  who  are  
registered  
to  
the  
trial  but  never  
receive  study  
intervention  
(for  a 
reason  other  than  because  they  were  deemed  ineligible)  must  still  complete  follow-up 
requirements as specified below. 
Patients who do not receive adjuvant therapy (regardless of study arm) are also required to have 
physical exam and labs 3 months (+/- 4 weeks) following surgery. 
Baseline,  on-study,  endpoint  (e.g.,  relapse  or  progression),  off  treatment,  and  survival  data 
submission required. 
12.3  Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient
's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
•   Document the reason(s) for discontinuation of therapy on data forms. 
•  Follow the patient for protocol endpoints as required by the Study Calendar. 
13.0  STATISTICAL CONSIDERATIONS 
13.1  Primary Endpoint 
The  primary  endpoint  of  this  study  is  overall  survival  (OS).  OS  is  defined  as  time  from 
randomization to death due to all causes. 
13.2  Secondary Endpoints  
13.2.1 Progression-free  survival:  PFS  is  defined  as  time  from  randomization  to  the  first 
documentation of disease progression or death due to all causes, whichever comes first. The 
distribution of PFS will be estimated using the method of Kaplan-Meier [36] in each arm 
for FDG-PET non-responders.  PFS will be compared between two treatment groups (Arm 
A and B) in FDG-PET non-responders using the log-rank test on ITT population.   
13.2.2 R0  resection  rate  
is  defined  as  
the  proportion  of  patients achieved R0  resection  during 
surgery. The R0 resection rate will be estimated by the number of patients had R0 resection 
divided by total number of patients who meet the analysis population definition. Confidence 
intervals for the true confirmed tumor response will be calculated according to the approach 
of Duffy and Santner [37]. Chi-sqaure test (or Fisher’s exact test if the data in contingency 
table is sparse) will be used to compare R0 resection rate between experiment and control 
arms in FDG-PET non-responder cohort (Arm A and B). 
13.2.3 Pathologic complete response rate is defined as the proportion of patients had pathologic 
complete  
response.  The  pCR  
rate  will  be  estimated  by  
the  number  of  patients  had  pCR 
divided by total number of patients who meet the analysis population definition. Confidence 
intervals for the true confirmed tumor response will be calculated according to the approach 
of Duffy and Santner [37]. Chi-sqaure test (or Fisher’s exact test if the data in contingency 
table is sparse) will be used to compare pCR rate between experiment and control arms in 
FDG-PET non-responder cohort (Arm A and B).  
13.2.4 Adverse  events  
(AE):  
  All  AE  and  
the  maximum  grade  
for  each  
type  of  adverse  events 
(including all adverse events and those that are possibly, probably or definitely related to 
study treatments) will be recorded for each patient.  The frequency tables will be reviewed 
to determine the patterns.  The overall adverse event rates will be compared between two 
treatment  groups  
in  FDG-PET  non-responders (Arm  A  and  B) using  Chi-square  
test  
(or 
Fisher’s exact test if the data in contingency table is sparse).  Analyses on AE data will be 


 
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based  on  safety  population. See Section  9.0 for  definitions  of  
routine  solicited  and  non-
reportable adverse events. 
13.2.5 FDG-PET  SUV  measures:  Within  the  FDG-PET  non-responders  receiving  salvage 
chemotherapy (Arm B), FDG-PET SUV measures will be obtained at before pre-registration 
chemotherapy, then after pre-registration chemotherapy and after 2 cycles of pre-operative 
savage  chemotherapy.  The  profile  of  FDG-PET  SUV  measures  over  time  will  be 
summarized graphically. Methods for analyzing repeated measurements (e.g., GEE models) 
will  be  used  
to  assess  whether  
there  
is  any  
time  
trend  
in  FDG-PET  SUV  measures,  
the 
potential  
impact  of  savage  chemotherapy,  and  any  baseline  patient  demographic/disease 
characteristic predicting the identified trend. The changes in FDG-PET SUV measures at 
two latter time points compared to baseline will be summaries, and be evaluated whether 
these changes are correlated with surgical outcomes by logistic regression and/or long-term 
survival outcomes by Cox model. 
13.3  Sample size 
There  will  be  81  FDG-PET non-responders randomized  
to  each  arm  
(i.e. surgery  vs salvage 
chemotherapy + surgery) of this study (total of 162 FDG-PET non-responding patients). 
13.4  Power justification 
The primary aim of this randomized phase II clinical trial is to examine and compare the overall 
survival  (OS)  of  patients  with  
locally advanced  gastric  cancer  classified  as  FDG-PET  non-
responders between the experimental (salvage chemotherapy and surgery) and control (surgery 
alone)  arms.  This  trial  implements  a  group  sequential  design  with  one  interim  analysis  for 
futility, adopting Rho family (Rho=1.5) beta spending function for controlling the overall type 
II error rates. Other endpoints of interest that will be evaluated include PFS, R0 resection rate, 
pCR, and AE profile. 
The median OS in the control arm is assumed to be 20 months based on the results from recent 
trials (Ott 2003, Ott 2008, MUNICON I, MUNICON II). We additionally assume an accrual 
rate of 3 FDG-PET non-responders patients per month, and a minimal follow-up of 24 months. 
A  sample  size  of  81  patients  in  each  group  (total of  81×2=162)  with  expected  120  events 
provides 80% power to detect a Hazard Ratio (HR, experimental arm related to control arm) of 
0.70 at the significance level of 0.15 with one-sided test for the comparisons between the control 
and experimental regimens.  With this design, we would target a median overall survival in the 
experimental arm of 28.57 months. 
Power and Significance Level:  The operating characteristics of current design can be tabulated 
according to various true hazard ratios, including the probabilities that the experimental regimen 
is superior to the control regimen, i.e. power which warrants further studies on experimental 
regimen, and probabilities of stopping the trial early due to futility of the experimental regimen. 
If the true hazard ratio is …  
1.00  0.925  0.850  0.775  0.700 
Then the probability of declaring that 
the experimental regimen warrants 
further studies is … 
0.15  0.26  0.42  0.62  0.80 
Probability of stopping at the interim 
analysis due to futility is … 
0.46  0.34  0.24  0.14  0.07 


