SAN FRANCISCO – The length of time between surgery and the start of adjuvant chemotherapy may mean the difference between life and death for patients with colorectal cancer, researchers reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.
Dr. James J. Biagi
In a systematic review and meta-analysis of nine studies involving more than 14,000 patients, each 4-week delay in the start of adjuvant chemotherapy was associated with a 12% increase in the risk of death.
At the population level, such delays could translate to thousands of lives at risk in the United States annually, according to lead investigator Dr. James J. Biagi, an oncologist with the Cancer Research Institute at Queen’s University in Kingston, Ont.
"We believe the level of evidence from our study – with the knowledge that this relationship will not be subjected to prospective assessment – provides sufficient proof of an adverse association," he commented. "We think these results support that clinicians and jurisdictions should make efforts to optimize logistics that minimize time to adjuvant chemotherapy."
He noted that there are two common clinical assumptions regarding adjuvant chemotherapy for colorectal cancer: It should begin as soon as practical after surgery, and it may not offer any benefit when it’s started more than 3 months after surgery. However, "these assumptions have not been subjected to randomized trials, nor are they likely to be."
Dr. Biagi and colleagues searched the Medline database for the years 1975-2009 and also the online American Society of Clinical Oncology (ASCO) proceedings for the years 2007-2009 for studies of colorectal cancer reported in articles or in abstracts (to reduce the effect of publication bias) that assessed the association between time to initiation of adjuvant chemotherapy and patient outcomes.
To be included, the studies also had to adequately describe relevant prognostic factors and had to either have patient comparison groups similar on these factors or adjust for any imbalances in these factors.
The search identified nine studies with a total of 14,357 patients for analyses of overall survival, and five of the studies had data for analyses of disease-free survival.
Results of the meta-analysis showed that each 4-week delay in the initiation of chemotherapy after surgery was associated with a 12% increase in mortality risk (95% confidence interval, 9%-15%) and a 14% increase in recurrence risk as assessed from disease-free survival (95% CI, 9%-19%).
Both findings were essentially the same when the data were subjected to funnel plot analysis to assess for publication bias, according to Dr. Biagi.
To show the implications of these results at the patient level, he used the hypothetical case of a 65-year-old man in good general health with a T3N2 moderately differentiated colon cancer and 5-fluorouracil–based adjuvant chemotherapy.
This patient would have a 45% probability of being alive at 5 years if he did not receive the chemotherapy, but a 60% probability if he did, according to the "Adjuvant! Online" tool (www.adjuvantonline.com/index.jsp).
Assuming that this benefit depends on starting the chemotherapy 4 weeks after surgery, the patient’s survival probability would fall to 55% if chemotherapy were delayed until 8 weeks, and to 50% if it were delayed until 12 weeks.
At the population level, Dr. Biagi noted that an estimated 49,000 U.S. patients received a new diagnosis of stage III colorectal cancer in 2009, perhaps half of whom were eligible to start adjuvant chemotherapy at 4 weeks after surgery. Delaying chemotherapy to 8 weeks in this group alone would put 1,225 lives at risk, and delaying it to 12 weeks would put 2,450 lives at risk.
At the same time, study results also provided some reassurance when it comes to long delays in the start of chemotherapy, according to Dr. Biagi. For that hypothetical patient who has a 60% survival probability with adjuvant chemotherapy, study results suggested it would be 50% if the start of chemotherapy were delayed to 3 months – still better than the 45% expected without chemotherapy.
"This would suggest that there may be some benefit to adjuvant chemotherapy beyond that arbitrary 3-month window," he commented.
The study had its limitations, according to Dr. Biagi, such as "the inherent bias that a patient’s postoperative course may independently prolong wait time."
"Our results are based on trials from the era of fluoropyrimidine-alone therapy, in the era prior to oxaliplatin introduction," he further noted. "And of course, our results are based on nonrandomized and retrospective data."
The time to adjuvant chemotherapy is an issue that has implications for both trial design and overall patient treatment, according to discussant Dr. Johanna Bendell, an oncologist with the Sarah Cannon Research Institute in Nashville, Tenn.