The ADAPTA Study: ADjuvant chemotherAPy After Curative Intent resecTion of Ampullary Cancer. A Pan-European Prospective Multicenter Double Single Arm Cohort Study.
Conditions: Ampullary Adenocarcinoma
Sponsor: Fondazione Poliambulanza Istituto Ospedaliero

     
 
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STUDY PROTOCOL – PROTOCOL FOR ETHICAL APPROVAL ITALY  
The ADAPTA Study: ADjuvant chemotherAPy after curative intent resecTion of Ampullary 
cancer. A pan-European prospective multicenter double single arm cohort study. 
 
Abbreviation title: ADAPTA 
Version: 1.1 17-11-2022 
Promotor:  
 
Fondazione Poliambulanza 
Coordination center 
 
U.O.  
Principle investigator 
 
Fondazione Poliambulanza, Brescia, Italy 
Professor Mohammed Abu Hilal 
Department of Surgery 
Tel: +39 375 632 6711 
Email: abuhilal9@gmail.com 
 
 
Dr. Alberto Zaniboni 
Department of Medical Oncology 
Email: zanibonialbert@gmail.com 
CO-investigators  
Fondazione Poliambulanza, Brescia, Italy 
Mr. D.H.L Lemmers 
Department of Surgery 
Tel: +31-645425610 

     
 
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Email: d.h.lemmers@amsterdamumc.nl 
 
Mr. B.A. Uijterwijk 
Department of Surgery 
Tel: +31-640380827 
Email: Bas.uijterwijk@poliambulanza.it 
 
 
 
 
 
 
 
 
 
 
 

     
 
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INTRODUCTION  
Background and Rationale  
The incidence of ampullary adenocarcinoma (AAC) resembles 0.2% to 0.5% of all gastro-intestinal cancers 
and 7% of all periampullary cancers [1,2]. The five-year overall survival (OS) varies between 30% and 70%. 
This wide range could be explained by the morphological heterogeneity of the three known subtypes of 
AAC consisting of the intestinal type, the pancreatobiliary (PB) type, and a mixed subtype. It is believed 
that the PB subtype has the most aggressive biological behavior [3,4]. To date there have been no 
prospective cohort studies evaluating the effect of adjuvant chemotherapy after curative intent resection 
of AAC designed to look at specific histological subtypes. Some studies suggest a benefit of adjuvant 
chemo-radiotherapy with 5-fluorouracil (5-FU), but to date no randomized trials confirm a survival 
improvement [21-24]. Adjuvant chemotherapy was studied in the international ESPAC-3 trial [25]. In this 
study 427 patients were included of which 297 had AAC. Patients were randomized to observation or 
adjuvant chemotherapy, with either gemcitabine or 5-FU. When the analysis was restricted to patients 
with AAC, those treated with gemcitabine had a median survival of 71 months versus 41 months in the 
observation alone group. The median survival in the 5-FU group was 57.8 months. There were no 
statistically significant differences in survival between ampullary subtypes. At the start of this trial, 
classification of AAC was not being widely applied and eighty ampullary tumors were classified as 
intestinal, 46 as PB, 9 as mixed, and 162 as indeterminate, which might be an explanation for finding no 
statistically significant outcomes. A recent retrospective study including 214 patients with resected AAC 
[26] demonstrated that only patients with the PB and mixed subtypes benefit from adjuvant therapy with 
an improved median overall survival of 85 months vs. 65 months for no adjuvant therapy, p = 0.005. For 
patients with the intestinal subtype, there was no benefit from adjuvant chemotherapy. A retrospective 
study of our own research group [9] demonstrated comparable results. This study included 887 patients 
with resected AAC. Adjuvant chemotherapy independently predicted an improved OS in the PB subtype 
(HR = 0.61 [0.40– 0.93]) and not in the intestinal subtype [9].  
Thus, although there is evidence of survival improvement of adjuvant treatment for ACC, this has to be 
proven in prospective studies. As described in literature, the PB and mixed subtype have the worst 5-year 

     
 
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OS (22% to 44%) and have the most aggressive biological behavior. In addition, the PB subtype resembles 
pancreatic adenocarcinoma. For pancreatic cancer, the 5-fluorouracil, irinotecan, oxaliplatin and 
leucovorin (FOLFIRINOX) regimen led to a significant longer survival compared to gemcitabine in patients 
with resected pancreatic cancer [27]. A phase II study by Overmann et al. [28] showed that the 
combination of Capecitabine and Oxaliplatin (CAPOX) is administered in patients with a good performance 
status was well tolerated and resulted in a superior response rate and longer OS compared with other 
regimens in patients with AAC (all subtypes) and duodenal cancer.  
Although retrospective research has shown beneficiary effect of adjuvant gemcitabine in the PB and MT 
subtype of AAC, no favorable effect in the intestinal subgroup has been observed.  Intestinal  subtype 
AAC has great resemblance with colonic and duodenal cancer, therefore we hypothesize that patients 
with intestinal subtype AAC will benefit from adjuvant treatment with CAPOX. Since FOLFIRINOX currently 
is the preferred adjuvant treatment instead of gemcitabine in pancreatic cancer, patients with the PB and 
mixed subtype might benefit from adjuvant treatment with FOLFIRINOX. In this prospective cohort study, 
we will investigate whether this adjuvant treatment strategy based on the histopathological subtypes of 
AAC will result in improved survival. In addition, we will conduct molecular sub-studies in the 
histopathological subtypes of AAC to gain more knowledge on the biological behavior of this rare disease. 
 
Short reference list 
 
1. 
Albores-Saavedra J, Schwartz AM, Batich K, et al. Cancers of the ampulla of vater: 
 
demographics, morphology, and survival based on 5,625 cases from the SEER program. J Surg  
 
Oncol  2009; 100(7):598-605. 
 
2. 
Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008; 58(2):7196. 
 
3. 
Chang DK, Jamieson NB, Johns AL, et al. Histomolecular phenotypes and outcome in 
 
adenocarcinoma of the ampulla of vater. J Clin Oncol 2013; 31(10):1348-56. 
 
4. 
Westgaard A, Tafjord S, Farstad IN, et al. Pancreatobiliary versus intestinal histologic type 
 
of  
differentiation is an independent prognostic factor in resected periampullary 
 
adenocarcinoma. BMC  Cancer 2008; 8:170. 
 
