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

1. Memorial Sloan-Kettering Cancer Center, New York, NY1. Corresponding author: Nancy E. Kemeny, MD, Memorial Sloan-Kettering Cancer Center, 300 East

66th St, New York, NY 10065; e-mail: kemenyn@mskcc.org.

It is not the most intellectual of the species that survives; it is not the strongest that survives; but the species that survives is the one that is able best to adapt and adjust to the changing environment in which it finds itself.

Leon C. Megginson, paraphrasing Charles Darwin1(p4)

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 al2 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%,3 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 with unresectable disease whose disease becomes resectable after chemotherapy have a similar prognosis as those whose disease was initially resectable, with 5-year survivals of 33% for the converted group.4 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.5 There was a greater chance of achieving long-term survival with fewer than three metastases. Others6 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) study7 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 pre- and 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 al2 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 Sloan-Kettering Cancer Center trial8 outlined the reasons for unresectability for each patient and then reported which of these patients had disease that was made resectable,6 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.9 Adding irinotecan to fluorouracil/leucovorin did not increase overall survival or DFS.10 Infusional fluorouracil, leucovorin, and oxaliplatin after resection has not been tested in a randomized study. Given that the majority of recurrences after hepatic resection are in the liver, adjuvant hepatic arterial infusion (HAI) may be useful. In the study by Ye et al,2 66.7% of patients experienced relapses: 16% in the lung, 16% in the abdomen, and 66.7% in the liver. Clearly, the liver has to be protected to prevent relapse. Of four randomized trials that compared adjuvant HAI after liver resection with systemic therapy or a control arm, three demonstrated a significant decrease in hepatic DFS as well as overall DFS.11–15The strengths of the study by Ye et al2 include a detailed description of patient characteristics and surgical review to decide when patients were appropriate for resection. The study could be improved by providing a clear explanation as to why patients were not believed to have resectable disease. Although reasons for unresectability are listed, factors such as the number of lesions and size may not have been accepted as valid by other investigators. The authors do not describe the technical reasons for not performing resection and how the patient's condition changed to make resection possible. The trial by Ye et al mentions that the patients were observed and voted on by a group of surgeons to assess resectability after therapy. But conversion trials should have a surgical review of patients to confirm that they are, in fact, considered to have unresectable disease before entry. The surgical review should also outline the reasons that the patients were initially not considered to have resectable disease and which types of patients had disease that ultimately became resectable.Response rate may be a more important end point in conversion trials. High response rates may allow more patients to undergo resection. For example, in the article by Ye et al,2 the Cetx group had a 57% response rate with a 25% resection rate, whereas with chemotherapy alone, there was a 24% response and only a 7% resection rate. The pathologic response may be even more important, and pathologic details about complete response, partial response, and fibrosis should be included and compared with outcomes.16The ability of anti–epidermal growth factor receptor agents to increase response rates and resection when added to chemotherapy has been clearly shown in a number of trials (Table 1). The resection rates are higher with chemotherapy plus Cetx, but, in general, lower rates are reported in the other trials compared with the trial by Ye et al.2 In the study by Ye et al, the majority of patients had one to four metastases, no major vessel involvement, and an intermediate risk score. Is their cohort therefore more favorable? The difference also may be that this study was organized by a surgical group who was clearly interested in performing liver resections. In large trials that are conducted by medical oncologists, an interest in liver resection may not be as strong.

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Table 1.Randomized Studies Using Chemotherapy With or Without Targeted Agents

Other ways of producing increased response rates have been studied, such as adding more active chemotherapy agents together, for instance, in the trials studying fluorouracil, leucovorin, oxaliplatin, and irinotecan, in which response rates are high. In one randomized study,17 the triple drug regimen increased the resection rate to 36% from 12% with fluorouracil, leucovorin, and irinotecan. If the goal is to decrease the maximum volume of disease, then HAI combined with systemic chemotherapy may be an option. In one study,8 70% of patients had a 75% or greater reduction in tumor volume, despite the fact that 56% of patients had received previous chemotherapy. For patients who progress while receiving systemic therapy, HAI may be another option to reduce tumor size and enable resection (Table 2).

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Table 2.Nonrandomized Conversion Studies Using Triple Therapy or HAI to Enable Conversion

Modern systemic chemotherapy has made increasing conversion rates a reality. Future studies should address which regimens are optimal. The trial by Ye et al2 adds to the other randomized trials in Table 1, suggesting a modest increase in response rate and resection rate by the addition of an anti–epidermal growth factor receptor agent to chemotherapy. Future trials should compare fluorouracil, leucovorin, oxaliplatin, and irinotecan or HAI plus systemic therapy to the regimen used by Ye et al. Once the patients undergo resection, the issue of recurrence, what type of recurrence, and which is the best salvage therapy should be addressed.

Does downstaging patients with unresectable hepatic metastases from colorectal carcinoma make a difference? Yes. Future studies should strive to increase the proportion of patients downstaged and to reduce the rate of recurrence.

 

AUTHOR'S 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.

The author(s) indicated no potential conflicts of interest.