Comparison of Adjuvant Chemotherapy Regimens in Treating Stage II/III Rectal Cancer

NCT00068692 | Completed Phase 3 Results DMC FDA Drug

• 3 other identifiers: NCI-2012-02959E3201U10CA021115
• Study Type: interventional
• Target: 225
• Locations: 1 country
• Sites: 1

Brief Summary

This randomized phase III trial is comparing the effectiveness of three adjuvant combination chemotherapy regimens in treating patients who are receiving radiation therapy and fluorouracil either before or after surgery for stage II or stage III rectal cancer. Drugs used in chemotherapy, such as irinotecan, fluorouracil, leucovorin, and oxaliplatin, 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. It is not yet known which adjuvant combination chemotherapy regimen is more effective in treating patients who are receiving radiation therapy and fluorouracil either before or after surgery for rectal cancer.

Conditions

Rectal Mucinous Adenocarcinoma; Rectal Signet Ring Cell Adenocarcinoma; Recurrent Rectal Carcinoma; Stage IIA Rectal Cancer AJCC v7; Stage IIB Rectal Cancer AJCC v7; Stage IIC Rectal Cancer AJCC v7; Stage IIIA Rectal Cancer AJCC v7; Stage IIIB Rectal Cancer AJCC v7; Stage IIIC Rectal Cancer AJCC v7; Stage IVA Rectal Cancer AJCC v7; Stage IVB Rectal Cancer AJCC v7

Keywords

rectal cancer; chemotherapy; irinotecan; oxaliplatin

Outcome Measures

Primary Outcomes (1)

• 3-year Overall Survival Rate

  Overall survival (OS) was defined as time from randomization to death from any cause. 3-year OS rate was estimated using Kaplan-Meier method.

  assessed every 3 months withihn 2 years of study entry, every 6 monhts between years 3-5 and then annually for 5 years, estimated at 3 years

Secondary Outcomes (3)

• 3-year Disease Free Survival

  assessed every 3 months withihn 2 years of study entry, every 6 monhts between years 3-5 and then annually for 5 years, estimated at 3 years

• Proportion of Sphincter Preservation

  assessed at primary surgery time

• Failure Pattern

  assessed every 3 months withihn 2 years of study entry, every 6 monhts between years 3-5 and then annually for 5 years

Study Arms (6)

Group I, Arm I

EXPERIMENTAL

Patients receive 1 of 3 preoperative chemo and radiotherapy treatment regimens, determined by the treating physician. Within 21-56 days after the completion of chemoradiotherapy, patients undergo surgical resection. Patients receive irinotecan IV over 90 minutes and leucovorin calcium IV over 2 hours followed immediately by fluorourcil IV bolus on day 1. Treatment continues in the absence of disease progression or unacceptable toxicity.

Radiation: Radiotherapy; Drug: Fluorouracil; Drug: Leucovorin Calcium; Drug: Irinotecan

Group I, Arm II

EXPERIMENTAL

Patients receive 1 of 3 preoperative chemo and radiotherapy treatment regimens, determined by the treating physician. Within 21-56 days after the completion of chemoradiotherapy, patients undergo surgical resection. Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours followed immediately by fluorourcil IV bolus on day 1. Patients also receive fluorouracil IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 8 courses. Treatment continues in the absence of disease progression or unacceptable toxicity.

Radiation: Radiotherapy; Drug: Fluorouracil; Drug: Leucovorin Calcium; Drug: Oxaliplatin

Group I, Arm III

EXPERIMENTAL

Patients receive 1 of 3 preoperative chemo and radiotherapy treatment regimens, determined by the treating physician. Within 21-56 days after the completion of chemoradiotherapy, patients undergo surgical resection. Patients receive leucovorin calcium IV over 2 hours and fluorouracil IV over 1 hour on days 1, 8, 15, 22, 29, and 36. Treatment repeats every 8 weeks for 3 courses. Treatment continues in the absence of disease progression or unacceptable toxicity.

