Editor’s Note: Recently, Professor Shichun Lu’s team from the Chinese PLA General Hospital published an article titled “Application of Proportion of Viable Tumor Cells in Prognosis Evaluation of Initial Unresectable Hepatocellular Carcinoma Patients Undergoing Sequential Surgical Treatment After Conversion Therapy” in the professional journal Chinese Journal of Hepatobiliary Surgery. The study retrospectively analyzed clinical data and pathological evaluations of 80 initially unresectable HCC patients who received PD-1 antibody combined with tyrosine kinase inhibitors (TKIs) as conversion therapy followed by sequential surgical treatment. The research team confirmed the value of the proportion of viable tumor cells (RVTCs) in surgical pathology specimens as a prognostic marker for patients undergoing conversion surgery and identified the optimal threshold for RVTCs (15%) and factors influencing achieving RVTCs ≤ 15% postoperatively.
Study Overview
Study Methods
Inclusion Criteria Patients with initially unresectable HCC due to one of the following:
- Presence of extrahepatic metastasis or major vascular invasion.
- Multiple tumors not confined to the same liver segment.
- Insufficient residual liver volume post-surgery.
Patients received conversion therapy based on PD-1 antibody combined with TKI, successfully converted to resectable status, and underwent curative surgical resection with pathological examination of surgical specimens.
Patients received postoperative adjuvant therapy: those achieving complete pathological response (CPR) received PD-1 antibody monotherapy for 6 months, while non-CPR patients continued the original conversion regimen for 12 months.
Initial diagnosis included abdominal lesions evaluated by enhanced MRI and systemic metastasis assessed by PET-CT. During treatment, abdominal enhanced MRI evaluated the treatment effect every three cycles, and preoperative enhanced MRI and PET-CT assessed abdominal lesions and systemic metastasis, respectively.
Main Observations Baseline characteristics of patients, tumor size, number, stage, tumor markers, conversion therapy regimen, treatment cycles, and imaging evaluations. Preoperative imaging was evaluated using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Pathological specimen examination procedures were designed by the Hepatobiliary and Pancreatic Surgery and Pathology Departments of the PLA General Hospital, based on conventional HCC pathology methods and the characteristics of advanced HCC immuno-targeted conversion therapy.
Statistical Analysis The relationship between RVTCs and patient recurrence-free survival time was analyzed using ROC curves to determine the optimal threshold for RVTCs. Survival analysis was performed using the Kaplan-Meier method, and survival rates were compared using the log-rank test. Logistic binary regression and multivariate regression analyses were used to identify prognostic factors. A P-value < 0.05 indicated statistical significance.
Main Study Results The study included 80 initially unresectable HCC patients, with initial stages as follows: CNLC stage Ib (4 cases), IIb (4 cases), IIIa (38 cases), and IIIb (34 cases). The median conversion therapy cycle was 5 (4, 6), with 24 patients receiving additional local treatments after the first imaging evaluation to promote conversion. After a median follow-up of 26 months, 34 patients experienced recurrence, and 13 patients died.
Among the 80 patients, 17 achieved a pathological RVTCs of 0, reaching CPR, while 63 did not achieve CPR. The CPR group had better recurrence-free survival (RFS) than the non-CPR group (median RFS 38 months vs. 14 months, P=0.029) and better overall survival (OS) (P=0.046).
The ROC curves for RVTCs predicting 1, 2, and 3-year RFS in initially unresectable HCC patients had areas under the curve of 0.850, 0.880, and 0.788, respectively, with an optimal RVTCs cutoff value of 15%.
Patients were divided into two groups based on the 15% threshold: RVTCs > 15% (n=37) and RVTCs ≤ 15% (n=43). The RVTCs ≤ 15% group had significantly better median RFS (38 months vs. 11 months, P<0.001) and OS (P=0.002) compared to the RVTCs > 15% group.
Multivariate logistic analysis showed that HBV infection (OR=8.114, P=0.023), preoperative mRECIST assessment as CR or PR (OR=4.423, P=0.042), and preoperative AFP ≤ 20μg/L (OR=5.939, P=0.008) were associated with a higher likelihood of achieving RVTCs ≤ 15% in surgical specimens of initially unresectable HCC patients.
