Thermal ablation in the curative treatment of colorectal liver metastasis: new standard of care?—lessons learned from the COLLISION trial

Colorectal cancer (CRC) is the third most common cancer worldwide and represents a serious global health issue. During the disease course, up to 50% of patients will develop liver metastases [colorectal liver metastasis (CRLM)] with a significant negative impact on survival (1,2).

Liver resection (LR), in combination with chemo- and targeted therapies, is the standard curative treatment for CRLM. In selected patients and in specialized centers, the 5-year overall survival (OS) after LR may reach 50% (3,4). Currently, parenchymal sparing liver surgery (PSLS) stands as the gold standard of the surgical management of CRLM (5-7). By avoiding unnecessary extensive resections, PSLS reduces significantly surgical morbidity and mortality without compromising local control (LC), survival and retreatment options when compared to large anatomical resection (5-7). Ablation techniques are widely used for the curative treatment of CRLM (3). Indications of ablation have witnessed a progressive shift moving from an exclusive treatment of unresectable lesions and/or of patients unfit for surgery towards a curative modality either as an adjunct to LR to increase resectability of multiple/bilobar disease or as a substitute to LR for small solitary lesions which would otherwise require a major or a technically challenging LR. In this setting, and by avoiding significant sacrifice of non-tumoral parenchyma, ablation satisfies the principles of PSLS. Several previous retrospective studies compared the results of ablation combined with LR to LR alone in the treatment of CRLM and reported lower rates of postoperative adverse events, shorter hospital stay with comparable survival when both techniques were associated (8,9). Similarly, the prospective non-randomised Microwave Ablation Versus Resection for Resectable Colorectal liver metastases (MAVERRIC) trial investigated the results of ablation versus LR in the treatment of CRLM smaller than 3 cm with no more than 5 nodules (10). The authors reported no differences in survival with however wider possibilities of retreatment in case of recurrence after ablation (10).

The COLLISION trial, recently published in Lancet Oncology, is the first randomised controlled phase 3 non-inferiority trial comparing thermal ablation (TA) to LR for CRLM ≤3 cm (11). The primary endpoint was the OS. The final analysis enrolled 148 patients from 14 centers in each arm.

The trial stopped early after a preplanned interim analysis that demonstrated a high likelihood of non-inferiority with TA regarding OS [hazard ratio (HR) =1.05; 95% confidence interval (CI): 0.69–1.58; P=0.83], per-patient (HR =0.13, 95% CI: 0.02–1.06; P=0.057) as well as per-tumor (HR =0.09, 95% CI: 0.01–0.74; P=0.024) LC with a lower complications rate when compared to LR. The 5-year OS was 51.2% (95% CI: 39.4–63.0%) for the TA group and 58.0% (95% CI: 53.4–62.9%) for the LR group. Subgroup analyses according to tumoral hepatic load subgroups, number of nodules, age, comorbidity index, primary tumor location and stage, molecular profile and preprocedural systemic therapy showed no differences between both groups.

Treatment-specific 90-days mortality rate was nil in the TA group versus 2% in the LR group. Similarly, adverse events were more frequent after LR for both low- and high-grade complications according to the CTCAE classification. Length of hospital stay was shorter in the TA group than in the LR group [1 (IQR, 1–44) versus 4 (IQR, 1–36) days, P<0.0001].

Notably, pathological R1 resection (<1 mm margins) rate was 12% and the imaging-based A1 ablation rate (<5 mm margins) was 5%. Both R1 and A1 were associated with local tumor progression with a recurrence rate of 36% after R1 resection and 47% after A1 TA during the follow-up period. Re-treatment of liver recurrence was more frequently achievable after TA (89% versus 33% in the LR group). Importantly, a close follow-up in case of A1 ablation is crucial for adequate and efficient re-treatment procedures.

Moreover, the COLLISION trial reported the results of percutaneous and intraoperative TA (mini-invasive and open) approaches. Post-hoc sensitivity analyses compared local tumor progression-free survival (LTPFS) and LC between the three different approaches and found no significant differences (LTPFS: HR =1.246; 95% CI: 0.747–2.080; P=0.399; LC: HR =0.074; 95% CI: 0.000–671.0; P=0.576). This relevant result may be considered as a reappraisal of intraoperative TA approaches especially in association with LR.

The COLLISION trial brings robust data about the safety and the oncological efficiency of TA in the treatment of small CRLM ≤3 cm. Nevertheless, several aspects warrant further discussion:

• The investigators enrolled patients with up to 10 CRLM. Patients were stratified into three subgroups according to the burden of the disease. Interestingly, in each group, median number of treated nodules was 2 and only 15% of patients had more than 5 nodules. Additionally, 118 patients (80%) in the TA group and 112 patients (76%) in the LR group had upfront treatment. This low rate of preoperative induction chemotherapy reflects the small proportion of high burden disease in the included population. Thereby, cautions must be taken in generalizing these results for patients with high-burden metastatic disease.
• The high rate of combined resection and ablation in both arms remains questionable. Indeed, 27 patients (18%) in the TA group had associated LR and TA was performed for 52 patients (35%) in the LR group. Importantly, only target lesions (ablated nodules in the TA group and resected nodules in the LR group) were considered for the local tumor control analysis. Nevertheless, the high rate of combined ablation-resection in the LR group may bias the interpretation of the primary endpoint OS.
• The trial suffered a high rate of missing data regarding molecular tumoral profile. In 101 patients (68%) in the TA group and 97 patients (65.5%) in the LR group, both RAS and BRAF status were lacking. Tumor biology is obviously among the strongest prognostic factors in the modern management of CRLM and previous reports highlighted the negative impact of both RAS and BRAF mutations on the oncological outcome after ablation and/or LR (12). Besides, RAS/KRAS mutations were associated with a higher rate of R1 resection (13,14) and requires larger ablation margin to achieve local control (15,16). A high rate of missing data may bias the interpretation of survival and even the local control results.

In conclusion, the prospective randomised controlled COLLISION trial showed the non-inferiority of TA compared to LR in terms of OS and local control for the management of small CRLM ≤3 cm, mainly in patients with oligometastatic disease. Ablation plays a pivotal role as a valid parenchymal-sparing technique avoiding the sacrifice of a large amount of parenchyma when a major LR is required and is no longer a palliative/rescue procedure when LR is deemed non-feasible. Ablation should always be considered for the management of early recurrences after LR. More importantly, LR and ablation are not mutually exclusive but should rather be combined as often as possible to increase resectability of CRLM which remains the best chance of long-term survival for patients.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article has undergone external peer review.

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