Radiation: Radiotherapy; Drug: Fluorouracil; Drug: Leucovorin Calcium

Group II, Arm I

EXPERIMENTAL

Patients receive irinotecan, leucovorin calcium, and fluorouracil as in group 1, arm I for 4 courses. Within 4 weeks after the completion of chemotherapy, all patients undergo concurrent pelvic chemoradiotherapy as described in group 1 preoperative chemo and radiotherapy Regimen A, B, or C, followed 4-6 weeks later by 4 additional courses of adjuvant chemotherapy for arms I and II and 2 additional courses of adjuvant chemotherapy for arm III. Treatment continues in the absence of disease progression or unacceptable toxicity.

Radiation: Radiotherapy; Drug: Fluorouracil; Drug: Leucovorin Calcium; Drug: Irinotecan

Group II, Arm II

EXPERIMENTAL

Patients receive oxaliplatin, leucovorin calcium, and fluorouracil as in group 1, arm II for 4 courses. Within 4 weeks after the completion of chemotherapy, all patients undergo concurrent pelvic chemoradiotherapy as described in group 1 preoperative chemo and radiotherapy Regimen A, B, or C, followed 4-6 weeks later by 4 additional courses of adjuvant chemotherapy for arms I and II and 2 additional courses of adjuvant chemotherapy for arm III. Treatment continues in the absence of disease progression or unacceptable toxicity.

Radiation: Radiotherapy; Drug: Fluorouracil; Drug: Leucovorin Calcium; Drug: Oxaliplatin

Group II, Arm III

EXPERIMENTAL

Patients receive leucovorin calcium and fluorouracil as in group 1, arm III for 1 course. Within 4 weeks after the completion of chemotherapy, all patients undergo concurrent pelvic chemoradiotherapy as described in group 1 preoperative chemo and radiotherapy Regimen A, B, or C, followed 4-6 weeks later by 4 additional courses of adjuvant chemotherapy for arms I and II and 2 additional courses of adjuvant chemotherapy for arm III. Treatment continues in the absence of disease progression or unacceptable toxicity.

Radiation: Radiotherapy; Drug: Fluorouracil; Drug: Leucovorin Calcium

Interventions

Radiotherapy RADIATION

Undergo external beam radiation therapy

Also known as: Definitive Radiation Therapy, EBRT, External Beam Radiotherapy, external radiation

Group I, Arm I; Group I, Arm II; Group I, Arm III; Group II, Arm I; Group II, Arm II; Group II, Arm III

Fluorouracil DRUG

Given IV

Also known as: Efudex, 5-FU, 5-Fluorouracil, Adrucil

Group I, Arm I; Group I, Arm II; Group I, Arm III; Group II, Arm I; Group II, Arm II; Group II, Arm III

Leucovorin Calcium DRUG

Given IV

Also known as: Leucovorin, Wellcovorin, citrovorun factor, folinic acid, LV, LCV, 5-formyl tetrahydrofolate

Group I, Arm I; Group I, Arm II; Group I, Arm III; Group II, Arm I; Group II, Arm II; Group II, Arm III

Oxaliplatin DRUG

Given IV

Also known as: 1-OHP, Dacplat, Eloxatin, Eloxatine, Trans-l-diaminocyclohexane oxalatoplatinum, Cis-[oxalato (trans-I-1 ,2-diaminocyclohexane) platinum(lI)], cis -[(1R,2R)-1,2-cyclohexanediamine- N,N'] [oxalate(2-)- 0,0'] platinum

