What is the standard chemotherapy for colorectal cancer patients with resectable liver metastases?

Bert H O'Neil and Richard M Goldberg*  About the authors

For many years patients with colorectal cancer and isolated, liver-confined or lung-confined distant metastases have been known to have a substantial chance of long-term survival after surgical metastatectomy. As such, one might want to include this population of patients in adjuvant chemotherapy studies, particularly given their favorable long-term prognosis, which lies somewhere between that observed for patients with stage IIIB–IIIC disease.¹ Historically, however, patients with resected metastatic disease have been excluded from adjuvant clinical trials, which has left clinicians to use extrapolation or guesswork for decision-making in regard to adjuvant therapy for this population. A few valiant efforts have been made at studying this patient group.² In the majority of these studies, however, patients were treated with hepatic arterial infusion.³ None of the trials was powered to demonstrate the small but meaningful differences in overall survival that have interested oncologists in stage III adjuvant studies.

One of the largest studies of postoperative fluorouracil (5-FU)-based therapy was conducted in France and Switzerland by the Fédération Francophone de la Cancérologie Digestive (FFCD) (the ACHBTH AURC 9002 trial); 173 patients were enrolled between the years 1991 and 2001.² Enrollment was adjusted from a planned 200 patients owing to slow accrual and lack of acceptance by participants of a surgery-only control arm. The primary end point of the study was disease-free survival, and in fact 5-FU given in accordance with the Mayo Clinic schedule resulted in a significant improvement in 5-year disease-free survival (from 26.7% to 33.5%, an absolute difference of 6.8%) compared with untreated patients. Median disease-free survival improved from 17.6 to 24.4 months for patients who received 5-FU postoperatively.² Multivariate analysis showed chemotherapy to be an independent predictor of improved progression-free survival. Overall survival was not significantly improved—perhaps because of the inadequate sample size—but a similar trend towards improvement was seen with overall survival at 5 years (41.9% versus 51.1% for control and 5-FU arms, respectively). The ACHBTH AURC 9002 study was not published until 2006,² at which time the EORTC Intergroup phase III study 40983 of perioperative FOLFOX4 versus observation after surgical resection (conducted in a similar population of patients to that of ACHBTH AURC 9002) was well underway.⁸

Given the difficulty of enrolling adequate numbers of patients to the FFCD trial, it is noteworthy that the EORTC was able to complete a study of chemotherapy versus observation in 4 years.⁸ The 40983 study was described as having a "pragmatic" design. This approach was sensible, insomuch as a bias remains among surgical and medical oncologists that synchronous metastatic colorectal cancer is best treated with chemotherapy to rule out aggressive and widespread disease, even when tumors are readily resectable.⁹ Thus, a design incorporating perioperative therapy allowed the study to be maximally inclusive of the target patient population. The goal of the 40983 study was not, therefore, to validate preoperative or perioperative chemotherapy per se, but rather to validate adjuvant chemotherapy in general in this difficult-to-recruit patient population.⁸

The investigators of the EORTC trial randomly allocated 364 patients to receive perioperative FOLFOX4 (three cycles of combined oxaliplatin, folinic acid and 5-FU before and after surgery) or observation. Importantly, 11 patients in each arm were ineligible for surgery, mostly because they had more than three liver metastases, the maximum allowable number. 159 (87%) versus 170 (93%) patients in the FOLFOX4 and control arms respectively, actually went to the operating room.⁸ Of those, 151 and 152 patients in the respective arms were completely resected, which suggests—unsurprisingly given the study population—that chemotherapy, in itself, did not influence resectability. Surgical complications were slightly more frequent in the perioperative chemotherapy group than the observation group. The complications that were different both related to liver function, biliary fistula and hepatic failure (including bilirubin >10 mg/dl for more than 3 days). Mortality did not differ significantly between the two groups.⁸

When data from the intention-to-treat population was analyzed for the primary end point of progression-free survival, the hazard ratio was 0.79 (P = 0.058), indicating a non-significant trend toward improved survival favoring chemotherapy.⁸ When only eligible patients were studied, the hazard ratio decreased to 0.77 (P = 0.041). For this group, the absolute difference in progression-free survival at 3 years was 8.1% (36.2% for the FOLFOX4 group versus 28.1% for controls).⁸ By contrast the FFCD study using 5-FU and leucovorin had a positive outcome (i.e. progression-free survival was improved) for the intention-to-treat population.²

These results raise two important questions. First, is FOLFOX4 the definitive standard of care for patients with resectable liver metastases? Second, is preoperative therapy either necessary or beneficial in this population of patients? In regard to the first question, an interesting feature is that the magnitude of benefit of FOLFOX4 in patients with resectable liver metastases⁸ does not seem to be greater than that of 5-FU/leucovorin alone in the FFCD study.² With the important caveat that these studies had different inclusion criteria, one would have expected that in a high-risk population oxaliplatin would have demonstrated a proportionally larger benefit than 5-FU/leucovorin. Does this finding mean a study of FOLFOX4 versus 5-FU/leucovorin should be carried out? For such a study to be undertaken when important questions about the efficacy of biologic agents are yet to be answered seems unlikely. The results of the EORTC study were in some ways disappointing,⁸ but on the basis of all available data we are confident that FOLFOX remains the standard adjuvant chemotherapy for patients with stage III–IV colorectal cancer. Preoperative randomization in the EORTC study⁸ resulted in an increased number of ineligible patients (owing to extensive disease found at surgery), which also makes the two studies somewhat difficult to compare.^{2, 8} In regard to the second question, the study was not designed to compare preoperative versus postoperative treatments, given the lack of any chemotherapy in the control arm.⁸ In spite of this limitation, many people have cited this study as evidence that perioperative chemotherapy is now the standard of care. One interesting surgical trend potentially confounds this interpretation; that of simultaneous resection of primary tumors and metastatic disease in the same operation. In fact, a large, multi-institutional, retrospective study confirmed in 2007 that the safety of simultaneous resection is equivalent to that of two-stage surgical resection in patients who require minor hepatic resection.¹⁰ As such, should we interpret these data as suggesting that both surgeries should be delayed in patients with synchronous disease until six cycles of chemotherapy have been given? In our opinion the answer is no; immediate surgical resection of primary and metastatic disease is very reasonable in this setting. A second argument for immediate surgery in a patient with metachronous metastatic disease is the opportunity to detect small liver or peritoneal metastases. Such small tumors could well become undetectable with chemotherapy, which could potentially give the physician and patient a false sense of security in the face of incurable disease. For example, in the EORTC 40983 study the tumors of 18 patients who went to surgery were not resected, mostly because of the discovery of more-advanced disease than expected from their preoperative staging. Only eight patients in the chemotherapy arm did not undergo resection, which suggests that a considerable number of actually incurable patients were deemed potentially curable.

To conclude, the combined results of the FFCD 9902 and EORTC 40983 studies validate the long-standard practice of administering adjuvant chemotherapy to patients with resected, metastatic colorectal cancer. Whether oxaliplatin adds benefit to 5-FU in this setting might never be answered definitively, but the weight of evidence from the 40983,⁸ MOSAIC¹¹ and NSABP C-07¹² studies suggest that FOLFOX should be the reference therapy for this group of patients. Finally, dependent upon clinical circumstances, we believe that either perioperative or postoperative chemotherapy are reasonable treatment options until head-to-head comparisons of preoperative and postoperative chemotherapy have been completed.

Competing interests

BH O'Neil has received honoraria and research support from Pfizer and Sanofi-Aventis. RM Goldberg declared no competing interests.

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