Treatment of Metastatic Colon Cancer: "The Times They Are A-Changing"

In the 1950s, colon cancer was the poor stepchild for chemotherapists, with a median survival of 12 months for patients with metastatic disease. Now patients with metastatic disease, even hepatic metastases, can survive 5 years when surgical techniques for liver resection and new chemotherapy, with or without targeted agents, are used. In the article that accompanies this editorial, Ye et al prospectively randomly assigned patients with unresectable, liver-limited metastases (KRAS wild type) to systemic chemotherapy with or without cetuximab (Cetx). The primary end point was the number of patients converted to hepatic resection. The patients receiving chemotherapy plus Cetx had a significantly higher resection rate: 25% versus 7.4%. The patients were well matched for individual prognostic factors, but the two study groups differed slightly: high clinical risk score of 25% versus 35%; rectal primaries, 38% versus 48%; lesion larger than 5 cm, 44% versus 55%; and major vessel involvement, 37% versus 44%, for the chemotherapy plus Cetx group versus chemotherapy group, respectively. Overall, the chemotherapy plus Cetx group had 22% fewer patients with poor prognostic indicators. This may explain why patients who underwent resection and did not receive Cetx had a shorter survival than those who received chemotherapy plus Cetx (median survival, 22 months v 34.8 months, respectively). The 5-year survival rates obtained with liver resection, 30% to 50%, are superior to rates of survival obtained with systemic chemotherapy alone. Early studies showed a 30% 5-year survival for patients who had resection of one to three liver metastases. More recent studies have shown that resection is possible in patients with a greater volume of disease. Currently, the main consideration is not the total number of liver metastases but whether enough viable liver can be preserved to provide adequate liver function. What about patients with initially unresectable disease that becomes resectable after chemotherapy— what is their survival? French investigators have shown that patients withunresectablediseasewhosediseasebecomesresectableafterchemotherapy have a similar prognosis as those whose disease was initially resectable, with 5-year survivals of 33% for the converted group. To examine long-term outcomes: of 184 patients with unresectable disease whose disease became resectable and who were followed for 5 years or more, 33% had a 5-year survival and 27% had a 10-year survival. There was a greater chance of achieving long-term survival with fewer than three metastases. Others have reported a 23% actual 5-year survival in downstaged patients. In patients with resectable disease, trials should address whether neoadjuvant therapy is useful and, if so, what type of therapy should be used. A European Organisation for Research and Treatment of Cancer (EORTC) study that used both preoperative and postoperative therapy stated that preoperative chemotherapy was beneficial, given that there was an increase in 3-year disease-free survival (DFS) in the treated group versus the surgery alone group (36.2% v 27.8%, respectively, for eligible patients). There was no difference in 5-year survival (51.2% v 47.8%). The benefit of preoperative chemotherapy is not clear because patients received both preand postoperative therapy. Ninety-four percent of these patients had one to three liver metastases and other favorable characteristics. Do patients with good characteristics need preoperative chemotherapy? Are there poor-risk groups who would be helped by preoperative chemotherapy? In patients with unresectable hepatic metastases whose disease can be converted to resectable disease, what is the best preoperative chemotherapy regimen? The article by Ye et al attempts to answer this conversion question. For this type of trial, what is the definition of resectability? A multidisciplinary hepatobiliary team is needed to address this question. Are certain types of patients less likely to have disease that can be made resectable, such as patients with involvement of hepatic veins or inferior vena cava involvement? A Memorial SloanKettering Cancer Center trial outlined the reasons for unresectability for each patient and then reported which of these patients had disease that was made resectable, thus providing a framework to compare studies. Are there patients whose disease can be made resectable but who do not benefit from resection? Do some patients have a higher recurrence rate? Do techniques that enable more patients to undergo resection, such as portal vein embolization, two-stage resection, and radiofrequency ablation, produce a higher rate of recurrence? These are questions that need to be addressed in future trials. Is adjuvant chemotherapy after hepatic resection useful? The initial randomized trials of fluorouracil/leucovorin versus no treatment did not show a clear increase in progression-free survival, but a multivariable pooled analysis of two studies showed a significant benefit. Adding irinotecan to fluorouracil/leucovorin did not increase overall survival or DFS. Infusional fluorouracil, leucovorin, and oxaliplatin after resection has not been tested in a randomized study. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 16 JUNE 1 2013