9. 
Moekotte AL, Lof S, Van Roessel S, et al. Histopathologic Predictors of Survival and 
 
Recurrence in Resected Ampullary Adenocarcinoma: International Multicenter Cohort Study. Ann 
 
Surg 2019. 

     
 
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21. 
Bhatia S, Miller RC, Haddock MG, et al. Adjuvant therapy for ampullary carcinomas: The 
 
Mayo  Clinic experience. International Journal of Radiation Oncology Biology Physics 2006; 
 
66:514-519. 
 
22. 
Narang AK, Miller RC, Hsu CC, et al. Evaluation of adjuvant chemoradiation therapy for 
 
ampullary adenocarcinoma: The Johns Hopkins Hospital - Mayo Clinic collaborative study. 
 
Radiation  
Oncology 2011:126. 
 
23. 
Zhou J, Hsu CC, Winter JM, et al. Adjuvant chemoradiation versus surgery alone for 
 
adenocarcinoma of the ampulla of Vater. Radiotherapy and Oncology 2009; 92:244-248. 
 
24. 
Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after 
 
curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC 
 
gastrointestinal tract cancer cooperative group. Annals of surgery 1999; 230:776-82; discussion 
 
782-4. 
 
25. 
Neoptolemos JP, Moore MJ, Cox TF, et al. Effect of adjuvant chemotherapy with 
 
fluorouracil  
plus folinic acid or gemcitabine vs observation on survival in patients with 
 
resected periampullary  adenocarcinoma: The ESPAC-3 periampullary cancer randomized trial. 
 
JAMA - Journal of the  American Medical Association 2012; 308:147-156. 
 
26. 
Bolm L et al. Adjuvant therapy is associated with improved overall survival in patients 
 
with  
pancreatobiliary or mixed subtype ampullary cancer after pancreatoduodenectomy - A 
 
multicenter cohort study, Pancreatology  2020  Apr;20(3):433-441;  
 
 
 
doi:  
10.1016/j.pan.2020.01.009. 
 
27. 
Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy 
 
for  
Pancreatic Cancer. N Engl J Med 2018; 379(25):2395-2406. 
 
28. 
Overman MJ, Varadhachary GR, Kopetz S, et al. Phase II study of capecitabine and 
 
oxaliplatin  
for advanced adenocarcinoma of the small bowel and ampulla of Vater. J Clin 
 
Oncol 2009;  
27(16):2598-603. 
 
 
STUDY DESIGN 
This study is a pan-European prospective multicenter observational cohort study. Eligible patients are 
after a curative resection of an AAC, have a good performance score of 0 or 1 and are expected to start 
adjuvant chemotherapy. All patients after curative resection of an AAC will be asked to participate in the 
study. Inclusion will take place after resection and central histopathological review of the resected 
specimen by a team of dedicated Hepato-pancreato-biliary pathologists of the participating center. Final 
diagnosis of PB/mixed or intestinal subtype will be reached by consensus based on morphological and 

     
 
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immunohistochemical characteristics. The primary endpoint is 3-year disease-free survival. In total we will 
include 200 patients, 100 with the PB and mixed subtype, and 100 with the intestinal subtype. 
After pancreatoduodenectomy, 8 cycles of systemic FOLFIRINOX or CAPOX will be administered. Adjuvant 
therapy should be started within 8 weeks after surgery. The follow up period is until recurrence of disease/ 
death or five years after randomization. The statistical analysis will take place 1.5 years after last inclusion.  
 
 
OBJECTIVES 
The primary objective of this prospective cohort study is to evaluate the efficacy of adjuvant CAPOX (in 
the intestinal subgroup of AAC after complete resection), and FOLFIRINOX (in the PB and mixed subgroup 
of AAC after complete resection) in terms of disease-free survival at 3-years.  
Secondary objectives include 5-year disease free survival, 5-year overall survival, safety and tolerability of 
treatment, delivered dose intensity, quality of life, patient-reported outcomes, patterns of disease 
recurrence, locoregional control, and molecular subtyping of AAC in relation to survival and recurrence. 
Results will be compared with literature finding (basically based on retrospective studies) in order to 
validate and eventually confirm the literature evidences regarding the AAC subtypes. 
 
 
 
STUDY POPULATION 
Eligible patients have (borderline) resectable non-metastatic AAC. Resectability is determined on 
preoperative imaging and defined by the Dutch Pancreatic Cancer Group definitions for resectability of 
pancreatic adenocarcinoma (DPCG, 2012, Table 1) Resectable disease is defined as no arterial (hepatic 
artery, superior mesenteric artery, or coeliac trunk) tumor contact and venous (portal vein or superior 
mesenteric vein) tumor contact of 90 degrees or less. Borderline resectable disease is defined as arterial 
tumor contact 90 degrees or less and venous contact of 90 to 270 degrees without occlusion. The 

     
 
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diagnosis of ampullary cancer must be confirmed by pathological evaluation of the resection specimen or 
a tumor biopsy/fine needle aspiration. Patients should have a good performance score of 0 or 1 (Table 2). 
 
Table 1 Dutch Pancreatic cancer group definitions for resectability of pancreatic 
adenocarcinoma 
 
SMA 
Celiac axis 
CHA 
SMV-PV 
Resectable (all 4 
required) 
No contact 
No contact 
No contact 
≤90° contact 
Borderline 
resectable 
(minimally one 
required) 
≤90° contact 
≤90° contact 
≤90° contact 
≤90°-270° 
contact and no 
occlusion 
Irresectable 
(minimally one 
required) 
Contact >90° 
Contact >90° 
Contact >90° 
Contact >270° 
or occlusion 
SMA superior mesenteric artery, CHA common hepatic artery, SMV superior mesenteric 
artery, PV portal vein 
 
              Table 2. 

