Clinical trial NCT00003216: Fluorouracil, Gemcitabine, and Radiation Therapy in Treating Patients With Cancer of the Pancreas
Official title: A Phase III Study of Pre and Post Chemoradiation 5-FU vs. Pre and Post Chemoradiation Gemcitabine for Postoperative Adjuvant Treatment of Resected Pancreatic Adenocarcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pancreatic Cancer
Keywords: stage I pancreatic cancer
stage II pancreatic cancer
stage III pancreatic cancer
adenocarcinoma of the pancreas
stage IV pancreatic cancer
Lead sponsor: Radiation Therapy Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
name: Eastern Cooperative Oncology Group
name: SWOG Cancer Research Network
First posted: 2003-01-27
Enrollment: 518
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining radiation therapy with chemotherapy may kill more tumor cells. It is not yet known which treatment regimen is most effective for pancreatic cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of fluorouracil and gemcitabine plus radiation therapy in treating patients with cancer of the pancreas who have undergone surgery.

Detailed description: OBJECTIVES:

* Compare the overall and disease-free survival of patients with resected adenocarcinoma of the pancreas treated with adjuvant fluorouracil-based chemoradiotherapy preceded and followed by fluorouracil vs gemcitabine.
* Compare the local-regional and distant disease control in patients treated with these regimens.
* Compare the acute and late toxic effects of these regimens in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to nodal involvement (yes vs no), tumor diameter (less than 3 cm vs 3 cm or greater), and surgical margins (negative vs positive vs unknown). Patients are randomized to one of two treatment arms.

* Arm I: Beginning 3-8 weeks after definitive surgical resection, patients receive fluorouracil IV continuously for 3 weeks. Beginning 1-2 weeks later, patients receive fluorouracil IV continuously concurrently with radiotherapy 5 days a week for 5.5 weeks. Beginning 3-5 weeks after completion of chemoradiotherapy, patients receive fluorouracil IV continuously for 4 weeks every 6 weeks for 2 courses.
* Arm II: Beginning 3-8 weeks after definitive surgical resection, patients receive gemcitabine IV once weekly for 3 weeks. Beginning 1-2 weeks later, patients receive chemoradiotherapy as in arm I. Beginning 3-5 weeks after completion of chemoradiotherapy, patients receive gemcitabine IV once weekly for 3 weeks every 4 weeks for 3 courses.

Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 518 patients will be accrued for this study within 8.6 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed adenocarcinoma of the pancreas

  * Stage T1-4, N0-1 (stage I-IVA)
  * No M1 or NX staging
  * Primary tumor of the pancreas (pancreatic head, neck, uncinate process, or body/tail) and maximum diameter/dimension and tumor status at surgical margin known
* Prior potentially curative gross resection within 3-8 weeks before study
* No non-adenocarcinomas, adenosquamous carcinomas, islet cell carcinomas, cystadenomas, cystadenocarcinomas, carcinoid tumors, duodenal carcinomas, distal bile duct carcinoma, or ampullary carcinoma
* No recurrent disease
* Post-resection CA-19-9 level required

PATIENT CHARACTERISTICS:

Age:

* 18 and over

Performance status:

* Karnofsky 60-100%

Life expectancy:

* Not specified

Hematopoietic:

* WBC at least 3,000/mm\^3
* Platelet count at least 100,000/mm\^3

Hepatic:

* Bilirubin no greater than 1.5 times upper limit of normal (ULN)
* SGOT no greater than 5 times ULN

Renal:

* Creatinine no greater than 1.5 times ULN

Other:

* No significant nausea or vomiting
* No prior malignancy within the past 5 years except nonmelanomatous skin cancer or carcinoma in situ of the cervix
* Able to maintain adequate nutrition (at least 1,500 calories/day)

  * Feeding tube allowed
* Not pregnant
* Negative pregnancy test
* Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* Not specified

Chemotherapy:

* No prior chemotherapy

Endocrine therapy:

* Not specified

Radiotherapy:

* No prior radiotherapy

Surgery:

