Radiation Therapy Oncology Group 0247: A Randomized Phase II Study of Neoadjuvant Capecitabine and Irinotecan or Capecitabine and Oxaliplatin With Concurrent Radiotherapy for Patients With Locally Advanced Rectal Cancer

doi:10.1016/j.ijrobp.2011.05.027

International Journal of Radiation OncologyBiologyPhysics

Volume 82, Issue 4, 15 March 2012, Pages 1367-1375

https://doi.org/10.1016/j.ijrobp.2011.05.027 Get rights and content

Purpose

To evaluate the rate of pathologic complete response (pCR) and the toxicity of two neoadjuvant chemoradiotherapy (chemoRT) regimens for Stage T3-T4 rectal cancer in a randomized Phase II study.

Methods and Materials

Patients with Stage T3 or T4 rectal cancer of <12 cm from the anal verge were randomized to preoperative RT (50.4 Gy in 1.8-Gy fractions) with concurrent capecitabine (1,200 mg/m²/d Mondays through Friday) and irinotecan (50 mg/m² weekly in four doses) (Arm 1) or concurrent capecitabine (1,650 mg/m²/d Monday through Friday) and oxaliplatin (50 mg/m² weekly in five doses) (Arm 2). Surgery was performed 4–8 weeks after chemoRT, and adjuvant chemotherapy 4–6 weeks after surgery. The primary endpoint was the pCR rate, requiring 48 evaluable patients per arm.

Results

A total of 146 patients were enrolled. The protocol chemotherapy was modified because of excessive gastrointestinal toxicity after treatment of 35 patients; 96 were assessed for the primary endpoint—the final regimen described above. The patient characteristics were similar for both arms. After chemoRT, the rate of tumor downstaging was 52% and 60% and the rate of nodal downstaging (excluding N0 patients) was 46% and 40%, for Arms 1 and 2, respectively. The pCR rate for Arm 1 was 10% and for Arm 2 was 21%. For Arm 1 and 2, the preoperative chemoRT rate of Grade 3-4 hematologic toxicity was 9% and 4% and the rate of Grade 3-4 nonhematologic toxicity was 26% and 27%, respectively.

Conclusions

Preoperative chemoRT with capecitabine plus oxaliplatin for distal rectal cancer has significant clinical activity (10 of 48 pCRs) and acceptable toxicity. This regimen is currently being evaluated in a Phase III randomized trial (National Surgical Adjuvant Breast and Bowel Project R04).

Introduction

Adenocarcinoma of the rectum is a common disease with >40,000 cases diagnosed each year in the United States (1). Despite the potentially high rate of curability with combined modality therapy, some patients experience significant treatment-associated morbidity, and other patients develop locoregional failure or distant metastasis. In addition to achieving cure, sphincter preservation is an important goal of therapy. Improvements in clinical outcome have been realized with wide acceptance of continuous infusion 5-fluorouracil (5-FU)–based neoadjuvant chemoradiotherapy (chemoRT) and the use of total mesorectal excision.

The results of large randomized trials comparing neoadjuvant pelvic radiotherapy (RT) alone versus RT plus concurrent 5-FU have demonstrated improvement in locoregional disease control with the addition of concurrent chemotherapy 2, 3. Attempts to improve on this approach have focused primarily on testing new agents added to the backbone of 5-FU plus RT to enhance the pathologic complete response (pCR) rate. Drugs with high activity in the metastatic disease setting have been of particular interest to apply to rectal cancer clinical studies. However, the integration of new RT techniques is also pertinent to this clinical research question.

The Radiation Oncology Group (RTOG) 0012 study was a Phase II trial in which patients were randomly assigned to either hyperfractionated pelvic RT plus continuous infusion 5-FU or standard pelvic RT plus continuous infusion 5-FU and irinotecan (4). That study was successful in that both arms achieved very high pCR rates, 26% in each arm. However, both arms were also associated with high rates of acute Grade 3 or greater toxicity (42% and 51%, respectively, for each arm), and therefore, neither regimen was suitable for further development.

