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Rectal Cancer: Integrating Oxaliplatin Into Chemoradiation Studies

Rectal Cancer: Integrating Oxaliplatin Into Chemoradiation Studies

ABSTRACT: The current standard of care for patients with stage T3 rectal cancer is adjuvant combined-modality treatment with radiation and fluorouracil (5-FU)-based chemotherapy. Although data from randomized phase III trials comparing preoperative and postoperative combined-modality therapy are lacking, preoperative therapy is an option in T3 disease and can be considered the standard of care for T4 disease. Given its effects in reducing systemic disease in stage IV rectal cancer and its potential for radiosensitization of target tumors, oxaliplatin (Eloxatin), a new cytotoxic agent from the diaminocyclohexane platinum family, is being evaluated in preoperative combined-modality regimens in a Cancer and Leukemia Group B (CALGB) phase I/II study (protocol 89901) in T4 disease and an Eastern Cooperative Group (ECOG) phase I study (E-1297) in locally advanced T3 or T4 disease. [ONCOLOGY 14(Suppl 11):38-41, 2000] 

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 (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 (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 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.

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