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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: capecitabine
* Drug: fluorouracil
* Drug: irinotecan hydrochloride
* Drug: leucovorin calcium
* Drug: oxaliplatin
* Radiation: radiation therapy
* Drug: Pyridoxine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Irinotecan + 5-FU + Leucovorin<br>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<br>* 825mg/m2 BID, PO, daily<br>Drug: fluorouracil<br>* Bolus + IV for 46 hrs on Day 1<br>Drug: irinotecan hydrochloride<br>* IV infusion over 90 min on Day 1<br>Drug: leucovorin calcium<br>* 200mg/m2 IV 2 hour infusion on Day 1<br>Radiation: radiation therapy<br>* 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.<br>Drug: Pyridoxine<br>* 50mg TID, PO daily<br>|
| Experimental: Irinotecan + Oxaliplatin<br>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<br>* 825mg/m2 BID, PO, daily<br>Drug: irinotecan hydrochloride<br>* IV infusion over 90 min on Day 1<br>Drug: oxaliplatin<br>* 85mg/m2 IV infusion for 90minutes on Day 1<br>Radiation: radiation therapy<br>* 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.<br>Drug: Pyridoxine<br>* 50mg TID, PO daily<br>|
| Experimental: Oxaliplatin + 5-FU + Leucovorin<br>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<br>* 825mg/m2 BID, PO, daily<br>Drug: fluorouracil<br>* Bolus + IV for 46 hrs on Day 1<br>Drug: leucovorin calcium<br>* 200mg/m2 IV 2 hour infusion on Day 1<br>Drug: oxaliplatin<br>* 85mg/m2 IV infusion for 90minutes on Day 1<br>Radiation: radiation therapy<br>* 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.<br>Drug: Pyridoxine<br>* 50mg TID, PO daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response (confirmed and unconfirmed response, complete response, partial response) |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage II rectal cancer, stage III rectal cancer, adenocarcinoma of the rectum