Neoadjuvant sorafenib treatment of clear cell renal cell carcinoma and release of circulating tumor fragments, "Beyond the Abstract," by William Leenders, PhD, et al

BERKELEY, CA (UroToday.com) - In our recent publication, we studied tumor histopathology, tumor shedding into the circulation, and clinical outcome in 7 patients with metastasized clear cell renal cell carcinoma who received 4 weeks of sorafenib treatment prior to tumor nephrectomy. This was a hypothesis-driven study, based on the earlier observation from our lab that hyperactivity of VEGF in clear cell renal cell cancers is responsible for a specific vascular phenotype which allows escape of tumor clusters into the circulation (J Pathol. 2009 Nov;219(3):287-93). The goal of this study was to investigate whether inhibition of VEGF activity in primary renal cancers would prevent this phenomenon.

Although treatment with the VEGFR inhibitor sorafenib did destroy the vascular phenotype, it surprisingly did not prevent escape of tumor clusters into the circulation but even seemed to promote it. Also, to our surprise, we observed in the clinical follow up that the patients who received neo-adjuvant treatment with sorafenib had a shorter overall survival compared to a control group that we matched for this occasion.

This study was a side study to one published early in 2014, in which we investigated the effects of neo-adjuvant treatment with sorafenib on tumor uptake of radio-labeled gerentuximab (J Nucl Med. 2014 Feb;55(2):242-7). This put a limit on the number of available patients, which we thus realize is a major limitation of our study. Also, the special perfusion technique used for analysis of tumor shedding into the circulation and subsequent analysis is highly laborious which is likely to preclude inclusion of larger numbers of patients in future studies. Apart from such logistic issues, the worsening of overall survival that we observed makes an additional future study with a similar patient group unethical, in our opinion. Assuming that the overall outcome of our study is relevant and not a result of heterogeneity in this small patient group, we believe that our study has important implications for patient management.

All patients who agreed to participate in this study had metastatic disease, probably already at start of treatment. Therefore it is not possible to draw conclusions about the clinical significance of shed tumor clusters and their relation to worsened survival. This would require a novel study including patients with clear cell renal cell carcinoma staged as N0M0. Indeed, officially the possibility cannot be ruled out that such patients would benefit from neo-adjuvant sorafenib treatment. However, we propose there is the distinct possibility that sorafenib induces tumor cluster shedding from the primary tumor in N0M0 patients and thus induces metastatic seeding by simply disrupting the vasculature and facilitating entrance of tumor cells in the circulation. Therefore, again, such a study would require extensive ethical considerations. All in all, our study emphasizes the importance of critically evaluating the results of ongoing trials which explore the effects of neo-adjuvant sorafenib.

Another important consideration is how sorafenib acts on metastatic lesions. Clear cell carcinoma constitutively expresses VEGF-A at high levels due to genetic aberrations. Therefore, the vasculature in metastatic lesions will be highly influenced by this growth factor and consequently will be mostly immature. It is a valid option that sorafenib destroys vasculature also in these lesions, inducing a second wave of metastasis. This warrants a careful evaluation of the patterns of disease progression in all patients under sorafenib, although we realize that these matters are difficult to investigate in a conclusive manner.

The detection of circulating tumor cells (CTCs) has become an important subject of investigation for a number of tumor types, as it may provide prognostic information and allows monitoring of therapy effects. Routinely, CTCs are detected in peripheral blood after depletion of blood cells and multiplex immunostainings. A highly interesting question would be whether tumor fragments that escape renal cell cancers become true circulating fragments or are captured in pulmonary vasculature on first pass, thereby escaping detection in peripheral venous blood. In this respect, studies are needed that compare renal venous blood samples to peripheral venous blood from the same patient and to profiles of tumor DNA or RNA in plasma. Such studies may give important answers to the effects of anti-angiogenic compounds on tumor behavior. Longitudinal collection of liquid biopsies in patients under neo-adjuvant treatment is therefore warranted.

Written by:
Gursah Kats-Ugurlu, MD;a Peter Mulders, MD, PhD;b Egbert Oosterwijk, PhD;b and William Leenders, PhDa as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

aDepartment of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
bDepartment of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Neoadjuvant sorafenib treatment of clear cell renal cell carcinoma and release of circulating tumor fragments - Abstract

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