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Intergroup Randomized Phase III Study of Postoperative Irinotecan, 5-Fluorouracil and Leucovorin vs. Oxaliplatin, 5-Fluorouracil and Leucovorin vs. 5-Fluorouracil and Leucovorin for Patients With Stage II or III Rectal Cancer Receiving Either Preoperative Radiation and 5-Fluorouracil or Postoperative Radiation and 5-Fluorouracil


Phase 3
18 Years
N/A
Not Enrolling
Both
Mucinous Adenocarcinoma of the Rectum, Recurrent Rectal Cancer, Signet Ring Adenocarcinoma of the Rectum, Stage IIA Rectal Cancer, Stage IIB Rectal Cancer, Stage IIC Rectal Cancer, Stage IIIA Rectal Cancer, Stage IIIB Rectal Cancer, Stage IIIC Rectal Cancer, Stage IVA Rectal Cancer, Stage IVB Rectal Cancer

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Trial Information

Intergroup Randomized Phase III Study of Postoperative Irinotecan, 5-Fluorouracil and Leucovorin vs. Oxaliplatin, 5-Fluorouracil and Leucovorin vs. 5-Fluorouracil and Leucovorin for Patients With Stage II or III Rectal Cancer Receiving Either Preoperative Radiation and 5-Fluorouracil or Postoperative Radiation and 5-Fluorouracil


PRIMARY OBJECTIVES:

I. To compare the overall survival of patients treated with irinotecan, 5-FU and leucovorin
versus those treated with oxaliplatin, leucovorin and 5-FU versus those treated with
leucovorin and 5-FU for patients with stage II and III rectal cancer.

SECONDARY OBJECTIVES:

I. To prospectively assess rectal function using the Patient Bowel Function/Uniscale
questionnaire and the FACT Diarrhea Subscale in patients treated with an adjuvant program of
pelvic radiation therapy and chemotherapy.

II. To correlate TS, DPD and TP expression (key targets for 5-FU); retention of chromosome
18q alleles and MSI with TGFβ1RII mutation (markers for 5-FU efficacy); ERCC1, ERCC2 and XPF
expression (participants in repair of adducts from oxaliplatin); and p53 gene mutation in
tumor tissue specimens with treatment efficacy.

III. To correlate tumor molecular prognostic markers (chromosome 18q allelic loss and MSI)
with survival.

IV. To determine physician preference in regard to the radiation-chemotherapy sequence in
the Intergroup.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to ECOG
performance status (0 vs 1), chemotherapy/radiotherapy sequence (preoperative vs
postoperative), and risk group (high risk [T3, N+, M0 or T4, any N, M0] vs low risk [T1-2,
N+, M0 or T3, N0, M0]). Patients are treated in 1 of 2 groups according to physician
preference and then randomized to 1 of 3 treatment arms.

GROUP I (preoperative chemoradiotherapy and additional adjuvant chemotherapy): Preoperative
chemoradiotherapy: Patients receive 1 of 3 treatment regimens, determined by the treating
physician.

REGIMEN A (radiotherapy and fluorouracil): Patients undergo external beam radiotherapy once
daily 5 days a week for 5 1/2 weeks (total of 28 fractions). Patients also receive
concurrent fluorouracil IV continuously 7 days a week for 5 1/2 weeks.

REGIMEN B (radiotherapy, fluorouracil, and leucovorin calcium): Patients undergo external
beam radiotherapy as in regimen A. Patients also receive concurrent fluorouracil IV and
leucovorin calcium IV continuously for 4 days on weeks 1 and 5.

REGIMEN C (radiotherapy and capecitabine)*: Patients undergo external beam radiotherapy as
in regimen A. Patients also receive concurrent oral capecitabine twice daily for 5 1/2
weeks.

NOTE: *Regimen C is allowed only for patients enrolled on protocol NSABP-R-04.

Surgery: Within 21-56 days after the completion of chemoradiotherapy, patients undergo
surgical resection.

Additional adjuvant chemotherapy: Within 21-56 days after complete surgical resection,
patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive irinotecan IV over 90 minutes 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.

ARM II: 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.

ARM III: 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.

In all arms, treatment continues in the absence of disease progression or unacceptable
toxicity.

GROUP 2 (postoperative chemoradiotherapy and additional adjuvant chemotherapy): Within 21-56
days after complete surgical resection, patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive irinotecan, leucovorin calcium, and fluorouracil as in group 1, arm
I for 4 courses.

