The Intention‐to‐Treat Effect of Bridging Treatments in the Setting of Milan Criteria–In Patients Waiting for Liver Transplantation

Abstract

In patients with hepatocellular carcinoma (HCC) meeting the Milan criteria (MC), the benefit of locoregional therapies (LRTs) in the context of liver transplantation (LT) is still debated. Initial biases in the selection between treated and untreated patients have yielded conflicting reported results. The study aimed to identify, using a competing risk analysis, risk factors for HCC‐dependent LT failure, defined as pretransplant tumor‐related delisting or posttransplant recurrence. The study was registered at http://www.clinicaltrials.gov (identification number NCT03723304). In order to offset the initial limitations of the investigated population, an inverse probability of treatment weighting (IPTW) analysis was used: 1083 MC‐in patients (no LRT = 182; LRT = 901) were balanced using 8 variables: age, sex, Model for End‐Stage Liver Disease (MELD) value, hepatitis C virus status, hepatitis B virus status, largest lesion diameter, number of nodules, and alpha‐fetoprotein (AFP). All the covariates were available at the first referral. After the IPTW, a pseudo‐population of 2019 patients listed for LT was analyzed, comparing 2 homogeneous groups of untreated (n = 1077) and LRT‐treated (n = 942) patients. Tumor progression after LRT was the most important independent risk factor for HCC‐dependent failure (subhazard ratio [SHR], 5.62; P < 0.001). Other independent risk factors were major tumor diameter, AFP, MELD, patient age, male sex, and period of wait‐list registration. One single LRT was protective compared with no treatment (SHR, 0.51; P < 0.001). The positive effect was still observed when 2‐3 treatments were performed (SHR, 0.66; P = 0.02), but it was lost in the case of ≥4 LRTs (SHR, 0.80; P = 0.27). In conclusion, for MC‐in patients, up to 3 LRTs are beneficial for success in intention‐to‐treat LT patients, with a 49% to 34% reduction in failure risk compared with untreated patients. This benefit is lost if more LRTs are required. A poor response to LRT is associated with a higher risk for HCC‐dependent transplant failure.

Liver transplantation as therapy for hepatocellular carcinoma

“…LRT prevents wait‐list drop‐off because of tumour progression. In a propensity matched analysis from the UK, one session of LRT was associated with a 49% lower risk of delisting for progression of HCC and/or post‐LT recurrence . This advantage was lost if more than 3 LRTs were needed, which might suggest that poorer tumour biology and/or longer waiting times are risks of a worse outcome.…”

“…In a propensity matched analysis from the UK, one session of LRT was associated with a 49% lower risk of delisting for progression of HCC and/or post-LT recurrence. 8 This advantage was lost if more than 3 LRTs were needed, which might suggest that poorer tumour biology and/or longer waiting times are risks of a worse outcome. The goal of these bridging therapies is to achieve a complete response, defined by the absence of viable tumour on cross-sectional imaging and AFP <100 ng/mL.…”

Oncological feasibility of liver transplantation for hepatocellular carcinoma

“…Это и этические причины, и разнородность пациентов с ГЦК, и необходимость анализировать всех рандомизированных пациентов ("intention-to-treat"), которые могут сталкиваться с противопоказаниями к ТП, и т.п. [12]. В связи с этим онкологическая целесообразность ТП при ГЦК реципиентам, не отвечающим Миланским критериям и UCSF, остается неясной.…”

“…Keywords: liver, hepatocellular carcinoma, locoregional therapy, liver transplantation. применение ЛРТ перед ТП даже у пациентов, соответствующих Миланским критериям, улучшает выживаемость после ТП [11][12][13].…”

Recent advances in liver transplantation for cancer: The future of transplant oncology

“…Lai et al have shown that patients with progressive disease despite LRT had a higher risk of dropout or posttransplant HCC recurrence (subdistribution HR 5.62, 95% CI 4.10-7.69). 31 Additionally, Mehta et al demonstrated significantly improved post-LT outcomes when restricting LT to patients with a reduction in AFP from >1,000 to <500 ng/ml after LRT. 32 In the near future, the assessment of tumour response on pre-LT imaging can be improved with artificial intelligence methods (e.g.…”