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Editorial |
Department of Surgery, Division of Surgical Oncology, University of Louisville School of Medicine, 315 East Broadway, Room 313, Louisville, Kentucky 40202
Correspondence: Address correspondence and reprint requests to: Robert C. G. Martin, MD; E-mail: robert.martin{at}louisville.edu.
In this issue of Annals of Surgical Oncology, Andréet al.1 present an exhaustive review of the controversial management in the use of adjuvant chemotherapy for stage II colon cancers. The authors review the results of the most recent clinical trials and meta-analyses investigating the value of adjuvant chemotherapy for stage II patients. They emphasize that this is a heterogenous patient population that includes patients with T2, T3, and T4 lesions, tumor perforation, and tumor differentiation, all of whom are believed to be N0. This heterogeneous population is the reason that 5-year survival rates for stage II colon cancer range from a high of 70% to a low of 30%.2
It is because of this same heterogeneity and the relatively rare event of stage II colon carcinoma that trials attempting to evaluate the treatment efficacy of adjuvant chemotherapy have had insufficient power. Even larger trials that have included both stage II and stage III colon carcinomas have been insufficient to demonstrate a durable benefit in this rare group.3–5 It has been estimated, as the authors have pointed out, that to detect a 4% survival benefit at 5 years in stage II colon cancer by using a median of 75% 5-year survival as a baseline would require 4700 patients.6
The rapid expansion in chemotherapeutic options has made the care of colon cancer patients more complex and optimistic. In the past, when only 5-fluorouracil chemotherapy was an option, there was little enthusiasm for giving chemotherapy in a subset of patients with a 5-year survival rate of 75%. However, now, with a myriad of options, there is considerable enthusiasm for identifying all stages and/or subsets of patients who may receive any form of benefit from additional chemotherapy. To most, this represents an advance in treatment, as has been seen in breast and prostate therapy.
The core question remains as to what is a clinically relevant benefit from additional chemotherapy? Is a 5-year increase of 4.3%7 for stage II colon cancers clinically relevant? If this translates into an improvement of 3 months in overall survival, which is half the duration of the treatment itself (6 months of adjuvant therapy), is it worthwhile in all stage II patients?
One of the key areas in which surgery has been lacking has been established surgical criteria for colon resections in cancer. Only until recently has there been a recommendation for at least 12 lymph nodes to be evaluated in all surgically treated colon cancers. This minimum number of lymph nodes retrieved has been demonstrated to improve 5-year survival,8 through a stage migration effect, and to be highly predictive of survival in both lymph node–negative and lymph node–positive patients.8 Adequate lymph node identification has been difficult to standardize because of the variability of both surgical technique and pathologic lymph harvest. One technique that may demonstrate the ability to increase lymph node retrieval and possibly improve lymph node stage sensitivity and specificity is sentinel lymph node biopsy. The successful conclusion of this multi-institutional trial of this technique demonstrated the feasibility and possible benefit (Bilchik et al., unpublished data).
There is uniform agreement that the cause of relapse in stage II colon cancer remains 25% to 35% secondary to unrecognized spread of disease through either the lymphatic or vascular system.9 It is unknown what effect a standard surgical resection with adequate lymph node retrieval would have on that relapse rate. Is it possible that a standard minimum requirement for surgical resection and lymph node retrieval could not demonstrate an increase in the number of patients who should receive chemotherapy, but, more importantly, identify patients who would not benefit from chemotherapy?
The cost of adjuvant therapy must be evaluated as we consider offering additional therapy to the 28% of patients with new stage II colon cancers diagnosed annually. In the United States alone, this would increase the number of patients receiving adjuvant therapy by approximately 50,000. With the cost of standard adjuvant therapy of fluorouracil and levamisole being approximately $10,000 in 2005, this translates into an increase of approximately $500 million to the US health care system. This increase could nearly triple if trials demonstrating efficacy of combined adjuvant chemotherapy, fluorouracil and oxaliplatin, for stage III cancers are extrapolated for use in stage II patients.
Finally, the toxicity of this therapy and its effect on a patient’s quality of life must also be discussed when the risk-benefit ratio is evaluated. The recent Multi-center International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial, in which grade 3 toxicity was seen in 17.5% of patients with fluorouracil treatment and 40% in combined therapy, calls into question whether this is worth a 4% increase in survival for stage II colon cancer.10
In conclusion, the treatment of colon cancer has become more complex, more demanding, and more optimistic across all stages in attempting to improve the overall quality of life for each and every patient. Since direct evidence from randomized control trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer,11 these decisions must be based on a case-by-case assessment. Physician assessment regarding the use of adjuvant therapy for stage II colon cancers should include the discussion of established prognostic factors within this stage, the considerable cost of therapy, and the risk of complications against the absolute improvement in survival by months gained. This assessment can be made by the treating surgeon in conjunction with a multidisciplinary approach/discussion and does not require that all stage II colon cancers be referred.
Received for publication November 29, 2005. Accepted for publication December 6, 2005.
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