     
 
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INCLUSION CRITERIA 
In order to be eligible to participate in this study, a subject must meet all of the following criteria: 
- 
Adult patients with histologically or cytologically confirmed AAC with  
 
subtyping of pancreatobiliary/mixed subtype or intestinal subtype 
- 
After curative resection for ampullary cancer without metastatic disease. 
- 
WHO performance status 0 or 1 
-  
Able and willing to receive adjuvant chemotherapy 
- 
R0/ R1 resection 
- 
Age ≥ 18 years 
- 
Written informed consent 
-  
DPYD mutation tested [REF. 29] 
-  
UGT1A mutation tested [REF. 29] 
-  
CTCAE graded [REF. 30] 
 
EXCLUSION CRITERIA 
A potential subject who meets any of the following criteria will be excluded from participation in this 
study: 
- 
Prior radiotherapy, chemotherapy, or resection for AAC. 
- 
Previous malignancy (excluding non-melanoma skin cancer), unless no  
 
evidence of disease and diagnosed more than 5 years before diagnosis of  
 
AAC. 
- 
Pregnancy. 
- 
R2 resection. 
-  
Adjuvant chemotherapy started more than 12 weeks after surgery (aim to start within 8 
 
weeks) 
- 
Serious concomitant systemic disorders that would compromise the safety  
 
of the patient or his/her ability to complete the study, at the discretion of the  
 
investigator. 
- 
Known hypersensitivity or contraindications against capecitabine, 5 FU, Irinotecan, or 
 
Oxaliplatin 
-  
Inadequate organ functions, characterized by:  
● Leucocytes (WBC) < 3.0 X 109/l 
● Neutrophils < 1.500 (count per microliter of blood) 
● Platelets < 100 x 109 /l 

     
 
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● Hemoglobin < 8 mmol/l 
● Renal function: E-GFR < 50 ml/min (serum creatinine < 1.5 x UNL) 
● cholestasis with elevated levels of bilirubin and/or alkaline phosphatase > 3x UNL (can 
be improved by biliary drainage if necessary) 
● elevated transaminases (ALAT/ASAT) ≥ 5 x UNL  
● hypoalbuminemia < 2.5 g/dl 
● Inadequate coagulation status INR > 2 or Quick < 50%, aPTT >50 sec in the absence of 
any  
drugs interfering with coagulation such as acenocoumarin, warfarin, 
phenprocoumon, NMH  
or UFH. 
 
 
STUDY DESIGN FLOWCHART 
 
 
 
 
 

     
 
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TREATMENT OF SUBJECTS 
Treatment 
This study focusses on patients after curative intent resection for AAC. Patients will be included after 
post-operative pathology report confirms an adenocarcinoma of the ampulla of Vater. The adjuvant 
chemotherapy will be started when the patient is recovered, aiming within 8 weeks from surgery.  
Patients operated with palliative intent or treated with palliative chemotherapy are not eligible for the 
ADAPTA study. Patients are eligible for a surgical exploration if they have non-metastatic (borderline) 
resectable disease on imaging. Surgery starts with a staging laparoscopy. During the same surgical 
procedure, a resection will be performed when no metastatic or locally advanced (unresectable) disease 
is found. Patients with distant metastasis or locally advanced disease at staging or surgery will continue 
with standard palliative care according to the national or local guideline for AAC and will be therefore 
unable to participate in this study.  
The adjuvant chemotherapy involves eight cycles of FOLFIRINOX/CAPOX. Cycles are repeated every 3 
weeks for CAPOX and every 2 weeks for FOLFIRINOX. the FOLFIRINOX regimen is based on the regimen 
of the phase III trial (ACCORD/PRODIGE trial) for metastatic pancreatic cancer. This trial follows the 
modified FOLFERINOX treatment described in [27]. mFOLFIRINOX is a dosed reduces version which can 
be used in standard practice, such as normal FOLFIRINOX:  
mFolfirinox: 
- 
Oxaliplatin (Eloxatin®) 85 mg/m² D1 over 2 hours, followed by 
- 
Irinotecan (Campto®) 150 mg/m² D1 over 90 minutes to begin 30 min.  
After the Folinic acid infusion is started. Folinic acid 400 mg/m² (racemic mixture) (or 200 
mg/m² if L-folinic acid is used), IV infusion over 2 hours. 5-FU 2.4 g/m² IV continuous infusion 
over 46 hours (1200 mg/m²/ day).  TREATMENT DURATION: 16 weeks 
 
 
The mFOLFIRINOX regimen is described in the table below: 
Day 
Drug 
Dose 
Route 
Diluent & Rate 
Day 1 
Oxaliplatin 
85mg/m2 
IV in 2h 
 
Immediately 
followed 
Leucovorin 
(folinic acid) 
400mg/m2 
IV 2h 
 

     
 
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After 30 
minutes 
Irinotecan 
150mg/m2 
IV 1h 
Over 90 minutes 
to begin 30 min 
after folinic 
acid infusion is 
started 
followed 
5Fluorouracil 
2400mg/m2 
IV in 48h 
 
 
The CAPOX regimen is described in the table below: 
 Day 
Drug 
Dose 
Route 
Diluent & Rate 
Day 1 
Oxaliplatin  
130mg/m2  
IV Infusion 
500mls Glucose 
5% over 2 
hours 
Days 1-14 
Capecitabine  
1000mg/m2  
Twice a day 
Oral  
 
 
 
Escape medication in case of acute toxicity 
Acute toxicity treatment for FOLFIRINOX/CAPOX: 
Indication  
Medication  
Cholinergic symptoms (early diarrhea)  
Prophylactic atropine may be 
considered in patients experiencing 
cholinergic symptoms  
Diarrhea  
abdominal cramp = diarrhea  
may be severe and delayed with 
irinotecan  
Loperamide 4 mg at the onset of 
diarrhea, then 2 mg every two hours 
once first liquid stool appears and 
continue until 12 hours after the last 
liquid stool. Do not use for longer than 
48 hours.  
Nausea and vomiting  
Anti-emetics  
 
Guidelines for dose adjustment of FOLFIRINOX/CAPOX are reported in Appendix. 
 
 

     
 
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Standard pre-medication 
Patients will receive co-medication as proposed below or according to standard procedures of local site. 
Administered 30-60 minutes prior to adjuvant FOLFIRINOX/CAPOX chemotherapy: 
• 
Dexamethasone 8mg IV bolus over 3-5 minutes or PO 
• 
Ondansetron 8mg IV bolus over 3-5 minutes or PO 
• 
Atropine 0.25 mg SC 5 minutes before start of Irinotecan 
• 
Glucose 5%flush should be administered before and after Oxaliplatin 
 
 
METHODS 
Primary Endpoint  
3-year Disease Free Survival (DFS), defined as survival without locoregional progressive disease, the 
occurrence of distant metastases, the occurrence of second or recurrent Ampullary cancer from the date 
of study participation. Death from any cause is also considered an event for this endpoint. Patients alive 
and free of all these events will be censored at the last follow-up.  
Secondary Endpoint  
Secondary objectives include 5-year disease-free survival, 5-year overall survival, safety  
and tolerability of treatment, delivered dose intensity, quality of life, patterns of disease  
recurrence, locoregional control, and molecular markers of AAC.  
In addition, the analysis of the molecular markers through the genetic test of tumor samples will be 
performed (substudy). 
 
