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Originally published as JCO Early Release 10.1200/JCO.2009.22.4626 on June 8 2009 © 2009 American Society of Clinical Oncology.
Colorectal Hepatic Metastases: Adjuvant Chemotherapy and SurvivalGastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center; Joan and Sanford Weill Medical College of Cornell University, New York, NY
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY To the Editor: We read the article by Blazer et al,1 entitled "Pathologic Response to Preoperative Chemotherapy: A New Outcome End Point After Resection of Hepatic Colorectal Metastases," with great interest. This study confirmed that pathologic response to preoperative chemotherapy predicts survival for patients with colorectal hepatic metastases, establishing pathologic response as a prognostic indicator and as a potential end point in clinical trials evaluating neoadjuvant chemotherapy. However, we are concerned by the omission of adjuvant chemotherapy in the survival analysis. Patients with colorectal hepatic metastases are frequently treated with both pre- and postoperative chemotherapy, an approach that is supported by the European Organisation for Research and Treatment of Cancer 40983 trial. In this study, 364 patients with resectable colorectal hepatic metastases were randomized to six cycles of neoadjuvant infusional fluorouracil/leucovorin (FOLFOX4) plus six cycles of adjuvant FOLFOX4 versus surgery alone, resulting in a 9.2% improvement in 3-year disease-free survival for the group that received perioperative chemotherapy and were resected (P = .03).2 Unfortunately, we do not know if both neoadjuvant and adjuvant approaches are necessary, and to date no clinical trial has addressed this issue. In the study by Blazer et al,1 197 (64.6%) of 305 patients received adjuvant chemotherapy after hepatic resection, with a median time to treatment of 7 weeks and a median duration of adjuvant chemotherapy of 12 weeks. However, adjuvant chemotherapy is not included as a variable in the univariate or multivariate models reported in the article. One of the inherent flaws of constructing a prognostic model from retrospective data is that it is difficult to include all known clinical predictive markers, but the omission of adjuvant chemotherapy from the survival analysis is important. Its inclusion could alter the results. The benefit of adjuvant chemotherapy after resection of colorectal hepatic metastases has been reported. In a multivariate analysis, adjuvant chemotherapy and size of metastases were significantly associated with overall survival (OS; hazard ratio [HR] for surgery alone = 1.39; 95% CI, 1.00 to 1.93; P = .046; HR for two or more metastases = 1.49; 95% CI, 1.06 to 2.11; P = .023).3 A retrospective review of 792 patients added further support for the importance of adjuvant chemotherapy.4 Even for poor-risk patients (four or more bilobar metastases) adjuvant chemotherapy improved OS compared with surgery alone (51.5 months v 23 months; P < .01),5 and for patients with synchronous disease, treatment with postoperative fluorouracil or hepatic arterial infusion floxuridine-based therapy demonstrated improved OS compared with surgery alone (HR = 0.62; 95% CI, 0.50 to 0.78; HR = 0.51; 95% CI, 0.28 to 0.97, respectively).6 Three randomized studies showed an increase in disease-free survival with the use of hepatic arterial infusion and systemic therapy after liver resection.7–9 In our opinion, this data mandates the inclusion of adjuvant chemotherapy in any multivariate model investigating survival.
We recently reported that radiologic response to neoadjvuant chemotherapy did not correlate with OS in patients with operable synchronous colorectal hepatic metastases.10 In our univariate analysis, response to neoadjuvant chemotherapy was not associated with OS, and in the multivariate Cox model, only margins, stage of primary and postoperative carcinoembryonic antigen
An association between pathological response to neoadjuvant chemotherapy and survival is not a new concept. It is well established, for example, in the management of muscle-invasive urothelial carcinoma, and it is likely that the association reported in this study is true.11 However, we believe that a survival analysis must consider the impact of adjuvant chemotherapy and are interested to learn if its inclusion in the univariate and multivariate models in the Blazer et al1 study changes the results. It would also be of clinical interest to test if duration of chemotherapy was related to pathologic response, and if predictors of complete response such as burden of disease can be identified. We would also welcome a comment from the authors on why different cutoff points were used for carcinoembryonic antigen (200 ng/mL v 5 ng/mL), and tumor size (5 cm v 3 cm) and number (multiple/solitary v AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Nancy E. Kemeny, sanofi-aventis Research Funding: Nancy E. Kemeny, Codman, Pfizer, sanofi-aventis Expert Testimony: None Other Remuneration: None REFERENCES
1. Blazer DG III, Kishi Y, Maru DM, et al: Pathologic response to preoperative chemotherapy: A new outcome end point after resection of hepatic colorectal metastases. J Clin Oncol 26:5344–5351, 2008. 2. Nordlinger B SH, Collette L, et al: Final results of the EORTC Intergroup randomized phase III study 40983 (EPOC) evaluating the benefit of perioperative FOLFOX4 chemotherapy for patients with potentially resectable colorectal cancer liver metastases. J Clin Oncol 25:2s; 2007 abstr LBA5. 3. Mitry E, Fields AL, Bleiberg H, et al: Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: A pooled analysis of two randomized trials. J Clin Oncol 26:4906–4911, 2008. 4. Parks R, Gonen M, Kemeny N, et al: Adjuvant chemotherapy improves survival after resection of hepatic colorectal metastases: Analysis of data from two continents. J Am Coll Surg 204:753–761, 2007.[CrossRef][Medline] 5. Tanaka K, Shimada H, Ueda M, et al: Role of hepatectomy in treating multiple bilobar colorectal cancer metastases. Surgery 143:259–270, 2008.[CrossRef][Medline] 6. Wang X, Hershman DL, Abrams JA, et al: Predictors of survival after hepatic resection among patients with colorectal liver metastasis. Br J Cancer 97:1606–1612, 2007.[CrossRef][Medline] 7. Kemeny N, Huang Y, Cohen AM, et al: Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 341:2039–2048, 1999. 8. Kemeny MM, Adak S, Gray B, et al: Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: Surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy—An intergroup study. J Clin Oncol 20:1499–1505, 2002. 9. Lygidakis NJ, Ziras N, Parissis J: Resection versus resection combined with adjuvant pre- and post-operative chemotherapy-immunotherapy for metastatic colorectal liver cancer: A new look at an old problem. Hepatogastroenterology 42:155–161, 1995.[Medline] 10. Gallagher DJ, Zheng J, Capanu M, et al: Response to neoadjuvant chemotherapy does not predict overall survival for patients with synchronous colorectal hepatic metastases. Ann Surg Oncol, 10.1245/s10434-009-0348-1, [epub ahead of print on February 18, 2009].[CrossRef] 11. Grossman HB, Natale RB, Tangen CM, et al: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349:859–866, 2003.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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5 ng/dL were significant (P = .04, P = .03, and P = .01, respectively). For patients who progressed on neoadjuvant chemotherapy, there was a trend towards improved 5-year OS for those who received adjuvant hepatic arterial infusion chemotherapy. 
4) in the two analyses. There was a high death rate (8%) in the postoperative period. Was there an association between type of neoadjuvant chemotherapy used and postoperative death? Lastly, as we saw in our study, some patients who progress on neoadjuvant chemotherapy appear to be responsive with adjuvant salvage treatment. It would be interesting to know how many of the 149 patients (55%) with minor response or progression achieved long-term survival, and if the use of adjuvant chemotherapy contributed to this. 
