Revolutionizing hepatocellular carcinoma treatment: the advent of a new era of adjuvant therapy

Hepatocellular carcinoma (HCC) is the 6^th most common cancer worldwide with poor long-term outcomes (1). Surgical resection and liver transplantation are still the most effective treatments. However, the prognosis of HCC patients after resection is poor with 5-year recurrence rates as high as 70% (2). There are multiple risk factors for tumour recurrence post resection. Microvascular invasion (MVI) is considered a significant poor prognostic factor in early recurrence (3).

MVI is defined as invasion of tumour cells in a portal vein, hepatic vein or a large capsular vessel of surrounding hepatic tissues, partially or totally lined by endothelial cells visible only by microscopy of resected surgical specimens (4). Cong et al. (4) have proposed a three-tiered MVI grading system, classifying specimens as M0 (no MVI), M1 (1–5 sites of MVI, located at ≤1 cm away from the tumor-adjacent liver tissue) and M2 (>5 MVI sites or at >1 cm away from the tumor-adjacent liver tissue). MVI is common in HCC and is an independent risk factor for the disease-free survival (DFS) and overall survival (OS) of HCC patients. There is still no consensus on adjuvant therapy type after R0 HCC liver resection (5) although some have been proven beneficial (6,7).

Nonami et al. (8) was the first to identify the potential role of adjuvant hepatic artery infusion chemotherapy (HAIC) after resection in 1991, however subsequent studies had conflicting results. Chemotherapy regimens have evolved over the decades with epirubicin-based, cisplatin-based and oxaliplatin-based chemotherapy regimens (9). Hsiao et al. (10) found that adjuvant HAIC benefited selected group of HCC patients with MVI and multiple tumours. Two recent randomized controlled trials (RCTs) (11,12) found that adjuvant HAIC conferred survival benefits to HCC in patients in terms of DFS and OS but the sample sizes were too small. A meta-analysis (9) of postoperative adjuvant HAIC versus surgical resection alone for HCC also showed that postoperative adjuvant HAIC could improve the long-term prognosis of HCC patients especially those with vascular invasion, regardless of chemotherapy regimens.

Li et al. reported a prospective multicentre phase III RCT analyzing adjuvant HAIC in HCC patients with MVI (12). Three hundred and fifteen histologically confirmed HCC patients with MVI were randomly assigned (1:1) to receive adjuvant 5-fluorouracil and oxaliplatin (FOLFOX) or routine follow-up between June 2016 and August 2021. Using intention-to-treat analysis, the treatment group showed longer median DFS with acceptable toxicities. The results are important to discuss.

Firstly, DFS is an accepted endpoint in clinical oncology research due to four reasons: (I) in many cancers, DFS is a surrogate of OS; (II) measuring DFS takes less time, is less resource consuming and is financially prudent; (III) many cancers become symptomatic with recurrence of disease and thus DFS is a clinically important milestone in a patients journey; and lastly (IV) regulatory bodies approve novel drugs based on DFS data and pharma industry or researchers have minimal incentive to invest resources to pursue to demonstrate the benefit of OS. Thus, it is commendable that Li et al. actually studied OS as an endpoint and thus we are enlightened with the dichotomy of oncology outcomes i.e., improvement in DFS but no difference in OS (12). This is important, as most of the HCC recurrences are not symptomatic. Further, as HCC is not a slowly progressive cancer, mere improvement in DFS and not OS is not a clinically meaningful outcome from the clinician’s perspective, though it is possible that patients may be inclined to accept (or even demand) adjuvant therapy as certainly a possibility of psychological gain prevails in “being free of disease”.

Secondly, it is paradoxical to believe that adjuvant therapy has no role in HCC management when the contrary is true in most surgical oncology. This begs the question of an ideal adjuvant therapy that not only improves DFS but actually improves OS, i.e., life span of HCC patients. At best, the results of Li et al. serve to reassure that adjuvant HAIC therapy is safe, well tolerated, and probably controls the HCC progression and further research is necessary to investigate if DFS benefits can translate to OS gains (12). A recent meta-analysis including 2 RCTs and 9 non-RCTs with 1,290 total patients concluded that adjuvant HAIC improves both DFS and OS in HCC patients treated by hepatic resection (13). Thus, it is possible that a longer follow-up duration or larger sample size might show improved OS in HCC patients. The survival gains may not be universally uniform in all patients and it is essential to identify the patients who will reap maximal gains so that personalized value-driven patient-centric care for HCC patients can improve survival outcomes.

There are several limitations. Firstly, the study did not define the grading of MVI in patients. Sheng et al. (14) have shown that in the presence of MVI, HCC patients with M2 classification showed a worse prognosis after radical resection than those with M1 classification. Hence, the MVI grading type is significant. Secondly, all the participants are Chinese and the participating institutions are located in the south of mainland China. This area has a high incidence of liver cancer due to hepatitis B infection. The results of this trial might not be applicable for patients from Western countries. Thirdly, the insertion of the HAIC catheter into the appropriate position and removal after drug delivery is preferred over an implanted port system due to a guaranteed catheter position, reduced risk of infection and thrombosis despite being more costly. However, the increased invasiveness coupled necessity for the patient to be bedbound for >50 hours can affect treatment acceptance or compliance. We wonder if instead of a groin puncture, a radial arterial puncture would mitigate the inconvenience to patients.

Nonetheless, we congratulate the authors for publishing the first phase III prospective multicentre clinical trial evaluating adjuvant HIAC with FOLFOX for HCC patients with MVI. The data is encouraging if not revolutionizing and certainly, herald the emergence of a new era in HCC therapy. As recent as last week, the results of an industry-sponsored phase III prospective multicentre clinical trial evaluating adjuvant atezolizumab plus bevacizumab were presented at the American Association for Cancer Research annual meeting in April 2023, and at 17.4 months median follow-up, the investigators reported improvements in recurrence-free survival with adjuvant therapy compared to surveillance along after liver resection (15). It remains evident that the final word on adjuvant therapy for HCC is yet unwritten, and until such time we advocate that individual clinicians embrace evidence-based practices, encourage patients to participate in clinical trials, and remain malleable to adopt new evidence into clinical practice so patients are not deprived of an opportunity to survive longer.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-23-41/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-23-41/coif). The authors have no conflicts of interest to declare.

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