Perioperative or Adjuvant Therapy for Resectable Colorectal Hepatic Metastases

No one will deny that the only potential curative treatment for patients with hepatic metastases from colorectal cancer is surgical resection. Although no more than 10% to 15% of patients with colorectal cancer metastases are considered resectable for cure, the 5-year survival in this population approaches 35%. Nevertheless, relapse can occur in 75% of patients, generally occurring within the first 2 years after surgery; 50% of relapses are in the liver. With these data, it would seem prudent to consider in these patients administering systemic agents to reduce the risk of recurrence and to potentially improve overall survival, based on the model of eradicating micrometastases with chemotherapy in early-stage primary colorectal cancer. A dilemma that we face today is whether these agents be given before hepatic resection or after surgery. It is therefore important to clarify definitions. For example, neoadjuvant therapy is the administration of preoperative systemic therapy for resectable hepatic metastases. In general, neoadjuvant therapy does not include any treatment after hepatic resection. The administration of chemotherapy before and after hepatic resection is referred to as perioperative. Adjuvant therapy is the administration of systemic therapy after hepatic resection. Lastly, conversion therapy refers to systemic chemotherapy used for patients with unresectable hepatic metastases in an attempt to make the metastases resectable. This Editorial will only use the definitions of either adjuvant or perioperative therapy for resectable hepatic metastases from colorectal cancer. This Editorial discusses two articles in this issue of Journal of Clinical Oncology. The first is by Mitry et al and the second is by Nordlinger et al, which recently appeared in the Lancet. Already, readers will detect that a major issue for resectable hepatic metastases is adjuvant therapy compared with perioperative chemotherapy. Mitry and associates have reported a pooled analysis based on individual data from two phase III trials (FFCD 9002 and the European Organisation for the Research and Treatment of Cancer [EORTC]/ National Cancer Institute of Canada Clinical Trials Group/GIVO [ENG] trial) which showed a strong trend toward improved progression-free survival favoring adjuvant chemotherapy after hepatic resection compared with surgery alone. However, both trials had to be closed prematurely because of slow accrual, thus lacking statistical power to demonstrate a difference in survival. The chemotherapy used in each trial was identical: fluorouracil and leucovorin for six cycles at 28-day intervals post hepatic resection. With 278 patients included in the pooled analysis, the median progression-free survival was 27.9 months in the chemotherapy arm compared with 18.8 months in the surgery alone arm (P .058). The median overall survival was 62.2 months in the chemotherapy arm compared with 47.3 months in the surgery alone arm (P .095). Adjuvant chemotherapy as reported by Mitry and associates was independently associated with both improved progression-free survival and overall survival in multivariable analysis. The authors concluded that the results of this pooled analysis of two randomized trials support the use of systemic adjuvant chemotherapy after potentially curative resection of liver metastases from colorectal cancer. The authors also state that it is possible that a greater benefit of adjuvant treatment would likely be achieved with currently available chemotherapy regimens that are more effective in the adjuvant stage II or III colon cancer setting than fluorouracil and leucovorin alone. Now let’s turn our attention to the perioperative chemotherapy trial reported by Nordlinger and associates. This phase III trial randomly assigned 364 patients with up to four resectable liver metastases to either six cycles of fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) before and six cycles after surgery or to surgery alone. It is important to emphasize that this trial design did not attempt to compare adjuvant to perioperative chemotherapy. The results demonstrated the absolute increase in rate of progression-free survival with perioperative chemotherapy at 3 years to be 7.3% (P .058) in randomly assigned patients, 8.1% in eligible patients (P .041), and 9.2% in patients undergoing resection (P .025). The authors concluded that perioperative chemotherapy with FOLFOX-4 reduced the risk of progression in eligible and resected patients. It is also important to note that in this phase III randomized trial, the postoperative complication rate was statistically significantly increased in those patients who receive perioperative chemotherapy versus surgery alone. Several of these complications included biliary fistula, hepatic failure, intra-abdominal infection, and the need for re-operation. One would have to attribute this increase in postoperative complications to specific chemotherapy-associated hepatic toxicity. We know that oxaliplatin is associated with sinusoidal and vascular injury as opposed to the steatohepatitis associated with irinotecan. Such specific chemotherapy-associated hepatic toxicity was not seen to this degree in the fluorouracil and leucovorin era. The authors state that this moderate increase in the risks of liver surgery after chemotherapy does not compromise the potential benefits of the treatment. I respectfully disagree since hepatic failure, re-operation, and intra-abdominal infections are serious complications. These risks can be lessened by administering chemotherapy postoperatively. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 30 OCTOBER 2

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