Study Procedure 
Eligible patients are informed about the study and written informed consent is required prior to inclusion. 
Study-specific assessments and evaluations will be performed after written informed consent is obtained 
for permission to prospectively observe the patients, send questionnaires, use peri-operative data and 
medical history anonymously. Within the informed consent there will be an advice to avoid pregnancy 
during chemotherapy 

     
 
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Patients will be included after surgery when post-operative pathology examination is complete. 
Therefore, the following information will be collected retrospectively after informed consent: 
• 
Medical history and physical exam.  
• 
Laboratory tests: hemoglobin, WBC, differential count, platelets, bilirubin, ALAT, ASAT, 
Alkaline Phosphatase, gamma-GT, creatinine, albumin, glucose, CRP, PTT.  
• 
Testing of the DPYD gene29 
• 
Testing of the UGT1A gene29 
• 
CT-scan of chest and abdomen, following CT protocol as described by Dutch Radiology 
Association (NVvR): max. 3 mm slices; 150 cc contrast at 4-5 cc/s (18 G i.v. catheter); 
Pancreas parenchyma phase preferably 15-30 sec after bolus tracking, otherwise 35-45 
sec p.i.; Porto-venous phase 70 sec p.i. or 45-44 sec after bolustracking.25  
• 
Endoscopic ultrasonography (EUS) with Fine Needle Aspiration or Biopsy (FNA or FNB) 
when performed. To obtain a cytological/histological diagnosis most patients will undergo 
EUS with FNA/FNB. A maximum of 2 EUS with FNA/FNB attempts in the pancreatic cancer 
center is allowed.  
• 
Biliary stenting when necessary. Required in patients with obstructive jaundice (defined 
as bilirubin > 1.5 times normal, which in clinical practice frequently translates to a cut-off 
value of 25μmol/L).  
 
Patients will be included after surgery when post-operative pathology examination is complete. 
Therefore, the following information will be collected retrospectively after informed consent: 
• 
Physical exam. 
• 
Laboratory tests: hemoglobin, WBC, platelets, bilirubin, ALAT, ASAT, alkaline 
phosphatase, gamma-GT, creatinine, albumin, glucose, PTT. 
• 
Pancreatic resection (open or minimally-invasive; minimally-invasive resection only by 
surgeons with experience of at least 50 minimally-invasive resections and at least 20 per 
year). 
• 
Postoperative complication within 90 days (Clavien-Dindo classification). 
• 
Tumor markers CA 19-9 and CEA, at time of follow-up imaging. 
• 
Serum (maximum of 40cc) for biomarkers including ctDNA, miRNA, glycomics, proteomics 
and TEPs just before surgery and within 45 days after surgery (before start adjuvant 
chemotherapy).  
 
A standardized histopathology protocol will be developed by pathologist from expert pancreatic centers 
participating in the trial for the pathological evaluation of the resection specimen. A team of dedicated 

     
 
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pathologist will be formed to reach consensus over every case included in the ADAPTA trial. After reaching 
consensus, cases will be included either in the Intestinal subgroup, or in the PB+Mixed subtype group and 
the adjuvant CAPOX (in intestina group) or adjuvant FOLFIRINOX (in PB+mixed group) will be 
administrated. 
The treatment of FOLFIRINOX, and CAPOX are registered for the treatment of pancreatic cancer and 
duodenal/ colon cancer respectively. We classified this study as low risk, there is only a slight chance of 
moderate damage. 
 
STATISTICAL ANALYSIS 
Primary endpoint analysis 
The endpoint for the primary analysis is 3-year Disease Free Survival (DFS). The formal test for difference 
in DFS between the two treatment arms will be performed with a multivariable Cox regression analysis 
with adjustment for the stratification factors (resectable versus borderline resectable, and institution). 
Additional post-hoc adjustment is performed for confounding factors that are not equally distributed 
across treatment arms due to chance. The actuarial method of Kaplan-Meier will be used to estimate DFS 
probabilities at appropriate time points, while the Greenwood estimate will be used to construct 
corresponding 95% confidence intervals (CIs). Kaplan-Meier curves will be generated to illustrate DFS, for 
all patients as well as per treatment arm individual. We will also retrospectively propensity score match 
all included patients with the retrospective registry of the ISGACA consortium to evaluate if there is a 
difference in DFS between patients without adjuvant FOLFIRINOX/CAPOX and patients enrolled in the 
ADAPTA trial. 
 
Secondary endpoints analysis 
• 
Chemotherapy rate will be compared using Fisher’s exact test.  
• 
5-year disease free survival will be compared with a multivariable Cox regression analysis 
• 
5-year overall survival will be compared with a multivariable Cox regression analysis 

     
 
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• 
3-year overall survival will be compared with a multivariable Cox regression analysis 
• 
Chemotherapy completion rate will be compared using Fisher’s exact test.  
• 
Resection rate will be compared using Fisher’s exact test.  
• 
R0 resection rate will be compared using Fisher’s exact test.  
• 
Progression-free survival (PFS) will be compared with a multivariable Cox regression analysis with 
adjustment for the stratification factors (i.e. resectable versus borderline resectable and 
institution).  
• 
Locoregional Failure Free Interval and Distant Metastases Free Interval will be compared with a 
multivariable Cox regression analysis with adjustment for the stratification factors (i.e. resectable 
versus borderline resectable and institution).  
• 
Toxicity of chemotherapy will be compared using the Fisher exact or chi-square test. 
• 
Postoperative complications will be compared using the Fisher exact or chi-square test.  
 
