Neoadjuvant S-1 and Concurrent Radiotherapy for Borderline Resectable Pancreatic Cancer

Study Overview
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Brief Summary
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Multicenter Prospective Phase II Study for Neoadjuvant S-1 and Concurrent Radiotherapy for Borderline Resectable Pancreatic Cancer RATIONALE: Borderline resectable pancreatic cancer is frequently related to a positive surgical margin and has a poor prognosis after resection. Neoadjuvant chemoradiation with intensive local effect may lead to substantial local control and prolongation of survival in borderline resectable pancreatic cancer. PURPOSE: This phase II trial assess efficacy and safety of neoadjuvant S-1 and concurrent radiotherapy for borderline resectable pancreatic cancer.

Detailed Description
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S-1: S-1 is an oral fluorinated pyrimidine agent which contains tegafur (FT, a prodrug of 5-FU), 5-chloro-2,4-dihydropyrimidine (CHDP) and potassium oxonate (Oxo) effective for gastric and various other types of cancers. S-1 is also active for pancreatic cancer: S-1 demonstrated non-inferiority to gemcitabine in overall survival for metastatic or locally advanced pancreatic cancer (LAPC). S-1 and Concurrent radiotherapy: S-1 therapy with concurrent radiation therapy (RT) had favorable activity with overall tumor response rate of 37%, as well as mild toxicity in patients with LAPC. The median survival time and the 2-year survival rate for LAPC patients treated by S-1/RT were 16.2 months and 26% respectively. Definition of Borderline Resectable Pancreatic Cancer:(1) Reconstructible bilateral impingement of superior mesenteric vein or portal vein; (2) Tumor contact with the superior mesenteric artery (SMA) of </= 180 degrees ; (3) Tumor contact with the common hepatic artery of </= 180 degrees (at the root of the gastroduodenal artery); and (4) Tumor contact with the celiac axis of </= 180 degrees. Tumor with portal vein tumor thrombus and tumor contact with the second or further jejunal SMA branch are considered as unresectable. Tumor which is contact with the common hepatic artery or celiac axis but can be resected by distal pancreatectomy with en bloc celiac axis resection, is not included in this study.

Official Title
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Phase II Study of Neoadjuvant S-1 and Concurrent Radiotherapy for Borderline Resectable Pancreatic Cancer

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: S-1
* Radiation: Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cytologic or histologic proof of pancreatic ductal carcinoma or adenosquamous carcinoma is required prior to study entry. Disease assessment by Multi Detector-row Computed Tomography (MDCT) scan within 2 weeks of study entry Borderline resectable pancreatic cancer No evidence of metastatic disease as determined by chest CT scan, and abdominal CT scan and laparoscopy. Paraaortic lymph node metastasis is considered as metastatic. Age >/=20 years old, </=75 years old Eastern Cooperative Oncology Group (ECOG) performance status 0-1 No prior chemotherapy or radiotherapy for pancreatic cancer A square 10 x 10 cm radiation field could encompass all pancreatic lesions and lymph node metastases Adequate oral intake Appropriate biliary drainage for obstructive jaundice Lab Values: hemoglobin concentration >/= 9.0 g/dL leukocyte count >/= 3,000/mm3 platelet count >/= 100,000/mm3 serum total bilirubin </= 2.0 mg dL, or </=3.0 mg/dL with biliary drainage Aspartate Transaminase (AST) and Alanine Transaminase (ALT) </= 100 U/L, or </= 150 U/L with biliary drainage serum albumin >/= 3.0 g/dl serum creatinine </= 1.2 mg dL Creatinine clearance >/= 50 ml/min Written informed consent Exclusion Criteria: Tumor invasion to the alimentary tract determined by abdominal CT scan or endoscopic examination Prior chemotherapy using fluoropyrimidine Prior radiation therapy to the abdomen Watery diarrhea Concurrent phenytoin, warfarin potassium, or flucytosine treatment Presence of contrast medium allergy Pulmonary fibrosis or interstitial pneumonia Pleural effusion or ascites Active infection Uncontrolled diabetes mellitus (FBS >/= 200mg/dL or HbA1c >/= 10.0) Active concomitant malignancy Active gastroduodenal ulcer Severe complications such as cardiac or renal disease Regular administration of systemic corticosteroid Psychiatric disorder History of drug hypersensitivity Pregnant and lactating women and women of childbearing age who were not using effective contraception

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant S-1/RT<br>This is a single arm prospective study. All eligible subjects will receive neoadjuvant S-1 and concurrent radiation followed by surgical resection. Subjects may receive adjuvant chemotherapy after surgical resection at the clinical discretion of the medical oncologists. | Drug: S-1<br>* S-1 is administered orally at a dose of 40 mg/m2 twice daily on the day of irradiation (Monday through Friday) during radiation therapy.<br>Radiation: Radiation Therapy<br>* Radiation therapy is delivered with >6-megavolts (MV) photons, using a multiple field technique. A total dose of 50.4 Gy is delivered in 28 fractions over 5.5 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| R0 resection rate | R0 resection rate of all patients enrolled in the study | Up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | up to 6 years | 
| Disease-free survival |  | up to 6 years | 
| Response rate after neoadjuvant chemoradiation | All responses will be measured by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 within 4 weeks after completion of neoadjuvant therapy. | Up to 4 years | 
| Pathological response rate | Evaluation of the pathological response of the primary tumor was performed using a classification by Evans et al. | Up to 4 years | 
| 2-year survival rate |  | up to 6 years | 
| Surgical morbidity rates | Both Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and Clavien-Dindo Classification will be used for all morbidity assessments. | With in 90 days | 
| Acute and late toxicity rates | All toxicities will be measured by CTCAE version 4.0. | With in 6 months | 
| R0 resection rate in borderline resectable pancreatic cancer | Diagnosis of borderline resectable pancreatic cancer will be fixed by Diagnostic Radiology Central Review. | Up to 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Borderline Resectable Pancreatic Cancer