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Intramural Distal Spread of Rectal Cancer Following Preoperative Radiotherapy: The Results of a Multicentre Randomized Clinical Study
Reviewer: Neha Vapiwala, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 21, 2003
Presenter: K. Bujko
Presenter's Affiliation: Cancer Centre and Institute of Oncology, Warsaw, Poland
Type of Session: Scientific
Preoperative radiotherapy regimens have generally followed one of two basic schema: 5 fractions of 5 Gy each, followed by immediate surgery, as was employed in the only rectal cancer study to show a survival benefit with preoperative radiotherapy compared to surgery alone (Swedish Rectal Cancer Study Group N Engl J Med.1997 Apr 3;336(14):980-7). An alternative and arguably more conventional regimen consists of concurrent chemoradiation with delayed surgery. The authors of this study noted that, regardless of the preoperative regimen used, surgeons often obtain at least a 1-2 cm distal bowel margin. The authors suggest that such generous resection may not be actually be warranted in some patients undergoing neoadjuvant treatment. This study seeks to evaluate and compare the effect of two preoperative regimens on sphincter preservation rates and on distal tumor status.
Materials and Methods
- Accrual goal of 316 patients to demonstrate a 15% improvement in sphincter preservation rate.
- 316 patients randomized from 19 different institutions
- Eligible patients had clinical T3 or resectable T4 rectal adenocarcinoma; lesions had to be palpable on DRE but without evidence of sphincter involvement
- Randomization into one of two arms:
- (n=155) 5 x 5 Gy with immediate surgery
- (n=157) 50.4 Gy in 1.8 Gy fractions + 2 courses of bolus 5-FU + leucovorin with delayed surgery ~6 weeks later
- Both arms well matched for age and stage.
- 75 cases excluded from analysis for various reasons, including 45 who had missing values
- Endpoints of interest include sphincter preservation rate, distal tumor spread and radial margin status. Distal tumor spread was measured as microscopic intramural spread located distally from mucosal ulceration.
- No statistically significant difference in sphincter preservation rates between two arms, either in the overall group or the subgroup of patients with tumors = 6 cm from anal verge.
- Statistically significant difference in pathologic T size; average tumor was ~1.9 cm smaller in the chemoRT arm compared to RT alone (p=0.001)
Arm 1 vs. Arm 2
- Positive distal margin 3% 0 (p=0.07)
- Distal spread >1 cm 12% 3% (p=0.006)
- Postive radial margin 13% 4% (p=0.017)
- Distal intramural spread of tumor beyond 1 cm (typically considered a safe cut-off point by most surgeons) was greater in the 5 x 5 Gy arm.
- Chemoradiation patients had lower rates of positive margins.
- Final analysis requires long-term follow-up, as pathologic disease seen on surgical specimens obtained shortly after radiation therapy may not represent viable, clonogenic cells. Thus, the clinical relevance of these positive pathologic findings may be overestimated.
This randomized study failed to demonstrate a statistically significant difference in sphincter preservation rates between short-course radiation and immediate surgery compared to a longer course of chemoradiation and delayed surgery. However, the statistically significant finding of smaller average tumor size in the latter arm suggests that a potential clinical benefit may in fact exist. Unfortunately, this benefit is difficult to demonstrate due to the reality of surgical practice. Despite efforts to train participating surgeons to operate on based on findings at the time of surgery, rather than based on pre-treatment characteristics, there were clearly violations of this rule. Of 18 patients with complete clinical response (CR) following preoperative treatment, 5 received abdominoperineal resections anyway, at the discretion of the surgeons. Although postoperative pathology did in fact show tumor cells in 10 of the 18 CR patients, the authors argue that these may be morphologically intact but nonviable tumor cells post-RT, and that more time between RT and surgery would have proven that to be true. Regardless, the authors acknowledge that the lack of surgeon cooperation or quality control for choice of surgical procedure are major shortcomings of this study.
Furthermore, the observed results could stem from the different intervals to surgery in the two arms, rather than a failure of chemoradiation to improve sphincter preservation rates. Finally, the distal and radial margin data include both APR and anterior resection patients; the former group would be expected to have a larger margin, and thus combining both of these groups does not truly allow one to make valid conclusions.
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