Rectal cancer involving the whole thickness of the intestinal wall and penetrating the perirectal fat or the adjacent organs, although technically resectable, is very likely to recur if treated with surgery alone. For this reason the current policy in these cases includes a preoperative course of chemoradiotherapy (radiation and chemotherapy are given concurrently in an overall time of approximately 5 weeks delaying surgery by 6-8 weeks); a short course of radiotherapy alone immediately followed by surgery is a further option. This policy was supported by some large randomized trial published in the last 5 years.

Postoperative adjuvant chemotherapy is also currently used based on the favourable impact on survival reported in some non recent trials in patients submitted to surgery alone and on the evidence achieved in colonic cancer demonstrating a significant benefit on survival.

In patients receiving preoperative chemoradiation the value of postoperative adjuvant chemotherapy is however not clearly supported by any randomized trial and it may potentially represent an overtreatment in a large number of cases. This question was specifically addressed in this study.

From September 1993 and December 2003, 655 patients presenting locally advanced cancer of the rectum (clinical stage T3-4), and treated with the same regimen of preoperative chemoradiation followed by surgery, were randomized to receive or observation (Arm A) or adjuvant postoperative chemotherapy with 6 cycles of a 5Fluorouracile regimen (Arm B). The study was supported by the Italian National Research Council (CNR) and accrued patients from 11 Italian radiotherapy Centres. The original study objectives were to answer to two questions: to confirm the feasibility of preoperative chemoradiation (only supported at that time by prospective non randomized studies), and to evaluate the benefit of adding postoperative adjuvant chemotherapy .

While the answer to the first question was already provided by the trials published in the last 5 years establishing preoperative chemoradiation as one of the standard in locally advanced rectal cancer, the second question is still open as none of the available studies provided a clear evidence that in patients receiving preoperative chemoradiation, the addition of postoperative chemotherapy is of some benefit.

The results of our study can be summarized as follows:

• Preoperative chemoradiation was confirmed to be able to determine a tumour pathologic downstaging in 60% of cases; the regression was complete (no evidence of residual tumour) in 17% of cases. Treatment toxicity was acceptable and 95% of patients were submitted to a radical surgery. These results are comparable with those of the other published trials.
• Tumour response to preoperative chemoradiation was clearly correlated with prognosis; patients downstaged to pT0 (no residual tumour) or to pT1-2 (tumour inside the intestinal wall) had a 5 years survival of 80% while in patients still presenting cancer cells outside the intestinal wall 5 years survival was around 50%.
• Distant metastases are the main modality of failure and occur in 24% of patientsDue to several reasons (slow recovery from surgery, excessive delay, refusal) a considerable fraction (22%) of patients randomized to postoperative chemotherapy (Arm B) did not actually received the treatment or received a lower number of cycles than planned.
• Postoperative chemotherapy did not result to have any impact on overall survival at 5 and 10 years and on the rate of distant metastases.
• In the patients group in Arm B survival was independent from the number of chemotherapy cycles actually received.

The results of this trial add further evidence to the lack of benefit of postoperative chemotherapy with 5Fluorouracile in patients with locally advanced cancer of the rectum receiving preoperative chemoradiation. Different adjuvant treatment modalities need to be explored to decrease the high incidence of distant metastases and to further improve prognosis in this very frequent tumour.

Source: ESTRO 29