Sample size calculation 
A study from Duke university [31], reported a 3-year recurrence-free survival of 48% in a group of patients 
with ampullary carcinoma who underwent Whipple procedure alone. A propensity score matched 
retrospective analyses after R0/R1 resection of Ampullary cancer from our study group the International 
Study Group on Ampullary Cancer (ISGACA) showed a beneficial effect of adjuvant treatment on overall 
survival with a hazard ratio of 0.57 [32]. Our primary endpoint is 3-year disease-free survival (DFS) rate, 
with DFS defined as the time from surgery until disease recurrence or death from any cause. A two-sided 
test based on the nonparametric estimate of the survival distribution calculated from a sample of 86 
patients achieved 90% power (1-beta) at a 0.05 significance level (alpha) to detect a hazard ratio of 0.57, 
when the proportion of patients free of recurrence at 3 years in the historic control group is 48% (as 
reported by Palta et al.). Patients are accrued over a 2-year period and followed for 2 more years. The 
probability that a patient experiences a recurrence at 3 years is 0.34 (corresponding to a 3-year 
recurrence-free survival =66%). To account for possible loss to follow-up, we intend to enroll 100 patients 
per stratum (intestinal or PB/mixed subtype). 

     
 
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SAFETY REPORTING  
Adverse Events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject during the study, 
whether or not considered related to [the investigational product / trial procedure/ the experimental 
intervention]. All adverse events reported spontaneously by the subject or observed by the investigator 
or his staff will be recorded. A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalization or prolongation of existing inpatients’ hospitalization; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed above due 
to medical or surgical intervention but could have been based upon appropriate judgement 
by the investigator. 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
 
 
REGULATION STATEMENT, RECRUITMENT AND CONSENT 
The principal investigator will ensure that this study is conducted in agreement with the Declaration of 
Helsinki (Tokyo, Venice, Hong Kong and Somerset West, Edinburgh, Washington, Tokyo and Seoul 
amendments), The protocol has been written, and the study will be conducted according to the ICH 
Harmonised Tripartite Guideline for Good Clinical Practice and the EU Directives EU clinical trials directive 
2001/20/EC and 2005/28/EC.  

     
 
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All patients will be informed of the aims of the study, the possible adverse events, the procedures and 
possible hazards to which he/she will be exposed. They will be informed of the strict confidentiality of 
their patient data, but that their medical records may be reviewed for trial purposes by authorized 
individuals other than their treating physician. It will be emphasized that participation is voluntary and 
that the patient is allowed to refuse further participation in the protocol whenever he/she wants. This will 
not prejudice the patient’s subsequent care. Documented informed consent must be obtained for all 
patients included in the study before they are randomized at the Data Center. This must be done in 
accordance with the WMO and ICH guidelines on Good Clinical Practice.  
Subjects can leave the study at any time for any reason if they wish to do so without any consequences. 
The investigator can decide to withdraw a subject from the study for urgent medical reasons. 
Before the study start, the current protocol and the other study documents will be notified to the Ethical 
Commitee of Brescia 
 
HANDLING AND STORAGE OF DATA AND DOCUMENTS 
The principal investigator and the trial management team will guide conduct of the trial according to Good 
Clinical Practice (GCP). The Local investigators will be responsible for the conduct within their site. Data 
will be handled confidentially. Each patient will receive an anonymous identification code. To trace data 
back to an individual patient, a subject identification code list will be used. Each participating site will 
safeguard the key to this code for patients included at their site. Data will be entered in eCRFs using the 
electronic online database CASTOR. Data to be collected on the CRF are derived from the protocol. The 
CRF and instructions for completing the CRF will be provided by the Clinical Trial Center. Automated and 
manual consistency checks will be performed on newly entered forms; queries will be issued in case of 
inconsistencies. Consistent forms will be validated by the Clinical Trial Center. Inconsistent forms will be 
kept "on-hold" until resolution of the inconsistencies. 
 

     
 
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Monitoring and Quality Assurance  
On behalf of the principal investigator, the study will be monitored by an experienced monitor team from 
the Clinical Trial Center throughout its duration by means of personal visits to the local investigator’s 
facilities and through other communications (e.g. telephone calls, e-mail).  
Monitoring visits will take place according to a study specific monitoring plan and will be scheduled at 
mutually agreeable times periodically throughout the study and at frequency deemed appropriate for the 
study. These visits will be conducted to evaluate the progress of the study, ensure the rights and well-
being of the subjects are protected, check that the reported clinical study data are accurate, complete 
and verifiable from source documents, and the conduct of study follows the approved protocol and 
amendments, GCP and applicable national regulatory requirements. 
A monitoring visit will include a review of essential clinical study documents (Investigator file, regulatory 
documents, CRFs, source documents, subject informed consent forms, etc.) as well as discussion on the 
conduct of the study with the local investigator and staff. Direct access to source documentation (medical 
records) must be allowed for the purpose of verifying that the data recorded in the CRF are consistent 
with the original source data. 
The principal investigator expects that during monitoring visits the relevant investigational staff will be 
available, the source documentation will be available and a suitable environment will be provided for 
review of study-related documents.  
Minor and major findings of the monitor will be discussed with the local investigator, and documented in 
a standard monitoring report that will be provided to the principal investigator. The principal investigator 
may decide to increase the monitoring frequency or intensity if the results of monitoring require this to 
ensure patient safety and/or data quality. 
 
 
REFERENCES 

     
 
