Extended hepatic metastasectomy for renal cell carcinoma—new aspects in times of targeted therapy: a single-center experience over three decades

Renal cell carcinoma (RCC) is a malignant disease with increasing incidence, ranging from 3 to 12 cases per 100,000 people in Europe and Northern America.

Despite entering the era of novel targeted therapies such as tyrosine kinase inhibitors, mortality rates are still at more than 2.4 per 100,000 people in many Western countries [1]. This is partially owed to the fact that around 30% of the patients initially present themselves with synchronous distant metastases, whereas another 30% suffer from metachronous metastases after nephrectomy in curative intent [2]. Although bone and lung lesions are most frequently observed in cases of metastatic disease, the liver is involved in 20% of the patients [3]. Studies in the past have analyzed the influence of metastasectomy in general on the disease-free and disease-specific survival and showed beneficial effects for surgical resection in selected patients [4, 5].

The role of hepatic resection is still a matter of debate: Grimes, Pikoulis, and Pinotti each published reviews on this issue with patient series ranging from 4 to 85 patients [6‐8]. However, patients with RCC liver metastases are often included in reports on resection of non-colorectal and non-endocrine liver metastases, limiting the significance of drawn conclusions. Furthermore, none of the studies present significant patient numbers after introduction of targeted therapy.

Several scores have been provided in the past to estimate the prognosis of patients in a metastatic stadium (stadium IV) of RCC. The Memorial Sloan-Kettering Prognostic Factors Model, which was introduced by Motzer et al. in 1999 and modified by Mekhail et al. in 2005, is currently the most widely accepted and validated model for larger patient series [9‐11].

The objective of the present study was to validate the latter prognostic model for patients undergoing resection of hepatic metastases and to further evaluate the influence of major and extended liver or multivisceral resection (among other selected variables) on the outcome in this special patient collective.

The influence of nominal and ordinal variables on binary study endpoints was analyzed with chi-squared test and Fisher’s exact test. Median and mean values between groups were compared with the Student’s t test or Mann-Whitney U test. Kaplan-Meier analyses including log-rank tests were performed where appropriate. Risk factors for patient survival were initially analyzed with univariable Cox regression analysis. Identification of independent risk factors influencing DFS and OS was achieved by using purposeful selection of variables with a rate of missing values < 10% and p values in univariable Cox regression of < 0.300 and consecutive stepwise forward selection.

The collected data was implemented and analyzed using SPSS statistical software (version 26; SPSS Inc.; IBM Corporation, Armonk, NY, USA) and GraphPad Prism (version 8.3.0 for Windows, GraphPad Software, La Jolla, CA, USA).

Despite several studies on metastasectomy in patients suffering from grade IV RCC, the role of resection of hepatic lesions, especially in times of efficient systemic therapy, remains elusive.

In the current study, we present the largest monocentric database on the matter since Staehler et al. published their patient series in 2010 and, to our knowledge, the first series investigating patient survival following hepatic metastasectomy in the era of targeted therapy [14].

We found a median OS of 37.8 months with 1-, 3-, and 5-year survival rates (78.9%, 52.6%, and 38.0%, respectively) in line with results reported in a review by Pikoulis and more recently Pinotti et al. [7, 8].

The published heterogeneous survival (16–142 months) is partially explained by the varying rates of simultaneous extrahepatic disease (0–37%) and the varying rates of major liver resections in reported patient series (14–85.7%) [14‐17]. In our study, extrahepatic metastases were observed in 14 patients (35.0%) and led to a significantly worse OS, as was reported by others in the past [17, 18]. The proportion of patients undergoing major hepatic surgery in our series was also comparatively large (60.0%). However, major or extended liver resections (22.5%) were not associated with inferior patient outcome, and although multivisceral resection (20.0%) was identified as an independent significant risk factor for inferior DFS and OS, the median OS in these patients was still considerable (19 months). Of note, multivisceral resections included pancreatic metastases since beneficiary survival has been shown in cases of pancreatic metastasectomy by others in the past [19, 20].

Even though high-volume oncologic liver surgery is performing at our institution, our observation period was long, spanning three decades due to the low incidence of resectable RCC liver metastases, like in most reports on the matter [7, 8, 21]. Since surgical protocols were refined and, even more importantly, systemic therapy has improved over time, we have analyzed our patient series according to the introduction of the tyrosine kinase inhibitor sunitinib for stage IV RCC in Europe in July 2006, taking into account the significant efficiency of targeted therapy [22‐24].

