Optimal Treatment Timing Improves Outcome in Rectal Cancer

Roxanne Nelson

January 23, 2015

SAN FRANCISCO — Timing might be everything, especially when it comes to the interval between radiation therapy and surgery in patients with rectal cancer.

There is a significant association between complete pathologic response and the interval between the two therapies (P = .0002), study author Jonathan C. Salo, MD, a surgical oncologist from Carolinas Medical Center in Charlotte, North Carolina, reported here at the 2015 Gastrointestinal Cancers Symposium.

An interval between radiation therapy and surgery of up to 60 days was associated with a higher rate of complete response.

"However, more than 60 days does not seem to increase this any further," Dr Salo explained. "But intervals greater than 60 days are associated with a higher rate of positive surgical margins."

When surgery was delayed by less than 30 days, 4.0% of patients achieved a complete response; when it was delayed by 75 days, 9.3% achieved a complete response.

But when the delay was greater than 75 days, the rate declined.

Increasing Delay and Higher Mortality

A delay of more than 60 days was associated with 20% increase in the risk for mortality (95% confidence interval [CI], 1.068 - 1.367). As the interval between treatments increased, this effect became more pronounced. An interval longer than 75 days was associated with a 28% increase (95% CI, 1.06 - 1.55) in the risk for mortality; when the interval was less than 60 days, a survival benefit was seen.

In a cohort of 6805 patients, long-term survival was equivalent in all subgroups when the interval was less than 60 days. However, overall survival decreased when the interval was longer than 60 days.

Retrospective studies have shown that the increase in the interval between radiation and surgery is responsible for increasing the pathologic complete response rate. "Most retrospective studies have not shown an increase in overall mortality, and some have even shown improved survival in patients who had a longer interval," explained Dr Salo.

But data from randomized clinical trials are scant; to date, there has only been one (J Clin Oncol. 1999;17:2396). "The results showed a higher pathologic response rate in patients who waited more than 6 to 8 weeks after radiation," said Dr Salo. "But there was no difference in overall survival in the updated long-term follow-up."

Biologic Phenomenon

In their study, Dr Salo and colleagues assessed patients in the National Cancer Database, which represents about 70% of newly diagnosed cancers. The patients were mostly white (87.2%) and male (63.9%), and were generally were treated with low anterior resection (57.3%), coloanal reanastomosis (8.4%), or abdominoperineal resection (28.4%). Median survival was 66.6 months.

All patients in the cohort received preoperative radiation therapy and most received preoperative chemotherapy.

The researchers looked at the prognostic factors for overall survival, and found that age, surgical margins, comorbidity index, time to discharge after surgery, TMN pathologic staging, surgical volume, and patient income significantly affected mortality after radiation and surgery (P < .05 for all).

"Not surprisingly, age, gender, and insurance status all were important in the multivariate analysis," said Dr Salo. "In similar fashion, patients treated in an academic institution had better long-term outcomes than those treated in the community."

Tumor grade was a prognostic indicator, as were tumor and pathologic classifications, but the type of resection did not appear to make a difference in terms of long-term survival. In addition, "surgical margins were a highly powerful prognostic indicator, as was postoperative length of stay," he said. "Radiation dose, radiation boost, and lapsed radiation did not make a difference in long-term survival, but the interval between radiation and surgery was important even in the multivariate analysis, and was an important prognosticator for overall survival."

Delay between therapies was longer for patients who were older, Hispanic, black, or uninsured.

Longer intervals related to comorbidities or poor access to care "might also cause poor overall survival," Dr Salo pointed out, although he noted that these factors would not directly cause an increase in surgical margins.

"Instead, we would say that there is a biologic phenomenon going on that is not accounted for by comorbidities or lack of access to care," he concluded.

This large retrospective study has given support to the concept that longer intervals between the end of chemoradiation and surgery is necessary to increase complete response, said Nancy E. Kemeny, MD, from the Memorial Sloan Kettering Cancer Center in New York City.

However, "waiting more than 60 days decreases survival," she said. "Complete response is predictive of outcomes and may allow more tailored treatment. Longer intervals may not be necessary for all rectal tumors, such as high rectal tumors. But low rectal tumors need a longer interval when sphincter preservation is sought."

"With incomplete tumor response, longer intervals may be harmful. Perhaps measuring response more frequently may be appropriate," Dr Kemeny noted.

The authors have disclosed no relevant financial relationships.

2015 Gastrointestinal Cancers Symposium (GICS): Abstract 510. Presented January 17, 2015.

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