 
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13.5  Analysis Populations 
The analysis populations for FDG-PET non-responders include the following: 
•  Intent-to-treat  (ITT)  population: The  ITT  population  includes  all eligible patients 
randomized  to  treatment, irrespective of  whether  or  not  they  receive  any  study 
medication. 
•  Per-protocol (PP) population: The PP population includes all eligible and randomized 
patients who receive at least one dose of pre-op study medication, and who have efficacy 
data post-randomization.  
•  Disease-specific  population  1  
(DSP): The  DSP  
includes  all  eligible  and  
randomized 
patients who received at least one dose of pre-op study medication, and who undergo 
surgery. 
•  Safety population: The safety population includes all randomized patients who receive 
at least one dose of study medication. 
The primary efficacy analysis will be based on the ITT population. Sensitivity analysis will be 
performed  on  PP  population.  All  safety  analyses  will  be  based  on safety  population. Other 
secondary and translational analyses will be conducted on the ITT, and/or PP population, and/or 
DSP as appropriate for the endpoint.  
13.6  Treatment Efficacy Decision Rules: 
13.6.1 Interim Analysis:  
An  interim  analysis  will  be  performed  to  assess  treatment  futility.  The  study  will  be 
terminated if there is strong evidence that the null hypothesis (i.e., no difference in treatment 
effect  between  experimental  and  control  regimen),  cannot  be  rejected. After  the  first 
observed 60 events (approximately 42 months after the first patient randomized, under null 
hypothesis),  the  interim  analysis  will  be  performed.    If  the  estimated  hazard  ratio 
(experimental arm related to control arm) is greater than 1.024, favoring the control arm, we 
will terminate accrual and conclude that the experimental regimen is not promising with 
respect to OS comparing to the control regimen in FDG-PET non-responders. Otherwise, 
we will continue to full accrual. The trial will not be halted while these patients are evaluated 
for interim analysis. However, if the accrual is especially rapid, we may temporarily suspend 
accrual to prevent missing important acute toxicity patterns.  
13.6.2 Final Analysis 
The  primary  efficacy  analysis  will  be  performed  on  OS  after  120  events  observed 
(approximately  70  months  after  
the  
first  patient  
randomized,  under  
the  null  hypothesis), 
assuming the trial proceeds to full enrollment. At the conclusion of the trial, the study will 
conclude that the experimental arm (surgery and salvage chemotherapy) is superior to the 
control arm (surgery alone) – i.e. the experimental regimen warrants further study – if the 
p-value  of  a  one-sided  log-rank  test  comparing  OS  between  arms  is  less  than  0.15 
(equivalently,  HR  <  0.828),  according  to  intent-to-treat  principle.  Otherwise,  we  will 
conclude that there is no statistically significant evidence of superiority of the experimental 
regimen. 
13.7  Analysis plan: 
The distribution of OS in each arm will be estimated using the method of Kaplan-Meier [36]. 
The stratified hazard ratio and OS rates at different time points (12 and 18, and 24 months, for 
example), along with corresponding confidence intervals (CIs) will be reported. 


