Two Chemotherapy Regimens Compared With Observation in Treating Patients With Completely Resected Pancreatic Cancer

European Study Group For Pancreatic Cancer - Trial 3

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known which chemotherapy regimen is more effective, or whether chemotherapy is more effective than observation, in treating pancreatic cancer after surgery.

PURPOSE: Phase III trial to compare the effectiveness of two chemotherapy regimens with no further therapy in treating patients who have completely resected pancreatic cancer.

Study Overview

• Status: Completed
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Drug: leucovorin calcium; Drug: fluorouracil; Drug: gemcitabine hydrochloride; Other: clinical observation

Detailed Description

OBJECTIVES:

Primary

• Compare the efficacy of adjuvant gemcitabine vs fluorouracil and leucovorin calcium (vs observation only in patients with ampullary or other pancreatic malignancy), in terms of overall survival, in patients with completely resected pancreatic cancer.

Secondary

• Compare the toxicity of these regimens in these patients.
• Compare the quality of life and 5-year survival of patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to histology (ductal adenocarcinoma vs ampullary or other pancreatic malignancy), resection margin status, and participating country. Patients are randomized to 1 of 2 treatment arms. Randomization for patients with ampullary or other pancreatic malignancy includes an observation arm.

• Arm I: Patients receive leucovorin calcium IV and fluorouracil IV on days 1-5.
• Arm II: Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15.
• Arm III (patients with ampullary or other pancreatic malignancy only): Patients undergo observation.

Treatment in arms I and II repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, 3, 6, and 12 months, and then annually for 5 years.

Patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 1,030 patients with pancreatic adenocarcinoma (515 per arms I and II) will be accrued for this study.

• Study Type: Interventional
• Enrollment (Anticipated): 1030
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • Institute of Oncology at Prince of Wales Hospital
  • South Australia
    • Bedford Park, South Australia, Australia, 5042
      • Flinders Medical Centre
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute at University of Alberta
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y 5L3
      • British Columbia Cancer Agency - Centre for the Southern Interior
    • Victoria, British Columbia, Canada, V8R 6V5
      • British Columbia Cancer Agency - Vancouver Island Centre
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
      • Nova Scotia Cancer Centre
  • Ontario
    • Kingston, Ontario, Canada, K7L 5P9
      • Cancer Centre of Southeastern Ontario At Kingston General Hospital
    • Kingston, Ontario, Canada, K7L 3N6
      • Cancer Research Institute at Queen's University
    • London, Ontario, Canada, N6A 4L6
      • London Regional Cancer Program at London Health Sciences Centre
    • Ottawa, Ontario, Canada, K1H 8L6
      • Ottawa Hospital Regional Cancer Centre - General Campus
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hospital
    • Toronto, Ontario, Canada, M6R 1B5
      • St. Joseph's Health Centre - Toronto
    • Toronto, Ontario, Canada, M4N 3M5
      • Edmond Odette Cancer Centre at Sunnybrook
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V 2H1
      • Hopital Charles LeMoyne
    • Montreal, Quebec, Canada, H2W 1S6
      • McGill Cancer Centre at McGill University
• Czech Republic
  • Preha 4, Czech Republic, 14021
    • Institute for Clinical and Experimental Medicine
• Finland
  • Tampere, Finland, 33521
    • Tampere university Hospital
• France
  • Paris, France, 75970
    • Hôpital Tenon
• Germany
  • Heidelberg, Germany, D-69120
    • Universitaets-Kinderklinik Heidelberg
• Greece
  • Athens, Greece, G-15233
    • Agia Olga Hospital
• Hungary
  • Gydr, Hungary, h-9024
    • Petz Aladar County Hospital
• Italy
  • Verona, Italy, 37134
    • Policlinico Borgo Roma
• Japan
  • Kyoto, Japan, 606-8507
    • Kyoto University Hospital
• Sweden
  • Uppsala, Sweden, S-75185
    • Uppsala University Hospital
• Switzerland
  • Bern, Switzerland, CH-3010
    • Inselspital Bern
• United Kingdom
  • England
    • Liverpool, England, United Kingdom, L69 3GA
      • Royal Liverpool University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed ductal adenocarcinoma of the pancreas OR

• Histologically confirmed diagnosis of 1 of the following types of cancer:

  • Acinar cell carcinoma or cystadenocarcinoma of the pancreas
  • Cancers of the periampullary region
  • Cancers of the intrapancreatic part of the bile duct
  • Periampullary cancers of uncertain origin

• Complete macroscopic resection (R0 or R1 resection)

  • Histological examination of all resection margins required
• No stage IVB disease
• No evidence of malignant ascites
• No liver or peritoneal metastases
• No evidence of spread to other distant abdominal or extra-abdominal organs
• No pancreatic lymphoma

