Resection of asymptomatic primary tumour in unresectable stage IV colorectal cancer: time to move on from propensity matched scores to randomized controlled trials

Colorectal cancer (CRC) remains a major global disease burden with over 1.2 million new cases each year – about half of those who get the disease will die within 5 years of diagnosis. At the time of diagnosis, some 20% already present with stage IV disease, of which only a minority (15-20%) are amenable for attempt at curative resection (usually for liver metastasis), either as an upfront combined resection or as a staged approach with or without combinations of neoadjuvant systemic treatment . Despite several improvements in systemic therapy and modern surgical strategies for attempts at cure, the majority of patients with stage IV disease are unresectable and only amenable to palliative strategies. For patients who have a symptomatic primary (e.g. obstruction, perforation or bleeding) a surgical resection or stoma may be warranted if other attempts at bypassing the problem or as a bridge to later surgery is not possible (e.g. endoscopic stenting). In contrast, for those patients with stage IV disease having an asymptomatic primary tumour (either in colon or rectum) the role and potential benefit (if any) – and, notably, also the potential harm – of resection of the primary tumour has been much more controversial. Thus, the debate continues. Contestants against primary resection would argue that palliation is not possible if the patient does not have any symptoms to “palliate” and the limiting factor for survival is control of the metastatic disease and so systemic therapy should be prioritized. Proponents for resection of the primary tumour argue that reducing the tumour load reduces the disease burden and even disease progress, makes systemic therapy more effective and pre-emptively manages potential complications from occurring. Both sides may be right – and wrong. Indeed, a more aggressive approach to unresectable stage IV disease was seen in the past, with every 3 in 4 patients having the primary tumour resected, with a drop to just over every one in two being resected in the latter time period. Of notice, as the resection rates have dropped, the survival rates doubled from 8.6% in 1988 to 17.8% in 2009 (P<0.001). However, using the same datasets, other investigators have come to different conclusions regarding resections of asymptomatic primary tumours in otherwise unresectable stage IV colorectal cancer. Notably, these cohort studies sampled over longer time periods are biased towards the multiple factors that changed with the time and development in diagnostics, management and available systemic treatment that have not been controlled for in the comparative analyses. In this issue of the Journal, a nationwide cohort study from the Netherlands investigated survival after primary tumour resection in unresectable stage IV CRC. Using a propensity score matched approach, they found a survival benefit for those who underwent primary tumour resection (n52746) compared to systemic chemotherapy (n53345). When matched by propensity scores in a 1:1 fashion, resection was beneficial for survival when combined with systemic therapy both before and after resection, yet resection upfront with subsequent chemotherapy proved to be best. The authors conclude that this treatment should be entertained more often as an option, even for those with no symptoms from the primary tumour. While the findings may truly be so that primary tumour resection provides for a survival benefit, several points need to be considered before jumping to conclusions. Notably, propensity scores can be used in several ways, of which propensity score matching is one. This involves a matched modelling of assembled pairs of two interventions (in this case resection or no resection) to selected baseline characteristics in an attempt to reduce bias. It works similar to a randomized trial, except it is not randomized and it is not a trial. Propensity score matching is still based on matching of the available, chosen data for matching. In the current study, a total of 1737 (28,5%) of the patients were not ‘matchable’ (one third resected primary, two thirds non-resected) and thus excluded. As the authors matched pairs based on year of diagnosis, age, tumour location, morphology and number of organs with metastases (1 or >1), several factors that may influence survival were not matched for. Notably, presence of comorbidity (e.g. ASA score, Charlson-Deyo score, presence of any organ function deficits etc) or functional status (e.g. ECOG status level) were not available and thus not controlled for. Also, TNM stage was not matchable due to the nature of those non-resected (lacking a pTNM status). Thus, it may still be so that those who received surgery up front were deemed fitter and more likely to tolerate a surgical procedure. Or, alternatively, had less extensive disease overall. Further, one needs to scrutinize the choice of endpoint in the current setting of non-curable disease. When there are no symptoms to alleviate, one may question if overall survival is the best outcome measure to address. The added months of survival may truly be valuable for the individual patient, but one should consider at which risk and at what price this comes. For one, the current study had a 30-day mortality rate in the resected patients at 9%, which was similar for the systemic therapy group. These numbers are staggering, and far beyond those seen in any controlled trial of systemic therapy. However, they may actually reflect the truth in a real-life setting and, also, points to the risk of adversary effects of “just doing something” in a palliative setting. Given that all emergency resections (known E di to ri al