Trial Information

Oncologic Outcomes of Surgical Versus Non-surgical Methods for the Treatment of Resectable Colorectal Liver-confined Metastases Converted From Initially Non-resectable Metastases by FOLFOX-4 Neoadjuvant Chemotherapy: A Randomized Clinical Trial

In 2000, de Gramont et al. and Giacchetti et al. reported that combination chemotherapy
including modulated infusional 5-Fu plus irinotecan and oxaliplatin could achieve a response
rate of approximately 50% and a median survival of in excess of 20 months. These encouraging
results implied that chemotherapy is likely to play an increasingly important role in
decreasing the size of metastasis to allow for liver resection. Interestingly, Adam and
Bismuth et al. reported that the 5-year overall survival of 50% (95% confidence interval
33-68%), observed in patients with resection following neoadjuvant chemotherapy, was
comparable to patients with primarily resectable hepatic metastasis as reported by Scheele
et al. (39%, 469 patients), Fong et al. (37%, 1001 patients), Nordlinger et al.(28%, 1568
patients), and Fiqueras et al. (36%, 235 patients). Recently, Zelek et al. reported that
intravenous and hepatic artery infusion of irinotecan/ 5-fluorouracil/ leucovorin could
facilitate complete resection of initially non-resectable hepatic metastases. Pozzo et al.
indicated that neoadjuvant treatment of unresectable liver disease with irinotecan/
5-fluorouracil/ leucovorin enabled a significant portion of patients to undergo surgical
resection. Alberts et al. showed that FOLFOX-4 therapy allowed for successful resection of
disease in a portion of patients initially not judged to be optimally resectable but with a
high recurrence rate after surgery. Masi et al. reported that neoadjuvant approach with
irinotecan plus FOLFOX-4 had significant antitumor activity and provided a radical surgical
resection of initially unresctable hepatic colorectal metastases with promising median
survival of patients. However, most studies published till now are retrospective analyses
without a control group or case series with limited patient number and/or short time of
follow-up. Therefore, the role of surgical resection in the subset of patients with
resectable hepatic metastases converted from initially non-resectable liver metastasis was
still not clearly established. To further explore the oncologic results of surgical versus
non-surgical methods for the treatment of this subset of patients, we designed and conducted
the present randomized prospective study beginning in 2002. The present study was based on
the following arguments against the predominant survival benefits of surgical resection in
previous reported series: (1) The initially non-resectable liver metastasis was basically a
disseminated disease, even though some metastases were highly responsive to chemotherapy and
become resectable; (2) Since the evaluation of resectability was based on the imaging
studies, it was difficult to consider the surgical resection as "curative" for the
resectable hepatic metastases converted from non-resectable ones, given the limitation of
the current imaging stools of high-technology; (3) The resectable hepatic metastases after
neoadjuvant chemotherapy might represent a subset of hepatic metastases biologically highly
responsive to chemotherapy and the time-to-progression for these metastases might be fairly
long after a response. Additionally, these metastases might be also biologically responsive
to other cytotoxic or targeted therapies that justified the patients' continuous adoption of
non-surgical treatment.