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• WHO 0-2

Life expectancy

• More than 3 months

Hematopoietic

• Not specified

Hepatic

• Not specified

Renal

• Not specified

Other

• Not pregnant
• Able to participate in long-term follow-up
• No other prior or concurrent malignancy except curatively treated basal cell skin cancer or carcinoma in situ of the cervix
• No serious medical or psychological condition that would preclude study treatment

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No neoadjuvant chemotherapy
• No other concurrent chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• See Disease Characteristics
• Recovered from prior resection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm I; Patients receive leucovorin calcium IV and fluorouracil IV on days 1-5.	Drug: leucovorin calcium; Given IV; Drug: fluorouracil; Given IV
Experimental: Arm II; Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15.	Drug: gemcitabine hydrochloride; Given IV
No Intervention: Arm III; Patients undergo observation.	Other: clinical observation; No intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Overall survival

Secondary Outcome Measures

Outcome Measure
Toxicity as measured by NCI CTC v2.0
Quality of life as measured by EORTC QLQ C-30 and ESPAC-QLQ at 3, 6, and 12 months, and then annually for 5 years
Survival rate at 2 and 5 years

Collaborators and Investigators

• Sponsor: Royal Liverpool University Hospital
• Collaborators: NCIC Clinical Trials Group; Australasian Gastro-Intestinal Trials Group
• Investigators: Study Chair: John P. Neoptolemos, MD, Royal Liverpool University Hospital; R. Padbury, Flinders Medical Centre; David Goldstein, MD, Institute of Oncology at Prince of Wales Hospital

Publications and helpful links

General Publications

• Neoptolemos JP, Moore MJ, Cox TF, Valle JW, Palmer DH, McDonald AC, Carter R, Tebbutt NC, Dervenis C, Smith D, Glimelius B, Charnley RM, Lacaine F, Scarfe AG, Middleton MR, Anthoney A, Ghaneh P, Halloran CM, Lerch MM, Olah A, Rawcliffe CL, Verbeke CS, Campbell F, Buchler MW; European Study Group for Pancreatic Cancer. 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. 2012 Jul 11;308(2):147-56. doi: 10.1001/jama.2012.7352. Erratum In: JAMA. 2012 Nov 14;308(18):1861.
• Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Olah A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Buchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010 Sep 8;304(10):1073-81. doi: 10.1001/jama.2010.1275.
• Jones RP, Psarelli EE, Jackson R, Ghaneh P, Halloran CM, Palmer DH, Campbell F, Valle JW, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ting Y, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Lerch MM, Mayerle J, Tjaden C, Strobel O, Hackert T, Buchler MW, Neoptolemos JP; European Study Group for Pancreatic Cancer. Patterns of Recurrence After Resection of Pancreatic Ductal Adenocarcinoma: A Secondary Analysis of the ESPAC-4 Randomized Adjuvant Chemotherapy Trial. JAMA Surg. 2019 Nov 1;154(11):1038-1048. doi: 10.1001/jamasurg.2019.3337.
• Ghaneh P, Kleeff J, Halloran CM, Raraty M, Jackson R, Melling J, Jones O, Palmer DH, Cox TF, Smith CJ, O'Reilly DA, Izbicki JR, Scarfe AG, Valle JW, McDonald AC, Carter R, Tebbutt NC, Goldstein D, Padbury R, Shannon J, Dervenis C, Glimelius B, Deakin M, Anthoney A, Lerch MM, Mayerle J, Olah A, Rawcliffe CL, Campbell F, Strobel O, Buchler MW, Neoptolemos JP; European Study Group for Pancreatic Cancer. The Impact of Positive Resection Margins on Survival and Recurrence Following Resection and Adjuvant Chemotherapy for Pancreatic Ductal Adenocarcinoma. Ann Surg. 2019 Mar;269(3):520-529. doi: 10.1097/SLA.0000000000002557.

Study record dates

Study Major Dates

• Study Start: July 1, 2001
• Primary Completion (Actual): April 1, 2008
• Study Completion (Actual): September 1, 2010

Study Registration Dates

• First Submitted: April 7, 2003
• First Submitted That Met QC Criteria: April 8, 2003
• First Posted (Estimate): April 9, 2003

Study Record Updates

• Last Update Posted (Estimate): December 18, 2013
• Last Update Submitted That Met QC Criteria: December 17, 2013
• Last Verified: May 1, 2008

More Information

Terms related to this study

• Keywords: stage IV pancreatic cancer; stage III pancreatic cancer; acinar cell adenocarcinoma of the pancreas; duct cell adenocarcinoma of the pancreas; stage I pancreatic cancer; stage II 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Antidotes; Vitamin B Complex; Gemcitabine; Fluorouracil; Leucovorin; Calcium; Levoleucovorin
• Other Study ID Numbers: CDR0000287023; RLUH-NCRI-ESPAC-3V2; EU-20043; CAN-NCIC-PA2; AGITG-ESPAC-3