Rectal Cancer: Integrating Oxaliplatin Into Chemoradiation Studies

Introduction

Colorectal cancer is the third most frequently occurring cancer and the third leading cause of cancer death in the United States.[1] It is estimated that 36,400 new cases of rectal cancer and 8,600 deaths due to rectal cancer will be reported during the current year. The current standard of care for rectal cancer reflects the findings of a number of clinical trials of adjuvant therapy conducted over the past 2 decades. Recent research programs have focused on the potential role of preoperative chemoradiation in locally advanced rectal cancer and optimal strategies for integrating new agents such as oxaliplatin(Drug information on oxaliplatin) (Eloxatin) into preoperative chemoradiation regimens.

Development of Adjuvant Therapy in Rectal Cancer

The current standard of care for rectal cancer was generally defined by outcomes from the GI Tumor Study Group (GITSG) report published in 1984[2] and an Intergroup trial reported in 1994.[3] In the GITSG trial, 202 patients with rectal adenocarcinoma with extension to perirectal fat or lymph nodes were randomized to fluorouracil(Drug information on fluorouracil) (5-FU)/semustine, radiation therapy, combined 5-FU/radiation plus chemotherapy, or surgery alone (control group), with a minimum follow-up of 5 years for surviving patients.

Combined-Modality Therapy

Combined-modality treatment was associated with a significant increase in disease-free survival (66% compared with 54% for chemotherapy, 52% for radiation therapy, and 45% in control patients; P = .009) and a marginally significant increase in overall survival (56% vs 46%, 46%, and 36%, respectively; P = .07) at 5 years, which became statistically significant with long follow-up (P = .005).[4] The local recurrence rate for combined-modality treatment was 11%, compared with 27% for chemotherapy alone, 20% for radiation alone, and 24% for control patients. Distant recurrence rates were 26% for patients receiving the combined-modality therapy, 27% for those receiving chemotherapy, 30% for the radiation group, and 42% for the control group.

Subsequently, in 1988, the National Surgical Adjuvant Breast and Bowel Project (NSABP) R-01 trial in 555 rectal cancer patients reported[5] that, at 5 years, semustine (methyl-CCNU)/vincristine (Oncovin)/5-FU (MOF) chemotherapy was associated with significantly better disease-free (42% vs 30% and 33%, respectively; P = .006) and overall survival rates (53% vs 43% and 43%; P = .05) than surgery or radiation therapy alone.[5]

In 1991, a North Central Cancer Treatment Group study in 204 patients with T3,4 or N1,2 rectal cancer[6] confirmed the effectiveness of combined- modality treatment, demonstrating the superiority of a 5-FU/semustine/radiation regimen to radiation therapy alone in prolonging disease-free (58% vs 37%; P = .0016) and overall survival (52% vs 32%; P = .043).[6]

Continuous-Infusion 5-FU vs Bolus

The Intergroup trial in 660 patients with T3,4 or N1,2 cancer reported in 1994[3] established the superiority of IV continuous-infusion 5-FU over bolus 5-FU during radiation therapy and demonstrated the lack of benefit of 5-FU in combination with semustine. Patients were randomized in a 2 ´ 2 factorial design to (1) bolus 5-FU administered prior to, during, and after radiation treatment or (2) 5-FU administered by IV continuous-infusion during radiation therapy, and bolus 5-FU after radiation therapy, with both regimens given with or without semustine.

Semustine was stopped after results from the first 445 patients showed no significant effect on outcome from the addition of the agent. Patients receiving continuous-infusion 5-FU during radiation therapy exhibited a significantly improved disease-free (63% vs 53%; P = .01) and overall survival (70% vs 60%; P = .005) at 4 years, and a significant decrease in the rate of distant recurrence (31% vs 40%; P = .03). Rates of local recurrence were comparable in the continuous-infusion and bolus groups (8% vs 11%, respectively).