 
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13.8  Early stopping rules based on R1/2 resection rate: 
We  include  early  stopping  rules  based  on  R1/R2  resection  rate.  If  R1/R2  resection  rate  in 
surgery+salvage chemo arm is higher than that in surgery alone arm then the study will stop 
accrual for safety concerns. This assessment will be performed at two time points: when the 
surgical data are available on 1) the first 30 patients per arm (total of 60) and 2) the first 60 
patients  per  arm  (total  of  120).  The  following  table  includes  the  stopping  rules  and  the 
probability of stopping accrual early under H0 or H1 assumptions.  
•  H0:  R1/R2  
resection  
rate  
in  surgery  + salvage  chemo  arm  
(30%)  
is  same  as  
that  
in 
surgery alone arm (30%) 
•  H1: R1/R2 resection rate in surgery + salvage chemo arm is higher (50%) than that in 
surgery alone arm (30%) 
 
 
Stop accrual if  
% of stopping 
under 
Interim 
look  
Cumulative # of 
patients 
the z statistic 
is: 
the difference 
in R1/R2 
resection rate 
is: 
H0  
H1 
1  
30 per arm (total of 
60) 
> 1.807 
> 0.224 
3.5%  
42.4% 
2  
60 per arm (total of 
120) 
> 1.367 
> 0.120 
10%  
83.0% 
The H0 R1/R2 resection rate of 30% was determined by the data reported in PET non-responders 
received surgery alone or continuing same neoadjuvant regimen from studies of 03-032[11], Ott 
et al[30], and Municon I[9]. The boundary was determined using Rho family (Rho=1.5) alpha 
spending function to control for type I error rate (EAST v6.2). With total of 120 patients (60 per 
arm) and the specified stopping rules, there is 83% power to detect a difference (experimental 
arm minus control arm) of 0.2 in R1/R2 resection rate at the significance level of 0.10 with one-
sided test. 
13.9  Adverse events stopping rule: 
The stopping rules specified below are based on the knowledge available at study development.  
We note that the Adverse Event Stopping Rule may be adjusted in the event of either (1) the 
study re-opening to accrual or (2) at any time during the conduct of the trial and in consideration 
of  newly  acquired  
information  
regarding  
the  adverse  event  profile  of  
the  
treatment(s)  under 
investigation.  The study team may choose to suspend accrual because of unexpected adverse 
event profiles that have not crossed the specified rule below. 
Accrual will be temporarily suspended to the study (both groups) to allow for a full review of 
data according to the following AE stopping rule:  
•  if at any time more than 10 of the first 20 patients enrolled in arm B (or > 50% of all 
patients after 20 patients are accrued) have experienced at least one Grade 3 or worse 
adverse events prior to surgical resection, regardless of attributions, with the exception 
of grade 3-4 electrolyte adverse events, alopecia, or lymphopenia.  
•  if the number of deaths in salvage arm is more than the number of deaths in the control 
arm as per the criteria below, then accrual will be suspended for full AE review and 
potential protocol amendment: 
-  In the first 90 patients (45 per arm), if the number of deaths within 90 days after 
surgery in the salvage arm is > 3x than the control arm when there is at least 


 
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one control arm, or > 4 deaths on salvage arm when there is no death on control 
arm. 
13.10  Study monitoring and reporting 
This study will be monitored by the Alliance Data Safety Monitoring Board (DSMB), an NCI-
approved  functioning  body.  Reports  containing  efficacy,  adverse  event,  and  administrative 
information will be provided to the DSMB every six months as per NCI guidelines. 
The study statistician will review adverse event data every week and a monthly team meeting 
including the study chair, study statistician and site PIs will take place to discuss any unexpected 
toxicity events and trial conduct concerns or issues.  
13.10.1 CTEP Monitoring 
This  study  will  be  monitored  by  
the  Clinical  Data  Update  System  
(CDUS)  Version  3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis, either by File Transfer Protocol (FTP) burst of data or via the 
CDS  web  application.  Reports  are  due  January  31,  April  30,  July  31,  and  October  31. 
Instructions  for  submitting  data  using  the  CDUS  can  be  found  on  the  CTEP  Web  site 
(http://ctep.cancer.gov/reporting/cdus.html). 
13.11 Inclusion of Women and Minorities 
This study will be available to all eligible patients, regardless of race, gender, or ethnic origin. 
There is no information currently available regarding differential effects of study treatment in 
subsets defined by race, gender, or ethnicity. Although there is insufficient power to detect small 
or moderate effects, we will, as always, report the results by gender and ethnicity in exploratory 
analyses. 
Domestic Accrual Targets 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino  Hispanic or Latino 
Female  
Male  Female  Male 
American Indian/ Alaska 
Native 
0  
0  
0  
0  
0 
Asian 
1  
2  
0  
0  
3 
Native Hawaiian or Other 
Pacific Islander 
0  
0  
0  
0  
0 
Black or African 
American 
2  
14  
0  
2  
18 
White 
17  
111  
2  
11  
141 
More Than One Race  
0  
0  
0  
0  
0 
Total 
20  
127  
2  
13 
162 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
 


