Radiation Therapy With or Without Chemotherapy Before Surgery in Treating Patients With Stage II or Stage III Rectal Cancer

Preoperative Radiotherapy With or Without Concurrent Chemotherapy (5-Fluorouracil and Leucovorin) in T3-4 Rectal Cancers - Randomized Trial

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as fluorouracil and leucovorin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy and chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving chemotherapy after surgery may kill any tumor cells that remain after surgery. It is not yet known whether radiation therapy is more effective with or without chemotherapy when given before surgery for rectal cancer.

PURPOSE: This randomized phase III trial is studying radiation therapy given together with fluorouracil and leucovorin to see how well they work compared to giving radiation therapy alone before surgery in treating patients with stage II or stage III rectal cancer.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: fluorouracil; Drug: leucovorin calcium; Radiation: radiation therapy; Procedure: conventional surgery

Detailed Description

OBJECTIVES:

• Compare the recurrence-free and overall survival of patients with resectable stage II or III adenocarcinoma of the rectum treated with neoadjuvant radiotherapy with or without concurrent chemotherapy comprising fluorouracil and leucovorin calcium followed by surgery and adjuvant fluorouracil and leucovorin calcium.

OUTLINE: This is a randomized, controlled, multicenter study. Patients are stratified according to participating center, gender, location of the tumor relative to the anal margin (0-5 cm vs > 5 cm), and tumor stage (T3 vs T4). Patients are randomized to 1 of 2 treatment arms.

• Neoadjuvant therapy: Patients are randomized to 1 of 2 neoadjuvant therapy arms.

  • Arm I: Patients receive leucovorin calcium IV and fluorouracil IV over 15 minutes on days 1-5. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients also undergo concurrent radiotherapy 5 days a week for 5 weeks.
  • Arm II: Patients undergo radiotherapy as in arm I.
• Surgery: In both arms, patients undergo surgical resection within 3-10 weeks after completing neoadjuvant therapy.
• Adjuvant therapy: Within 3-10 weeks after surgery, all patients receive adjuvant chemotherapy comprising leucovorin calcium IV and fluorouracil IV over 15 minutes on days 1-5. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 6 months for at least 5 years.

PROJECTED ACCRUAL: A total of 762 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 762
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the rectum meeting 1 of the following stage criteria:

  • Stage T3, N0-2, M0 disease meeting 1 of the following criteria:

    • Invasive disease in entire circumference (circular tumor)
    • Tumor fixed laterally or posteriorly to pelvic structures
    • Tumor adherent to the prostate and/or seminal vesicles
    • Tumor infiltration into the vaginal-rectal septum
    • Tumor classified as uT3 by rectal endoscopy

  • Stage T4, N0-2, M0 disease meeting 1 of the following criteria:

    • Clinical or radiologic evidence of pelvic organ extension (vagina, prostate, seminal vesicles, or bladder)
    • Tumor extension to the anal canal or sphincter
    • Tumor classified as uT4 by rectal endoscopy
• Tumor accessible by digital rectal exam
• Resectable disease
• No distant metastases

PATIENT CHARACTERISTICS:

• WHO performance status 0-1
• Creatinine < 1.36 mg/dL
• Granulocyte count > 2,000/mm^3
• Platelet count > 130,000/mm^3
• No progressive ischemic cardiomyopathy
• No acute or chronic obstruction unless treated with diversion colostomy
• No chronic inflammation of the ileum and/or colon
• No other prior or concurrent malignancy except basal cell skin cancer or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy, radiotherapy, or surgery for this cancer

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Radiotherapy; RT was delivered with photons from a linear accelerator with an energy level of 8MVor above.	Radiation: radiation therapy; Procedure: conventional surgery
Experimental: Chemotherapy and radiotherapy; The first CT cycle was administered from days 1 to 5 of the RT treatment. LV 20 mg/m2/d was delivered intravenously immediately before administration of FU. FU 350 mg/m2/d was delivered during 20 minutes in 100 mL of saline infusion, 1 hour before RT. The second cycle was administered from days 29 to 33 of the RT treatment using the same schedule.	Drug: fluorouracil; Drug: leucovorin calcium; Radiation: radiation therapy; Procedure: conventional surgery

Collaborators and Investigators

• Sponsor: Federation Francophone de Cancerologie Digestive
• Investigators: Study Chair: Jean-Pierre Gerard, MD, Centre Antoine Lacassagne

Publications and helpful links

General Publications

• Bonnetain F, Bosset JF, Gerard JP, Calais G, Conroy T, Mineur L, Bouche O, Maingon P, Chapet O, Radosevic-Jelic L, Methy N, Collette L. What is the clinical benefit of preoperative chemoradiotherapy with 5FU/leucovorin for T3-4 rectal cancer in a pooled analysis of EORTC 22921 and FFCD 9203 trials: surrogacy in question? Eur J Cancer. 2012 Aug;48(12):1781-90. doi: 10.1016/j.ejca.2012.03.016. Epub 2012 Apr 14.
• Methy N, Bedenne L, Conroy T, Bouche O, Chapet O, Ducreux M, Gerard JP, Bonnetain F. Surrogate end points for overall survival and local control in neoadjuvant rectal cancer trials: statistical evaluation based on the FFCD 9203 trial. Ann Oncol. 2010 Mar;21(3):518-524. doi: 10.1093/annonc/mdp340. Epub 2009 Sep 16.
• Methy N, Bedenne L, Gerard J, et al.: Surrogate endpoints in neoadjuvant rectal cancer trials: statistical evaluation using data from the FFCD 9203 trial. [Abstract] American Society of Clinical Oncology 2008 Gastrointestinal Cancers Symposium, 25-27 January 2008, Orlando, FL. A-466, 2008.
• Gerard JP, Conroy T, Bonnetain F, Bouche O, Chapet O, Closon-Dejardin MT, Untereiner M, Leduc B, Francois E, Maurel J, Seitz JF, Buecher B, Mackiewicz R, Ducreux M, Bedenne L. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol. 2006 Oct 1;24(28):4620-5. doi: 10.1200/JCO.2006.06.7629.
• Gerard J, Romestaing P, Bonnetain F, et al.: Preoperative chemotherapy (CT-RT) improves local control in T3-4 rectal cancers: results of the FFCD 9203 randomized trial. [Abstract] Int J Radiat Oncol Biol Phys 63 (2 Suppl 1): A-4, S2, 2005.

Study record dates

Study Major Dates

• Study Start: April 1, 1993
• Primary Completion (Actual): August 1, 2008
• Study Completion (Actual): August 1, 2008

Study Registration Dates

• First Submitted: February 24, 2006
• First Submitted That Met QC Criteria: February 24, 2006
• First Posted (Estimate): February 27, 2006

Study Record Updates

• Last Update Posted (Estimate): May 30, 2016
• Last Update Submitted That Met QC Criteria: May 27, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: adenocarcinoma of the rectum; stage II rectal cancer; stage III rectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Antidotes; Vitamin B Complex; Fluorouracil; Leucovorin; Calcium; Levoleucovorin
• Other Study ID Numbers: CDR0000466625; FFCD-9203; EU-20600