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NCI HIGH PRIORITY CLINICAL TRIAL --- Phase III Randomized Comparison of Four Systemic Regimens Combined with Pelvic Irradiation as Adjuvant Therapy for Totally Resected Stage II/III Adenocarcinoma of the Rectum: 5-FU vs 5-FU/CF vs 5-FU/LEV vs 5-FU/CF/LEV

Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentClosedover 18NCICLB-9081
CAN-NCIC-CO6, EST-4290, NCCTG-904751, RTOG-9014, SWOG-9040, INT-0114, CO6

Objectives

I.  Compare, in a Phase III Intergroup setting, local recurrence rates, 
probability of distant metastases, disease-free survival, and overall survival 
of patients with totally resected adenocarcinoma of the rectum randomly 
assigned to one of four systemic regimens, each combined with the same regimen 
of pelvic irradiation:  fluorouracil alone vs. fluorouracil/leucovorin vs. 
fluorouracil/levamisole vs. fluorouracil/leucovorin/levamisole.

Entry Criteria

Disease Characteristics:


Histologically documented adenocarcinoma of the rectum that
has undergone potentially curative en bloc resection with
neither gross nor microscopic evidence of disease

  Resection margins must be negative in case of adherent
  tumor

Poor prognosis must be indicated by either of the following:

  Pathologic evidence of extension through the muscularis
  propria into the subserosa or into nonperitonealized
  pericolic or perirectal tissue

  Pathologically proven regional nodal involvement, i.e.,
  modified Astler-Coller Stage B2, B3, or C or TNM Stage
  T3N0, T4N0, or N1-3

No evidence of distant metastasis, including even grossly
resected peritoneal metastases

Tumor must be of rectal and not colonic origin, i.e.,:

  Lower edge of the tumor mass must be below the peritoneal
  reflection, or a portion of the tumor must be defined as
  being retroperitoneal by the surgeon

  If the lower margin of the tumor is within 12 cm of the
  anal verge on proctoscopic examination, the tumor is
  defined as being of rectal origin unless it is found to
  lie entirely above the peritoneal reflection at surgery

Tumor extension to the dentate line or below excludes

No synchronous colon cancer allowed other than completely
resected modified Astler-Coller Stage A or B1 (TNM Stage I,
no nodal involvement or penetration beyond the muscularis
propria)


Prior/Concurrent Therapy:


Biologic therapy:
  No prior immunotherapy

Chemotherapy:
  No prior chemotherapy

Endocrine therapy:
  Not specified

Radiotherapy:
  No prior radiotherapy to the pelvis

Surgery:
  3-10 weeks since definitive surgery
  Recovery from surgery required


Patient Characteristics:


Age:
  Over 18

Performance status:
  CALGB (Zubrod) 0-2

Hematopoietic:
  WBC at least 4,000
  Platelets at least 130,000

Hepatic:
  Not specified

Renal:
  Not specified

Other:
  Adequate oral nutrition required
  No serious medical illness that would preclude protocol
    therapy
  No psychiatric condition that would preclude informed
    consent
  No active second malignancy within previous 5 years except:
    Nonmelanomatous skin cancer
    In situ cervical cancer
  No pregnant or lactating women
  Treatment must begin within 10 days of randomization


Expected Enrollment

1,752 patients will be entered in less than 4 years.

Outline

Randomized study.

Arm I:  Single-agent Chemotherapy followed by Radiotherapy with 
Radiosensitization followed by Single-agent Chemotherapy.  Fluorouracil, 5-FU, 
NSC-19893; followed by pelvic irradiation using linear accelerators with 
minimum energies of 4 MeV; with 5-FU; followed by 5-FU.

Arm II:  Single-agent Chemotherapy with Drug Modulation followed by 
Radiotherapy with Radiosensitization followed by Single-agent Chemotherapy 
with Drug Modulation.  5-FU; with Leucovorin calcium, Citrovorum Factor, CF, 
NSC-3590; followed by pelvic irradiation as in Arm I; with 5-FU and CF; 
followed by 5-FU; with CF.

Arm III:  Single-agent Chemotherapy plus Biological Response Modifier Therapy 
followed by Radiotherapy with Radiosensitization followed by Single-agent 
Chemotherapy plus Biological Response Modifier Therapy.  5-FU; plus 
Levamisole, LEV, NSC-177023; followed by pelvic irradiation as in Arm I; with 
5-FU; followed by 5-FU; plus LEV.

