Impact of waiting time on post-transplant survival for recipients with hepatocellular carcinoma: A natural experiment randomized by blood group

Abstract

Background & aims: When listing for liver transplantation, one can transplant as soon as possible or introduce a test-of-time to better select patients, as the tumor's biological behavior is observed. Knowing the degree of harm caused by time itself is essential to advise patients and decide on the maximum duration of the test-of-time. Therefore, we investigated the causal effect of waiting time on post-transplant survival for patients with hepatocellular carcinoma.

Methods: We analyzed the UNOS-OPTN dataset and exploited a natural experiment created by blood groups. Relations between variables and assumptions were described in a causal graph. Selection bias was addressed by inverse probability weighting. Confounding was avoided using instrumental variable analysis, with an additive hazards model in the second stage. The causal effect was evaluated by estimating the difference in 5-year overall survival if all patients waited 2 months instead of 12 months. Upper bounds of the test-of-time were evaluated for probable scenarios by means of simulation.

Results: The F-statistic of the first stage was 86.3. The effect of waiting 12 months vs. 2 months corresponded with a drop in overall survival rate of 5.07% (95% CI 0.277-9.69) and 8.33% (95% CI 0.47-15.60) at 5- and 10-years post-transplant, respectively. The median survival dropped by 3.41 years from 16.21 years (95% CI 15.98-16.60) for those waiting 2 months to 12.80 years (95% CI 10.72-15.90) for those waiting 12 months.

Conclusions: From a patient's perspective, the choice between ablate-and-wait vs. immediate transplantation is in favor of immediate transplantation. From a policy perspective, the extra waiting time can be used to increase the utility of scarce donor livers. However, the duration of the test-of-time is bounded, and it likely should not exceed 8 months.

Impact and implications: When listing patients with liver cancer for transplantation, it is unclear whether a test-of-time or immediate transplantation offer better outcomes at the population level. In this study, we found that increased liver transplant waiting times are detrimental in patients with liver cancer. Furthermore, our simulation showed that a pre-operative observational period can be useful to ensure good donor liver allocation, but that its duration should not exceed 8 months.

Keywords: AFP, alpha-fetoprotein; ALBI score, albumin-bilirubin score; ATE, average treatment effect; Causal inference; HCC, hepatocellular carcinoma; Hepatocellular carcinoma; IPW, inverse probability weighting; Instrumental variable analysis; LRT, loco-regional therapy; LT, liver transplantation; Liver transplantation; Mendelian randomization; OPTN, Organ Procurement and Transplantation Network; Quasi randomized controlled trial; UNOS, United Network for Organ Sharing; Waiting time.

Graphical abstract

Fig. 1

The causal graph that guides the analysis to identify the harm of waiting time. LF, liver function.

Fig. 2

Waiting time distribution. The distribution of the waiting time on the linear scale (A) and on the logarithmic scale (B).

Fig. 3

Average treatment effect of waiting time. The average treatment effect of waiting time on post-transplant survival. (A) The time constant and time varying cumulative hazard function for waiting time. (B) The cumulative coefficient for waiting time is translated to the survival scale and shows a contrast between if all patients wait 2 months vs. 12 months.