* See Disease Characteristics

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham Comprehensive Cancer Center
state: Alabama
city: Mobile
country: United States
facility: MBCCOP - Gulf Coast
state: Alabama
city: Phoenix
country: United States
facility: CCOP - Greater Phoenix
state: Arizona
city: Phoenix
country: United States
facility: Veterans Affairs Medical Center - Phoenix (Carl T. Hayden)
state: Arizona
city: Tucson
country: United States
facility: Veterans Affairs Medical Center - Tucson
state: Arizona
city: Tucson
country: United States
facility: Arizona Cancer Center
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Little Rock
country: United States
facility: Veterans Affairs Medical Center - Little Rock (McClellan)
state: Arkansas
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center and Hospital
state: California
city: Los Angeles
country: United States
facility: Veterans Affairs Medical Center - West Los Angeles
state: California
city: Los Angeles
country: United States
facility: Jonsson Comprehensive Cancer Center, UCLA
state: California
city: Martinez
country: United States
facility: Veterans Affairs Outpatient Clinic - Martinez
state: California
city: Oakland
country: United States
facility: CCOP - Bay Area Tumor Institute
state: California
city: Orange
country: United States
facility: Chao Family Comprehensive Cancer Center
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: San Francisco
country: United States
facility: Veterans Affairs Medical Center - San Francisco
state: California
city: Santa Rosa
country: United States
facility: CCOP - Santa Rosa Memorial Hospital
state: California
city: Travis Air Force Base
country: United States
facility: David Grant Medical Center
state: California
city: Denver
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Denver
country: United States
facility: Veterans Affairs Medical Center - Denver
state: Colorado
city: Washington
country: United States
facility: MBCCOP - Howard University Cancer Center
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Atlanta
country: United States
facility: CCOP - Atlanta Regional
state: Georgia
city: Fort Gordon
country: United States
facility: Dwight David Eisenhower Army Medical Center
state: Georgia
city: Honolulu
country: United States
facility: Cancer Research Center of Hawaii
state: Hawaii
city: Honolulu
country: United States
facility: Tripler Army Medical Center
state: Hawaii
city: Chicago
country: United States
facility: Robert H. Lurie Comprehensive Cancer Center, Northwestern University
state: Illinois
city: Chicago
country: United States
facility: MBCCOP - University of Illinois at Chicago
state: Illinois
city: Chicago
country: United States
facility: Veterans Affairs Medical Center - Chicago (Westside Hospital)
state: Illinois
city: Decatur
country: United States
facility: CCOP - Central Illinois
state: Illinois
city: Hines
country: United States
facility: Veterans Affairs Medical Center - Hines (Hines Junior VA Hospital)
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Wichita
country: United States
facility: CCOP - Wichita
state: Kansas
city: Wichita
country: United States
facility: Veterans Affairs Medical Center - Wichita
state: Kansas
city: Lexington
country: United States
facility: Veterans Affairs Medical Center - Lexington
state: Kentucky
city: Lexington
country: United States
facility: Albert B. Chandler Medical Center, University of Kentucky
state: Kentucky
city: New Orleans
country: United States
facility: MBCCOP - LSU Medical Center
state: Louisiana
city: New Orleans
country: United States
facility: Tulane University School of Medicine
state: Louisiana
city: New Orleans
country: United States
facility: Veterans Affairs Medical Center - New Orleans
state: Louisiana
city: Shreveport
country: United States
facility: Louisiana State University Health Sciences Center - Shreveport
state: Louisiana
city: Shreveport
country: United States
facility: Veterans Affairs Medical Center - Shreveport