PROTOCOL – Study ADAPTA  
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1.  
Albores-Saavedra J, Schwartz AM, Batich K, et al. Cancers of the ampulla of vater: demographics, 
morphology, and survival based on 5,625 cases from the SEER program. J Surg Oncol 2009; 
100(7):598-605. 
2.  
Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008; 58(2):71-96. 
3.  
Chang DK, Jamieson NB, Johns AL, et al. Histomolecular phenotypes and outcome in 
adenocarcinoma of the ampulla of vater. J Clin Oncol 2013; 31(10):1348-56. 
4.  
Westgaard A, Tafjord S, Farstad IN, et al. Pancreatobiliary versus intestinal histologic type of 
differentiation is an independent prognostic factor in resected periampullary adenocarcinoma. 
BMC Cancer 2008; 8:170. 
5.  
Rostain F HS, Drouillard A, Faivre J, Bouvier AM, Lepage C. Trends in incidence and management 
of cancer of the ampulla of Vater. World J Gastroenterol. 2014;20(29):10144–10150. 
doi:10.3748/wjg.v20.i29.10144. 
6.  
Riall TS, Cameron JL, Lillemoe KD, et al. Resected periampullary adenocarcinoma: 5-year 
survivors and their 6- to 10-year follow-up. Surgery 2006; 140(5):764-72. 
7.  
Howe JR, Klimstra DS, Moccia RD, et al. Factors predictive of survival in ampullary carcinoma. 
Ann Surg 1998; 228(1):87-94. 
8.  
CANCER AJCO. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer 
staging manual. 2010. 
9.  
Moekotte AL, Lof S, Van Roessel S, et al. Histopathologic Predictors of Survival and Recurrence in 
Resected Ampullary Adenocarcinoma: International Multicenter Cohort Study. Ann Surg 2019. 
10. 
Zimmermann C, Wolk S, Aust DE, et al. The pathohistological subtype strongly predicts survival 
in patients with ampullary carcinoma. Scientific Reports 2019; 9. 
11. 
Kimura W, Ohtsubo K. Incidence, sites of origin, and immunohistochemical and histochemical 
characteristics of atypical epithelium and minute carcinoma of the papilla of Vater. Cancer 1988; 
61(7):1394-402. 
12. 
Zhou H, Schaefer N, Wolff M, et al. Carcinoma of the ampulla of Vater: comparative 
histologic/immunohistochemical classification and follow-up. Am J Surg Pathol 2004; 28(7):875-
82. 
13. 
Baczako K, Buchler M, Beger HG, et al. Morphogenesis and possible precursor lesions of invasive 
carcinoma of the papilla of Vater: epithelial dysplasia and adenoma. Hum Pathol 1985; 
16(3):305-10. 
14. 
Neoptolemos JP, Talbot IC, Shaw DC, et al. Long-term survival after resection of ampullary 
carcinoma is associated independently with tumor grade and a new staging classification that 
assesses local invasiveness. Cancer 1988; 61(7):1403-7. 
15. 
Ang DC, Shia J, Tang LH, et al. The Utility of Immunohistochemistry in Subtyping 
Adenocarcinoma of the Ampulla of Vater. American Journal of Surgical Pathology 2014; 
38:1371-1379. 
16. 
Kim WS, Choi DW, Choi SH, et al. Clinical significance of pathologic subtype in curatively resected 
ampulla of vater cancer. Journal of Surgical Oncology 2012; 105:266-72. 

     
 
PROTOCOL – Study ADAPTA  
Version 1.1 - 17-11-2022  
 
 
 
17. 
Zimmermann C, Wolk S, Aust DE, et al. The pathohistological subtype strongly predicts survival 
in patients with ampullary carcinoma. Sci Rep 2019; 9(1):12676. 
18. 
Hsu HP, Shan YS, Hsieh YH, et al. Predictors of recurrence after pancreaticoduodenectomy in 
ampullary cancer: comparison between non-, early and late recurrence. J Formos Med Assoc 
2007; 106(6):432-43. 
19. 
Kim H, Kwon W, Kim JR, et al. Recurrence patterns after pancreaticoduodenectomy for 
ampullary cancer. J Hepatobiliary Pancreat Sci 2019; 26(5):179-186. 
20. 
Park JS, Yoon DS, Kim KS, et al. Factors influencing recurrence after curative resection for 
ampulla of Vater carcinoma. J Surg Oncol 2007; 95(4):286-90. 
21. 
Bhatia S, Miller RC, Haddock MG, et al. Adjuvant therapy for ampullary carcinomas: The Mayo 
Clinic experience. International Journal of Radiation Oncology Biology Physics 2006; 66:514-519. 
22. 
Narang AK, Miller RC, Hsu CC, et al. Evaluation of adjuvant chemoradiation therapy for 
ampullary adenocarcinoma: The Johns Hopkins Hospital - Mayo Clinic collaborative study. 
Radiation Oncology 2011:126. 
23. 
Zhou J, Hsu CC, Winter JM, et al. Adjuvant chemoradiation versus surgery alone for 
adenocarcinoma of the ampulla of Vater. Radiotherapy and Oncology 2009; 92:244-248. 
24. 
Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative 
resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC 
gastrointestinal tract cancer cooperative group. Annals of surgery 1999; 230:776-82; discussion 
782-4. 
25. 
Neoptolemos JP, Moore MJ, Cox TF, et al. Effect of adjuvant chemotherapy with fluorouracil 
plus folinic acid or gemcitabine vs observation on survival in patients with resected 
periampullary adenocarcinoma: The ESPAC-3 periampullary cancer randomized trial. JAMA - 
Journal of the American Medical Association 2012; 308:147-156. 
26. 
Bolm L et al. Adjuvant therapy is associated with improved overall survival in patients  with 
 
pancreatobiliary or mixed subtype ampullary cancer after  
pancreatoduodenectomy - A 
 
multicenter cohort study, Pancreatology  2020  Apr;20(3):433-441;  doi: 
10.1016/j.pan.2020.01.009. 
27. 
Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for 
Pancreatic Cancer. N Engl J Med 2018; 379(25):2395-2406. 
28. 
Overman MJ, Varadhachary GR, Kopetz S, et al. Phase II study of capecitabine and oxaliplatin for 
advanced adenocarcinoma of the small bowel and ampulla of Vater. J Clin Oncol 2009; 
27(16):2598-603. 
29. 
Rossi M. APPLICAZIONE DELLE RACCOMANDAZIONI AIOM-SIF PER L’ANALISI 
FARMACOGENETICA DEL GENE DPYD. 2021. https://unire.unige.it/handle/123456789/3553 
30. 
SERVICES USDOHAH. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 
2017 
 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Refer
ence_5x7.pdf. 

     
 
PROTOCOL – Study ADAPTA  
Version 1.1 - 17-11-2022  
 
 
 
