Patient with unresectable colorectal liver metastases and asymptomatic primary tumor: end of the debate!

In patients with definitively unresectable colorectal liver metastases, whether the primary tumor should be resected prior to chemotherapy is an old question.

Several retrospective studies (1-5) and a meta-analysis with individual data (6) had suggested that primary resection of the primary tumor followed by chemotherapy was associated with better survival than the chemotherapy-first strategy. The prevention of complications related to the primary tumor (occlusion, perforation, bleeding) as well as a better response to chemotherapy were usual justifications to explain the superiority of primary tumor resection-first.

However, the absence of any randomized study made it difficult to conclude on this question due to the numerous selection biases related to these retrospective analyses.

The year 2021 was marked by the publication of two randomized trials (a Japanese iPACS and a European trial: CAIRO4) (7,8) comparing upfront surgery for the primary tumor versus chemotherapy-first in patients with colorectal liver metastases and asymptomatic primary tumor.

In a Japanese multicenter randomized trial, Kanemitsu et al. (7) have included 165 patients with asymptomatic colorectal cancer (excluding cancers of the lower and middle rectum) and unresectable liver metastases, thus constituting two comparable groups, one treated by resection-first of the primary tumor followed by chemotherapy (experimental group) and the other by chemotherapy-first (control group). The hypothesis tested by the authors was that surgery-first may be superior to chemotherapy-first for overall survival.

After a median follow-up of 22 months, the first interim analysis concluded that the probability of demonstrating the superiority of the primary resection-first was very low, which led to stopping the trial prematurely. The median overall survival was 25.9 months in the experimental arm and 26.7 months in the control group, with postoperative mortality of 4% after colorectal surgery. Resection of the primary tumor was finally required in only 13% of patients in the chemotherapy-first group because of the onset of primary tumor-related complications. The subgroup analysis failed to identify a particular group of patients who might benefit from surgery of the primary. Still, it showed that surgery in patients with a performance status of 1 (outpatient but decreased physical activity) was associated with an increased risk of postoperative mortality. Finally, 6% of patients in the chemotherapy-first group underwent a secondary R0 resection of the metastatic lesions, after an excellent response to chemotherapy, compared to only 2% of patients in the primary resection group.

With similar inclusion criteria and design, the CAIROS-3 trial (196 patients included) conducted by a Danish-Dutch group reported a 60-day mortality of 11% in the primary surgery group versus 3% in the chemotherapy-first group. Among the 5 early deaths after primary tumor resection, one was attributed to surgical complications, and the other four were related to disease progression after colorectal surgery. So far, these results are those of preliminary analysis, and the data on overall survival are not yet available. However, there was a significantly increased risk of early mortality after surgery of the primary tumor compared to chemotherapy-first.

These two trials concluded that primary surgery in patients with unresectable liver metastases and an asymptomatic primary tumor could not be recommended. In addition, a subgroup that could potentially benefit from primary surgery could be identified.

While some methodological purists will argue that these results do not demonstrate the superiority of chemotherapy-first in terms of overall survival, our analysis of these results is different. Indeed, given the increased early mortality observed after surgery, the low risk of primary tumor-related complications while on chemotherapy, and the trend towards better control of the disease with a higher chance of secondary resection after chemotherapy, we believe that primary chemotherapy should be the standard treatment in these patients with unresectable liver metastases and asymptomatic primary tumor.

Two trials are currently underway (9,10) and will probably provide additional answers to this question if it has not already been definitively settled.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Hepatobiliary Surgery and Nutrition. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-22-176/coif). RA serves as an unpaid editorial board member of Hepatobiliary Surgery and Nutrition. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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