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Abstract & Commentary
Synopsis: Ongoing randomized trials seek to define the optimal adjuvant therapy for locally advanced rectal cancer. Neoadjuvant chemoradiation is one approach that is being explored. Tumor response to preoperative therapy may have important postoperative ramifications in terms of the necessity for additional therapy. Mohiuddin and associates retrospectively reviewed their experience with a cohort of patients who had unfavorable rectal cancers and found that pathologic stage was prognostically significant.
Source: Mohiuddin M, et al. Int I Radiat Oncol Biol Phys. 2000;48:1075-1080.
The use of preoperative radiotherapy and chemotherapy in sphincter-conserving surgery for low-lying rectal cancers and in the resection of fixed/tethered rectal tumors is now widely acknowledged. However, the prognostic significance of the degree of tumor response following up-front chemoradiation has not been described. Mohiuddin et al reviewed their experience with patients who presented with fixed or tethered primary or locally recurrent lesions in order to define the prognostic effect of tumor response on local control and survival.
Mohiuddin et al reported on 77 patients who presented with fixed or tethered lesions of the upper and lower rectum. These patients were treated with neoadjuvant chemoradiation and then followed for a median of 3 years (range, 1-8 years) after surgery. All patients were treated with 4-field irradiation to the pelvis to 45 Gy at 1.8-2 Gy per fraction, followed by a conedown boost for an additional 5-15 Gy. Median RT dose was 55.8 Gy. 5-fluorouracil was given to all patients during RT, either as a weekly 1000 mg/m2 bolus, as a 3-5 day 1000 mg/m2 infusion during weeks 1 and 5, or towards the end of the study period as a 225 mg/m2 continuous infusion. Surgery was then performed after a median of 7.5 weeks (range, 6-10 weeks). Twenty-eight patients underwent APR and the remainder had sphincter-sparing procedures. No patient received additional chemotherapy following surgery.
Twelve patients (16%) achieved a pathologic complete response (pT0N0) following neoadjuvant therapy, and an additional 10 (13%) were downstaged to pT1-2N0. There were 31 patients (40%) who were noted to be node-positive at surgery. Multivariate analysis was done to assess the significance of pathologic response, gender, age, tumor location, and type of surgery on local control and survival.
Actuarial five-year disease-free survival for the entire group was 85%. No patients with pT0-2N0 disease failed locally or distantly at 5 years. This was statistically significantly better than the 80% disease-free survival for pT3 patients and 73% for node-positive patients (P = .001). The local recurrence rate was 14% for pT3-4N0 patients and 16% for node-positive patients (P = .08).
Mohiuddin et al concluded that pathologic stage post-chemoradiation was the only prognostically important variable among those studied, and that patients with pT3-4 and/or node-positive disease at surgery may benefit from further adjuvant therapy.
COMMENT BY EDWARD J. KAPLAN, MD
Guidelines for the treatment of locally advanced rectal cancer are currently being developed, and ultimately will be based on the outcomes of several ongoing randomized trials. At present, it is generally acceptable to treat these types of tumors with either preoperative or postoperative adjuvant therapy.
Postoperative radiotherapy, like that reported for the NSABP R-01 trial by Fisher et al in 1988, has failed to yield an improvement in survival despite the fact that better local control has been demonstrated.1 In 1991, Krook published the results of NCCG-Mayo randomized trial and showed that the addition of 5-FU + semustine to radiotherapy resulted in a statistically significant improvement in local control and survival compared to radiotherapy alone.2 Based on these types of results, postoperative adjuvant treatment is still considered standard therapy for pT3-4 and/or node-positive patients.
A recent overview of the results of 14 trials evaluating preoperative radiotherapy vs. surgery alone was published as a meta-analysis by Camma et al and included data on 6426 patients.3 A significant benefit in overall mortality, cancer-related mortality, and local recurrence was reported. Postoperative morbidity was not significantly increased as a result of the RT. So far, though, no randomized trials incorporating preoperative chemoradiation have been reported, but several are under way. These include the four-arm EORTC 22921 trial for patients with T3-4 lesions which compares preoperative 45 Gy vs. 45 Gy + 5-FU/LV vs. 45 Gy + postoperative 5-FU/LV vs. 45 Gy + pre- and postoperative 5-FU/LV; the NSABP R-03 trial which compares pre- vs. postoperative combined modality therapy for resectable T3 lesions; and the MRC-CR07 trial which randomizes patients to preoperative RT or postoperative chemoradiation. The Intergroup trial R9401 comparing 50.4 Gy + 5-FU/LV pre- vs. postoperatively was closed prematurely because of poor patient accrual and will not yield useful data.
If pre- and postoperative chemoradiation prove to be of equivalent efficacy in the randomized trials mentioned above, then the prognostic information gained from analysis of the pathologic specimens following neoadjuvant therapy may make it the more valuable approach. The prognostic information gained from downstaged tumors may allow clinicians to select out those patients who can benefit from additional systemic therapy, thereby improving outcomes further. The Mohiuddin et al paper suggests that such patient selection may be possible. Such a hypothesis would have to be tested in a randomized setting.
(Dr. Kaplan is acting Chairman, Department of Radiation Oncology, Cleveland Clinic Florida, Ft. Lauderdale, Fla, and Medical Director, Boca Raton Radiation Therapy Regional Center, Deerfield Beach, Fla.)
1. Fisher B, et al. J Natl Cancer Inst. 1988;80:21-29.
2. Krook JE, et al. N Engl J Med. 1991;324:709-715.
3. Camma C, et al. JAMA. 2000;284:1008-1015.