state: Louisiana
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Jamaica Plain
country: United States
facility: Veterans Affairs Medical Center - Boston (Jamaica Plain)
state: Massachusetts
city: Ann Arbor
country: United States
facility: Veterans Affairs Medical Center - Ann Arbor
state: Michigan
city: Ann Arbor
country: United States
facility: CCOP - Ann Arbor Regional
state: Michigan
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Detroit
country: United States
facility: Veterans Affairs Medical Center - Detroit
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Royal Oak
country: United States
facility: CCOP - Beaumont
state: Michigan
city: Southfield
country: United States
facility: Providence Hospital - Southfield
state: Michigan
city: Duluth
country: United States
facility: CCOP - Duluth
state: Minnesota
city: Biloxi
country: United States
facility: Veterans Affairs Medical Center - Biloxi
state: Mississippi
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Jackson
country: United States
facility: Veterans Affairs Medical Center - Jackson
state: Mississippi
city: Keesler AFB
country: United States
facility: Keesler Medical Center - Keesler AFB
state: Mississippi
city: Kansas City
country: United States
facility: Veterans Affairs Medical Center - Kansas City
state: Missouri
city: Kansas City
country: United States
facility: CCOP - Kansas City
state: Missouri
city: Saint Louis
country: United States
facility: St. Louis University Health Sciences Center
state: Missouri
city: Saint Louis
country: United States
facility: CCOP - St. Louis-Cape Girardeau
state: Missouri
city: Springfield
country: United States
facility: CCOP - Cancer Research for the Ozarks
state: Missouri
city: Billings
country: United States
facility: CCOP - Montana Cancer Consortium
state: Montana
city: Albuquerque
country: United States
facility: Veterans Affairs Medical Center - Albuquerque
state: New Mexico
city: Albuquerque
country: United States
facility: MBCCOP - University of New Mexico HSC
state: New Mexico
city: Albany
country: United States
facility: Veterans Affairs Medical Center - Albany
state: New York
city: Buffalo
country: United States
facility: Western New York Urology Associates
state: New York
city: New York
country: United States
facility: St. Vincents Comprehensive Cancer Center
state: New York
city: New York
country: United States
facility: Herbert Irving Comprehensive Cancer Center
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Winston-Salem
country: United States
facility: CCOP - Southeast Cancer Control Consortium
state: North Carolina
city: Cincinnati
country: United States
facility: Veterans Affairs Medical Center - Cincinnati
state: Ohio
city: Cincinnati
country: United States
facility: Barrett Cancer Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center
state: Ohio
city: Columbus
country: United States
facility: CCOP - Columbus
state: Ohio
city: Columbus
country: United States
facility: Arthur G. James Cancer Hospital - Ohio State University
state: Ohio
city: Dayton
country: United States
facility: Veterans Affairs Medical Center - Dayton
state: Ohio
city: Kettering
country: United States
facility: CCOP - Dayton
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma Medical Research Foundation
state: Oklahoma
city: Oklahoma City
country: United States
facility: Veterans Affairs Medical Center - Oklahoma City
state: Oklahoma
city: Portland
country: United States
facility: Veterans Affairs Medical Center - Portland
state: Oregon
city: Portland
country: United States
facility: CCOP - Columbia River Program
state: Oregon
city: Portland
country: United States
facility: Oregon Cancer Institute
state: Oregon
city: Charleston
country: United States
facility: Veterans Affairs Medical Center - Charleston
state: South Carolina
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Greenville
country: United States
facility: CCOP - Greenville
state: South Carolina
city: Spartanburg
country: United States
facility: CCOP - Upstate Carolina