These randomized trials established that combined-modality treatment improved disease-free and overall survival compared with radiation therapy by decreasing both local and distant disease recurrences. The trials also demonstrated that continuous-infusion 5-FU during radiation therapy improved disease-free and overall survival compared with bolus 5-FU by reducing the incidence of distant recurrences.

Other 5-FU Modulation Strategies

Intergroup trial 0114 in 1,696 patients with T3,4 or N1,2 rectal cancer[7] assessed the effect of different 5-FU modulation strategies, but found no differences in local disease control or survival associated with the various regimens. (Results were published in the Journal of Clinical Oncology in 1997.) The study’s treatment arms were (1) 5-FU followed by 5-FU/radiation, (2) 5-FU/leucovorin followed by 5-FU/leucovorin/radiation, (3) 5-FU/levamisole (Ergamisol) followed by 5-FU and radiation, or (4) 5-FU/leucovorin/levamisole followed by 5-FU/leucovorin and radiation.

An ongoing Intergroup trial is comparing the effects of (1) standard treatment (bolus 5-FU followed by IV continuous-infusion 5-FU/radiation followed by bolus 5-FU) with the results of (2) continuous-infusion 5-FU preradiation, during, and postradiation therapy, and (3) 5-FU/leucovorin/levamisole preradiation and postradiation vs 5-FU/leucovorin during radiation treatment. Given the lack of benefit associated with the inclusion of levamisole(Drug information on levamisole) in Intergroup study 0144, no additional benefit is expected from levamisole in this current Intergroup trial. This trial should, however, be instrumental in establishing the benefit of IV continuous-infusion 5-FU before and after radiation therapy.

Recent results from NSABP trial R-02 brought into question the value of adding chemoradiation to adjuvant chemotherapy in the management of patients with rectal cancer.[8] In this study, 694 patients with T3, T4, or node-positive rectal cancer were randomized to postoperative chemotherapy alone or with postoperative radiotherapy. Although there was a statistically significant reduction in the 5-year cumulative incidence of locoregional recurrence in patients receiving chemoradiation (from 13% to 8%), there was no significant effect on relapse-free, disease-free, or overall survival.

In addition to the NSABP R-02 trial, two recent retrospective series have suggested that certain patients with T3, N0 rectal cancers are at minimal risk of locoregional recurrence.[9,10] These studies have spurred great debate among medical, radiation, and surgical gastrointestinal oncologists regarding the role of chemoradiation in patients with rectal cancer, particularly for those at low risk of locoregional recurrence.

Preoperative Chemoradiation

Available evidence[10-12] suggests that preoperative chemoradiation in rectal cancer is associated with greater sphincter preservation, a lower incidence of acute toxicity, and improved resectability of T4 tumors. However, there are currently no mature data from randomized trials on the effect of preoperative chemoradiation in standard fractionation as opposed to postoperative radiation. Important issues regarding its use include determining the necessity of postoperative chemotherapy in this setting (particularly in patients with T3 disease), and the potential for overtreating T1/2 disease with preoperative combined-modality therapy.

Over the past several years, a number of phase II trials examined the effect of preoperative chemoradiation. One study of 77 patients at The University of Texas M. D. Anderson Cancer Center[11] reported a pathologic complete response in 29% of patients, with local failure in 4%.

A Duke University study[12] in 43 patients found 51% of patients achieved a complete clinical response and 27% achieved a pathologic complete response, with local failure in 5%. In a Northwestern University study in 30 patients,[13] a clinical complete response was observed in 27% and a pathologic complete response in 20%, with local failure occurring in 4%. Unfortunately, phase III randomized trial data on the comparative effects of preoperative and postoperative chemoradiation will not be readily available in the United States. Two randomized trials, the NSABP R03 study and an Intergroup study, have closed due to poor patient accrual; a German randomized trial is ongoing.

The results of studies[14-19] of preoperative chemoradiation in patients with T4 tumors are shown in Table 1. The majority of these studies used continuous infusion 5-FU with radiation therapy in the treatment regimens and some included intraoperative radiation. Complete resection rates ranged from 80% to 97% in these studies, and 3- to 5-year overall survival rates have been high.