Surgical treatment strategies for multifocal hepatocellular carcinomas

The multifocality of hepatocellular carcinoma (HCC) still represents considerable challenges, with generally poorer outcomes compared to the single HCC (SH). According to the Barcelona Clinic Liver Cancer (BCLC) guideline, only patients with early-stage multifocal HCCs (MHs) (≤3 nodules and each ≤3 cm) or those meeting the extended liver transplant criteria are recommended to undergo liver transplantation (LT) or ablation [e.g., radiofrequency ablation (RFA) or microwave ablation (MWA)]. However, other countries, such as China, Japan and Korea, have controversy over the therapeutic strategy recommended by BCLC for MHs, believing that it is strict, resulting in loss of survival benefits from surgical treatments for some patients with intermediate-stage or even advanced MHs. Since 2014, we have been engaging in a series of clinical studies on MHs (1-8), and have proposed the surgical treatment strategies for MHs. Herein, we will share some viewpoints in surgical treatment strategies for MHs, aiming to provide the optimal treatment decision-making for surgeons.

MHs meeting the Milan criteria

LT is considered as the optimal treatment for patients with early MHs because it involves the largest possible hepatectomy and removal of underlying cirrhotic tissue. In 2014, we conducted a study (1) to compare the outcomes of Child-Pugh A patients with MHs meeting the Milan criteria between undergoing living donor liver transplantation (LDLT) and hepatic resection (HR). It showed the overall survival (OS) and recurrence-free survival (RFS) were significantly better in group LDLT than that in group HR (Table 1). Nevertheless, LT is not offered to all early MHs patients owing to the organ shortage and high dropout rates while on the waitlist. Hence, HR is still recommended as an alternative treatment for patients with early MHs in China. In contrast, BCLC staging only recommends the RFA as an alternative treatment of LT for the early MHs.

To assess whether HR can be as effective as RFA in treating early MHs, we designed a study, in 2015, to compare the outcomes of patients with early MHs undergoing HR or RFA (2). Our findings indicated that OS rates for patients undergoing HR were comparable to those receiving RFA. However, HR demonstrated a superior RFS rate (5-year RFS: 20.1% vs. 9.7%; P=0.001). Further stratified analysis highlighted that HR provided better RFS rates for patients with up to two lesions, while the HR’s advantage in RFS diminished when the number of lesions increased to 3. Moreover, HR showed better RFS for all lesions confined to a single lobe or sector, but when lesions dispersed different lobes or sectors, HR’s benefit in RFS was lost.

In 2015, we conducted additional study (3) to evaluate the impact of MHs’ anatomical distribution on the long-term outcomes post-hepatectomy. It showed that significantly higher OS and RFS rates for lesions located within the same sector, underlining the importance of lesion distribution in treatment planning and prognosis.

In 2016, we next carried out a study (4) to investigate the OS and RFS in patients with early-stage MHs undergoing various RFA techniques, including percutaneous, laparoscopic, and open RFA. It revealed no significant differences in postoperative complications, OS, and RFS rates among the three groups.

Likewise, in a recent cohort study from Italy (9), including 720 patients with MHs within the Milan criteria, HR exhibited a significant survival benefit over percutaneous RFA and transcatheter arterial chemoembolization (TACE).

MHs meeting the University of California San Francisco (UCSF) criteria

We further extended the MHs staging to the UCSF criteria and investigated their corresponding surgical treatment strategies. In clinical practice, combining HR and ablation permits the surgeon to remove larger lesions while simultaneously ablating any smaller residual lesions (≤3 cm) to achieve complete eradication of all lesions as HR. However, the decision between using HR plus ablation and HR alone for the early to moderately advanced MHs remains a topic of ongoing discussion.

In 2020, we designed a study (5) to compare the outcomes of patients with MHs meeting the UCSF criteria after HR plus intraoperative RFA or HR alone, and found that no significant difference existing in postoperative complications between two groups. Moreover, both modalities yielded comparable OS and RFS rates. Further stratified analysis found that HR alone resulted in better RFS than did HR + RFA for patients with two lesions, however, HR’s advantage in RFS diminished when the number of lesions increased to three. Moreover, HR alone was associated with better RFS than HR + RFA when the major lesion size was less than 3 cm, but this benefit for HR alone was not observed when the major lesion size exceeded 3 cm.

On the other hand, how much difference there is between HR + RFA and LDLT in treatment of MHs meeting the UCSF criteria remains unclear. In 2021, we conducted a study (6) to compare the outcomes of patients with MHs meeting UCSF criteria, treated either by LDLT or HR + RFA. Unsurprisingly, it demonstrated that LDLT offered significantly better OS and RFS than did HR + RFA, the fundamental reasons may be that transplant has the advantage of getting rid of the underlying chronic liver disease, but HR or RFA cannot do this and likely misses the smaller lesions.

Selected patients with moderately advanced MHs

The 2019 China Liver Cancer Staging (CNLC) recommended HR for selected MHs patients, specifically for those with three or fewer nodules. Next, we expanded our research to include patients with moderately advanced MHs characterized by 3 or fewer lesions, with the largest lesion >4.5 cm and the residual lesion(s) ≤3 cm, to investigate their appropriate surgical treatment strategies. In 2022, we conducted a study (7) assessing the outcomes of these patients following HR plus intraoperative RFA vs. HR alone, which showed that no significant difference in OS and RFS between the two groups. Further stratified analysis revealed that for patients with two tumors, HR alone was associated with better RFS than HR + RFA. However, this advantage of HR in RFS was not observed when the number of lesions increased to three. Moreover, HR alone yielded better RFS for patients whose lesions were all located within the same lobe. Conversely, when lesions were distributed across different lobes, HR alone did not maintain its advantage in RFS. Notably, en-bloc resection resulted in higher RFS compared to separate resection for patients with all lesions within the same lobe.

