Chemotherapy, Radiation Therapy, and Surgery in Treating Patients With Locally Advanced Rectal Cancer

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00003799

Collaborator

(none)

Enrollment

Location

Arm

Study Details

Study Description

Brief Summary

Phase I trial to study the effectiveness of radiation therapy plus chemotherapy followed by surgery and additional chemotherapy in treating patients who have advanced nonmetastatic primary cancer of the rectum. 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 chemotherapy, radiation therapy, and surgery may be an effective treatment for rectal cancer

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of the Rectum Mucinous Adenocarcinoma of the Rectum 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	Drug: fluorouracil Drug: oxaliplatin Radiation: radiation therapy Drug: leucovorin calcium Procedure: therapeutic conventional surgery	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

To identify maximally tolerated dose (MTD) and dose limiting toxicity (DLT) of oxaliplatin when combined preoperatively with concurrent radiation therapy (XRT) and fluorouracil (5-FU) by PVI.
To evaluate the resection rate for T4 rectal cancers, the pathologic CR rate for T3 and T4 rectal cancers, and the expected versus actual type of resection (APR vs. LAR vs. LAR/coloanal anastomosis).
To make preliminary observations of patient survival and patterns of recurrence for this treatment combination.
To evaluate anastomotic and sphincter function following pre-op combined modality therapy.

OUTLINE: This is a dose-escalation study of preoperative oxaliplatin.

Patients receive fluorouracil IV continuously with concurrent radiotherapy for 5.5 weeks. Patients also receive oxaliplatin IV over 2 hours on day 1 of weeks 1, 3, and 5.

Cohorts of 5 patients each receive escalating doses of oxaliplatin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 5 patients experience dose-limiting toxicity. Additional patients are treated at the MTD.

Patients undergo surgery 6-8 weeks after completing preoperative chemotherapy and radiotherapy. The surgical procedure is determined by the extent of the tumor before preoperative therapy. The type of operative procedure may be abdominoperineal resection, low anterior resection (LAR), or LAR/coloanal anastomosis.

Postoperative chemotherapy begins within 6 weeks after surgery, comprising leucovorin calcium and fluorouracil IV on days 1-5. Treatment repeats every 21 days for 4 courses.

Patients are followed every 3 months for 2.5 years, every 6 months for 3 years, then annually for 5 years.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

20 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I Study of Preoperative Radiation Therapy With Concurrent Protracted Continuous Infusion 5-FU and Dose Escalating Oxaliplatin Followed by Surgery, 5-FU, and Leucovorin for Locally Advanced (T3 and T4) Rectal Adenocarcinoma

Study Start Date :

May 1, 1999

Actual Primary Completion Date :

Sep 1, 2003

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (chemotherapy, radiotherapy, surgery) Patients receive fluorouracil IV continuously with concurrent radiotherapy for 5.5 weeks. Patients also receive oxaliplatin IV over 2 hours on day 1 of weeks 1, 3, and 5. Patients undergo surgery 6-8 weeks after completing preoperative chemotherapy and radiotherapy. The surgical procedure is determined by the extent of the tumor before preoperative therapy. The type of operative procedure may be abdominoperineal resection, low anterior resection (LAR), or LAR/coloanal anastomosis. Postoperative chemotherapy begins within 6 weeks after surgery, comprising leucovorin calcium and fluorouracil IV on days 1-5. Treatment repeats every 21 days for 4 courses.	Drug: fluorouracil Given IV Other Names: 5-fluorouracil 5-Fluracil 5-FU Drug: oxaliplatin Given IV Other Names: 1-OHP Dacotin Dacplat Eloxatin L-OHP Radiation: radiation therapy Undergo radiotherapy Other Names: irradiation radiotherapy therapy, radiation Drug: leucovorin calcium Given IV Other Names: CF CFR LV Procedure: therapeutic conventional surgery Undergo surgery

Arm

Intervention/Treatment

Experimental: Treatment (chemotherapy, radiotherapy, surgery)

Patients receive fluorouracil IV continuously with concurrent radiotherapy for 5.5 weeks. Patients also receive oxaliplatin IV over 2 hours on day 1 of weeks 1, 3, and 5. Patients undergo surgery 6-8 weeks after completing preoperative chemotherapy and radiotherapy. The surgical procedure is determined by the extent of the tumor before preoperative therapy. The type of operative procedure may be abdominoperineal resection, low anterior resection (LAR), or LAR/coloanal anastomosis. Postoperative chemotherapy begins within 6 weeks after surgery, comprising leucovorin calcium and fluorouracil IV on days 1-5. Treatment repeats every 21 days for 4 courses.

Drug: fluorouracil

Given IV

Other Names:

5-fluorouracil

5-Fluracil

5-FU

Drug: oxaliplatin

Given IV

Other Names:

1-OHP

Dacotin

Dacplat

Eloxatin

L-OHP

Radiation: radiation therapy

Undergo radiotherapy

Other Names:

irradiation

radiotherapy

therapy, radiation

Drug: leucovorin calcium

Given IV

Other Names:

CFR

Procedure: therapeutic conventional surgery

Undergo surgery

Outcome Measures

Primary Outcome Measures

MTD of oxaliplatin when combined with radiation therapy and fluorouracil based on the incidence of DLT as assessed by CTC version 2.0 [5 weeks]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed, locally advanced, non-metastatic primary T3 or T4 primary adenocarcinoma of the rectum
No evidence of tumor outside of the pelvis including liver metastases, peritoneal seeding, or metastatic inguinal lymphadenopathy
No intra-operative radiotherapy (IORT) or brachytherapy will be allowed
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
Transmural penetration of tumor through the muscularis propria must be demonstrated by either of the following:
CT scan plus endorectal 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 mobile 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
Sciatica attributed to sacral root invasion with CT scan/MRI evidence of the lack of clear tissue plane will be considered evidence of fixation
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
ECOG performance status 0-2 and surgical evaluation confirms the patient's medical condition would tolerate the proposed surgical procedure
Caloric intake should be >= 1500 kilocalories/d
WBC >= 3500/uL
Platelets >= 100,000/uL
Serum creatinine =< 2.0 mg/dL
Serum bilirubin less than 2.0 mg/dL
Alk Phos =< 2 x ULN
SGOT =< 2 x ULN
CEA should be determined prior to initiation of therapy
Absence of clinical evidence of high-grade (lumen diameter < 1cm) large bowel obstruction, unless diverting colostomy has been performed
Pregnant or lactating women are not eligible
Women of childbearing potential and sexually active males are strongly advised to use an accepted and effective method of contraception
No prior chemotherapy or pelvic irradiation therapy
No previous or concurrent malignancy is allowed, except:
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
No active inflammatory bowel disease or other serious medical illness which might limit the ability of the patient to receive protocol therapy