state: South Carolina
city: Fort Sam Houston
country: United States
facility: Brooke Army Medical Center
state: Texas
city: Galveston
country: United States
facility: University of Texas Medical Branch
state: Texas
city: Houston
country: United States
facility: University of Texas - MD Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: Veterans Affairs Medical Center - Houston
state: Texas
city: Lubbock
country: United States
facility: Texas Tech University Health Science Center
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: San Antonio
country: United States
facility: Veterans Affairs Medical Center - San Antonio (Murphy)
state: Texas
city: Temple
country: United States
facility: Veterans Affairs Medical Center - Temple
state: Texas
city: Temple
country: United States
facility: CCOP - Scott and White Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Salt Lake City
country: United States
facility: Veterans Affairs Medical Center - Salt Lake City
state: Utah
city: Norfolk
country: United States
facility: Eastern Virginia Medical School
state: Virginia
city: Seattle
country: United States
facility: CCOP - Virginia Mason Research Center
state: Washington
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
city: Seattle
country: United States
facility: Veterans Affairs Medical Center - Seattle
state: Washington
city: Tacoma
country: United States
facility: CCOP - Northwest
state: Washington
city: Tacoma
country: United States
facility: Madigan Army Medical Center
state: Washington
city: Vancouver
country: Canada
facility: British Columbia Cancer Agency
state: British Columbia
Study officials:
affiliation: Lucille P. Markey Cancer Center at University of Kentucky
name: William F. Regine, MD
role: STUDY_CHAIR
affiliation: Robert H. Lurie Cancer Center
name: Al B. Benson, MD, FACP
role: STUDY_CHAIR
affiliation: Beth Israel Comprehensive Cancer Center - West Side Campus
name: John S. MacDonald, MD
role: STUDY_CHAIR
References:
citation: Abrams RA, Winter KA, Regine WF, Safran H, Hoffman JP, Lustig R, Konski AA, Benson AB, Macdonald JS, Rich TA, Willett CG. Failure to adhere to protocol specified radiation therapy guidelines was associated with decreased survival in RTOG 9704--a phase III trial of adjuvant chemotherapy and chemoradiotherapy for patients with resected adenocarcinoma of the pancreas. Int J Radiat Oncol Biol Phys. 2012 Feb 1;82(2):809-16. doi: 10.1016/j.ijrobp.2010.11.039. Epub 2011 Feb 1.
citation: Berger AC, Winter K, Hoffman JP, Regine WF, Abrams RA, Safran H, Freedman GM, Benson AB 3rd, Macdonald J, Willett CG. Five year results of US intergroup/RTOG 9704 with postoperative CA 19-9 </=90 U/mL and comparison to the CONKO-001 trial. Int J Radiat Oncol Biol Phys. 2012 Nov 1;84(3):e291-7. doi: 10.1016/j.ijrobp.2012.04.035. Epub 2012 Jun 9.
citation: Farrell JJ, Bae K, Wong J, Guha C, Dicker AP, Elsaleh H. Cytidine deaminase single-nucleotide polymorphism is predictive of toxicity from gemcitabine in patients with pancreatic cancer: RTOG 9704. Pharmacogenomics J. 2012 Oct;12(5):395-403. doi: 10.1038/tpj.2011.22. Epub 2011 May 31.
citation: Regine WF, Winter KA, Abrams R, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Rich TA, Willett CG. Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the U.S. Intergroup/RTOG 9704 phase III trial. Ann Surg Oncol. 2011 May;18(5):1319-26. doi: 10.1245/s10434-011-1630-6. Epub 2011 Mar 10.
citation: Showalter TN, Winter KA, Berger AC, Regine WF, Abrams RA, Safran H, Hoffman JP, Benson AB, MacDonald JS, Willett CG. The influence of total nodes examined, number of positive nodes, and lymph node ratio on survival after surgical resection and adjuvant chemoradiation for pancreatic cancer: a secondary analysis of RTOG 9704. Int J Radiat Oncol Biol Phys. 2011 Dec 1;81(5):1328-35. doi: 10.1016/j.ijrobp.2010.07.1993. Epub 2010 Oct 8.
citation: Tempero MA, Winter KA, Kim GE, et al.: S100A2 as a prognostic marker in patients receiving adjuvant therapy for pancreatic cancer (PC): A secondary analysis of RTOG 9704. [Abstract] J Clin Oncol 29 (Suppl 15): A-4118, 2011.
