According to reports of the 2018 International Agency for Research on Cancer, colorectal cancer (CRC) is the third most common cancer worldwide. In this report, the Korean incidence of CRC was the highest worldwide, although there has been a recent decrease in the annual domestic statistics [1, 2]. When the disease is diagnosed without metastasis, the 5-year survival rate is over 70%. However, more than 20% of CRC cases are found with distant metastases, and overall survival (OS) is only about 14% to 20% [3]. Even for stage IV CRC, radical resection, including metastatic lesions, is mandatory to achieve long-term survival. However, in 65% of patients with stage IV CRC, radical surgery is not possible [4]. Upfront active chemotherapy, including various biological agents, is recommended in the current treatment guidelines [5]. However, primary tumor resection (PTR) or other palliative surgical treatments such as stoma formation or bypass surgeries are inevitable in cases of complications such as intestinal obstruction, hemorrhage, or perforation for symptomatic relief and further medical treatment. In asymptomatic patients at the time of diagnosis, many clinicians have performed upfront PTR before chemotherapy [6] because of the concern of future complications from the primary lesion during chemotherapy despite the debate about the usefulness of PTR in those situations [4, 6-15].

The treatment for these cases should be provided by a multidisciplinary team approach consisting of surgical, medical, and radiation oncologists, along with pathologists and radiologists [16, 17]. By considering the resectability, location, and size of the primary/metastatic tumor, the treatment strategies are decided in consideration with the patient’s preference, socioeconomic status, symptoms, and general condition. Therefore, various combinations of medical or nonmedical pretreatment factors can be involved in treatment decisions. To date, the reason why the debate about the advantage of PTR for asymptomatic CRC patients with unresectable metastasis continues is because of the lack of confirmative results of a well-controlled randomized trial [18, 19]. For studies supporting PTR, most points of criticism have been about their selection bias because of the various pretreatment factors mentioned earlier, which cannot be easily controlled [20].

In this study, we evaluated the effectiveness of PTR using the IPTW method, a recently emerging statistical tool to minimize selection bias by adjusting the baseline confounders.

In this study, we showed that asymptomatic CRC patients with unresectable metastases could achieve a survival gain by upfront PTR independently from the patients’ likelihood of undergoing PTR based on their baseline characteristics by analysis with the IPTW method.

There are significant conflicts in the study of the impact of PTR on survival [6]. According to a study, PTR is performed in over 50% of patients with stage IV CRC, and many doctors still prefer routine use of this treatment. This may be because many current studies suggest that PTR can provide significant survival benefits [7, 10, 12, 15, 23-25]. In a Canadian study of stage IV CRC patients who underwent chemotherapy between and 2006 to 2010, 199 patients underwent upfront PTR, and 127 patients did not [24]. Ninety-one percent and 67% of patients received doublet chemotherapy and biologic agents, respectively. The median OS was significantly higher in the PTR group (27 months vs. 14 months). However, their results were not free from selection bias because there was a significant imbalance in the distribution of confounders, a higher rate of multiple organ metastasis (M1b), and worse performance status in the non-PTR group. In a post hoc analysis of 294 patients with non-resectable CRC metastases who were enrolled in a phase III randomized controlled trial (RCT), patients who underwent PTR before enrollment showed higher rates of OS than non-PTR patients [23]. However, the majority of PTR patients had single organ metastases (M1a) in the liver. Similarly, in a meta-analysis using survival data from 21 retrospective studies with a total of 44,226 patients with metastatic CRC, the mortality rate was lower with PTR than with chemotherapy alone. However, all but 2 of the studies in the analysis were single-center and the other 2 studies used administrative databases with limited information about how patients were selected for the PTR [7].

These continued conflicts are because of the lack of firm results of the level I study. To answer this question, some clinical trials are ongoing [18, 19, 26, 27]. Kanemitsu et al. [28] reported their interim analysis results of an RCT at the 2020 American Society of Clinical Oncology meeting after early termination due to 50% of the expected event. They enrolled 160 patients, which was about half of the target enrollment number (n= 280). The upfront PTR showed no survival benefit over the chemotherapy alone; the PTR group’s median progression-free survival was 10.4 months (8.6–13.4 months) and that of chemotherapy alone was 12.1 months (9.4–13.2 months; HR, 1.08; 95% CI, 0.77–1.50). Although the overall results of the remaining RCTs are expected, Kanemitsu’s assertions imply that they would not be easy to see. Because all RCTs on this issue carry numerous intrinsic difficulties caused by strict eligibility criteria, patient preferences, and clinician bias lead to poor acceptance of the randomized assignment and difficulties in patient accrual.

In this retrospective study, we could see the survival benefit of upfront PTR. However, as mentioned earlier, this study has a fundamental limitation that cannot be free in this kind of study. The metastatic tumor burden and personal response to chemotherapy may be different for each patient. However, because of the lack of information on retrospective medical record review, we could not obtain detailed data. Although a sincere effort to reduce the selection bias, the patients selected from our database are those who visited our department of surgical oncology. Therefore, doctors in this department might have a strong tendency to prefer PTR. Additionally, because of the long period of study, most of the earlier decisions were not made with multidisciplinary team discussions. Inevitably, the patients enrolled in this study have a strong likelihood of getting upfront PTR. To overcome this issue, we used the weight from the average treatment effect on the treated (ATT). ATT is the one of the generally used treatment effects typically considered in causal inference. The other is the average treatment effect (ATE), which is the average effect of the treatment across the entire eligible sample, including the control sample’s treatment effect. In a well-constructed RCT with perfect compliance to treatment assignment, both values must be the same. However, in the nonrandomized, observational studies like ours, the assignment of treatment can be influenced by various confounders such as patients’ willingness or surgeon’s preference for the PTR, which is not easily measurable. Endogenous selection bias is inevitable when using the ATE, referring to the entire study population, including those who did not receive the PTR. However, by using the ATT weight focusing only among those who received the PTR, we can estimate the effect of PTR in patients who received the real PTR by comparing in an assumed situation where the PTR patients might not receive the PTR [21, 29].

In conclusion, after minimizing the fundamental limitations of this retrospective study, this study demonstrated the beneficial impact of PTR on unresectable stage IV CRC patients. However, the debate about this issue will continue until the confirmative results of ongoing RCTs.