Another retrospective study from Lin et al. (10) in 2020, including 428 patients with MHs within the BCLC stage B, also showed that HR group had higher OS than the TACE + RFA and TACE groups.

Moderately advanced MHs (CNLC IIb stage)

In recent guidelines for HCC, including BCLC and CNLC system, surgical modalities have not been recommended to be the first-line treatment for the MHs with 4 or more nodules. But encouraging is that systemic therapies have improved the management of HCC. In 2022, we proposed that local therapies, including TACE or hepatic arterial infusion chemotherapy (HAIC), combined with systemic treatments, such as atezolizumab-bevacizumab, sorafenib, or lenvatinib, may increase the success rate of translational therapy for the CNLC IIb stage MHs (8). Then, surgical treatments in the main form of HR could also be adopted. However, there are few studies concerning this field so far. Well-designed, randomized trials are needed to investigate the therapeutic efficacy of this strategy for the CNLC IIb stage MHs.

In addition, MHs, compared to the SH, represent a high risk for HCC recurrence. Postoperative adjuvant therapies, such as local chemotherapy (HAIC) combined with systemic therapies may be applied in all MHs.

Based on the above clinical studies on MHs, we have delineated surgical treatment strategies for MHs, as illustrated in Figure 1.

Figure 1 The flow chart of surgical treatment strategies for multifocal hepatocellular carcinomas. For patients with MHs meeting the Milan criteria, LT is the first treatment option. If the patients have no condition for LT, HR should be recommended as the second treatment option, especially for those with two lesions or with all lesions within a single lobe or sector. Then if the patients have no condition for HR, due to poor liver reserve function or insufficient residual liver volume, ablation (e.g., RFA or MWA) is recommended as the third treatment option. For patients with MHs meeting the UCSF criteria, LT remains the first treatment option. If LT is unattainable, HR should be suggested as the second treatment option, especially for those with two lesions or the major tumor size of ≤3 cm. If the patients have no condition for HR alone because of insufficient residual liver volume, HR combined with intraoperative ablation (e.g., RFA or MWA) should be recommended as the third treatment option. For selected patients with moderately advanced MHs [3 or fewer lesions, with the largest lesion >4.5 cm and the residual lesion(s) ≤3 cm], HR alone is advocated as the first treatment option, especially for those with two lesions or all lesions within the same lobe. Furthermore, for all lesions within a single lobe, ER is recommended firstly because of higher RFS. If HR is unattainable, HR plus intraoperative ablation (e.g., RFA or MWA) is then recommended as the second treatment option. For patients with moderately advanced MHs (CNLC IIb stage), if the patients meet the “Up to seven” criteria, LT should remain the first treatment option; if not, local therapies (e.g., TACE or HAIC) combined with systemic treatments should be the first option. For those patients, if the tumor down-staging (the number of lesions ≤3) has been achieved, they should enter into the therapeutic process of above staging (e.g., MHs in Milan or UCSF or “Up to seven” criteria or selected moderately advanced MHs); if failed, previous local and systemic treatments should be maintained. For all patients with MHs undergoing surgical treatments, the postoperative adjuvant therapies (e.g., TACE or HAIC combined with systemic treatment) should be recommended. MHs, multifocal hepatocellular carcinomas; UCSF, University of California San Francisco; CNLC, China Liver Cancer Staging; LT, liver transplantation; HR, hepatic resection; ER, en-bloc resection; SR, separate resection; TACE, transcatheter arterial chemoembolization; HAIC, hepatic arterial infusion chemotherapy; RFA, radiofrequency ablation; RFS, recurrence-free survival; MWA, microwave ablation.

Acknowledgments

The authors thank Lunan Yan, MD, Yong Zeng, MD, Bo Li, MD, Tianfu Wen, MD, Hong Wu, MD, Wentao Wang, MD, Jiayin Yang, MD, Mingqing Xu, Zheyu Chen, MD, Jiwei Huang, MD and Yonggang Wei, MD for their guidance in this manuscript. The authors thank Yang Huang, MD and Junlong Dai, MD for his assistance in hand drawing.

Funding: This study was supported by the National Natural Science Foundation of China (No. 82470652 to L.J.), Sichuan Province Key Research and Development Project (No. 2019YFS0203 to L.J.), Key Clinical Research Incubation Project of West China Hospital of Sichuan University (No. 2020HXFH028 to L.J.), Key R&D Support Plan of Chengdu Science and Technology Bureau (No. 2021-YF05-00703-SN to L.J.), Sichuan Province Key Research and Development Project (No. 2022YFS0090 to L.J.) and Sichuan Natural Science Foundation project (No. 24NSFSC0237 to L.J.).

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-408/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-408/coif). L.J. reports funding from the National Natural Science Foundation of China (No. 82470652), Sichuan Province Key Research and Development Project (No. 2019YFS0203), Key Clinical Research Incubation Project of West China Hospital of Sichuan University (No. 2020HXFH028), Key R&D Support Plan of Chengdu Science and Technology Bureau (No. 2021-YF05-00703-SN), Sichuan Province Key Research and Development Project (No. 2022YFS0090) and Sichuan Natural Science Foundation project (No. 24NSFSC0237). The other authors have no conflicts of interest to declare.

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