In this study, we have shown that a lower pre-transplant KPS score was associated with higher waiting list mortality and was an independent predictor for both inferior intent-to-treat survival and OS in patients with HCC awaiting or having had LT, after adjustment for other clinical risk factors. A lower KPS score was also associated with a higher probability of post-transplant HCC recurrence, but did not reach significance in the multivariable competing risk regression analysis.
These findings add to the current knowledge about the impact of functional status on LT in the HCC patient. The role of KPS in LT has been emphasized in recent years. The previous liver transplant allocation system was based on the severity of candidate liver disease as determined by laboratory MELD score. Although the MELD score was objective, it did not include clinical variables that may affect transplant outcomes. With the aging of the population, there is also an increasing proportion of candidates of older age listed for LT [2, 16]. Older candidates have less physiologic reserve and are more likely to have clinical complications, including sarcopenia and malnutrition, which makes them more vulnerable to stress. This may lead to disadvantage in survival for patients waiting for LT. Thus there is an urgent need to co-opt the factors reflecting patient frailty status to better predict survival in LT patients.
Previous studies have already shown that poor pre-transplant KPS was associated with increased mortality in patients with cirrhosis on the LT waiting list, especially in those without HCC [9]. In another study, poor, as well as unknown, pre-transplant KPS was also associated with post-transplant mortality [17]. The study by Thulavath et al. [18] also evaluated the dynamic change in KPS before and after LT, and found it an independent predictor for graft and patient survival ]. Their group also investigated the dynamic change in KPS following LT in patients with acute on chronic liver failure (ACLF) and found that good performance improvements in these patients may also be a consideration in clinical practice of whether to allocate a donor liver to a patient with multi-organ failure [19].
Attempts have been made to develop and use other prognostic measurements of frailty in patients with cirrhosis, including objective tools such as the ECOG functional status, 6-minute walk test, sarcopenia (determined by psoas muscle area), and the Fried model of frailty [8, 20–23]. However, the information gained on their application in epidemiological studies of potential LT candidates has been limited.
The KPS has also been utilized in oncological practice to predict prognosis. Excellent inter-rater reliability and reproducibility have been achieved in clinical practice [24–26]. The KPS has been included in the scoring system developed for patients with HCC by one French group, as one of the five independent predictors for prognosis [27]. A later study also validated the prognostic value of this system from a Chinese HCC cohort, which showed superior predictive value over other scoring systems such as CLIP score, CUPI, JIS score, and AJCC TNM classification [28]. The author concluded that the inferiority in the discrimination of later systems was possibly because they do not include functional status, which is important to establishing prognosis in HCC patients.
In the setting of LT, the study by Orman et al. found that higher KPS score was observed in HCC patients and was also significantly associated with waiting list mortality. Yet the relationship of KPS with transplantation rate was only significant in univariable analysis. These observations are also consistent with current guidelines that favor the HCC population with better functional status as reflected by lower native laboratory MELD scores. The use of other functional status evaluation systems has also been assessed in LT for HCC patients. A recent study by Wallace et al. assessed the time-dependent impact of functional status, as stratified by ECOG scale, on outcomes after LT, and found that it was not associated with 1-year post-transplant survival for HCC patients.
Our study demonstrated that poor functional status, as determined by KPS score, was significantly associated with higher likelihood of removal from the waiting list, which is consistent with the observation by Orman et al [9]. However, we observed that lower KPS score was not only associated with long-term intent-to-treat survival but also with long-term overall survival. Also, pre-transplant KPS was an independent prognostic factor for both intent-to-treat survival and overall survival. This is different to Wallace et al. [11], which may be due to the differing demographics of UK and US HCC patients, as well as the different functional status assessment tools used in the studies. In the study by Wallace et al. [11], functional status was determined by ECOG scale score, which was stratified into five levels. The HCC patients in the lowest level showed a trend of inferior survival probability; however, because the number of patients in this group was small (24) compared with other the groups, evaluating performance-specific difference was difficult, as the authors suggested. Our study included 17,726 HCC patients listed for LT in the US, which was larger than the UK cohort, and would make statistical evaluation of the impact of functional status more robust.
We also observed that lower KPS score was associated with increased probability of post-transplant tumor recurrence, especially in KPS III patients. However, this was only significant in the univariable competing regression analysis, not in the multivariable analysis. Tumor recurrence was one of the most important factors impairing post-transplant outcomes in HCC patients. Previous recipient selection criteria have been established based on tumor characteristics including tumor number, tumor size, and tumor biology reflected by AFP level, which are closed related to tumor recurrence [29–31]. In our study, although KPS was not independently associated with tumor recurrence, lower KPS impaired long-term survival of HCC patients, after adjusting for other confounders including tumor characteristics. This suggests the potential importance of the management of functional status in HCC patients. As HCC patients tend to be in a better functional state with more preserved liver function at listing, we have previously placed more emphasis on tumor characteristics to select appropriate patients. However, with the aging of the general population, more aged HCC patients than ever are being listed for LT, and are more likely to have accompanying complications brought on by frailty. This impaired functional status might persist during the post-transplant period and would impair survival in the follow-up period.
The current findings underscore the importance of assessment of functional status in HCC candidates in addition to conventional clinical risk factors, to better predict post-transplant survival for those patients. Patients of low KPS are more likely to drop out of the waiting list and are less likely to be considered for LT. Factoring in the aging population, we might expect a trend of more removals from the waiting list and fewer transplants in those patients [9]. Meticulous pre-transplant evaluation in addition to intervention such as exercise therapy and nutritional support to improve patient functional status is needed. The study by Lai et al. analyzed data from the Functional Assessment in Liver Transplantation (FrAILT) Study and found that pre-transplant frailty status worsened in the 3 months after LT, making patients vulnerable to early post-transplant death and increasing the length of hospital stay [32]. Although this status did improve modestly within 12 months, less than 40% of patients achieved a robust status, which ultimately adversely affected post-transplant outcomes. With regard to this, pre-transplant assessment of functional status has been suggested for incorporation into the decision-making procedure for LT, to indicate the suitability of candidates at listing, as well as guide prehabilitative intervention for individual candidates to achieve better transplant outcomes [33].
Our study has several limitations. First, the assessment of KPS is based on patient report or clinician evaluation, which may vary between observers and raises concern of lower reliability than objective assessments such as 6-minute walk test and muscle bulk assessment using radiography. However, previous studies have verified the excellent inter-rater reliability of the KPS scale in many clinical settings. Objective assessments may be less cost-effective or require more specific training and need to be validated in clinical practice. Indeed, the KPS has been collected by the SRTR for more than 10 years and its advantages in terms of simplicity and validity have been demonstrated. Second, as the KPS is only a clinical observational assessment of functional status, we could not investigate the underlying mechanisms that influenced KPS status, despite the importance of this in informing further modifications to pre-transplant nutritional and physical therapies for candidate status improvement. Despite these limitations, our study provides a comprehensive investigation of the influence of pre-transplant KPS on HCC patients listed for LT in the US, based on a large sample from the SRTR database, which adds new insights into decision making on LT for HCC patients.