Arm IV:  Single-agent Chemotherapy with Drug Modulation plus Biological 
Response Modifier Therapy followed by Radiotherapy with Radiosensitization 
followed by Single-agent Chemotherapy with Drug Modulation plus Biological 
Response Modifier Therapy.  5-FU; with CF; plus LEV; followed by pelvic 
irradiation as in Arm I; with 5-FU and CF; followed by 5-FU; with CF; plus LEV.

Published Results

Meyers MO, Hollis DR, Mayer RJ, et al.: Ratio of metastatic to examined lymph nodes is a powerful predictor of overall survival in rectal cancer: an analysis of Intergroup 0114. [Abstract] J Clin Oncol 25 (Suppl 18): A-4006, 2007.

Meyerhardt JA, Tepper JE, Niedzwiecki D, et al.: Impact of body mass index on outcomes and treatment-related toxicity in patients with stage II and III rectal cancer: findings from Intergroup Trial 0114. J Clin Oncol 22 (4): 648-57, 2004.[PUBMED Abstract]

Meyerhardt JA, Tepper JE, Niedzwiecki D, et al.: Impact of hospital procedure volume on surgical operation and long-term outcomes in high-risk curatively resected rectal cancer: findings from the Intergroup 0114 Study. J Clin Oncol 22 (1): 166-74, 2004.[PUBMED Abstract]

Miller RC, Sargent DJ, Martenson JA, et al.: Acute diarrhea during adjuvant therapy for rectal cancer: a detailed analysis from a randomized intergroup trial. Int J Radiat Oncol Biol Phys 54 (2): 409-13, 2002.[PUBMED Abstract]

Tepper JE, O'Connell M, Donna H, et al.: Analysis of surgical salvage after failure of primary therapy in rectal cancer: results from INT 0114. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-507, 2002.

Tepper JE, O'Connell M, Niedzwiecki D, et al.: Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114. J Clin Oncol 20 (7): 1744-50, 2002.[PUBMED Abstract]

Tepper JE, O'Connell MJ, Niedzwiecki D, et al.: Final report of INT 0114: adjuvant therapy in rectal cancer: analysis by treatment, stage and gender. [Abstract] Proceedings of the American Society of Clinical Oncology 20: A-489, 123a, 2001.

Tepper JE, O'Connell MJ, Niedzwiecki D, et al.: Impact of number of nodes retrieved on outcome in patients with rectal cancer. J Clin Oncol 19 (1): 157-63, 2001.[PUBMED Abstract]

Tepper JE, O'Connell MJ, Petroni GR, et al.: Adjuvant postoperative fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of intergroup 0114. J Clin Oncol 15 (5): 2030-9, 1997.[PUBMED Abstract]

Tepper J, O'Connell M, Petroni G, et al.: Toxicity in the adjuvant therapy of rectal cancer: a preliminary report of Intergroup 0114 (CALGB 9081). [Abstract] Proceedings of the American Society of Clinical Oncology 15: A-481, 210a, 1996.

Related Publications

Stocchi L, Nelson H, Sargent DJ, et al.: Impact of surgical and pathologic variables in rectal cancer: a United States community and cooperative group report. J Clin Oncol 19 (18): 3895-902, 2001.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Cancer and Leukemia Group B

Joel Tepper, MD, Protocol chair
Ph: 919-445-5216
Email: tepper@med.unc.edu

Eastern Cooperative Oncology Group

Daniel Haller, MD, Protocol chair
Ph: 215-662-6318

Radiation Therapy Oncology Group

Leonard Gunderson, MD, Protocol chair
Ph: 480-301-7351
Email: gunderson.leonard@mayo.edu

Southwest Oncology Group

John MacDonald, MD, Protocol chair
Ph: 212-604-6011; 888-442-2623

North Central Cancer Treatment Group

Michael O'Connell, MD, Protocol chair (Contact information may not be current)
Ph: 507-284-2511

NCIC-Clinical Trials Group

Anthony Fields, MD, FRCPC, Protocol chair
Ph: 780-432-8756
Email: alaf@cancerboard.ab.ca

Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.

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