Researcher Insights In recent years, with the advancement of clinical research and the strengthening of multidisciplinary cooperation, the survival of liver cancer patients has significantly improved. Especially with the active promotion by Chinese scholars, conversion therapy for unresectable liver cancer is gradually bringing more hope for improving patient prognosis. However, late-stage liver cancer patients undergoing sequential surgical treatment after conversion therapy still face tumor recurrence and recurrence-related death. Therefore, accurately assessing the risk of recurrence and conducting targeted postoperative follow-up and adjuvant therapy are crucial for individualized and standardized comprehensive management of patients. In various solid tumors, pathological response assessed by RVTCs has been proven to be associated with recurrence and long-term survival. However, for liver cancer, the use of RVTCs as a prognostic predictor and the determination of the threshold for prognosis stratification remain to be established. Previous studies on neoadjuvant and conversion therapy for liver cancer suggest that patients achieving major pathological response (MPR) have significantly better prognosis than those not achieving MPR, but different studies have used varying MPR thresholds (≤10% or ≤30%), posing challenges for the consistency and summary of research and data.
Combining previous research and clinical application experience, the “Chinese Expert Consensus on Conversion Therapy for Advanced Hepatocellular Carcinoma Based on Immuno-Targeted Regimens (2021 Edition)” recommends that patients achieving pathological complete response receive 6 months of ICIs monotherapy, while those achieving partial pathological response continue the original immuno-targeted regimen for 6-12 months. The adjuvant therapy strategy in this study was consistent with the consensus recommendations. The results showed that based on the pathological assessment of liver cancer specimens after sequential surgical resection following conversion therapy, patients achieving pathological complete response had better recurrence-free survival and overall survival than those in the non-complete response group, even if the latter received more intensive and prolonged postoperative adjuvant therapy. This further validates the feasibility of RVTCs as a prognostic predictor for patients undergoing conversion therapy.
Furthermore, in this study, using 15% as the optimal threshold determined by the ROC curve, the RVTCs ≤ 15% group had better recurrence-free survival and overall survival than the RVTCs > 15% group. A higher proportion of viable tumor cells may indicate tumor resistance and metastasis not confined to the primary lesion. For such patients, exploring more targeted and sensitive adjuvant treatment interventions might be a breakthrough to further improve survival.
Additionally, the study showed that patients with HBV infection, preoperative mRECIST assessment as CR or PR, and preoperative AFP ≤ 20 μg/L had a higher likelihood of achieving RVTCs ≤ 15% in surgical specimens. These indicators may play a valuable role in evaluating the effect of conversion therapy and the appropriateness of surgical timing before resection.
Currently, conversion therapy primarily based on immuno-targeted ± local treatment faces a series of controversies and challenges, including “how to screen benefiting patients,” “how to choose the best regimen,” “how to determine the timing of surgery,” and “how to manage postoperative adjuvant therapy.” This study, along with the team’s previously reported research on “adjuvant therapy outcomes” and “long-term survival benefits” after conversion therapy, provides a reference for addressing these hot issues in conversion therapy. With extended follow-up time and expanded sample size, the field of conversion therapy based on immuno-targeted regimens will form a more valuable evidence chain, aiding in the standardization, homogenization, and systematization of conversion therapy.
Expert Profile
Shichun Lu
Chief Physician, Professor, Doctor, Ph.D. Supervisor State Council Special Allowance Expert Currently Academic Director of Hepatobiliary and Pancreatic Surgery, Chinese PLA General Hospital Chairman of the Hepatobiliary and Pancreatic Disease Prevention and Control Professional Committee, Chinese Preventive Medicine Association Ninth Member of the Organ Transplantation Branch, Chinese Medical Association Deputy Chairman of the Organ Transplantation Branch, Beijing Medical Association Standing Member of the Organ Transplantation Professional Committee, PLA Deputy Editor-in-Chief of Chinese Journal of Hepatobiliary Surgery Editorial Board Member of Chinese Journal of Surgery, Chinese Journal of Organ Transplantation, and Chinese Journal of Liver Diseases
