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Surgical resection alone is regarded as the standard of care for patients with liver metastases from colorectal cancer, but relapse is common. We assessed the combination of perioperative chemotherapy and surgery compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer.

This parallel-group study reports the trial’s final data for progression-free survival for a protocol unspecified interim time-point, prodail overall survival is still being monitored.

Patients were centrally randomised by minimisation, adjusting for centre and risk score. Primary analysis was by intention to treat. Analyses were repeated for all eligible vs and resected patients vs This trial is registered with ClinicalTrials.

After surgery we recorded two deaths in the surgery alone group and one in the perioperative chemotherapy group. Perioperative chemotherapy with FOLFOX4 is compatible with major liver surgery and reduces the risk of events of progression-free survival in eligible and resected patients.

Chemotherapy and surgery combined can reduce the risk of relapse. Preoperative chemotherapy potentially allows surgery on small tumours that have become smaller after preoperative chemotherapy or in response to chemotherapy. Postoperative chemotherapy should theoretically be effective in dormant cancer cells in the remnant liver.

It improves the outcome of patients with stage III colon cancers 4 and therefore might also be effective in stage IV disease after surgery. Previous phase III trials comparing combined treatment to surgery alone did not recruit the targeted number of patients and thus did not have sufficient statistical power.

Some trials used intrahepatic arterial infusion and others intravenous chemotherapy. Consequently, a varied pattern of practice has evolved. Although surgical resection alone is still regarded as the standard of care, many patients are given combined treatment. Others receive chemotherapy alone and are not referred to liver surgeons, even though their hepatic metastases are resectable. Thus, there remains a need for clear evidence for whether combined treatment with chemotherapy is better than surgery alone in patients with resectable liver metastases from colorectal cancer.

The present European Intergroup trial aimed to compare perioperative chemotherapy—ie, before and after surgery—with surgery alone in patients with one to four hepatic colorectal cancer metastases that are considered to be resectable on imaging. The trial design did not attempt to assess preoperative versus postoperative chemotherapy. To be eligible for enrolment, patients had to be aged between 18 and 80 years with a WHO performance status of 2 or less, histologically proven colorectal cancer, one to four liver metastases that were potentially resectable, and no detectable extrahepatic tumour.

The primary tumour had to be either already resected R0 resection or judged to be resectable in case of synchronous metastases by the multidisciplinary team at the treating hospital. Patients with previous chemotherapy with oxaliplatin were excluded. Pregnant or breastfeeding women were also excluded. Clinical examination, chest radiography, abdomino-pelvic CT scan with contrast medium spiral CT was recommended or MRI, electrocardiogram, and standard laboratory work-up were undertaken within 14 days of study entry.

The trial was approved by the medical ethics committees of all participating centres. Written informed consent was obtained from all patients before randomisation. Randomisation was done at the European Organisation for Research and Treatment of Cancer EORTC Headquarters in Brussels with the minimisation technique, 11 and was stratified for centre, previous adjuvant chemotherapy to primary surgery for colorectal cancer, and a risk score derived from Nordlinger and colleagues.

Each cycle of chemotherapy lasted 14 days, with the subsequent cycle to start on day In both groups, the study treatment had to start within 3 weeks of randomisation.

In the perioperative chemotherapy group, liver resection was done 2—5 weeks after the last administration of preoperative chemotherapy, and whenever patients had completely recovered from side-effects of chemotherapy with a WHO performance status of 0 or 1, and adequate liver function. Surgical exploration consisted of inspection of the peritoneal cavity to exclude extrahepatic involvement, and histological examination of frozen sections of any suspicious lesion. We used intraoperative ultrasonography to detect and localise all hepatic metastases.

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Prorakl type and vao of curative liver resection wedge resection, or monosegmentectomy or plurisegmentectomy was decided by the surgeon with the multidisciplinary team at the treating hospital at the time of randomisation, but was modified if previously undetected deposits were discovered, or if the tumour was larger than was expected.

Clinical and neurological examination and assessment of haematology, biochemistry, and toxic effects 12 were undertaken before each chemotherapy cycle, and up to 30 days after treatment.

An abdomino-pelvic CT scan or MRI was done after the first three chemotherapy cycles, and before and after liver surgery. The tumour response in the liver was assessed by contrast CT scan after three and six cycles of preoperative chemotherapy and was scored according to response criteria in solid pforail RECIST 14 by the local radiologist; no confirmation of response was needed.

Chest radiography, abdominal ultrasound or CT scan, and carcinoembryonic antigen concentrations were assessed every 3 months for 2 years after the end of treatment and every 6 months thereafter. Recurrence was diagnosed by imaging, cytology, or histology. When deemed unresectable or ;rorail recurrence, patients were treated at the physician’s discretion. The primary trial endpoint was progression-free survival, counted from randomisation to the date of either progressive or recurrent disease, surgery if metastases were deemed not resectable, or death of any cause.

To address the lead-time bias that was inherent to the design, the event time to have occurred at 10 weeks was assigned proeail both treatment groups in the following circumstances: Week 10 was chosen as pforail in the middle of these 20 weeks. Rates of progression-free survival were estimated by the Kaplan-Meier method 16 and compared by the logrank test. In all analyses, patients stayed assigned to the group that they had been randomly allocated to.