Group I, Arm II; Group II, Arm II

Irinotecan DRUG

Given IV

Also known as: Camptosar, CPT-11, Camptothecin-11

Group I, Arm I; Group II, Arm I

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically proven adenocarcinoma of the rectum with no distant metastases. Clinical staging is required (T3N0M0, T4N0M0, TanyN1-3M0).
• Patients must not have evidence of tumor outside of the pelvis including liver metastases, peritoneal seeding, or metastatic inguinal lymphadenopathy.
• The distal border of the tumor must be at or below the peritoneal reflection, defined as within 12 cm of anal verge by proctoscopic examination. In addition, patients who have had a portion of their tumors confirmed to be below the peritoneal reflection at the time of surgery are eligible regardless of the distance determined by endoscopy.
• Transmural penetration of tumor through the muscularis propria must be demonstrated by CT scan, endo-rectal ultrasound or MRI.
• Tumors must be defined prospectively by the surgeon as clinically resectable or not.
• Clinically resectable tumors will be defined by the surgeon as not fixed and completely resectable with negative margins based on the routine examination of the non-anesthetized patient.
• Before pre-op treatment, the surgeon should estimate and record the type of resection anticipated: APR, LAR or LAR/coloanal anastomosis.
• The tumor may be clinically fixed or initially not completely resectable, clinical stage T4 N0-2 M0 based on the presence of at least one of the following criteria:
• Clinically fixed tumors on rectal examination with tumor adherent to the pelvic sidewall or sacrum.
• Hydronephrosis on CT scan or IVP or ureteric or bladder invasion as documented by cystoscopy and cytology or biopsy, or invasion into prostate.
• Vaginal or uterine involvement.
• Patients must not have a previous or concurrent malignancy, with the exception of:
• Nonmelanoma skin cancer or in situ cervical cancer.
• Treated non-pelvic cancer from which the patient has been continuously disease-free for \>5 years.
• Patients must have ECOG performance status 0-1.

You may not qualify if:

• Patients have received prior chemotherapy or pelvic irradiation therapy.
• Female patients must not be pregnant or breast-feeding.
• Patients have an active inflammatory bowel disease or other serious medical illness which might limit the ability of the patient to receive protocol therapy.
• Group II (Post-operative) Registration
• Patients must have had histologically proven adenocarcinoma of the rectum with no distant metastases. Pathologic staging is required (T3N0M0, T4N0M0, TanyN1-3M0).
• Patients must not have evidence of tumor outside of the pelvis including liver metastases, peritoneal seeding, or metastatic inguinal lymphadenopathy.
• The distal border of the tumor must have been at or below the peritoneal reflection, defined as within 12 centimeters of anal verge by proctoscopic examination. In addition, patients who have had a portion of their tumors confirmed to be below the peritoneal reflection at the time of the surgery are eligible regardless of the distance determined by endoscopy.
• Patients must not have received prior chemotherapy or pelvic irradiation therapy.
• Patients must not have a previous or concurrent malignancy, with the exception of:
• Non-melanoma skin cancer or in situ cervical cancer.
• Treated non-pelvic cancer from which the patient has been continuously disease-free for \>5 years.
• Patients must have ECOG performance status 0-1.
• Patients must be \> 18 years of age.
• All females of childbearing potential must have a blood or urine test within 2 weeks prior to registration to rule out pregnancy.
• Sexually active women of childbearing potential and sexually active males are strongly advised to use an accepted and effective method of contraception.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

Eastern Cooperative Oncology Group

Boston, Massachusetts, 02215, United States

Location

Related Publications (1)

• Kam AE, Zhao F, Meropol NJ, Giantonio BJ, Diasio RB, Flynn PJ, Catalano P, Hartner L, Rowland KM, Song W, Mulcahy MF, Sinicrope FA, Whitehead RP, Mayer RJ, Petrelli N, O'Dwyer PJ, Hamilton SR, Cella D, Benson AB. Intergroup randomized phase III study of adjuvant FOLFIRI, FOLFOX, or 5-FU/leucovorin for stage II/III rectal cancer: ECOG-ACRIN E3201. Oncologist. 2025 Dec 27;31(1):oyaf416. doi: 10.1093/oncolo/oyaf416.

  PMID: 41397917 DERIVED

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

Radiotherapy; Fluorouracil; Leucovorin; Oxaliplatin; Platinum; Irinotecan

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Therapeutics; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Coordination Complexes; Organic Chemicals; Metals, Heavy; Elements; Inorganic Chemicals; Transition Elements; Metals; Camptothecin; Alkaloids

Results Point of Contact

• Title: Statistician
• Organization: ECOG-ACRIN statistical office

eatrials@jimmy.harvard.edu

Study Officials

• Al Benson

  Eastern Cooperative Oncology Group

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 10, 2003
• First Posted: September 11, 2003
• Study Start: October 15, 2003
• Primary Completion: November 15, 2016
• Study Completion: November 15, 2016
• Last Updated: December 4, 2018
• Results First Posted: December 4, 2018

Record last verified: 2018-12

Data Sharing

• IPD Sharing: Will share

Locations

US (1)