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Journal of Clinical Oncology, Vol 25, No 10 (April 1), 2007: pp. 1299-1300 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.9069
Control Arm for Surgery Alone Is Needed but Difficult to Obtain in Randomized Trials for Adjuvant Chemotherapy After Liver Resection for Colorectal MetastasesDepartment of Surgery, Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, the University of Tokyo, Tokyo, Japan To the Editor: The recent publication by Portier et al1 has provided very important evidence favoring systemic adjuvant chemotherapy after curative liver resection for colorectal metastases. The report has been accepted as the first adequately powered randomized phase III trial comparing systemic chemotherapy after surgery and surgery alone,2 a comparison that is currently very difficult to conduct. Since the benefit of adjuvant chemotherapy for resected stage III colorectal cancer without liver metastases has been established, clinical trials with a surgery-alone arm for this patient population are considered ethically unacceptable. What about patients with resectable liver-only metastases? The scarcity of evidence showing a survival benefit of adjuvant chemotherapy over liver resection alone may demand clinical trials with a control arm for surgery alone. However, both physicians and patients seem to stay away from such study designs. According to Portier et al,1 their study suffered from a slow rate of patient accrual, requiring as long as 10 years to complete. The monthly accrual rate was calculated to be only 1.44 patients/month among 47 hospitals. We have been conducting a phase III trial similar to that (FFCD ACHBTH AURC 9002 trial) reported by Portier et al and shared the same problem of a low rate of accrual. In February 2004, we started a study titled, "A randomized controlled trial by a parallel group design in multi-institutions to evaluate the effectiveness of oral adjuvant chemotherapy using leucovorin and tegaful/uracil to prevent recurrence after resection of liver metastasis from colorectal carcinoma" (UMIN-CTR: C000000013). 3 We chose an oral leucovorin and tegafur/uracil regimen4 for the therapeutic arm to balance chemotherapeutic potency and patient compliance as an adjuvant therapy. The adverse event rate (grade 3 or 4) of 24.7% and the completion rate of 66.7% in the FFCD ACHBTH AURC 9002 trial may indicate that a therapeutic regimen consisting of fluorouracil and folinic acid is barely acceptable as an adjuvant therapy after potentially curative liver resection. Oral leucovorin and tegafur/uracil have been reported to be equally potent but less toxic compared with intravenous fluorouracil and folinic acid.4 The control arm in UMIN-CTR: C000000013 was surgery alone because no concrete evidence showing the superiority of adjuvant chemotherapy over surgery alone has been reported, as previously mentioned.2 The Japanese clinical practice guidelines for the treatment of colorectal cancer published in 2005 do not recommend any type of adjuvant therapy after liver resection.5 Furthermore, our routine treatment strategy has been surgery alone, with a 5-year survival rate of approximately 37%.6 The 5-year survival rate of 41.9% in the FFCD ACHBTH AURC 9002 trial was even higher than those of previously reported series of liver resections. However, our approach is in a minority because no other clinical trials with a control arm consisting of surgery alone have been registered in Japan since 2000. During the period between February 2004 and March 2006, a total of 109 patients underwent liver resections for colorectal metastases at our institution, one of the main hospitals in UMIN-CTR: C000000013. Of these patients, 62 (57%) were excluded because of pulmonary metastases (14 patients), peritoneal dissemination or noncurative resection (14 patients), comorbidity or a history of very recent chemotherapy (19 patients), repeat liver resection (12 patients), or age (> 80 years, three patients). Of the 47 eligible patients, only 19 (17.4% of the original candidates) were finally enrolled in the study. Twenty-four patients refused to participate, and six of them wished to take leucovorin and tegaful/uracil. The remaining four of the nonenrolled patients were scheduled to undergo other chemotherapy regimens by their referring doctors. Some of the colorectal surgeons refused to skip adjuvant chemotherapy for patients with synchronous liver metastases, which also seems to have been the case in the report by Portier et al.1 Thirty-five months have elapsed since the initiation of UMIN-CTR: C000000013, and 60 patients have been enrolled to date (1.71 patients/month). Although the monthly accrual rate has improved to 2.50 during the most recent 12 months, this rate should be further accelerated to ensure the completion of the study. While no shortcuts can be taken, both patients and colorectal surgeons should be made aware of the little evidence that is available, including the study by Portier et al,1 and the significance of conducting this type of trial. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: Norihiro Kokudo, Taiho Pharmaceutical Co Ltd; Masatoshi Makuuchi, Taiho Pharmaceutical Co Ltd Testimony: N/A Other: N/A REFERENCES
1. Pontier G, Elias D, Bouche O, et al: Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 Trial. J Clin Oncol 24:4976-4982, 2006 2. Alberts SR: Evolving role of chemotherapy in resected liver metastases. J Clin Oncol 24:4952-4953, 2006 3. UMIN-CTR: University Hospital Medical Information Network. http://center.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi 4. Douillard JY, Hoff PM, Skillings JR, et al: Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 20:3605-3616, 2002 5. Japanese Society for Cancer of the Colon and Rectum: Clinical practice guidelines for the treatment of colorectal cancer [in Japanese]. Tokyo, Japan, Kanehara & Co Ltd, 2005 6. Kokudo N, Seki M, Ohta H, et al: Effects of systemic and regional chemotherapy after hepatic resection for colorectal metastases. Ann Surg Oncol 5:706-712, 1998[CrossRef][Medline]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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