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

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

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.

Study Overview

• Status: Completed
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Drug: S-1; Radiation: Radiation Therapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Chiba, Japan, 260-8717
    • Chiba Cancer Center
  • Fukuoka, Japan, 811-1395
    • National Hospital Organization Kyusyu Cancer Center
  • Yamagata, Japan, 990-9585
    • Yamagata University Hospital
  • Aichi
    • Nagoya, Aichi, Japan, 464-8681
      • Aichi Cancer Center
    • Nagoya, Aichi, Japan, 466-8560
      • Nagoya University Hospital
  • Aomori
    • Hirosaki, Aomori, Japan, 036-8563
      • Hirosaki University Hospital
  • Chiba
    • Kashiwa, Chiba, Japan, 277-8577
      • National Cancer Center Hospital East
  • Ehime
    • Matsuyama, Ehime, Japan, 791-0280
      • Shikoku Cancer Center
  • Hiroshima
    • Fukuyama, Hiroshima, Japan, 721-8511
      • Fukuyama City Hospital
    • Kure, Hiroshima, Japan, 737-0023
      • National Hospital Organization Kure Medical Center
  • Hokkaido
    • Asahikawa, Hokkaido, Japan, 078-8510
      • Asahikawa Medical University
    • Sapporo, Hokkaido, Japan, 060-8648
      • Hokkaido University Hospital
  • Hyogo
    • Kobe, Hyogo, Japan, 650-0017
      • Kobe University Hospital
  • Kanagawa
    • Kawasaki, Kanagawa, Japan, 216-8511
      • St. Marianna University School of Medicine Hospital
    • Yokohama, Kanagawa, Japan, 241-8515
      • Kanagawa Cancer Center
  • Osaka
    • Chuo-ku, Osaka, Japan, 540-0006
      • National Hospital Organization Osaka National Hospital
  • Saitama
    • Kita-adachigun Inamachi, Saitama, Japan, 362-0806
      • Saitama Cancer Center
  • Shizuoka
    • Hamamatsu, Shizuoka, Japan, 433-8558
      • Seirei Mikatahara General Hospital
    • Suntohgun, Nagaizumityo, Shizuoka, Japan, 411-8777
      • Shizuoka Cancer Center
  • Tochigi
    • Shimotsuke, Tochigi, Japan, 329-0498
      • Jichi Medical University Hospital
    • Utsunomiya, Tochigi, Japan, 320-0834
      • Tochigi Cancer Center
  • Tokyo
    • Shinjuku, Tokyo, Japan, 162-8666
      • Tokyo Women's Medical University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Neoadjuvant S-1/RT; 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; 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.; Radiation: Radiation Therapy; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Japan Adjuvant Study Group of Pancreatic Cancer
• Collaborators: Japan Agency for Medical Research and Development; Pharma Valley Center
• Investigators: Principal Investigator: Masafumi Ikeda, M.D., Ph.D., National Cancer Center Hospital East, Department of Hepatobiliary Pancreatic Oncology; Study Chair: Katsuhiko Uesaka, M.D., Ph.D., Shizuoka Cancer Center Hospital

Publications and helpful links

General Publications

• Takahashi S, Ohno I, Ikeda M, Kobayashi T, Akimoto T, Kojima M, Konishi M, Uesaka K. Neoadjuvant S-1 with concurrent radiotherapy followed by surgery for borderline resectable pancreatic cancer: study protocol for an open-label, multicentre, prospective phase II trial (JASPAC05). BMJ Open. 2017 Oct 22;7(10):e018445. doi: 10.1136/bmjopen-2017-018445.
• Takahashi S, Ohno I, Ikeda M, Konishi M, Kobayashi T, Akimoto T, Kojima M, Morinaga S, Toyama H, Shimizu Y, Miyamoto A, Tomikawa M, Takakura N, Takayama W, Hirano S, Otsubo T, Nagino M, Kimura W, Sugimachi K, Uesaka K. Neoadjuvant S-1 With Concurrent Radiotherapy Followed by Surgery for Borderline Resectable Pancreatic Cancer: A Phase II Open-label Multicenter Prospective Trial (JASPAC05). Ann Surg. 2022 Nov 1;276(5):e510-e517. doi: 10.1097/SLA.0000000000004535. Epub 2020 Oct 15.

Study record dates

Study Major Dates

• Study Start (Actual): December 28, 2012
• Primary Completion (Actual): May 13, 2016
• Study Completion (Actual): July 17, 2018

Study Registration Dates

• First Submitted: May 29, 2015
• First Submitted That Met QC Criteria: May 29, 2015
• First Posted (Estimate): June 2, 2015

Study Record Updates

• Last Update Posted (Actual): October 27, 2020
• Last Update Submitted That Met QC Criteria: October 25, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Borderline Resectable Pancreatic Cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms
• Other Study ID Numbers: JASPAC 05