 
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Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
14.0  CORRELATIVE AND COMPANION STUDIES  
Section 14.1 describes the potential use of the optional banked biospecimens. 
14.1  Tissue Specimens for Banking 
14.1.1 Background 
Please note that, as per CTEP guidance, the specific biomarker studies to be performed will 
be  re-evaluated  at  the  completion  of  
the  study  and  collection  of  tissue.  
  Our  ability  to 
interrogate tissue samples is evolving at a very rapid rate.  Current technology (using the 
Nimblegen or Haloplex platforms, for example) will allow for a majority of the collected 
biospecimens to undergo whole exome sequencing from FFPE tissue.  This is an enormous 
opportunity  to  address  several  questions  regarding  markers  that predict  sensitivity  and 
resistance to platinum based therapy (i.e. the EOX responding patients), predict sensitivity 
and  resistance  
to  docetaxel  and  
irinotecan  (i.e.  
the  salvage  regimen),  associate  with  
the 
metabolic  state  of  the  cancer  (i.e.  correlation  with  FDG-PET  SUV),  and  prognostic 
biomarkers for patient outcome (i.e. response vs. non-response and survival).   
14.1.2 Hypothesis 
We  hypothesize  
that  underlying  genetic  aberrations  may  predict  
treatment  response  and 
patient outcome.  (Funding for this correlative aim will be sought separately) 
14.1.3 Methods 
Tissue processing:  Neoplastic epithelium will be identified by microscopic examination of 
tissue sections, and the same areas will be targeted in the corresponding paraffin-embedded 
tissue  blocks  
to  minimize  contamination  by  non-lesional  
tissues.  Tissue  cores  (1-2  mm 
diameter) from the areas of interest will be taken for DNA analysis using standard operating 
procedures [38]. The diagnosis in each case will be confirmed by a reference pathologist. 
Tumor-rich areas (>80% tumor volume based on review of a hematoxylin and eosin–stained 
slide) will be targeted for evaluation, and genomic DNA will be extracted, using a QIAamp 
DNI Mini kit (Qiagen, Valencia, CA), in accordance with the manufacturer
's instructions. 
Extraction will occur in a 96-well plate format using the CyBi-Well liquid handling system 
(CyBio  AG,  Jenna,  Germany).  For  sequencing,  whole  genome  amplification  will  be 
performed, followed by high-throughput (384 well plate) bidirectional dideoxynucleotide 
sequencing of PCR-amplified gene products using standard protocols. 


 
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Sequencing:  Please  note,  this  is  subject  to  re-review  at  a  later  date,  once  the  tissue  is 
available, to take advantage of the current technology at the time. Using current technology, 
whole-exome  sequencing  (WES)  will  be  performed  using  the  HiSeq2500  sequencers 
available at the Weill Cornell Epigenomic Core (or Institute of Precision Medicine). 3-4ug 
DNA will be extracted from tumors and matched tissue using Promega DNA extraction kits. 
DNA content and quality will be analyzed using Qubit and Bioanalyzer. In cases where low 
amount of DNA is available (<1ug), we will use the TruSeq Nano DNA Sample Prep Kit. 
Sequencing will then be performed using paired-end (PE) 101x2 targeting coverage of 80X 
coverage  for  tumors  (8  HiSeq2500  lanes)  and  40X  for  matched  normal  samples  (4 
HiSeq2500 lanes).   
10 cc whole blood sample will be collected prior to resection in patients enrolled in the study 
for the  purpose  of  WES  
for  normal  DNA  comparison.  
  We  will  consider  examining  
the 
whole blood for polymorphisms thought to be important in drug metabolism and correlate 
with toxicity and efficacy (as an exploratory sub-aim of this correlative aim). 
14.1.4 Statistical Design 
WES analysis will include the following steps for each sample: i) initial QC of fastq files 
for base quality and duplications, ii) alignment using bwa aligner to a modified reference 
human genome from the 1000 genome project, and retaining only the uniquely mapped PE 
reads, iii) collapse duplicate reads using Picard tool, iv) local realignment for indel detection 
and recalibration of base quality scores using GATK, v) additional QC evaluation such as 
percent alignment, percent of exome covered and mean coverage. The result of this pipeline 
is a single BAM file suitable for variant analysis. To maximize the specificity and sensitivity 
of SNV detection sample-specific and somatic point nucleotide and indel variants will be 
called using three methods: MuTect, VarScan, and SNVmix. The results from these tools 
will  be  merged  using  ad-hoc  rank-based  algorithm  
that  will  combine  
results  
to  a  single 
unified list of candidate SNPs and indels. Further QC will be performed using SNP panel 
identification  assay  
(SPIA)  
to  ensure  
that  
tumor  and  normal  samples  are  
from  
the  same 
individual  as  well  as  analysis  to  estimate  and  confirm  tumor  cell  content.  Functional 
interpretation of the variants will be performed using Mutation Assessor tool that predicts 
the  functional  impact  of  amino-acid  substitutions,  as  a  result  of  somatic  mutations,  in 
proteins.  Finally,  copy  number  alteration  detection  and  segmentation  will  be  performed 
using several approaches such as CoNIFER and VarScan. 
A formal statistical plan will be developed prior to WES analysis, based on the quality of 
the tissue collected, current sequencing technology, and responses observed on the clinical 
trial. 
 
