S0304 Induct Chemo Then Chemo-RT in Pts w/Locally Advanced Adenocarcinoma of the Rectum

A Phase II Feasibility Translational Research Trial of Induction Chemotherapy Followed by Concomitant Chemoradiation in Patients With Clinical T4 Rectal Cancer

RATIONALE: Drugs used in chemotherapy, such as irinotecan, leucovorin, fluorouracil, 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. Combining radiation therapy with chemotherapy may kill more tumor cells.

PURPOSE: This phase II trial is studying how well different regimens of induction chemotherapy followed by chemoradiotherapy work in treating patients with locally advanced adenocarcinoma of the rectum.

Study Overview

• Status: Withdrawn
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: capecitabine; Drug: fluorouracil; Drug: irinotecan hydrochloride; Drug: leucovorin calcium; Radiation: radiation therapy; Drug: Pyridoxine; Drug: oxaliplatin

Detailed Description

OBJECTIVES:

• Determine the feasibility of obtaining a pre-treatment determination of intratumoral molecular markers (TS, DPD, and ERCC-1) for use in selection of the appropriate regimen for induction cytotoxic combination chemotherapy in patients with cT3-4 rectal adenocarcinoma.
• Determine the response probability (unconfirmed, complete and partial) in patients treated with targeted induction cytotoxic chemotherapy.
• Determine the toxicity of targeted induction cytotoxic chemotherapy and chemoradiotherapy in these patients.
• Determine the response probability in these patients treated with chemoradiotherapy.

OUTLINE: This is a multicenter study.

• Induction chemotherapy: Patients are assigned to 1 of 3 treatment groups based on molecular analysis of the pretreatment tumor specimen.

  • Group I (lower likelihood of resistance to a fluorouracil-based regimen): Patients receive irinotecan IV over 90 minutes and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV over 46 hours beginning on day 1.
  • Group II (higher likelihood of resistance to a fluorouracil-based regimen): Patients receive oxaliplatin IV over 2 hours and irinotecan IV over 90 minutes on day 1.
  • Group III (high likelihood of sensitivity to oxaliplatin and fluorouracil therapy): Patients receive oxaliplatin IV over 90 minutes and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV over 46 hours beginning on day 1.

Treatment in all groups repeats every 2 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

Patients are evaluated for response approximately 2 weeks after the completion of induction chemotherapy. Patients with stable disease or better receive chemoradiotherapy.

• Chemoradiotherapy: Beginning approximately 3 weeks after the completion of induction chemotherapy, patients receive oral capecitabine twice daily continuously for 5 weeks and concurrent radiotherapy once daily 5 days a week for 5 weeks.

After chemoradiotherapy, patients may undergo attempted surgical resection at the discretion of the treating physician.

Patients are followed every 3 months for 1 year and then every 6 months for 2 years.

PROJECTED ACCRUAL: A total of 10-65 patients will be accrued for this study.

• Study Type: Interventional
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed primary adenocarcinoma of the rectum

• Locally advanced disease (clinical T3-4, N0-2, M0) based on at least 1 of the following criteria:

  • Clinically fixed tumors on rectal examination with tumor adherent to the pelvic sidewall and/or sacrum
  • Sciatica attributed to sacral root invasion with CT scan/MRI evidence of the lack of clear tissue plane is considered evidence of fixation
  • Hydronephrosis on CT scan or intravenous pyelogram of ureteric or bladder invasion by cystoscopy and cytology or biopsy
  • Invasion into the prostate, vagina, or uterus
• Transmural penetration of tumor through the muscularis propria as evidenced by CT scan or MRI and endorectal ultrasound
• Distal border of the tumor must be at or below the peritoneal reflection (within 12 cm of the anal verge) by proctoscopic examination
• Measurable disease by x-ray, scans, or physical examination
• Available tumor tissue to determine molecular profile of the tumor before study treatment
• No clinical evidence of high-grade (lumen diameter < 1 cm) large bowel obstruction unless a diverting colostomy has been performed

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• Zubrod 0-2

Life expectancy

• Not specified

Hematopoietic

• WBC ≥ 3,500/mm^3
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥100,000/mm^3

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• SGOT or SGPT ≤ 2.5 times ULN
• Alkaline phosphatase ≤ 2.5 times ULN

Renal

• See Disease Characteristics
• Creatinine ≤ 1.5 times ULN OR
• Estimated creatinine clearance > 50 mL/min

Cardiovascular

• No significant cardiac disease
• No recent myocardial infarction

Gastrointestinal

• See Disease Characteristics
• Able to swallow oral medication
• No active inflammatory bowel disease

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• No prior unanticipated severe reaction to study drugs
• No known dihydropyrimidine dehydrogenase deficiency
• No serious uncontrolled infection
• No other serious medical illness that would preclude study treatment

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior chemotherapy for colon or rectal cancer

Endocrine therapy

• Not specified

Radiotherapy

• No prior pelvic radiotherapy
• No prior intra-operative radiotherapy or brachytherapy
• No concurrent intra-operative radiotherapy or brachytherapy
• No concurrent intensity-modulated radiotherapy

