Trans-arterial Chemo-embolization Is Safe and Effective for Elderly Advanced Hepatocellular Carcinoma Patients

Results From an International Database

Matan J. Cohen; Izhar Levy; Orly Barak; Allan I. Bloom; Mario Fernández-Ruiz; Massimo Di Maio; Francesco Perrone; Ronnie T. Poon; Daniel Shouval; Thomas Yau; Oren Shibolet

Disclosures

Liver International. 2014;34(7):1109-1117. 

In This Article

Discussion

In the absence of trials dedicated to elderly patients, the results of our study demonstrate that TACE is safe and provides similar benefits to elderly eligible patients with HCC as it does to younger HCC patients. We merged several institutional databases to analyse the largest population of elderly patients treated with TACE to date. Elderly patients, included in this study, did not suffer more adverse events compared with younger patients. Furthermore, the results show that these outcomes are similar for patients diagnosed over a 20-year period and in different countries. Most notable are the similarities between Chinese patients and patients from Mediterranean and European countries.

Current literature of TACE for HCC includes inconsistent age cut-offs to define "elderly". In a 2002 meta-analysis of randomized controlled trials, the mean patient age in the included trials ranged between 41 and 66.[24] These studies defined elderly patients as those above 60 or 65 years of age.[19,25–28] As is the case of the available information for other diseases and treatments, there is notable misrepresentation of the elderly in the data published so far on HCC.[29] Given the increasing longevity, there is a need for relevant novel and confirmatory data regarding septagenerians, octogenerians and even older patients.

Only a few studies have estimated survival among HCC patients older than 70, treated by different treatment modalities. A study of a cohort of patients with a mean age of 70, treated with TACE, provided survival estimates of 91%, 86% and 80% at 1, 2 and 3 years respectively.[30] Another study that included patients older than 70 (though younger than 75) demonstrated survival rates of 51%, 36% and 23% at 1, 2 and 3 years.[31] A Japanese report of 136 patients older than 75 reported 80% survival at 3 years.[32]

Studies that were not restricted to TACE, but included other treatment modalities, found that disease stage rather than age was the main independent determinant of prognosis when comparing younger and older patients.[17,18,32,33] Dohmen et al. found similar results among 36 patients with HCC older than 80 (20 treated with TACE, some also receiving percutaneous ethanol/acetic acid injections, surgery and chemotherapy) compared to younger patients.[15] Among HCC patients, older than 70 but younger than 75, selected to undergo hepatic resection or radiofrequency ablation, age was not associated with worse outcomes.[10–13] A recent American data collection from two medical centres did not find differences in the outcome of HCC patients, younger and older than 70.[34] In addition, sorafenib was shown to have a similar survival benefit among patients older and younger than 70.[35]

There are however some other reports which suggest that treatment outcomes are worse for patients with HCC older than 75 when compared to younger patients.[20,21] A study that compared HCC patients aged 70–79 (N = 131) to patients older than 80 (N = 69) showed that age was a predictor of increased mortality.[36] Kao et al. recently reported that the outcome of radiofrequency ablation among elderly patients was worse than that of younger patients.[37]

Hepatic insufficiency and cholecystitis have been reported to occur in up to 50% and 10% of HCC patients who undergo TACE respectively.[27] Incidence rates of post-embolization syndrome have been reported to occur between 2% and 80% of the procedures.[38,39] These estimates were not limited to elderly patients. A study assessing acute kidney injury among patients undergoing TACE found no association between this adverse event and age.[36] Our results are of value as they compare adverse events in elderly and younger patients (although they are derived from only two included data sets). Unfortunately, post-embolization syndrome rates were not collected in the included databases, except for the Israeli cohort, which reported these results separately.[22] We observed a deterioration of liver function after TACE that was more frequent in younger patients. This might indicate that the treatment procedure was more aggressive in the younger patients. However, this was not reported in the original papers and could not be confirmed by our co-authors.

All patient included in this data set were selected for TACE treatment based on the clinical judgment of the treating physicians. Thus, one of the limitations of this study is selection bias. However, selection bias is an inherent problem in any study allocating patients to these treatments and a randomized prospective study to assess their efficacy is unlikely ever to be preformed. Furthermore, the results suggest that physicians around the world are making consistent and appropriate selection, as the prognosis of the selected patients is not dependant on age.

We controlled for disease staging systems that were documented in all/most data sets and all analyses were repeated with CPT, Okuda and CLIP scores, with similar results. We did not have patient-specific records of anatomical and invasion characteristics of the tumour, thus for patients with CLIP scores, we could not differentiate these disease features.

Current guidelines endorse the BCLC scoring system to promote standardized patient assessment and decrease cross-study variability.[4,3,40] Unfortunately, a minority of the patients in the combined data set had BCLC scores. However, the combined analysis of available staging systems clearly identifies disease stage as an important prognostic factor and we do not believe that having controlled for BCLC would have generated different results.[40–42]

It should also be noted that as diagnostic imaging capabilities have evolved during the period covered in this analysis, the ability to compare stages over time should be appreciated with caution. However, all data sets came from centres maintaining the highest professional standards and similar disease staging scores performed according to professional guidelines are comparable. TACE protocols have also evolved. As mentioned in the methods, the TACE technique used was not identical among all patients (using either doxorubicin or cisplatin and with several arterial closure methods), additionally, the appraisals of hepatic and tumour anatomy and decision on the selectiveness of the procedure were operator dependant. Our data represent 'real-life' experience in regional centres of excellence. It is unlikely that an identical TACE protocol will be implemented given the complexity and highly technical nature of the procedure. Despite the advancement of TACE procedures, the protocols used were specific for each centre and were employed both in young and in old patients making intercentre variations less likely to play a confounding role in our analyses. Furthermore, to limit the effect of technical advancement over time, we assessed outcome both before and after the year 2000 and did not find differences. Hence, despite possible changes in TACE techniques over time, the differences did not translate into different outcomes between young and old patients.

In conclusion, in this large international database, age was not an independent determinant of prognosis among patients with HCC who are treated with TACE. This includes patient older than 75 and 80 years old at time of diagnosis. These findings were true for patients around the world and do not demonstrate geographical variation. Unfortunately, the study design does not allow for a strong statement concerning the relative frequency of adverse events following TACE in elderly patients. Informed decision-making would benefit from such data. The findings of this collaborative study would be complemented if future groups publish data about complete HCC patient cohorts and provide insight into age stratified patient selection to treatment modalities.

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