Influence of the Interval Between Preoperative Radiation Therapy and Surgery on Downstaging and on the Rate of Sphincter-Sparing Surgery for Rectal Cancer: The Lyon R90-01 Randomized Trial
Reviewers: John Han-Chih Chang, MD
Source: Journal of Clinical Oncology Volume 17 (Number 8): pages 2396 - 2402
There will be 56,000 colorectal cancers in the US in 1999. It remains the third leading cause of cancer deaths nationwide. Treatment consists of surgery if the patient is operable. For rectal cancer, one of the goals of surgery is to preserve sphincter function in the rectum. This is possible if the lesion is relatively small and away from the anal canal. For significantly large lesions, it may be more ideal to perform preoperative radiation therapy (RT) to reduce the tumor bulk to facilitate a sphincter sparing surgery without compromising survival or local control of the tumor. The utilization of preoperative RT has been documented since the 1960's. Gross and microscopic tumor regression with subsequent downstaging of the primary lesion has been observed. However, randomized trials from the Princess Margaret Hospital, British MRC, European Organization of Research and Treatment of Cancer and Stockholm it did not demonstrate a survival benefit over surgery alone. In 1997, the Swedish Rectal Cancer Trial randomized over 1000 patients to preoperative RT versus surgery alone and demonstrated a 10% survival advantage at 5 years. The fractionation was intense (5 Gy per day for 5 consecutive days followed by surgery 1 week later). A follow-up report demonstrated that late gastrointestinal toxicities were significantly increased in the RT arm. Much of what we know about radiobiology has prompted a decrease in the fractionation intensity, such that the daily dose is well under 5 Gy to minimize the late toxicities. The next issue to address is the timing of the surgery after RT. Some have argued for waiting over 3 - 4 weeks to allow optimal tumor response prior to attempting the sphincter preserving surgery. Others advocate early surgery as to operate before any significant amount of radiation reaction (edema and fibrosis) occurs.
This randomized trial stems from clinical observations of retrospective data from Lyon, France. These investigators found that when some of their patients had surgery within 2 weeks post RT, their probability of a pathological complete response was 6%. In contrast, if the surgery was performed over 6 weeks post RT, the pathological complete response rate was 15%. The rate of sphincter preserving surgery was 40% and 60%, respectively. Thus, the investigators developed this randomized trial (R 90-01) to determine the optimal timing of surgery after preoperative RT.
There was a significant increase in the response rate (53% versus 72%) favoring LI. However, the rate of sphincter sparing surgery was not significantly improved with LI, despite a trend favoring LI. The overall survival was not different between the SI and LI, but median follow up less than 3 years.
The rate of patients receiving LI and having sphincter sparing surgery is not significantly different than SI. In addition, there is no assessment of sphincter function. Memorial Sloan Kettering (ASTRO meeting 1997) has created a scale (excellent - no soiling, good - some soiling, fair - over 4 BM's/day with moderate soiling, poor - incontinent), which would have been useful in comparing the two arms. The morbidity of the treatment was also fairly high compared to national standards. The anastomotic leak and reoperation rates are 4 - 5 times that of other reported series. This may be related to the high fraction size (3 Gy per day).
The data are limited, and more information and studies may be necessary before advocating delays over 6 weeks after preoperative RT before performing surgery. Most have advocated a middle ground of 3 - 4 weeks after more standardized fractionation RT (1.8 to 2 Gy/day) with the addition of chemotherapy for more advanced stage lesions. Still others have utilized a more rigorous 1.5 - 1.6 Gy twice a day fractionation to hasten the treatment and avoid increasing late toxicity. The benefit of preoperative RT has been demonstrated, but optimum timing is yet to be determined.