Watch and Wait Versus Surgical Treatment for Clinical Complete Responders After Non-Curative Therapy for Hepatocellular Carcinoma

Study Overview
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Brief Summary
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Hepatocellular carcinoma (HCC) accounts for more than 90% of primary liver cancers and is the sixth most common cancer in the world and ranked third in mortality. Most patients with HCC are diagnosed at an advanced stage and miss the opportunity for radical surgical resection, therefore, most patients receive mainly non-curative local and systemic treatments. Anti-angiogenic drugs with immunotherapy for unresectable HCC has achieved an objective response rate of about 30%. In addition, transarterial hepatic artery chemoembolization and hepatic artery infusion chemotherapy have further increased the objective response rate and depth of tumor regression. For patients with initially unresectable HCC, conversion therapy can result tumor shrinkage and downstaging, ultimately allowing patients the opportunity to undergo resection. However, it raise the question of whether surgical resection of the tumor is still necessary after achieving clinical complete response? On the one hand, some researchers believe that as long as resection is feasible, the tumor must be completely removed. Viable tumor cells may still remain and become a source of tumor recurrence. On the other hand, some researchers believe that patients who achieve clinical complete response after conversion therapy can consider a non-surgical watch and wait strategy. Whether the inactive lesions with clinical complete response still require surgical resection is still inconclusive. This study compared the efficacy and safety of surgical resection versus non-surgical resection in the treatment of hepatocellular carcinoma patients who achieved clinical complete response after hepatic arterial intervention (chemoembolization/infusion chemotherapy) combined with targeted and immunosuppressive therapy. It is expected to provide reliable clinical evidence support for guiding the treatment of such patients.

Official Title
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Watch and Wait Versus Surgical Treatment for Clinical Complete Responders After Non-Curative Therapy for Hepatocellular Carcinoma: A Phase II Randomized Clinical Trial

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Procedure: Liver Resection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years old. Patients with clinical diagnosis of hepatocellular carcinoma without extrahepatic metastasis, and two liver surgeons evaluated as unresectable. AFP≥400ug/L or PIVKA-II≥1000mAU/mL before initial treatment. Initial treatment is hepatic arterial intervention (chemoembolization/infusion chemotherapy), combined targeted therapy (sorafenib, lenvatinib, donafenib, apatinib, bevacizumab) and immune checkpoint inhibitor therapy (PD-1\PD-L1). After transarterial infusion chemotherapy combined with targeted and immunotherapy treatment, the tumor evaluation is clinical complete response, that is, the following two criteria are met: 1. Two consecutive imaging assessments (one month apart) tumor complete response (CR, mRECIST) standard) 2. Two consecutive tumor markers (one month apart) AFP and PIVKA-II ≤ the upper limit of the normal value The patients with clinical complete response were evaluated by two liver surgeons as resectable. Normal hematological function (platelets>75×109/L; leukocytes>3.0×109/L; neutrophils>1.5×109/L) Serum bilirubin ≤ 1.5 times the upper limit of normal (ULN), transaminases ≤ 3 times ULN No ascites, normal coagulation function, albumin≥30g/L Child-Pugh class A Serum creatinine less than 1.5 times the upper limit of normal (ULN) ECOG score 0-1 Life expectancy > 3 months Exclusion Criteria: Received other tumor treatments other than hepatic artery interventional therapy, targeted and immunotherapy Any of the following conditions within the first 12 months of the study: myocardial infarction, severe/unstable angina, coronary artery bypass grafting, congestive heart failure, cerebrovascular accident (including transient ischemic attack), Pulmonary embolism; ongoing: arrhythmia of grade ≥2 by NCI-CTCAE criteria, QTc prolongation (>450 ms in men, >470 ms in women); Renal insufficiency requires peritoneal dialysis or hemodialysis; Serious dysfunction of other important organs; A second primary malignant tumor was diagnosed in the past; Known or new evidence of brain or leptomeningeal lesions; Hemophilia or bleeding tendency, taking anticoagulation therapy such as coumarin derivatives in therapeutic doses; Pregnant or lactating women, all female patients of childbearing potential must undergo a pregnancy test (serum or urine) within 7 days before enrollment, and the result is negative; History of previous organ transplantation; Known HIV infection; Allergy to chemotherapy drugs; Patients with other serious acute or chronic physical or psychiatric diseases or abnormal laboratory tests that may increase the risk associated with participating in the study, or may interfere with the interpretation of the study results or the investigators consider unsuitable for enrollment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Resection group<br>Surgical resection group: The patients underwent liver cancer resection and were followed up regularly after surgery. | Procedure: Liver Resection<br>* Surgical resection treatment: laparoscopic or open liver resection is performed, and targeted and immunotherapy are not continued after surgery.<br>|
| No Intervention: Non-surgical resection group<br>Stop hepatic artery interventional therapy (chemoembolization/infusion chemotherapy), continue the original targeted and immunotherapy for no more than 1 year | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | assessed using mRECIST criteria, defined as the survival rate of patients without tumor progression from randomization to the end. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to treatment failure | Defined as the time from randomization to the first documented treatment failure (ie, local recurrence or progression or death from any cause). | 24 months | 
| Overall survival | defined as the time from randomization to death from any cause. | 24 months | 
| pCR rate in surgery group | Pathological complete response (pCR) was defined as the absence of residual viable tumor cells on hematoxylin and eosin staining on completely resected tumor specimen sections. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Conversion Reaction