Pulmonary Metastasectomy versus Continued Active Monitoring in Colorectal Cancer (PulMiCC): a multicentre randomised clinical trial

Abstract

BackgroundLung metastasectomy in the treatment of advanced colorectal cancer has been widely adopted without good evidence of survival or palliative benefit. We aimed to test its effectiveness in a randomised controlled trial (RCT).MethodsMultidisciplinary teams in 13 hospitals recruited participants with potentially resectable lung metastases to a multicentre, two-arm RCT comparing active monitoring with or without metastasectomy. Other local or systemic treatments were decided by the local team. Randomisation was remote and stratified by site with minimisation for age, sex, primary cancer stage, interval since primary resection, prior liver involvement, the number of metastases, and carcinoembryonic antigen level. The central Trial Management Group were blind to patient allocation until completion of the analysis. Analysis was on intention to treat with a margin for non-inferiority of 10%.ResultsBetween December 2010 and December 2016, 65 participants were randomised. Characteristics were well-matched in the two arms and similar to those in reported studies: age 35 to 86 years (interquartile range (IQR) 60 to 74); primary resection IQR 16 to 35 months previously; stage at resection T1, 2 or 3 in 3, 8 and 46; N1 or N2 in 31 and 26; unknown in 8. Lung metastases 1 to 5 (median 2); 16/65 had previous liver metastases; carcinoembryonic antigen normal in 55/65. There were no other interventions in the first 6 months, no crossovers from control to treatment, and no treatment-related deaths or major adverse events. The Hazard ratio for death within 5 years, comparing metastasectomy with control, was 0.82 (95%CI 0.43, 1.56).ConclusionsBecause of poor and worsening recruitment, the study was stopped. The small number of participants in the trial (N = 65) precludes a conclusive answer to the research question given the large overlap in the confidence intervals in the proportions still alive at all time points. A widely held belief is that the 5-year absolute survival benefit with metastasectomy is about 35%: 40% after metastasectomy compared to < 5% in controls. The estimated survival in this study was 38% (23–62%) for metastasectomy patients and 29% (16–52%) in the well-matched controls. That is the new and important finding of this RCT.Trial registrationClinicalTrials.gov, ID: NCT01106261. Registered on 19 April 2010

Long-Term Outcomes in Percutaneous Radiofrequency Ablation for Histologically Proven Colorectal Lung Metastasis

“…Currently, no RCT exists that compares thoracic surgery versus image-guided ablation and will be difficult to achieve. The recent Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) trial (comparing surgery vs active monitoring) had to be stopped due to failure to recruit the required number of patients [44]. An RCT in the setting of colorectal lung metastases would also be of questionable value, given many patients receive multiple different treatment modalities throughout their course.…”

Questioning the benefit of lung metastasectomy in colorectal cancer

“…But a controlled trial provides data on survival of patients who were eligible for lung metastasectomy but who were randomly assigned to not have the operation. Estimated survival at four years for the control group was 40% (26% to 63%) and at five years was 29% (16% to 52%) 2. This far exceeds the common assumption that survival for these patients is close to zero.…”

“…In The BMJ five years ago my colleagues and I questioned the appropriateness of a policy of early detection of colorectal metastases for surgical resection 1. We now have direct evidence from a randomised controlled trial (RCT) that any survival advantage from resection of colorectal lung metastases is, in all likelihood, very much smaller than has been assumed 2…”

“…There have been many uncontrolled reports of lung metastasectomy with five year survival of around 40%,3 a figure matched in the Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) trial (38%, 95% confidence interval 23% to 62%) 2. But a controlled trial provides data on survival of patients who were eligible for lung metastasectomy but who were randomly assigned to not have the operation.…”

Another Brick in the Wall: Further Evidence Supporting the Efficacy of Thermal Ablation

“…Resection, thermal ablation and radiation therapy of colorectal lung metastases are common clinical practices and recommended by the ESMO (European Society of Medical Oncology) guidelines in oligometastatic patients although the proof of clinical benefit on overall survival remains unclear. Some randomized control trials like the PulMiCC Trial aimed at evaluating this benefit but failed to enroll patient [1]. Clear benefits in terms of delaying chemotherapy [2] and low invasiveness of thermal ablation made the technique popular among referring medical oncologist and patients.…”