The results of a systematic review and meta-analysis suggest that the mortality risk for colon cancer patients begins to increase with any avoidable delay in adjuvant chemotherapy beyond 4 weeks. Starting adjuvant therapy 8 weeks after surgery increased the mortality hazard by 12% compared with starting at 4 weeks, and the excess risk jumped to 25% with a 12-week delay. Avoiding such delays could extend the survival of as many as 2500 patients a year in the United States, according to data reported at the Gastrointestinal Cancers Symposium.
"The results of our analysis indicate a significant adverse association between time to adjuvant chemotherapy and survival in colorectal cancer," said James J. Biagi, MD, of Queen's University Cancer Research Institute in Kingston, Ontario, Canada. "The level of evidence from our study, with knowledge that this relationship will not be subjected to prospective assessment, provides sufficient proof of an adverse association. The results support the position that clinicians and jurisdictions should make efforts to optimize logistics to minimize the time to adjuvant chemotherapy."
Biagi noted that with regard to adjuvant chemotherapy for colorectal cancer, 2 general assumptions underlie clinical practice: the therapy should begin as soon as possible after surgery and the benefits of chemotherapy become uncertain if it begins more than 12 weeks after surgery.
To examine and quantify the effects of delayed chemotherapy in patients with colorectal cancer, investigators performed a systematic review of the medical literature and a meta-analysis of relevant data. They identified studies that had clearly defined intervals from surgery to the start of chemotherapy and that also evaluated the relationship between the interval and chemotherapy survival. Biagi and colleagues found 9 studies suitable for inclusion in the analysis. The studies involved a total of 14,357 patients with colorectal cancer. Five of the 9 studies included analyses of disease-free survival (DFS).
Each of the studies showed that the hazard for overall survival increased with the length of delay from surgery to adjuvant chemotherapy. Similar associations emerged from an overall analysis and a separate analysis of the incremental impact per each 4-week delay. The cumulative hazard for overall survival was 1.12 (95% CI, 1.09-1.15). Adjustment for potential publication bias yielded a hazard of 1.11. The 5 studies that analyzed DFS showed a hazard ratio of 1.14 (1.15 after adjustment). Confidence intervals did not overlap in either analysis.
If a patient could begin adjuvant chemotherapy 4 weeks after surgery, an additional 4-week delay was associated with a 12% rise in mortality risk. A 12-week delay increased the hazard by 25%. To illustrate the association between delay and mortality risk, Biagi described a hypothetical 65-yearold man with T3N2 colon cancer treated with 5 FU (fluorouracil)- based chemotherapy. The patient would have an estimated 5-year overall survival of 60% with chemotherapy versus 45% without chemotherapy.
Biagi said, "Assuming that the estimate depends on a time to adjuvant chemotherapy of 4 weeks, the patient would have an estimated 5-year survival of 55% with a delay of 8 weeks, decreasing to 50% with a delay of 12 weeks."
In the United States, about 140,000 new cases of colorectal cancer are diagnosed each year, he said. Assuming that 35% (49,000) have stage III disease and half of them would begin adjuvant chemotherapy within 4 weeks of surgery, an 8-week delay would put 1225 lives at risk. A 12-week delay would double that number.
Noting the 45% estimated 5-year survival without chemotherapy, Biagi said the data suggest that chemotherapy offers a survival benefit beyond 12 weeks.
________________________________________________________Biagi JJ, Raphael M, King WD, Kong W, Mackillop WJ, Booth C. The impact of time to adjuvant chemotherapy on survival in colorectal cancer: A systematic review and meta-analysis. Paper presented at: 2011 Gastrointestinal Cancers Symposium; January 2011; San Francisco, CA.Published in Oncology & Biotech News. February 2011.