 




 
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16.0  REFERENCES 
1.   
Cunningham, D., et al., Perioperative chemotherapy versus surgery alone for resectable 
gastroesophageal cancer. New England Journal of Medicine, 2006. 355(1): p. 11-20. 
2.   
MacDonald, J., et al., Chemoradiotherapy after surgery compared with surgery alone for 
adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med, 2001. 345(10): p. 725-30. 
3.  
Macdonald, J.S., et al., Chemoradiation of resected gastric cancer: A 10-year follow-up of the 
phase III trial INT0116 (SWOG 9008). J Clin Oncol, 2009. 27: p. abs 4515. 
4.   
Bang, Y.J., et al., Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy 
(CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet, 2012. 379(9813): p. 315-21. 
5.   
Sakuramoto, S., et al., Adjuvant chemotherapy for gastric cancer with S-1, an oral 
fluoropyrimidine. N Engl J Med, 2007. 357(18): p. 1810-20. 
6.   
Group, G., et al., Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-
analysis. JAMA, 2010. 303(17): p. 1729-37. 
7.  
Wieder, H.A., et al., Time course of tumor metabolic activity during chemoradiotherapy of 
esophageal squamous cell carcinoma and response to treatment. J Clin Oncol, 2004. 22(5): p. 900-8. 
8.   
Ott, K., et al., Metabolic imaging predicts response, survival, and recurrence in 
adenocarcinomas of the esophagogastric junction. J Clin Oncol, 2006. 24(29): p. 4692-8. 
9.   
Lordick, F., et al., PET to assess early metabolic response and to guide treatment of 
adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial. Lancet Oncol, 2007. 
8(9): p. 797-805. 
10.   Ott, K., et al., Early metabolic response evaluation by fluorine-18 fluorodeoxyglucose positron 
emission tomography allows in vivo testing of chemosensitivity in gastric cancer: long-term results of a 
prospective study. Clin Cancer Res, 2008. 14(7): p. 2012-8. 
11.  Shah, M.A., et al., A phase II study of preoperative chemotherapy with irinotecan(CPT) and 
cisplatin(CIS) for gastric cancer(NCI 5917): FDG-PET/CT predicts patient outcome. Amercan Society of 
Clinical Oncology, Annual Proceedings, Orlando, FL., 2007: p. Anstract #4502. 
12.   Buschenfelde, C.M.Z., et al., (18)F-FDG PET-guided salvage neoadjuvant radiochemotherapy of 
adenocarcinoma of the esophagogastric junction: the MUNICON II trial. J Nucl Med, 2011. 52(8): p. 
1189-96. 
13.   Lordick, F., et al., Salvage radiochemotherapy in locally advanced gastroesophageal junction 
tumors that are metabolically resistant to induction chemotherapy: The MUNICON-2 trial. 
Gastrointestinal Cancers Sympsium, Orlando, FL, 2008: p. Abstract #104. 
14.  Fuchs, C.S., et al., Postoperative adjuvant chemoradiation for gastric or gastroesophageal 
junction (GEJ) adenocarcinoma using epirubicin, cisplatin, and infusional (CI) 5-FU (ECF) before and 
after CI 5-FU and radiotherapy (CRT) compared with bolus 5-FV/LV before and after CRT: Intergroup 
trial CALGB 80101 J Clin Oncol, 2011. 29: p. abs4003. 
15.   Power, D.G., D.P. Kelsen, and M.A. Shah, Advanced gastric cancer - Slow but steady progress. 
Cancer Treat Rev, 2010. 36(5): p. 384-92. 
16.   Kang, J.H., et al., Salvage chemotherapy for pretreated gastric cancer: a randomized phase III 
trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol, 
2012. 30(13): p. 1513-8. 
17.  Thuss-Patience, P.C., et al., Survival advantage for irinotecan versus best supportive care as 
second-line chemotherapy in gastric cancer - a randomised phase III study of the Arbeitsgemeinschaft 
Internistische Onkologie (AIO). Eur J Cancer, 2011. 47(15): p. 2306-14. 
18.   Mandard, A.M., et al., Pathologic assessment of tumor regression after preoperative 
chemoradiotherapy of esophageal carcinoma: Clinicopathologic correlations. Cancer, 1994. 73: p. 2680-
86. 
19.  Weber, W., et al., Prediction of response to preoperative chemotherapy in adenocarcinoma of the 
esophagogastric junction by metabolic imaging. J of Clin Oncol, 2001. 19(12): p. 3058-65. 


