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

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

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.

Study Overview

• Status: Completed
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Procedure: Liver Resection

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510000
      • Sun Yat-sen University Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Resection group; Surgical resection group: The patients underwent liver cancer resection and were followed up regularly after surgery.	Procedure: Liver Resection; Surgical resection treatment: laparoscopic or open liver resection is performed, and targeted and immunotherapy are not continued after surgery.
No Intervention: Non-surgical resection group; 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?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival	Resection group: time from start of randomization to first recurrence/death. Non-resection group: time from start of randomization to first tumor progression/death.	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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation of serum tumor molecular marker with survival	Correlation of serum tumor molecular marker methylation level with pCR in surgery group and tumor progression in non-surgery group.	24 months

Collaborators and Investigators

• Sponsor: Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Actual): May 5, 2022
• Primary Completion (Actual): December 31, 2025
• Study Completion (Actual): January 14, 2026

Study Registration Dates

• First Submitted: April 22, 2022
• First Submitted That Met QC Criteria: April 22, 2022
• First Posted (Actual): April 27, 2022

Study Record Updates

• Last Update Posted (Actual): January 15, 2026
• Last Update Submitted That Met QC Criteria: January 14, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Conversion Reaction
• Additional Relevant MeSH Terms: Mental Disorders; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Carcinoma; Somatoform Disorders; Carcinoma, Hepatocellular; Conversion Disorder; Surgical Procedures, Operative; Digestive System Surgical Procedures; Hepatectomy
• Other Study ID Numbers: B2022-119-X01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No