BERKELEY, CA (UroToday.com) - Until recently, immunotherapy was considered the only therapeutic option for patients with advanced and metastatic renal cell carcinoma (RCC).
Considering the fact that RCC is resistant to radiotherapy and to the standard cytotoxic chemotherapy, interferon-a (IFN-a) and interleukin-2 (IL-2) were considered the therapy with the most consistent antitumor effect providing modest response rates (RR) and survival benefit mainly in patients with lung metastases and previous nephrectomy. Surgery, in terms of cytoreductive nephrectomy, remains an option in patients with good performance status. However, it has been used less over the last decade due to the introduction of targeted therapies.
The understanding of VHL gene in the RCC pathogenesis and the identification of cellular signaling pathways have lead to the development of several new agents targeting RCC in a molecular level, with sorafenib being the first targeted agent to be approved in 2005.
The concept of our study was to review the contemporary data regarding the therapy of advanced and metastatic RCC (mRCC). Mainly, we focused on the major phase III trials that have revolutionized therapeutic strategies. Furthermore, we have presented a number of early studying agents and we analyzed the first results.
Tyrosine kinase inhibitors (sunitinib, sorafenib, pazopanib), monoclonal antibodies (bevacizumab) and mammalian target of rapamycin inhibitors (temsirolimus, everolimus) are widely used nowadays as first or second line therapies following patients stratification in risk groups according to the MSKCC criteria. Sunitinib has been studied as first line therapy providing a significant higher progression free survival (PFS) compared to IFN-a. These results have established sunitinib as the most commonly used targeted therapeutical agent for low- and medium-risk mRCC patients. Significant results have been reported for bevacizumab+IFN-a and pazopanib as well. Concerning high-risk patients, temsirolimus is considered the appropriate first line therapy, since a 25mg dose has provided a significant higher PFS and overall survival (OS) compared to IFN-a. Similar results have been reported for the 15mg regimen. Sorafenib and pazopanib have been studied and are recommended as second line therapies (prior cytokine) while everolimus is the recommended regimen in patients who have failed previous anti-VEGFR treatment.
The contemporary treatment protocols and guidelines are based on the above studies. Although the results on RR and PFS are significant, at least from a statistical point of view, great concern remains for OS. With the exception of phase III study of Sternberg et al. on pazopanib, none of the other studies succeed in significantly improving OS over the control arm. This observation has two possible explanations. The first ,which is the most pessimistic, is that none of the antiangiogenetic agents can prolong OS and their benefits are limiting. The second one consists on the studies’ design. PFS is used as a surrogate endpoint of OS and is widely used in metastatic cancer trials. This minimizes the cost and the time needed for study completion while it provides direct conclusions on studied drug efficacy. However, since the validity of PFS as a surrogate endpoint over OS in mRCC has not been established yet, there should be an awareness of this issue in the development of future studies. Prolongation of OS should be the primary and ultimate goal of every new therapy that is planned to enter in mRCC treatment armamentarium.
In an effort to increase cancer control rates, combination and sequential therapy is a field of ongoing research. Horizontal (simultaneous inhibition of multiple pathways) or vertical blockade (combining drugs that target a certain pathway at different steps) of mRCC biological pathways might increase response and delay or even prevent refractory disease. Despite promising efficacy from the first results, increased toxicity is limiting their widespread use.
Given the above, it is difficult to predict the future of mRCC treatment. Despite the established positive results on efficacy, tolerability and outcome of targeted therapies, the need for further improvement in disease control and OS is imperative. Even though combination strategies seem the most promising future modality, clinical evidence is missing regarding the cost effect and quality of life of treated patients. After all, the need for new molecules development still remains since most of the mRCC patients will eventually acquire drug resistance and will die from progressive disease. In an era of economic changes and conflicting results on targeted therapies cancer control rates, cytoreductive nephrectomy should be re-evaluated since it represents a low-cost treatment option. Its efficacy as a stand-alone therapy or in combination protocols as adjuvant or neoadjuvant to targeted therapies should be examined since the first published results (few in number however positive) justifying further evaluation.
Sfoungaristos Stavros, Giannitsas Konstantinos, and Perimenis Petros 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.
Urology Department, University Hospital of Patras, Greece
Beyond the Abstract - Present and future therapeutic options for locally advanced and metastatic renal cell carcinoma, by Sfoungaristos Stavros, MD, et al.