 
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20.   Won, E., et al., Phase II study of preoperative chemotherapy plus bevacizumab with early salvage 
therapy based on FDG-PET response in patients with locally advanced gastric and GEJ 
adenocarcinoma. J Clin Oncol, 2013. 30(supple 34): p. abs 94. 
21.   Bang, Y.J., et al., Trastuzumab in combination with chemotherapy versus chemotherapy alone for 
treatment of Her2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, 
open-label, randomised controlled trial. Lancet, 2010. 376(9742): p. 687-97. 
22.   Bang, Y.-J. and e. al., A randomized, open label, phase III study of lapatinib in combination with 
weekly paclitaxel versus weekly paclitaxel alone in second-line treatment of HER2 amplified advanced 
gastric cancer (AGC) in Aian population: Tytan study. ASCO Meeting Abstracts, 2013. 31(4 supple): p. 
11. 
23.   Waddell, T.S. and e. al., A randomized multicenter trial of epirubicin, oxaliplatin, and 
capecitabine (EOC) plus panitumumab in advanced esophagogastric cancer (REAL3). J Clin Oncol, 
2012. 30: p. LBA4000. 
24.   Lordick, F. and e. al., Cetuximab in combination with capecitabine and cisplatin as first line 
treatment in advanced gastric cancer: randomized controlled phase III EXPAND study. . Ann Oncol, 
2012. 23: p. LBA3. 
25.   Ohtsu, A., et al., Bevacizumab in combination with chemotherapy as first-line therapy in 
advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol, 
2001. 29(30): p. 3968-76. 
26.  Shah, M.A., et al., Survival analysis according to disease subtype in AVAGAST: First-line 
capecitabine and cisplatin plus bevacizumab (bev) or placebo in patients with advanced gastric cancer. J 
Clin Oncol, 2012. 30(suppl 4): p. abs 5. 
27.   Fuchs, C. and e. al, REGARD: A phase III, randomized, double-blinded trial of ramucirumab and 
best supportive care (BSC) versus placebo and BSC in the treatment of metastatic gastric or 
gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line platinum- 
and/or fluoropyrimidine-containing combination therapy. . ASCO Meeting Abstracts, 2013. 31(4 supple): 
p. LBA5. 
28.   Hawkes, E., et al., Docetaxel and irinotecan as second-line therapy for advanced oesophageal 
cancer. . European Journal of Cancer, 2011. 47: p. 1146-51. 
29.   Won, E., et al., Phase II study of preoperative chemotherapy plus bevacizumab with early salvage 
therapy based on FDG-PET response in patients with locally advanced gastric and GEJ 
adenocarcinoma. J Clin Oncol, 2013. suppl 4: p. Abs 94. 
30.   Ott, K., et al., Prediction of response to preoperative chemotherapy in gastric carcinoma by 
metabolic imaging: results of a prospective trial. J Clin Oncol, 2003. 21(24): p. 4604-10. 
31.   Wahl, R.L., et al., From RECIST to PERCIST: Evolving considerations for PET response criteria 
in solid tumors. J Nucl Med, 2009. 50 Suppl 1: p. 122S-50S. 
32.   Tan, A.D., et al., A patient-level meta-analytic investigation of the prognostic significance of 
baseline quality of life (QOL) for overall survival (OS) among 3,704 patients participating in 24 North 
Central Cancer Treatment Group (NCCTG) and Mayo Clinic Cancer Center (MC) oncology clinical 
trials. J Clin Oncol, 2008. 26(May 20 suppl): p. abs 9515. 
33.   Sloan, J.A., et al., A patient-level pooled analysis of the prognostic significance of baseline 
fatigue for overall survival (OS) among 3,915 patients participating in 43 North Central Cancer 
Treatment Group (NCCTG) and Mayo Clinic Cancer Center (MC) oncology clinical trials.  . J Clin 
Oncol, 2009. 27: p. 507s. 
34.   Cunningham, D., et al., Capecitabine and oxaliplatin for advanced esophagogastric cancer. N 
Engl J Med, 2008. 358(1): p. 36-46. 
35.   Brucher, B.L., et al., Neoadjuvant therapy of esophageal squamous cell carcinoma: response 
evaluation by positron emission tomography. Ann Surg, 2001. 233(3): p. 300-9. 
36.   Kaplan, E.L. and P. Meier, Nonparametric estimation from incomplete observations. J of the 
Amer Statistical Association, 1958. 53: p. 457-81. 


