Surgery vs. Watch-and-Wait Strategy in Complete Responders for Hepatocellular Carcinoma

Prior treatment

• Inability to undergo safe curative liver resection, an expectation that R0 resection cannot be achieved, or another medical factor that prevents surgical consolidation.
• Previous liver transplantation or current plans for liver transplantation.
• Active gastrointestinal bleeding within 4 weeks before randomization or a coagulation disorder that continues to fall outside study requirements after appropriate correction.
• Previous immune-related adverse events not recovered to Grade 1 or lower that may affect the safety of surgery or continued systemic treatment. Stable endocrine immune-related adverse events controlled with replacement therapy are permitted.
• Another active malignancy within the previous 5 years, except for a malignancy treated with curative intent and considered to have a low risk of recurrence, such as carcinoma in situ of the cervix or nonmelanoma skin cancer.

Other illness

• Clinically significant and uncontrolled portal hypertension or another condition that substantially increases the perioperative risk of liver resection, including recurrent gastroesophageal variceal bleeding or refractory ascites.
• Active infection, sepsis, or another serious infectious disease requiring systemic anti-infective treatment that may affect the safety of surgery or systemic therapy.
• Severe cardiac, pulmonary, renal, or other major organ dysfunction, or another serious comorbidity that would prevent tolerance of curative liver resection and/or continued systemic treatment.
• Inability to undergo standardized multiphase contrast-enhanced CT or MRI, or a condition that may substantially interfere with accurate radiologic assessment.
• Any other condition that, in the investigator's judgment, may affect participant safety, study adherence, or the reliability of study results and makes the individual unsuitable for participation.

Other

• Fibrolamellar HCC, sarcomatoid HCC, combined hepatocellular-cholangiocarcinoma, or another atypical HCC histologic subtype.
• Definite extrahepatic metastasis before initiation of the treatment that resulted in the current rCR, or any extrahepatic metastasis identified before randomization.
• Decompensated cirrhosis or Child-Pugh class B or C hepatic function.
• Pregnancy or breastfeeding.
• A medical, psychological, social, or adherence-related factor that would prevent receipt of either randomized treatment strategy.

• Voluntary participation and provision of written informed consent.
• Age 18 to 80 years, inclusive.
• HCC confirmed by histology or cytology or diagnosed according to accepted clinical diagnostic criteria. Histologic or cytologic confirmation is generally required for participants without cirrhosis.
• No definite extrahepatic metastasis before initiation of the anticancer treatment that resulted in the current radiologic complete response (rCR).
• Previous treatment with a PD-1/PD-L1 inhibitor combined with a targeted or anti-angiogenic agent, with or without locoregional treatment such as transarterial chemoembolization, hepatic arterial infusion chemotherapy, radiotherapy, or ablation.
• Continued use of the same systemic regimen between the first documented rCR and confirmatory imaging. Dose modification or temporary interruption for toxicity is permitted, but changing treatment because of insufficient efficacy is not permitted.
• rCR confirmed according to mRECIST by repeat imaging performed 4 to 8 weeks after the first documented rCR.
• Multidisciplinary team assessment confirming that curative-intent liver resection is medically and technically feasible, R0 resection is expected to be achievable, and perioperative risk is acceptable.
• Child-Pugh class A and indocyanine green retention rate at 15 minutes (ICG R15) \<30%.
• Future liver remnant (FLR) generally \>=40% of standard liver volume (SLV) for participants with chronic liver disease, substantial hepatic parenchymal injury, or cirrhosis, and generally \>=30% of SLV for participants without substantial fibrosis or cirrhosis.
• Pretreatment tumor thrombus involving the portal vein, hepatic vein, and/or inferior vena cava is permitted, but atrial tumor thrombus is not permitted. Previously present macrovascular tumor thrombus must show no definite radiologic activity after treatment and must be considered completely resectable by the multidisciplinary team.
• No extrahepatic metastasis or other active HCC lesion on contrast-enhanced CT and/or MRI of the chest, abdomen, and pelvis before randomization.
• Eastern Cooperative Oncology Group performance status of 0 or 1.
• Adequate organ function before randomization, including:
• Hemoglobin \>=90 g/L;
• Absolute neutrophil count \>=1.5 x 10\^9/L;
• Platelet count \>=60 x 10\^9/L;
• Total bilirubin \<=1.5 times the upper limit of normal (ULN);
• AST, ALT, and alkaline phosphatase \<=2.5 times the ULN;
• Serum creatinine \<=1.5 times the ULN or endogenous creatinine clearance \>=50 mL/min;
• Urine protein \<2+, or 24-hour urinary protein \<1.0 g.
• No active bleeding, with international normalized ratio \<=1.5 times the ULN and activated partial thromboplastin time \<=1.5 times the ULN.
• Participants with hepatitis B virus infection must receive appropriate antiviral treatment according to local standards and agree to continue treatment during the study. Participants with an indication for antiviral treatment must start treatment during screening if they are not already receiving it.
• Participants with hepatitis C virus antibodies must undergo hepatitis C virus RNA testing and must not have active hepatitis C virus infection.
• Medically eligible for both surgical consolidation and continued systemic maintenance therapy and willing to receive the randomly assigned strategy.
• Women of childbearing potential must have a negative pregnancy test before randomization and agree to use effective contraception during study treatment and for the required period after the last dose. Nonsterilized men with partners of childbearing potential must also agree to use effective contraception.