After radical resection or local ablation, 50% to 70% of patients with hepatocellular carcinoma will experience intrahepatic or extrahepatic metastases within five years, which is the most common cause of hepatocellular carcinoma-related death. For example, according to the BCLC HCC staging system, the recurrence rate for patients with primary hepatocellular carcinoma at "very early" or "early" stages is 40.7% at 5 years after liver resection and 29.3% after local ablation, while the recurrence rate after hepatic resection drops to 18% to 25% if hepatocellular carcinoma is "intermediate" or "advanced". Therefore, in order to prolong recurrence-free survival, many patients receive adjuvant therapy after radical resection or ablation. However, there is no international consensus on many aspects of adjuvant therapy, including which type of therapy is best for a particular type of patient, when it should be started, and how long it should be continued. There are even questions raised about whether adjuvant therapies are really effective in some cases.
Who can benefit from adjuvant therapy?
Adjuvant therapy is not recommended for all patients who have completely removed the tumour by surgery or ablation, and only specific patient populations at high risk of recurrence are recommended. Risk factors include tumor size greater than 5 cm, number of tumors greater than 3, vascular invasion, or poor tumor differentiation. Current guidelines recommend adjuvant therapy based on these factors, but other potential risk factors such as tumor capsule, tumor rupture, resection margin stenosis, or high alpha-fetoprotein levels are also associated with the risk of recurrence and may need to be considered in future guidelines.
Which adjuvant therapies work best?
The Chinese guidelines for liver cancer recommend transarterial chemoembolization, hepatic arterial perfusion chemotherapy, molecularly targeted drugs, and cellular immunotherapy. Topical therapy is not recommended in US and Korean guidelines, with the latest US guidelines recommending immune checkpoint inhibitors as adjuvant therapy for the first time. For patients with hepatitis B virus-associated hepatocellular carcinoma, US and Chinese guidelines recommend adjuvant antiviral therapy. Evidence on the efficacy of adjuvant therapy is still accumulating, and the following are the available phase 3 adjuvant clinical data:
| trial | treat | Median follow-up | RFS | THE |
| IMbrave 050a | atezolizumab + bevacizumab (334) versus active surveillance (334) | 17.4 | Not reached (HR 0.72, 95% CI 0.56–0.93) | not applicable |
| Mazzaferro等 | Interferon α (76) versus no treatment (74) | 45 | 5-year 24.3% vs 5.8% | 5 years 58.5% |
| Yoshida等 | Vitamin K2 45 mg (182), 90 mg (185) vs Placebo (181) | not applicable | 17.8 months in all arms (HR 1.15, 95% CI 0.84–1.57) | 99.2%, 98.7% and 97.2% respectively for 1 year |
| Chen等 | Interferon α-2b(133) versus no treatment (135) | 63.8 | 42.8 vs 48.6 months | 5-year 75.4% vs 72.5% |
| Lee et al | CIK cells (115) versus placebo (115) | 40 and 36.5, respectively | 44 versus 30 months (HR 0.63, 95% CI 0.43–0.94) | NR(HR 0.21, 95% CI 0.06–0.75) |
| NIK-333 | Peretinoin 600mg (134,300mg) vs 129 | 30 | 43.7%, 24.9% and 29.3% over 3 years | not applicable |
| STORM | Sorafenib (556) vs Placebo (558) | 23 and 22, respectively | 33.3 versus 33.7 months (HR 0.94, 95% CI 0.78–1.13) | NR(HR 1.00, 95% CI 0.76–1.3) |
| SiLVER | Based on sirolimus (261) versus no sirolimus (264) immunosuppressive regimen | 96 | 70.2% versus 64.5% at five years (HR 0.84, 95% CI 0.62–1.15) | 74.6% vs 68.4%(HR 0.81, 95% CI 0.58–1.13) |
| Li et al | FOLFOX-HAIC(157) versus no treatment(158) | 23.7 and 21.5, respectively | 20.3 versus 10.0 months (HR 0.59, 95% CI 0.43–0.81) | 80.4% versus 74.9% at three years (HR 0.64, 95% CI 0.36–1.14) |
When should adjuvant therapy be started?
Although adjuvant therapies can have some side effects that are difficult to avoid, there is no single major guideline that recommends when to start using them. Most clinical studies are conducted 4 to 8 weeks after surgery. The specific initiation time is related to perioperative complications, wound healing, residual liver function, the patient's own condition, and comorbidities.
How long should adjuvant therapy last?
The optimal duration of adjuvant therapy has not been established. In some studies, although the planned duration of treatment was as long as 48 months, the actual duration of treatment was actually shortened to about 12-13 months due to poor treatment response and the appearance of side effects. For example, the combination of atezolizumab and bevacizumab was planned to last 12 months, but the actual median duration was 11 months. However, a prospective study showed that only 6 months of treatment was sufficient to prolong recurrence-free survival.
This suggests that 12 months of treatment may be too long for some patients. The duration of adjuvant therapy should be based on the mechanism of action of the treatment and the specific circumstances of the patient. In particular, patients with early, resectable disease may not need the same treatment regimen as patients with unresectable hepatocellular carcinoma. For example, patients with chronic hepatitis B virus infection may require long-term or even lifelong antiviral therapy. In summary, the treatment plan should be individualized, taking into account efficacy, patient tolerability, and disease characteristics.
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1.Llovet JM, Pinyol R, Yarchoan M, et al. Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma. Nat Rev Clin Oncol. 2024; 21(4):294-311. doi:10.1038/s41571-024-00868-0
2.Zhong JH. Adjuvant therapy for hepatocellular carcinoma: Dilemmas at the start of a new era. World J Gastroenterol. 2024; 30(8):806-810. doi:10.3748/wjg.v30.i8.806
Source: International Hepatobiliary Information