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Journal of Clinical Oncology, Vol 24, No 14 (May 10), 2006: pp. 2217-2218 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.6358
Neoadjuvant Chemotherapy for Metastatic Colon Cancer: Too Much Caution and Still Too Much to Be AssessedIstituto Regina Elena, Rome, Italy To the Editor: We read with great interest the Comment and Controversies article "Neoadjuvant Chemotherapy for Metastastic Colon Cancer: A cautionary note," by Bilchik et al.1 We would add some comments to the discussion. This report has been published almost 10 years after the first report by Bismuth et al2 in 1996, when, for the first time, it was shown that a chronomodulated regimen of fluorouracil (FU)/leucovorin (LV) and oxaliplatin (L-OHP) was shown to induce tumor shrinkage in liver metastases to make them resectable. The recommendations made by Bilchik et al reflect more a surgical point of view than a medical oncology perspective, and we think this discrepancy needs to be clarified. There is one definite important point in the treatment of colorectal liver metastases that should be clearly declared before questioning toxicity: The combined treatment strategy of neoadjuvant chemotherapy plus surgery is the most successful way to increase patient survival beyond 30 months for this category of patients, a result never reached before with any of the two approaches alone. At the same time, up to 80% of resected patients die as a result of colorectal disease because of recurrence within or outside of the liver. We need more efforts to cure the diease, not only to prolong survival. We are aware that there are still many end points to be addressed in this context, but the issue of liver toxicity using L-OHP, irinotecan (CPT-11), and FU may not be on the top of the list. There is no agreement among surgical teams on the definition of inoperability, nor is there an indication of which, if any, is the best schedule of chemotherapy in terms of activity and tolerability, how long the chemotherapy treatment should last, how to proceed after surgery, or in what ways and to what extent is healthy liver damaged. The simple definition of patient inclusion in the retrospective series of the Paul Brousse Hospital,2 size, location, and extrahepatic and multinodular disease, are no longer considered an absolute contraindication to liver surgery, per se. Other proposals, such as that by Pozzo et al,3 seem to be more complicated and not practical. The necessity to control liver metastases in patients with rapidly evolving technically resectable disease could represent another indication to neoadjuvant chemotherapy, together with the delay of liver surgery in patients with low rectal cancer at the time of surgery on the primary tumor. When we look at unselected metastatic colorectal cancer patients, L-OHP–containing regimens seem more effective than CPT-11 ones, as shown in the Tournigand et al trial,4 in which more patients were resected with L-OHP rather than CPT-11. Concerning the schedule, in the recent European Organisation for Research and Treatment of Cancer (EORTC) 05963 trial, no difference in response rate and survival was found in 554 patients randomly assigned to chronomodulated FU/LV + L-OHP or standard FOLFOX2 administration. In this trial, the number of patients who underwent surgery after chemotherapy was the same, 50 for each arm.5 There is no trial in the current literature concerning this specific end point of the best oxaliplatin-containing regimens, either with infusional FU or with oral fluoropyrimidines. The potential to include all three active drugs in triplet combination6 offer new possibilities not only in order to have more responses, but also to reduce the number of courses and, as such, the exposure of healthy liver to anticancer agents. A recent trial coordinated by Masi et al7 clearly showed that a triplet combination of CPT-11 + L-OHP + FU/LV is better than a simple doublet with CPT-11 + FU/LV in terms of resectability of colorectal liver metastases. Thus, the question of toxicity seems to be overemphasized. Despite the thousands of patients treated with L-OHP, the report by Tisman et al8 is the only one concerning a veno-occlusive liver disease that was responsible for liver failure. There is no reported incidence of more severe complications in patients resected after chemotherapy, with no case of mortality as a result of chemotherapy, and patients eligible for resection had, in any case, already received treatment for their metastatic disease. In our experience, none of 57 patients resected for liver metastases after chronomodulated infusion of doublet (FU/LV + L-OHP) or triplet (CPT-11 + FU/LV + L-OHP) suffered from severe postoperative complications or death and all of them were able to restart chemotherapy after surgery (unpublished data). Sebagh et al9 stated that the severe sinusoidal obstruction observed with L-OHP cannot constitute a limit to the increasing use of chemotherapy for these patients because of the limited clinical significance of these findings. In this view, we do not agree with Bilchik et al on final recommendations. The categories of "low risk" or "poorer prognosis pattern of resectable metastatic disease" are artificial unless adequate trials are designed for these patients and definitive estimation of optimal treatment duration can be made. It is time for the oncology community to start new types of trials in which different strategies for treating this distinct group of patients are compared, and in which patient outcome and not only different drugs are studied. We believe, as others have claimed, that interdisciplinary collaboration between all specialists in this field will bring new knowledge and cure opportunities for our patients. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Bilchik AJ, Poston G, Curley SA, et al: Neoadjuvant chemotherapy for metastatic colon cancer: A cautionary note. J Clin Oncol 23:9073-9078, 2005 2. Bismuth H, Adam R, Lévi F, et al: Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 224:509-520, 1996[CrossRef][Medline] 3. Pozzo C, Basso M, Cassano A, et al: Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients. Ann Oncol 15:933-939, 2004 4. Tournigand C, Andre T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 22:229-237, 2004 5. Giacchetti S, Bjarnason G, Garufi C, et al: First line infusion of 5-fluorouracil, leucovorin and oxaliplatin for metastatic colorectal cancer: 4-day chronomodulated (FFL4-10) versus 2-day FOLFOX2—A multicenter randomized Phase III trial of the Chronotherapy Group of the European Organization for Research and Treatment of Cancer (EORTC 05963). J Clin Oncol 22:251s, 2004 (suppl; abstr 3526) 6. Garufi C, Bria E, Vanni B, et al: A phase II study of irinotecan plus chronomodulated oxaliplatin, 5-fluorouracil and folinic acid in advanced colorectal cancer patients. Br J Cancer 89:1870-1875, 2003[CrossRef][Medline] 7. Masi G, Allegrini G, Brunetti I, et al: Biweekly irinotecan, oxaliplatin and infusional 5FU/LV (FOLFOXIRI) versus FOLFIRI as first-line treatment of metas cancer (MCRC): Results of a randomised phase III trial by the Gruppo Oncologico Nord Ovest (GONO). Ann Oncol 16:vii7, 2005 (suppl 7) 8. Tisman G, MacDonald D, Shindell N, et al: Oxaliplatin toxicity masquerading as recurrent colon cancer. J Clin Oncol 22:3202-3204, 2004 9. Sebagh M, Plasse M, Lévi F, et al: Severe hepatic sinusoidal obstruction and oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer: A real entity? Ann Oncol: 16:331, 2005
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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