The RTOG 0247 trial was designed to evaluate two experimental neoadjuvant chemotherapy regimens, capecitabine plus irinotecan or capecitabine plus oxaliplatin, with concurrent standard fractionated pelvic RT in a multicenter randomized Phase II trial. We sought to examine the efficacy of these two neoadjuvant regimens as determined by the primary endpoint, the pCR rate, and to evaluate the adverse events for these regimens.

Section snippets

Patient characteristics

All patients gave written informed consent in accordance with each center’s institutional review board guidelines. The eligible patients were ≥18 years old. They had a Zubrod performance of 0–2; adequate hematologic, renal, cardiac, and hepatic function; potentially resectable adenocarcinoma of the rectum originating at or below 12 cm from the anal verge without evidence of distant metastases; and clinical Stage T3, as determined by endorectal ultrasonography, or clinical Stage T4, as

Results

A total of 146 patients from 59 institutions were entered into the study between March 2004 and February 2007. In January 2005, both arms were temporarily closed because of excessive GI AEs associated with neoadjuvant therapy. Of the 18 patients, 7 developed Grade 3-4 diarrhea in Arm 1. In Arm 2, 5 of 17 patients developed Grade 3 diarrhea and 1 patient died after hospitalization for diarrhea. The protocol was amended to decrease the duration of neoadjuvant capecitabine in both arms from 7 to 5

Discussion

The important goals of rectal cancer therapy include improvement of survival, local control, and sphincter preservation. For the development of new neoadjuvant approaches, overall survival is indisputably the reference standard study endpoint by which efficacy is measured. However, several studies have demonstrated that the pCR is predictive of other clinically relevant endpoints, including sphincter preservation, relapse-free survival, and a reduction in distant metastasis 7, 8, 9, 10, 11.

Conclusions

We have shown that neoadjuvant pelvic RT with capecitabine and oxaliplatin for clinical Stage T3 and T4 rectal cancer is associated with manageable toxicity and yields a high pCR rate. The National Surgical Adjuvant Breast and Bowel Project R04 trial is testing whether the oxaliplatin regimen in the RTOG 0247 trial is superior to infusion 5-FU/oxaliplatin and also whether the addition of oxaliplatin improves the pCR rate compared with fluoropyrimidines alone. Although the results of the RTOG

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: Supported by Radiation Therapy Oncology Group U10 CA21661 and CCOP U10 CA37422 grants from the National Cancer Institute and Roche Laboratories.

: Conflict of interest: none.

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Clinical InvestigationRadiation Therapy Oncology Group 0247: A Randomized Phase II Study of Neoadjuvant Capecitabine and Irinotecan or Capecitabine and Oxaliplatin With Concurrent Radiotherapy for Patients With Locally Advanced Rectal Cancer

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Patient characteristics

Results

Discussion

Conclusions

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Ann Oncol

Int J Radiat Oncol Biol Phys

Cancer statistics, 2009

CA Cancer J Clin

Chemotherapy with preoperative radiotherapy in rectal cancer

N Engl J Med

Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: Results of FFCD 9203

J Clin Oncol

Randomized phase II study of neoadjuvant combined-modality chemoradiation for distal rectal cancer: Radiation Therapy Oncology Group trial 0012

J Clin Oncol

One-sample multiple testing procedure for phase II clinical trials

Biometrics

The use of confidence or fiducial limits illustrated in the case of the binomial

Biometrika

A pathologic complete response of rectal cancer to preoperative combined-modality therapy results in improved oncological outcome compared with those who achieve no downstaging on the basis of preoperative endorectal ultrasonography

Ann Surg Oncol

Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: Does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group

J Clin Oncol

A pathologic complete response to preoperative chemoradiation is associated with lower local recurrence and improved survival in rectal cancer patients treated by mesorectal excision

Dis Colon Rectum

Chemotherapy with preoperative radiotherapy in rectal cancer

N Engl J Med

Pre-operative chemoradiotherapy with oral capecitabine in locally advanced, resectable rectal cancer

Anticancer Res

Clinical Investigation
Radiation Therapy Oncology Group 0247: A Randomized Phase II Study of Neoadjuvant Capecitabine and Irinotecan or Capecitabine and Oxaliplatin With Concurrent Radiotherapy for Patients With Locally Advanced Rectal Cancer