Real-world practice of conversion surgery for unresectable hepatocellular carcinoma - a single center data of 26 consecutive patients

Patients

From June 1st, 2019 to June 1st, 2022, consecutive HCC patients at our center (“the Department of Hepatobiliary Surgery of Shandong Cancer Hospital Affiliated to Shandong First Medical University”) were retrospectively reviewed. The diagnosis of HCC were based on the AASLD guideline [13] and the “Guidelines For The Diagnosis And Treatment Of Primary Liver Cancer” by the Chinese Ministry of Health [14]. The treatments of all patients were discussed in a multidisciplinary team (MDT) meeting consisting of hepatologists, liver surgeons, medical oncologists, radiation oncologists, interventional radiologists, pathologists and radiologists with expertise covering all potential treatment options. For surgically-treated patients (upfront or conversion surgeries), diagnoses were confirmed through pathologic examination. Those who were diagnosed as uHCC and receive systemic and/or loco-regional therapies, then following by the curative resection were defined as patients of conversion surgery, their clinicopathological features, responses to the systemic and/or loco-regional treatments, safety and the preliminary outcomes of conversion surgery and conversion rate were analyzed.

Patients were considered initially unresectable if they met any of the following criteria: extra-hepatic metastasis (EHM), major venous tumor thrombosis or giant solitary tumor with insufficient future liver remnant (FLR). The exact reasons of unresectability of each patient are presented in the “ Results”.

All research in this study was conducted in accordance with both the Declarations of Helsinki and Istanbul. The study was approved by the Ethics Committee of Shandong Cancer Hospital Affiliated to Shandong First Medical University, with waiver of informed consent. There are three reasons. First, the period of this study is long. Second, no patient privacy information is involved. Third, this is a retrospective study, it did not intervene the decisions of the treatments.

Treatments

For systemic therapies, a number of regimens were used according to the international and local practice guidelines. The TKIs used in this study were lenvatinib (8mg/day), apatinib (250 mg/day) or sorafenib (800mg/day). Anti PD-1 antibodies were intravenously administered as follows: sintilimab 200 mg, or camrelizumab 200 mg, every 3 to 4 weeks.

TACE treatment was carried out according to the standard procedure. Formal angiographic assessment was performed in all patients in whom TACE was felt appropriate. In conventional TACE (cTACE), a mixture of lipiodol plus epirubicin was injected followed by embolic agents (gelatin sponge particles or microspheres), while in dTACE, microspheres (Callispheres®) loaded with epirubicin 80mg/g were used with or without supplementary particles.

Hepatic artery infusion chemotherapy (HAIC) treatment was carried out according to the reported procedure [15] and divided into 3-week cycles. If tumor also got arterial feeding from the right inferior phrenic artery or other collateral vessels, the collateral vessels were to be embolized to achieve blood flow redistribution, thus ensuring the efficiency of following drug infusion.

Patients were then transferred back to the inpatient ward and received drug infusion via the hepatic artery: oxaliplatin, 130 mg/m2 from hour 0-2 on day 1; leucovorin, 400 mg/m2 from hour 2-3 on day 1; and fluorouracil, 400 mg/m2 bolus at hour 3 on day 1 and 2,400 mg/m2 over 24 or 46 hours. After HAIC was completed, the catheter and sheath were removed. Repetitive femoral artery puncture and catheterization were performed in the next HAIC cycle to re-evaluate the blood supply of the tumor and adjusted the superselective location if necessary.

Response and toxicity evaluation

All patients were monitored and evaluated regularly. Briefly, lab tests (complete blood count, liver, renal, thyroid and cardiac functions, and tumor markers) were repeated before each treatment cycle. Tumor response and resectability were evaluated via contrast-enhanced magnetic resonance imaging/computed tomography (MRI/CT) at least every 2 treatment cycles by the multidisciplinary team of hepatobiliary tumors. Tumor responses were graded as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) according to RECIST v1.1 and modified RECIST (mRECIST) criteria. The objective response rate (ORR) was calculated as the sum of CR and PR. The disease control rate (DCR) was calculated as the sum of CR, PR, and SD. Adverse events were assessed and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0, immune-related AEs (irAEs) were also assessed.

To evaluate the safety of conversion surgery, serial perioperative data, including the changes of the percentages of blood and liver test parameters (ΔRBC%, ΔHb%, ΔALT%, ΔAST%, Δbilirubin%, Δalbumin%), the operation time, the mean blood loss, the postoperative hospital stay and the drainage time, as well as the incidences of the postoperative complications, including infection, bile leakage, hypoproteinemia, significant ascites, hydrothorax, etc., were collected.

OS was defined using the time from initial diagnosis, and from the date of surgery. Recurrence-free survival was defined as the interval between the date of surgery and the date of recurrence.

Postoperative management

TKIs and/or anti-PD-1 antibodies were resumed approximately 4 weeks after hepatectomy when patients were fully recovered from surgery. Postoperative radiographic (contrast enhanced abdominal CT or MRI) as well as biochemical (AFP) assessments were performed at least every 3 months in the first year and at least every 6 months in the following year. Adjuvant therapy was discontinued 12 months after surgery, following MDT discussion as well as the consideration of patients’ preference. For recurrent patients, the treatment modalities were based on the pattern of tumor recurrence and MDT suggestion.

Statistical analysis

Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS, version 17.0; SPSS Inc., Chicago, IL, USA). Quantitative variables are presented as the mean ± standard deviation. Student’s t test or Mann–Whitney U test was performed to compare differences between groups. Chi‑square (χ2) test was used to assess the ECOG PS scores and post-operative complications in different groups. Categorical data was expressed as frequencies (percentages). The association between successful conversion and those baseline stratification factors were analysed by Cox proportional-hazards model to generate HRs and 95% CIs.

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