ARM II: Patients receive oxaliplatin, leucovorin calcium, and fluorouracil as in group 1,
arm II for 4 courses.

ARM III: 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 chemoradiotherapy 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.

Patients are followed every 3 months for 3 years, every 6 months for 2 years, and then
annually for 5 years.


Inclusion Criteria:



- GROUP I: Patients must have histologically proven adenocarcinoma of the rectum with
no distant metastases; clinical staging is required (T3N0M0, T4N0M0, TanyN1-3M0)

- GROUP I: Patients must not have evidence of tumor outside of the pelvis including
liver metastases, peritoneal seeding, or metastatic inguinal lymphadenopathy

- GROUP I: Patients must have ECOG performance status 0-1

- GROUP I: The distal border of the tumor must be 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 surgery are eligible regardless
of the distance determined by endoscopy

- GROUP I: Transmural penetration of tumor through the muscularis propria must be
demonstrated by CT scan, endo-rectal ultrasound or MRI

- GROUP I: 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

- GROUP I: 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

- GROUP I: Patients must not have received prior chemotherapy or pelvic irradiation
therapy

- GROUP I: 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 more than five years

- GROUP I: Patients must not have an active inflammatory bowel disease or other serious
medical illness which might limit the ability of the patient to receive protocol
therapy

- GROUP I: Female patients must not be pregnant or breast-feeding; all females of
childbearing potential must have a blood or urine test within 2 weeks prior to
registration to rule out pregnancy

- GROUP I: Sexually-active women of childbearing potential and sexually active males
are strongly advised to use an accepted and effective method of contraception

- GROUP II: Patients must have had histologically proven adenocarcinoma of the rectum
with no distant metastases; pathologic staging is required (T3N0M0, T4N0M0,
TanyN1-3M0)

- GROUP II: Patients must not have evidence of tumor outside of the pelvis including
liver metastases, peritoneal seeding, or metastatic inguinal lymphadenopathy

- GROUP II: Patients must have ECOG performance status 0-1

- GROUP II: 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

- GROUP II: Patients must not have received prior chemotherapy or pelvic irradiation
therapy

- GROUP II: 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 more than five years

- GROUP II: Patients must not 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: Female patients must not be pregnant or breast-feeding because of the
potentially teratogenic and abortifacient effects of this regimen and there is no
information on the excretion of the agents or their metabolites into breast milk; all
females of childbearing potential must have a blood or urine test within 2 weeks
prior to registration to rule out pregnancy

- GROUP II: Sexually active women of childbearing potential and sexually active males
are strongly advised to use an accepted and effective method of contraception

- RANDOMIZATION: Patients must have a completely resected tumor and be within 21 - 56
days from the date of surgery

- RANDOMIZATION: Patients who received combination chemotherapy/radiation prior to
randomization (Group I) must have had a minimum radiation dose of 50.4 Gy

- RANDOMIZATION: Patients must have ECOG performance status 0-1

- RANDOMIZATION: Creatinine =< 1.5 x ULN obtained =< 4 weeks prior to randomization

- RANDOMIZATION: Bilirubin =< 1.5 x ULN

- RANDOMIZATION: SGOT (AST) =< 3 x ULN obtained =< 4 weeks prior to randomization

- RANDOMIZATION: Absolute neutrophil count >= 1500/mm3

- RANDOMIZATION: Platelet count >= 100,000/mm3 =< 4 weeks prior to randomization

- RANDOMIZATION: Patients must not have an active inflammatory bowel disease or other
serious medical illness which might limit the ability of the patient to receive
protocol therapy

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall survival

Outcome Time Frame:

3 years

Safety Issue:

No

Principal Investigator

Al Benson

Investigator Role:

Principal Investigator

Investigator Affiliation:

Eastern Cooperative Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-02959

NCT ID:

NCT00068692

Start Date:

October 2003

Completion Date:

Related Keywords:

  • Mucinous Adenocarcinoma of the Rectum
  • Recurrent Rectal Cancer
  • Signet Ring Adenocarcinoma of the Rectum
  • Stage IIA Rectal Cancer
  • Stage IIB Rectal Cancer
  • Stage IIC Rectal Cancer
  • Stage IIIA Rectal Cancer
  • Stage IIIB Rectal Cancer
  • Stage IIIC Rectal Cancer
  • Stage IVA Rectal Cancer
  • Stage IVB Rectal Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Rectal Neoplasms
  • Cystadenocarcinoma

Name

Location

Eastern Cooperative Oncology GroupBoston, Massachusetts  02215