Liver metastases are found in 40 to 50% of the nearly one million people diagnosed in the world each year with colorectal cancer.  Despite advances in chemotherapy five year survival for metastatic colorectal cancer is less than 5%. In the subset of patients where surgery to remove liver metastases (resection) is possible, five year survival increases to 60 %.  Recurrence after surgery in this group, however, is common. It has been suggested that the combination of chemotherapy and surgery can reduce the risk of relapse. The rationale for this is that preoperative chemotherapy allows surgery to be undertaken on tumours that have shrunk in size, while postoperative chemotherapy acts on any cancer cells remaining in the liver.

This multi-centre trial, which was led by Bernard Nordlinger, from the Hôpital Ambroise Paré ( Paris, France), and involved researchers from Europe, Australia and Hong Kong, set out to investigate whether combining perioperative chemotherapy with surgery could reduce the risk of relapse compared to surgery alone. The collaboration represents one of the few studies to have investigated combining chemotherapy with surgery in such patients, and is the first to assess the benefits of preoperative chemotherapy.

In the trial, 364 patients, with histologically proven colorectal cancer and up to four operable liver metastases, were randomised to receive surgery alone (n=182) or surgery plus the FOLFOX4 chemotherapy regimen with six cycles before and six cycles after (n=182).  The FOLFOX4 regimen consisted of calcium folinate (leucovorin), followed by bolus injection of 5-fluorouracil and a 22 hour infusion of 5-fluorouracil on days one and two, and oxaliplatin on day one.  Patients were recruited from 78 hospitals in 11 countries.

Upon further evaluation, 11 patients in each arm were found to be ineligible for inclusion so that in total 152 patients in the surgery alone group and 151 in the chemotherapy and surgery group underwent liver surgery.

In an intention to treat analysis results show that progression free survival does not differ significantly between the two groups (P=0.058 versus the required P=0.0434). However a second analysis,  just including the patients who were able to undergo surgery, shows that the progression free survival at three years was 33.2 % in the surgery only group versus 42.4 % in the adjuvant chemotherapy group (HR 0.73, P=.025). This was statistically significant and represents an absolute increase in progression free survival of 9.2 %.  Progression free survival is defined as the time until progression, recurrence or death. Overall survival is still being monitored.

The most common adverse events seen with preoperative chemotherapy included neutropenia, diarrhoea, stomatitis/pharyngitis and neurological toxicities. Similar side effects were seen following postoperative chemotherapy with the exception of stomatitis/pharyngitis. Reversible post operative complications (such as biliary fistula, hepatic failure, wound infection and urinary infection) occurred more frequently in patients who had received chemotherapy than the surgery only group (25 % versus 16%, p=0.04).

“We conclude that perioperative FOLFOX4 chemotherapy reduced the risk of events of progression free survival by a quarter and was compatible with major surgery,” writes Nordlinger and colleagues, adding that although the trial was restricted to patients with four or fewer metastases, the conclusions are likely to be valid for those at higher risk.  Future trials, they add, should look at more intense chemotherapy or combinations with targeted agents.

In an accompanying editorial Scott Kopetz and Jean-Nicolas Vauthey, (University of Texas MD Andersen Cancer Centre, Houston, TX),write: “Despite the modest benefits on progression-free survival, this study clearly shows the advantage of preoperative FOLFOX to select the patients most likely to benefit from hepatic resection.”

The study, they add, confirms the importance of multidisciplinary care and the improved outcomes that can be achieved when the best of medical and surgical oncology are integrated.

Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial.
Bernard Nordlinger et al.  Lancet 2008, 371:1007-16.