Timing means everything, maybe.

Many patients with colorectal cancer will have liver metastases at the time of their initial diagnosis (synchronous) or will develop liver metastases at some point after undergoing potentially curative therapy for their primary disease (metachronous). For a large proportion of patients with metastatic colorectal cancer, whether synchronous or metachronous, the metastases will be restricted to the liver. A number of questions exist on how best to care for patients with liver metastases from colorectal cancer. These include the role and timing of chemotherapy, as well as the role and timing of surgery. To date, much of what we have learned about the appropriate care of patients with liver metastases has come from retrospective summaries of institutional experience. However, a small but growing number of clinical trials exist. One area of uncertainty surrounds the management of patients with synchronous liver metastases that may be resectable. In particular, is it best to initially resect both the primary and the metastases, to initially give chemotherapy, or a combination of these two approaches such as to resect the liver metastases, give chemotherapy, and then remove the primary? 1 In general, patients with synchronous disease do not do as well as patients with metachronous disease. 2 Overall survival appears to be shorter and the rate of recurrence after a potentially curative resection appears to be higher. It has therefore been advocated by some to use neoadjuvant chemotherapy as a surrogate method of determining outcome. In prior retrospective series, patients with stable or responding disease have done better than those with progressive disease. Based on this information it had been suggested that the appropriate approach is to give neoadjuvant chemotherapy to assess response. In the current issue of Annals of Surgical Oncology Dr. Gallagher and colleagues summarize the approximately 9year experience of management of patients with potentially resectable synchronous liver metastases from colorectal cancer. 3 The retrospective analysis specifically addresses the relationship of response to preoperative chemotherapy to outcome in 111 patients undergoing resection. In this series the response of patients receiving neoadjuvant chemotherapy did not predict overall survival. Patients with a partial or complete response had a median overall survival of 58 months compared with 61 months for patients with evidence of progression. This result is surprising for several reasons. First, it appears to contradict prior reports. Second, the patients in this series undergoing resection with evidence of progressive disease had a higher rate of positive surgical margins (39%) compared with those with responding disease (5%) and yet seemed to have lived as long. We are therefore let to ponder how long-held beliefs of factors predicting outcome could now be less relevant. In an earlier retrospective series Dr. Adam and colleagues showed that response to neoadjuvant therapy is a meaningful predictor of outcome in patients with potentially resectable liver metastases from either synchronous or metachronous disease. 4 In this series 78% of patients with stable or responding disease had synchronous disease compared with 53% of patients with progressive disease. In addition, the proportion of patients with a curative resection was lower in patients with progressive disease. In a separate retrospective study Dr. Allen and colleagues specifically reviewed the impact of neoadjuvant chemotherapy in patients with synchronous disease. 2 Using a group of 106 patients, 52 who received neoadjuvant chemotherapy and 54 who went initially to surgery, 5-year survival was shown to be statistically similar between the two groups. Of note 28% of patients going directly to surgery did not receive postoperative chemotherapy. However, when a comparison was made between patients receiving neoadjuvant chemotherapy who did not progress