citation: Farrell J, Bae K, Guha C, et al.: Correlation of cytidine deaminase single nucleotide polymorphism and toxicity from gemcitabine in patients with pancreatic cancer from RTOG 9704. [Abstract] American Society of Clinical Oncology 2009 Gastrointestinal Cancers Symposium, 15-17 January 2009, San Francisco, CA. A-115, 2009.
citation: Farrell JJ, Elsaleh H, Garcia M, Lai R, Ammar A, Regine WF, Abrams R, Benson AB, Macdonald J, Cass CE, Dicker AP, Mackey JR. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology. 2009 Jan;136(1):187-95. doi: 10.1053/j.gastro.2008.09.067. Epub 2008 Oct 7.
citation: Piperdi B, Ng S, Piperdi M, et al.: Single institutional experience with oral capecitabine (Cap) in adjuvant therapy for pancreatic cancer: Gemcitabine (G) followed by Cap/RT followed by G. [Abstract] American Society of Clinical Oncology 2009 Gastrointestinal Cancers Symposium, 15-17 January 2009, San Francisco, CA. A-229, 2009.
citation: Berger AC, Garcia M Jr, Hoffman JP, Regine WF, Abrams RA, Safran H, Konski A, Benson AB 3rd, MacDonald J, Willett CG. Postresection CA 19-9 predicts overall survival in patients with pancreatic cancer treated with adjuvant chemoradiation: a prospective validation by RTOG 9704. J Clin Oncol. 2008 Dec 20;26(36):5918-22. doi: 10.1200/JCO.2008.18.6288. Epub 2008 Nov 24.
citation: Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. doi: 10.1001/jama.299.9.1019.
citation: Abrams RA, Winter KA, Regine WF, et al.: Correlation of RTOG 9704 (adjuvant therapy (rx) of pancreatic adenocarcinoma (pan ca)) radiation therapy quality assurance scores (RTQASc) with survival (S). [Abstract] J Clin Oncol 25 (Suppl 18): A-4523, 2007.
citation: Berger AC, Winter K, Hoffman J, et al.: Post-resection CA 19-9 predicts overall survival (OS) in patients treated with adjuvant chemoradiation: a secondary endpoint of RTOG 9704. [Abstract] J Clin Oncol 25 (Suppl 18): A-4522, 2007.
citation: Regine WF, Garcia M, Berger AC, et al.: Post-resectional CA 19-9 values >90 are associated with significantly worse survival in patients with pancreatic carcinoma treated with adjuvant therapy on RTOG 9704: implications for current and future trials. [Abstract] Int J Radiat Oncol Biol Phys 69 (3 Suppl): A-137, S78, 2007.
citation: Abrams RA, Winter KA, Regine WF, et al.: RTOG 9704: radiotherapy quality assurance (QA) review and survival. [Abstract] Int J Radiat Oncol Biol Phys 66 (3 Suppl 1): A-39, S22, 2006.
citation: Regine WF, Winter KA, Abrams R, et al.: A phase III intergroup trial (RTOG 97-04) of adjuvant pre and post chemoradiation (CRT) 5-FU vs. gemcitabine (G) for resected pancreatic adenocarcinoma. [Abstract] Int J Radiat Oncol Biol Phys 66 (3 Suppl 1): A-42, S23-4, 2006.
citation: Regine WF, Winter KW, Abrams R, et al.: RTOG 9704 a phase III study of adjuvant pre and post chemoradiation (CRT) 5-FU vs. gemcitabine (G) for resected pancreatic adenocarcinoma. [Abstract] J Clin Oncol 24 (Suppl 18): A-4007, 180s, 2006.
citation: Reyngold M, Winter KA, Regine WF, Abrams RA, Safran H, Hoffman JP, Mowat RB, Hayes JP, Kessel IL, DiPetrillo T, Narayan S, Chen Y, Ben-Josef E, Delouya G, Suh JH, Meyer J, Haddock MG, Feldman M, Gaur R, Yost K, Peterson RA, Sherr DL, Moughan J, Crane CH. Marital Status and Overall Survival in Patients with Resectable Pancreatic Cancer: Results of an Ancillary Analysis of NRG Oncology/RTOG 9704. Oncologist. 2020 Mar;25(3):e477-e483. doi: 10.1634/theoncologist.2019-0562. Epub 2019 Dec 16.
citation: Lawrence YR, Moughan J, Magliocco AM, Klimowicz AC, Regine WF, Mowat RB, DiPetrillo TA, Small W Jr, Simko JP, Golan T, Winter KA, Guha C, Crane CH, Dicker AP. Expression of the DNA repair gene MLH1 correlates with survival in patients who have resected pancreatic cancer and have received adjuvant chemoradiation: NRG Oncology RTOG Study 9704. Cancer. 2018 Feb 1;124(3):491-498. doi: 10.1002/cncr.31058. Epub 2017 Oct 20.