Despite entering the era of targeted therapy, surgical resection is still regarded as the only chance for long-time survival of metastatic RCC [4, 5]. Accordingly, results from a study of McKay et al. investigating the outcome of metastasized RCC with liver metastases (alone or in combination with extrahepatic sites) under targeted therapy showed a median OS of up to 18.2 months, which is significantly inferior to the outcome reported in the current study. However, the authors did not comment on patient factors excluding surgical resection as an additional or alternative therapeutic strategy [25].

Although several reports of beneficial effects of metastasectomy in combination with targeted therapy were published in the past, the specific role of hepatic metastasectomy remains unclear, since only few studies examining the latter included patients resected in the era of targeted therapy [5, 8, 26]. To our knowledge, Staehler et al. were the first and to date only group of authors, that included a control group receiving systemic therapy instead of surgical resection. However, the study was performed before wider use of targeted therapy such as sunitinib, with only 5 patients receiving targeted therapy [14].

In our patient series, the outcome in general significantly improved in case of hepatic metastasectomy after July 2006. Nonetheless, multivariable analysis did not show an independent significant influence of hepatic metastasectomy after July 2006 on OS. This could be partially due to the fact, that the maximum follow-up time was shorter in this subgroup, with 10 patients (64.3%) still being alive at the time of analysis as opposed to only one patient (4.2%) out of the subgroup undergoing liver surgery before introduction of targeted therapy. Another potential confounder observed was a longer disease-free interval between primary nephrectomy and liver resection, known as an independent significant factor for better survival, in patients undergoing hepatic metastasectomy after July 2006 (48.0 versus 25.9 months) [15‐18, 27, 28]. Furthermore, a tendency toward lesser extended hepatic surgery, reflected by significantly shorter operating times and lower rates of major and extended liver resections (46.7% versus 68.0%), since the introduction of targeted therapy was found. Despite these observations, we cannot prove that solely the option of targeted therapy led to less (aggressive) hepatic surgery in our patients, due to the retrospective nature of the study. Other developments in the treatment of hepatic malignancies, such as the introduction and widespread use of less invasive technologies, including radiofrequency ablation, selective internal radiation therapy, or transarterial chemoembolization, also have to be discussed as an explanation for our findings.

We analyzed further factors supposedly influencing postoperative outcome. These included positive resection margins which were associated with a higher hazard ratio but did not significantly influence patient survival, as opposed to several reports in the past [27‐30]. An explanation could be the small number of only three patients showing positive resection margins, reflecting an aggressive approach and resulting in a comparatively high rate of major and extended hepatic and multivisceral resections.

As summarized by the review from Pikoulis et al., neither the number, the size, nor the laterality of liver metastases had an impact on patient outcome [7].

The modified Memorial Sloan-Kettering Prognostic Factors Model for patients with metastasized RCC could not be validated in our patient series, despite a trend toward superior survival for the favorable-risk group. This could be the result of a comparatively small sample size, with only four patients allocated to the poor-risk group. We suggest that larger patient series, preferably in multi-center studies, should be analyzed in the future to clarify the role of the abovementioned prognostic model in patients with RCC liver metastases.

Limitations of the present study are the retrospective nature combined with a heterogeneous patient selection and missing control groups, diminishing the statistical power of our observations. Of note, collection of complete clinical and histopathological data of patients undergoing hepatic metastasectomy, especially in the early observation period, was partially not possible since patients, relatives, and even physicians in charge were deceased at the time of analysis. We believe, however, that it is essential to report on patient series with a comparatively rare surgical indication and that our findings could contribute to facilitating optimal patient selection and subsequent outcome in the future of a rapidly evolving therapeutic landscape [31].

Despite the introduction of novel targeted therapies, surgical concepts still remain the only chance for long-term survival or cure in selected patients. Hepatic metastasectomy on patients with RCC stage IV disease can be performed safely and allows long-term survival, albeit with an increased risk of postoperative complications especially following multivisceral surgery. It will be crucial to define the role of hepatic metastasectomy with a focus on patients suffering from an extended metastatic disease in the context of future multimodal therapy strategies.