The primary analysis was done in all randomised patients. Sensitivity analyses not protocol-specified but decided before data analysis were undertaken both in all eligible patients and all those with resectable liver metastases. Inference about overall survival is deferred until longer follow-up becomes available.

The trial is registered with ClinicalTrials. The study design, management, data analysis, and data interpretation were done at the EORTC headquarters Brussels, Belgium independently of any commercial interest and from all funding bodies. BN and LC had full access to all the data in the study.

The corresponding author had final responsibility for the decision to submit for publication. Figure 1 shows the trial profile. No log was kept of the number of patients who were screened for eligibility.

Patient and tumour characteristics were much the same between the two groups at baseline table 1. The reasons for ineligibility were more advanced disease than was allowed by the protocol five in perioperative chemotherapy group and six in surgery groupprimary liver cancer one in both groupsno data two in perioperative chemotherapy group and three in surgery groupsecond cancer one in surgery group with colon cancerlate informed consent one in perioperative chemotherapy grouphigh serum creatinine one in perioperative chemotherapy groupand resection of primary less than 14 days of randomisation one in perioperative chemotherapy group.

Table 2 shows compliance, treatment tolerance, and treatment response in the perioperative chemotherapy group, and table 3 the toxic effects. We recorded no deaths due to toxic effects. Partial or complete response according to RECIST was recorded in more than two-fifths of patients and the total lesion diameter was reduced by about a quarter after chemotherapy table 2.

Of the eight patients who could not undergo resection, unresectability was due to appearance of new lesions in four. None of these patients started the postoperative protocol chemotherapy.

Apart from one patient randomly assigned to surgery alone who received the whole perioperative chemotherapy at his request, none of the patients in the surgery group received chemotherapy before recurrence.

Patients may have several complications, therefore number of complications does not add up to the total number of patients.

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Common toxicity criteria 10 version 2. More patients received the operation in the surgery group than in the perioperative chemotherapy group table 4. In both groups, a similar number of patients received potentially curative resection table 4.

The most frequent reason for non-resectability was disease that was more advanced than was expected table 4. In one patient, resection was not done because of macroscopic liver damage, which was most probably related to chemotherapy. Further results regarding the translational research and pathology will be presented elsewhere.

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Table 3 shows the tolerance to postoperative chemotherapy. Figure 1 shows the reasons why postoperative protocol chemotherapy was not started in the remaining patients. We recorded events of progression-free survival the primary endpoint in all randomised patients figure 1including events in eligible patients. A total of patients have died figure 1. A All randomly assigned patients.

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B All eligible patients. C All resected patients. For all patients randomly assigned and those who were eligible, no surgery or no resection were regarded as events for the primary endpoint of progression-free survival. Adjustment of the primary analysis for the stratification factors risk grouping and previous adjuvant chemotherapy did not change the results data not shown. We have shown that perioperative chemotherapy with FOLFOX4 reduced the risk of progression-free survival events at 3 years by a quarter in patients with resectable liver metastases.

In all patients randomly assigned to study treatments, the study showed a trend favouring administration of chemotherapy, which was not significant when a correction was used for the different timings of surgery in the two treatment groups.

In all eligible and all resected patients the benefit was statistically significant. Our results have shown that perioperative chemotherapy was compatible with major liver surgery. Reversible complications of surgery were more frequent in patients who had received preoperative chemotherapy than in those who had received surgery alone, but remained within the range commonly noted after resection of liver metastases.

In patients with advanced colorectal cancer, several studies have compared various chemotherapy regimens. However, very few prospective studies have investigated the combination of chemotherapy with surgery, and none has assessed perioperative chemotherapy.

Most trials did not achieve the planned recruitment for multifactorial reasons table 5. This trial met its target accrual, thanks to an intercontinental collaboration involving Europe, Australia, and Hong Kong. Any future trial of this type is unlikely to have a surgery-only group. Previous studies of adjuvant chemotherapy in patients with resected liver metastases from colorectal cancer.

The primary objective of this trial was to assess perioperative chemotherapy in patients qualifying for resection of their metastatic disease. Had we assessed postoperative chemotherapy only, randomisation could have been done after successful resection of the metastases, and no patient would have been excluded because of ineligibility or unresectability. Because of the specific objective in our trial, patients had to be randomly assigned imperatively before surgery—ie, without any certainty that metastases assessed by imaging were actually resectable.

This uncertainty represents a fundamental difficulty for all studies assessing preoperative treatment and makes such studies difficult to undertake and analyse. For example, in the MAGIC Medical Research Council Adjuvant Gastric Infusional Chemotherapy trial 13 that assessed perioperative chemotherapy in gastric cancer, many randomised patients did not undergo complete resection of the cancer.

In our trial, some metastases that were initially considered to be resectable at randomisation were actually more advanced and not resectable at surgical examination. Therefore we examined not only all randomised and eligible patients, but also those who received resection.

All analyses were done according to the allocated treatment group ie, including the patients who did not receive the allocated treatment. The number of patients who finally underwent resection was much the same in both treatment groups.