31. 
Palta M, Patel P, Broadwater G, et al. Carcinoma of the ampulla of Vater: patterns of failure 
following resection and benefit of chemoradiotherapy. Ann Surg Oncol 2012; 19(5):1535-40. 
32. 
Moekotte AL, Malleo G, van Roessel S, et al. Gemcitabine-based adjuvant chemotherapy in 
subtypes of ampullary adenocarcinoma: international propensity score-matched cohort study. 
Br J Surg 2020. 
33. 
Hoffman-La Roche. XELODA® product monograph. Mississauga OJ. 
34. 
Dean L. Irinotecan Therapy and UGT1A1 Genotype. In: Pratt VM, Scott SA, Pirmohamed M, et 
al., eds. Medical Genetics Summaries. Bethesda (MD); 2012. 
35. 
Gingras MC, Covington KR, Chang DK, et al. Ampullary Cancers Harbor ELF3 Tumor Suppressor 
Gene Mutations and Exhibit Frequent WNT Dysregulation. Cell Rep 2016; 14(4):907-919. 
36. 
Yachida S, Wood LD, Suzuki M, et al. Genomic Sequencing Identifies ELF3 as a Driver of 
Ampullary Carcinoma. Cancer Cell 2016; 29(2):229-40. 
37. 
Corbo V, Ritelli R, Barbi S, et al. Mutational profiling of kinases in human tumours of pancreatic 
origin identifies candidate cancer genes in ductal and ampulla of vater carcinomas. PLoS One 
2010; 5(9):e12653. 
38. 
Mafficini A, Amato E, Cataldo I, et al. Ampulla of Vater Carcinoma: Sequencing Analysis Identifies 
TP53 Status as a Novel Independent Prognostic Factor and Potentially Actionable ERBB, PI3K, 
and WNT Pathways Gene Mutations. Ann Surg 2018; 267(1):149-156. 
39. 
Lof S, Rajak R, Vissers F, et al. DIPLOMA Approach for Standardized Pathology Assessment of 
Distal Pancreatectomy Specimens. J Vis Exp 2020(156). 
40. 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials 
in oncology. J Natl Cancer Inst 1993; 85(5):365-76. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX 
Dosages, dosage modifications and method of administration 

     
 
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FOLFIRINOX is a combination of systemic chemotherapy agents. mFOLFIRINOX consists of oxaliplatin at a dose of 85 
mg/m2, given as a 2-hour intravenous infusion, immediately followed by leucovorin at a dose of 400 mg/m2 given 
as a 2-hour intravenous infusion, with the addition, after 30 minutes, of irinotecan at a dose of 150 mg/m2, given as 
a 90-minute intravenous infusion through a Y-connector. This is followed by a continuous intravenous infusion of 
2400 mg/m2 over a 48-hour period, every 2 weeks.  
About 10% of patients has a (partial) deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme (encoded 
by the DPYD gene) resulting in increased fluorouracil toxicity. Testing of the DPYD gene is mandatory.29  
Fluorouracil dose is adjusted or withheld in patients with a (partial) deficiency of the DPD enzyme following AIOM 
recommendations. The fluorouracil bolus may be withheld in patients with a WHO/PS 1 and/or age above 75. A 
modified regimen starting at the first cycle is also allowed at the discretion of the treating physician: irinotecan and 
oxaliplatin starting dose may be reduced to 80%, and the fluorouracil bolus may be withheld.  
Irinotecan is converted in the body to an active metabolite known as SN-38, which is then inactivated and detoxified 
by a UDP-glucuronosyltransferase (UGT) enzyme encoded by the UGT1A1 gene. The UGT enzymes are responsible 
for glucuronidation, a process that transforms lipophilic metabolites into water-soluble metabolites that can be 
excreted from the body.34 Therefore, it is necessary to test UGT1A1 mutation before the start of the adjuvant 
therapy. In case of mutations, dose adjustments are required. During treatment the dose reduction should 
be based on the maximum graded toxicity within the previous cycle, graded using the National Cancer 
Institute Common Toxicity Criteria (version 4.0.3, see Appendix 2). Dose adjustments follow the AIOM 
recommendations 2019.29 
 
 
 
FOLFIRINOX dose adjustment guidelines 
Toxicities will be managed by treatment interruption for a maximum of 2 weeks, to allow resolution of 
toxicity. In the case of illness other than toxicity (i.e. cholangitis), the treatment will be delayed for a 
maximum of 4 weeks. If a patient’s treatment is delayed for longer than 2 weeks because of toxicity or 
longer than 4 weeks because of illness other than toxicity the patient will discontinue FOLFIRINOX. 
After treatment interruption because of toxicity, the dose of one or more agents of the FOLFIRINOX 
regimen may be reduced according to maximum graded toxicity within the previous cycle as described 
below. If a dose is reduced because of toxicity, the patient will stay on the reduced dose for the remainder 
of the study. A second dose reduction is allowed before the patient discontinues from study treatment. 
Hematologic toxicity 
Do not restart chemotherapy until the granulocyte count is ≥ 1.0 x 109 per liter, the platelet count is ≥ 
75x109/L and ≥ 1.500 neutrophils per microliter. Granulocyte colony stimulating factor may be used. See 
tables below.  

     
 
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Table A1. Doses according to the blood counts at the beginning of a cycle (Day 1) 
Blood counts Day 1 
Delay of cycle 
Doses reduction 
 
 
Irinotecan 
Oxaliplatin 
Fluorouracil 
Granulocyte count 
< 1.5 x 109/l 
Hold treatment  
until  
granulocytes ≥  
1.0 x 109/L (one  
or two weeks if  
necessary).  
In case of non  
recovery after 2  
weeks delay,  
stop treatment*  
1st occurrence: 
Reduction of dose 
to 150mg/m2 
 
2nd occurrence: 
Maintain the dose 
at 150mg/m2 
 
3rd occurrence: 
Treatment 
discontinuation 
1st occurrence: 
No reduction of 
dose 
 
 
2nd occurrence: 
Reduce the dose to 
60mg/m2 
 
3rd occurrence: 
Treatment 
discontinuation 
1st occurrence: 
Delete bolus 5FU 
Platelets 
<75x109/l= 
Hold the  
treatment until  
recovery  
platelets ≥ 75 x  
109/L.  
 
In case of non  
recovery after 2  
weeks delay,  
stop treatment  
1st occurrence: 
no reduction of  
dose  
 
 
2nd occurrence: 
Reduction of dose 
to 150mg/m2 
 
3rd occurrence: 
Treatment 
discontinuation 
1st occurrence: 
Reduce the dose to 
60mg/m2 
 
2nd occurrence: 
Maintain the dose 
at 60mg/m2 
 
3rd occurrence: 
Treatment 
discontinuation 
1st occurrence: 
Reduce both the 
bolus and the 
continuous  
infusion to 75% of 
the original doses  
 
 
Table A2. Doses according to the low nadir blood counts or in case of infection. 
Adverse events  
Reduction of dose for subsequent cycles  
Febrile neutropenia  
OR  
Grade 4 neutropenia during more than 7 days  
OR  
Infection with concomitant grade 3-4 neutropenia  
1st occurrence: reduce the dose of irinotecan to 150 
mg/m² and delete the bolus 5FU dose   
 
2nd occurrence: reduce also the dose of oxaliplatin to 
60 mg/m²  
 
3rd occurrence: treatment discontinuation 

     
 
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Table A3. Gastrointestinal toxicities.
 