 
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37.   Duffy, D.E. and T.J. Santner, Confidence intervals for a binomial parameter based on multistage 
tests. Rev. June 1986. ed. Technical report1986, Ithaca, N.Y.: Mathematical Sciences Institute, Cornell 
University. 18 p. 
38.  Setlur, S.R., et al., Estrogen-dependent signaling in a molecularly distinct subclass of aggressive 
prostate cancer. J Natl Cancer Inst, 2008. 100(11): p. 815-25. 
 


 
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APPENDIX I -
 REGISTRATION FATIGUE/U
NISCALE ASSESSMENTS 
 
 
Registration Fatigue/Uniscale Assessments 
 
At patient registration, this form is to be administered by a nurse/CRA, completed by the patient, 
and entered into Medidata Rave at the time of registration. 
 
If needed, this appendix can be adapted to use as a source document.  A booklet containing this 
assessment does not exist – please do not order this booklet. 
 
 
 
 
How would you describe: 
 
your level of fatigue, on the average in the past week including today? 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10 
No 
Fatigue 
  
  
  
  
  
  
  
  
  
Fatigue 
as bad  
as it can be 
 
your overall quality of life in the past week including today? 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10 
As bad as 
it can be 
  
  
  
  
  
  
  
  
 
As good as 
it can be 
 
 
 
 


 
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APPENDIX II: OPTIONAL PATIENT CAPECITABINE MEDICATION DIARY 
Optional Patient Capecitabine Medication Diary (Optional; does not need to 
be submitted to the Alliance) 
 
Patient Capecitabine Medication Diary 
A021302 
 
Study ID#:                      __________________________ 
 
Patients Initials:            __________________________ 
 
Starting Dose:               __________________________ 
 
 
INSTRUCTIONS TO PATIENT: 
 
1. Complete form for the entire period during which you receive radiation therapy and 
capecitabine. The duration of treatment is usually 5 weeks but may be a bit longer if treatment 
is interrupted for any reasons. 
2. Please follow the dosing instructions carefully. 
3. Please record the date and approximate times you take the capecitabine tablets. Your 
physician or nurse will write down your dose and explain to you how many tablets are in your 
dose. 
4. Start taking capecitabine on day 1 and take Monday through Friday while you are receiving 
radiation treatment. 
5. You should take the capecitabine dose prescribed for you by mouth twice a day on Days 1-5, 
8-12, 15-19, 22-26, and 29-33. Take a dose every morning and a dose every evening, about 12 
hours apart. Take the dose with 8 ounces of water each time. It is best to take the dose within 
30 minutes after eating food. 
6. If you vomit after taking a dose, or if you forget to take a dose, please note it on this diary, 
and do not take capecitabine again until your next scheduled dose. 
7. The use of a daily moisturizer to hands, feet and face are recommended. Please use sunscreen 
if you are going outdoors. 
8. Please contact your health care team with any questions or for help understanding exactly 
how to take your medicine. 
9. Bring this Medication diary with you when you meet with your doctor each week. 
10. Your doctor might instruct you to temporarily stop the capecitabine due to side effects. 
Follow their instructions for stopping the medicine, and resume the medication when your 
doctor tells you that you have recovered from side effects and can restart the medicine 
11. If your radiation is temporarily stopped due to side effects, do NOT take the capecitabine. 
Only take the capecitabine on days that you receive radiation.  
 
PLEASE CONTINUE TO PAGE 2 
 
 
 
 


 
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Day 
Date 
Approximate times tablets taken 
a m. 
p m. 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
Do not take capecitabine tablets today 
-- 
-- 
7 
Do not take capecitabine tablets today 
-- 
-- 
8 
 
 
 
9 
 
 
 
10 
 
 
 
11 
 
 
 
12 
 
 
 
13 
Do not take capecitabine tablets today 
-- 
-- 
14 
Do not take capecitabine tablets today 
-- 
-- 
15 
 
 
 
16 
 
 
 
17 
 
 
 
18 
 
 
 
19 
 
 
 
20 
Do not take capecitabine tablets today 
-- 
-- 
21 
Do not take capecitabine tablets today 
-- 
-- 
22 
 
 
 
23 
 
 
 
24 
 
 
 
25 
 
 
 
26 
 
 
 
27 
Do not take capecitabine tablets today 
-- 
-- 
28 
Do not take capecitabine tablets today 
-- 
-- 
29 
 
 
 
30 
 
 
 
31 
 
 
 
32 
 
 
 
33 
 
 
 
34 
Do not take capecitabine tablets today 
 
 
35 
Do not take capecitabine tablets today 
 
 
 
___________________________________                 ______________________________ 
      Patient signature                                                                  Date 
Physician’s office will complete this section: 
 