Surgery

• See Disease Characteristics
• See Radiotherapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Irinotecan + 5-FU + Leucovorin; Irinotecan 180mg/m2, IV for 90min on Day 1, q 2 wk x 4 cycles; 5-FU 400 mg/m2, IV bolus on Day 1, q 2 wk x 4 cycles; 5-FU 2.4 g/m2 IV for 46 hours on Day 1, q 2 wk x 4 cycles; Leucovorin 200 mg/m2 IV for 2 hours on Day 1, q 2 wk x4 cycles.	Drug: capecitabine; 825mg/m2 BID, PO, daily; Drug: fluorouracil; Bolus + IV for 46 hrs on Day 1; Drug: irinotecan hydrochloride; IV infusion over 90 min on Day 1; Drug: leucovorin calcium; 200mg/m2 IV 2 hour infusion on Day 1; Radiation: radiation therapy; Original Planning Target Volume (PTV1): The total dose to the prescription point shall be 4500 cGy in 25 fractions (Monday - Friday inclusive). Boost Planning Target Volume (PTV2): The cumulative dose within the boost volume to the prescription point shall be 5,040 - 5,400 cGy (per Section 7.5b). Daily Dose: The daily dose to the prescription point of the original and boost volumes shall be 180 cGy. Fractionation: Treatment shall be given 5 days/week. All radiation fields shall be treated once daily.; Drug: Pyridoxine; 50mg TID, PO daily
EXPERIMENTAL: Irinotecan + Oxaliplatin; Irinotecan 175mg/m2 IV for 90 minutes on Day 1, q 2wk x4 cycles; Oxaliplatin 85mg/m2 IV for 2 hours on Day 1, q 2wk x4 cycles	Drug: capecitabine; 825mg/m2 BID, PO, daily; Drug: irinotecan hydrochloride; IV infusion over 90 min on Day 1; Radiation: radiation therapy; Original Planning Target Volume (PTV1): The total dose to the prescription point shall be 4500 cGy in 25 fractions (Monday - Friday inclusive). Boost Planning Target Volume (PTV2): The cumulative dose within the boost volume to the prescription point shall be 5,040 - 5,400 cGy (per Section 7.5b). Daily Dose: The daily dose to the prescription point of the original and boost volumes shall be 180 cGy. Fractionation: Treatment shall be given 5 days/week. All radiation fields shall be treated once daily.; Drug: Pyridoxine; 50mg TID, PO daily; Drug: oxaliplatin; 85mg/m2 IV infusion for 90minutes on Day 1
EXPERIMENTAL: Oxaliplatin + 5-FU + Leucovorin; Oxaliplatin 85mg/m2 IV for 90 minutes on Day 1, q 2wk x4 cycles; 5-FU 400mg/m2 IV bolus on Day 1, q 2wk x4 cycles; 5-FU 2.4g/m2 IV for 46 hours on Day 1, q 2wk x4 cycles; Leucovorin 200mg/m2 IV for 2 hours on Day 1, q 2wk x4 cycles.	Drug: capecitabine; 825mg/m2 BID, PO, daily; Drug: fluorouracil; Bolus + IV for 46 hrs on Day 1; Drug: leucovorin calcium; 200mg/m2 IV 2 hour infusion on Day 1; Radiation: radiation therapy; Original Planning Target Volume (PTV1): The total dose to the prescription point shall be 4500 cGy in 25 fractions (Monday - Friday inclusive). Boost Planning Target Volume (PTV2): The cumulative dose within the boost volume to the prescription point shall be 5,040 - 5,400 cGy (per Section 7.5b). Daily Dose: The daily dose to the prescription point of the original and boost volumes shall be 180 cGy. Fractionation: Treatment shall be given 5 days/week. All radiation fields shall be treated once daily.; Drug: Pyridoxine; 50mg TID, PO daily; Drug: oxaliplatin; 85mg/m2 IV infusion for 90minutes on Day 1

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Response (confirmed and unconfirmed response, complete response, partial response)

Collaborators and Investigators

• Sponsor: Southwest Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Charles R. Thomas, MD, The University of Texas Health Science Center at San Antonio; Study Chair: Stephen R. Smalley, MD, Radiation Oncology Center of Olathe; Study Chair: Morton S. Kahlenberg, MD, The University of Texas Health Science Center at San Antonio

Study record dates

Study Major Dates

• Study Start: August 1, 2004
• Primary Completion (ACTUAL): February 1, 2006

Study Registration Dates

• First Submitted: October 3, 2003
• First Submitted That Met QC Criteria: October 6, 2003
• First Posted (ESTIMATE): October 7, 2003

Study Record Updates

• Last Update Posted (ESTIMATE): June 7, 2012
• Last Update Submitted That Met QC Criteria: June 5, 2012
• Last Verified: June 1, 2012

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 by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Adenocarcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Capecitabine; Oxaliplatin; Leucovorin; Irinotecan; Levoleucovorin; Pyridoxine
• Other Study ID Numbers: CDR0000334469; U10CA032102 (U.S. NIH Grant/Contract); S0304 (OTHER: SWOG)