Patients are instructed to use loperamide for diarrhea, and have a supply of this drug upon starting 
FOLFIRINOX. Patients should not be retreated with irinotecan until recovery to CTCAE grade ≤1 diarrhea 
has occurred. See table 10 for details. 
 
Mucositis or “hand-foot” syndrome  
In case of grade 3-4 toxicity, delete bolus and reduce continuous 5FU with 25% or the subsequent cycles.  
 
 
Adverse events  
Reduction of dose for subsequent 
cycles  
Diarrhea grade 3-4  
or  
Diarrhea + fever  
and/or  
neutropenia grade 3-4  
1st occurrence: reduce the irinotecan dose 
to 150 mg/m2 and delete the bolus 5FU 
dose  
 
2nd occurrence: reduce also the oxaliplatin 
dose to 60 mg/m² and reduce the dose of 
continuous 5FU to 75 % of the original dose 
  
3rd occurrence: treatment discontinuation  
Diarrhea ≥ 48 h despite high doses 
loperamide  
No systematic reduction of the irinotecan, 
oxaliplatin or 5FU doses after complete 
recovery, unless grade 3-4 diarrhea, or 
diarrhea + fever, and/or concomitant 
neutropenia grade 3-4  

     
 
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Cardiac toxicity  
In case of angina pectoris or of myocardial infarction, 5FU has to be stopped.  
 
Hyperbilirubinemia  
In case of elevation of bilirubin, it is suggested to exclude an obstruction of the biliary stent or progressive 
disease and to postpone chemotherapy. If bilirubin is >1.5xULN, irinotecan is not recommended. If 
chemotherapy is medically indicated, it is necessary to provide a dose adjustment of irinotecan: 
 
 
Table A4. 
 
Irinotecan 
Oxaliplatin 
5-FU 
Bilirubin 1.0 – 1.5 x ULN  
75% 
100% 
100% 
Bilirubin 1.5 – 3.0 x ULN  
50% 
100% 
100% 
Bilirubin > 3 x ULN  
Discontinuation 
100% 
50% 
 
Other toxicities 
Any other toxicity ≥ grade 2, except anemia and alopecia, can justify a reduction of dose if medically 
indicated, for example reduction of irinotecan to 150mg/m2 and/or oxaliplatin 60mg/m2 and or 5-FU 25% 
depending of the type of adverse event. 
 
CAPOX dose adjustment guidelines 
Hematological toxicity  
• 
Delay 1 week if ANC < 1.0 and Platelets < 75  
• 
If delay > 1 week, patient will need a 25% dose reduction of Oxaliplatin and Capecitabine  
• 
No dose reduction for CTC grade I/II ANC  

     
 
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• 
Grade III/IV ANC → delay chemotherapy until recovered, then proceed at 25% capecitabine and 
oxaliplatin dose reduction  
• 
If further delay(s) for bone marrow suppression occur despite a 25% dose reduction, consider a 
further 25% dose reduction 
 
Non-hematological toxicities  
Hepatic impairment  
• 
Administration of CAPOX should be interrupted if treatment-related elevations in bilirubin of > 2 
x ULN or treatment-related elevations in hepatic aminotransferases (ALT, AST) of > 2.5 x ULN 
occur.  
• 
Treatment may be resumed when bilirubin decreases to ≤ 2.0 x ULN or hepatic 
aminotransferases decrease to ≤ 2.5 x ULN. 
 
Table A5. Renal function 
GFR 
Capecitabine 
Oxaliplatin 
30-50 ml/min  
25% dose reduction  
No action 
< 30 ml/min 
Contact prescriber 
Contact prescriber 
 
 
 
Neurotoxicity 
Cold related paresthesia of hands/feet or dysesthesia/laryngeal spasm syndrome lasting a few hours 
does not require treatment or dose reduction.  
If severe laryngeal spasm occurs, increase oxaliplatin infusion duration to 6 hours  
If symptoms persist for 14 days and/or there is pain, functional loss, omit oxaliplatin and continue with 
capecitabine until recovered, then restart oxaliplatin at 25% dose reduction. 
 
 

     
 
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Table A6. Diarrhea 
Grade 1 (watery stool 2-3 times/day)  
Loperamide 4mg then 2mg QDS PRN 
Grade 2 (watery stool 4-6 times/day)  
Delay treatment until recovered and give full dose 
Grade 3/4 (watery stool >7 times/day)  
Delay until recovered and resume treatment at 25% 
reduced dose of oxaliplatin and capecitabine 
 
Table A7.  PPE (hand/foot syndrome) toxicity grading for capecitabine only 
Grade  
Clinical  
Functional  
Management 
1 
Numbness, 
dysesthesia/paresthesia,  
 
Discomfort but no 
interruption of normal 
activities 
- 
2 
Painful erythema with 
swelling 
Discomfort which affects 
activities of daily living 
Interrupt treatment until 
grade ≤1 
3 
Moist desquamation, 
ulceration, Blistering, 
severe pain 
Severe discomfort, 
unable to work or 
perform activities of 
daily living 
Interrupt treatment until 
grade ≤1 and reduce 
dose by 25% 
 
Table A8. Dose adjustments according to CTC toxicity (Not PPE/hand/foot syndrome) 
 
Grade 2  
Grade 3  
Grade 4 
1 st appearance 
Interrupt treatment until 
resolved to grade 0/1, 
then continue at 100% 
of original dose with 
prophylaxis where 
possible 
Interrupt treatment until 
resolved to grade 0/1, 
then continue at 75% of 
original dose with 
prophylaxis where 
possible 
Discontinue treatment 
 
2 nd appearance 
Interrupt treatment until 
resolved to grade 0/1, 
then continue at 75% of 
original dose 
Interrupt treatment until 
resolved to grade 0/1, 
then continue at 50% of 
original dose 
 
3 rd appearance 
Interrupt treatment until 
resolved to grade 0/1, 
then continue at 50% of 
original dose 
Discontinue treatment 
 
 
4 th appearance  
Discontinue treatment 
 
 
 

     
 
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Once the capecitabine dose has been reduced, it should not be increased at a later time. Omitted doses 
are not replaced or restored, instead the patient should resume the planned treatment cycle.