1.  Date patient started radiation therapy:         ____________________ 
2.  Date patient completed radiation therapy:   ____________________ 
3.  Date patient started capecitabine:                ____________________ 
4.  Date patient finished capecitabine:              ____________________ 
 
Physician/Nurse/Data Manager’s signature ______________________________Date___________________ 
 
 
 


 
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APPENDIX III: I
NFORMATION ON POSSIBLE DRUG I
NTERACTIONS 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers and 
Non-Study Healthcare Team 
 
[Note to investigators: This appendix consists of an “information sheet” to be handed to the patient at the 
time of enrollment. Use or modify the text as appropriate for the study agent, so that the patient is aware 
of the risks and can communicate with their regular prescriber(s) and pharmacist. A convenient wallet-
sized information card is also included for the patient to clip out and retain at all times. If you choose to 
use them, please note that the information sheet and wallet card will require IRB approval before 
distribution to patients.] 
 
The patient ____________________________ is enrolled on a clinical trial using docetaxel. This clinical 
trial is sponsored by the National Cancer Institute. This form is addressed to the patient, but includes 
important information for others who care for this patient.  
 
Docetaxel interacts with many drugs that are processed by your liver. Because of this, it is very important 
to tell your study doctors about all of your medicine before you start this study. It is also very important to 
tell them if you stop taking any regular medicine, or if you start taking a new medicine while you take 
part in this study. When you talk about your medicine with your study doctor, include medicine you buy 
without a prescription at the drug store (over-the-counter remedy), or herbal supplements such as St. 
John’s wort. It is helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care prescribers can write prescriptions. You must also tell your other prescribers (doctors, 
physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. Bring this paper 
with you and keep the attached information card in your wallet. These are the things that you and 
they need to know:  
 
Docetaxel interacts with a certain specific enzyme in your liver.  
•  The enzyme in question is CYP3A4. Docetaxel is broken down by this enzyme. The dose of 
docetaxel which you are taking assumes that these enzymes are working normally. 
•  Certain drugs may reduce the activity of CYP3A4, which can increase the amount of active drug 
in your system. This increases your chances of experiencing harmful side effects.  Other drugs 
might increase the activity of CYP3A4, reducing the level of active drug in your system and 
making it less effective. 
•  Docetaxel must be used very carefully with such drugs; it is therefore vitally important that you 
provide your study doctor with a complete list of your medications.  Before you begin the study, 
your study doctor will work with your regular prescriber to switch any medicines that are 
considered “strong inhibitors or inducers of CYP3A4.” 
•  Once the study begins, you and your healthcare providers must be very careful about adding or 
removing any drugs in this category.  Your prescribers should look at the web site 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx, consult a medical reference, or contact your 
study doctor to see if any medicine they want to prescribe is on a list of drugs to avoid. 
•  Please be very careful! Over-the-counter drugs have a brand name on the label—it’s usually big 
and catches your eye. They also have a generic name—it’s usually small and located above or 
below the brand name, and printed in the ingredient list. Find the generic name and determine, 
with the pharmacist’s help, whether there could be an adverse interaction. 
•  [The following are examples of text for common over-the-counter medications or supplements that 
may interact with the study agent.] Be careful: 
o If you take acetaminophen regularly: You should not take more than 4 grams a day if you 


 
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Update #04 
are an adult or 2.4 grams a day if you are older than 65 years of age. Read labels carefully! 
Acetaminophen is an ingredient in many medicines for pain, flu, and cold. 
o If you drink grapefruit juice or eat grapefruit: Avoid these until the study is over. 
o If you take herbal medicine regularly: You should not take St. John’s wort while you are 
taking docetaxel. 
o [Add other specific medications here, if necessary.] 
 
Other medicines can be a problem with your study drugs. 
•  You should check with your doctor or pharmacist whenever you need to use an over-the-counter 
medicine or herbal supplement. 
•  Your regular prescriber should check a medical reference or call your study doctor before 
prescribing any new medicine for you.  Your study doctor’s name is  
 
 
_____________________________________ 
 
and he or she can be contacted at 
 
_____________________________________. 
 
 


 
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 [Note to investigators:  This convenient wallet-sized information card is to be completed and then 
provided for the patient to clip out and retain at all times.] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Docetaxel interacts with a specific liver enzyme called CYP3A4, and 
must be used very carefully with other medicines that interact with 
this enzyme.  
 Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
“strong inducers/inhibitors or substrates of CYP3A4.” 
 Before prescribing new medicines, your regular prescribers should 
go to http://medicine.iupui.edu/clinpharm/ddis/ 
for a list of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent 
docetaxel.  This clinical trial is sponsored by the NCI.  Docetaxel 
interacts with drugs that are processed by your liver.  Because of this, 
it is very important to: 
 Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
 Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
 Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement.