Colorectal cancer (CRC) is the third leading cause of cancer mortality in the Western world (Global Cancer Statistics, 2002, Parkin DM, Bray F, Ferlay J, Pisani P. CA Cancer J Clin. 2005;55(2):74–108). Initially, patients with stage I-III CRC have their tumors surgically resected. After surgery, many patients will still eventually relapse and die from their disease. Studies show that adjuvant chemotherapy (AC) can increase overall survival (OS) and disease free survival (DFS) in colon cancer through the eradication of micrometastases that remain following surgical resection. However, the optimal timing from surgery to initiation of AC has not been well defined. The time to adjuvant chemotherapy’ (TTAC) from surgery can be critical to the continued care of colorectal patients.
Recent published literature on the treatment of CRC has addressed the subject of optimal timing in commencing adjuvant chemotherapy after surgical resection. More specifically, studies have examined the role of delays in such treatment and their impact on patient OS and DFS. An article, “Does Delay of Adjuvant Chemotherapy Impact Survival in Patients With Resected Stage II and III Colon Adenocarcinoma?” (published in the June 1, 2011 of Cancer by the American Cancer Society), indicated from prospective clinical trials that delaying AC treatment for more than 60 days following surgery can place Stage II and III patients at greater risk of relapse. Still, trials have reported conflicting results and the role and timing of adjuvant chemotherapy remains controversial.”
To address this issue, a systematic review of clinical research in the literature was conducted in 2011 by J. J. Biagi, M. Raphael, W. D. King, W. Kong, W. J. Mackillop, and C. Booth “Association Between Time To Initiation of Adjuvant
Chemotherapy and Survival in Colorectal Cancer: A Systematic Review and Meta-analysis”: June 4, 2011, doi:10.1001 /jama.2011.749. It was published by the American Society of Clinical Oncology (www.asco.org) and also appeared in the Journal of the American Medical Association. Relevant studies were identified using keyword searches and through a structured literature search of MEDLINE (1975 to the end of January 2011). Medical subject headings used included adjuvant chemotherapy, colorectal neoplasms, drug administration schedules, time factors, survival rate, and survival analysis. These selected studies involved a total of 14,357 patients (4 published articles, 5 abstracts).
The review was presented by Dr. James Joseph Biagi at the 2011 “Symposium on Gastrointestinal Cancers.” The meta-analysis of TTAC concluded that a “longer time to AC was associated with worse survival among patients with resected colorectal cancer,” and in particular, “a 12% increase in the risk of death for each 4 week of delay in the start of AC for CRC.” They found “that patients who had received adjuvant chemotherapy within 60 days of surgical resection for colon cancer had a better OS than those who began adjuvant chemotherapy >60 days after the resection.” The study called for more extensive retrospective studies to “confirm the impact of adjuvant chemotherapy delay on colon cancer survival independent of confounding factors.” Common causes for delays in treatment cited by the study were administrative system and patient-related. It concluded: “It is possible that disparities in clinical outcomes in colon cancer could be reduced by precisely identifying all major factors that lead to significant delays (>60 days) in initiating adjuvant chemotherapy and devising strategies that are effective in decreasing the time to chemotherapy.” Even though beginning AC within 60 days seemed optimal, the results also suggested that even after a three-month delay in TTAC, the treatment could still have some benefit.
The review by Biagi et al. states that “Adjuvant chemotherapy is recommended routinely following curative surgical resection of stage II-III rectal cancer, stage III (node-positive) colon cancer, and stage II (node-negative) colon cancer in which high-risk features are present.” It further recommends that, “Physicians may need to more carefully consider timing when discussing AC with patients,” and that the population at risk is considerable given that there were approximately 140,000 new cases of CRC diagnosed in the United States in 2009. The review “results demonstrate a significant adverse association between time to AC and survival in CRC, supporting a position that clinicians and jurisdictions need to optimize patient flow logistics to minimize time to AC.” Finally, the authors suggest, “the timing of chemotherapy may need to be more strictly controlled as a variable in future adjuvant trials.”