Renal cell carcinoma (RCC) accounts for 2% to 3% of all adult malignancies.1,2 It is the most common type of kidney cancer in adults, responsible for approximately 90% to 95% of cases. Approximately, one-third of patients with RCC present, at the time of diagnosis, with metastatic disease. In addition, approximately one-third of patients who present with localized disease also end up developing metastatic disease. However, metastatic RCC (mRCC), stage 4 in particular, has a poor prognosis with a 5-year survival of approximately 2% to 8%. The biggest challenge in the treatment of RCC is how to treat mRCC.2
Because mRCC was long known to be resistant to conventional chemotherapy and radiation therapy, other strategies were developed. Immunotherapy with interleukin-2 and interferon, with or without surgery, was the standard of care until the emergence of therapies that targeted angiogenesis (targeted therapy).
However, it has been increasingly recognized that even with the availability of targeted therapies, patients with mRCC have very great variability in their outcomes. Deciding what treatment is best, and predicting whether to add cytoreductive surgery3 to targeted therapy has relied on risk stratification into three patient categories: favorable, intermediate, or poor. Studies have demonstrated that patients classified into the poor category, characterized by the presence of systemic features such as anemia and hypercalcemia and low performance status, do worse when both cytoreductive strategy and immunotherapy are compared with targeted therapy alone.3 However, information has been elusive about what should happen with respect to adding cytoreductive surgery when patients are being treated with targeted therapy over immunotherapy.
A plethora of agents that inhibit growth factors have now been approved4,5. For favorable-risk and intermediate-risk mRCC, two vascular endothelial growth factor (VEGF) receptor inhibitors, sunitinib and pazopanib (both tyrosine kinase inhibitors), and the anti-VEGF monoclonal antibody bevacizumab, represent standard therapy. And for poor risk patients, the mTOR inhibitor temsirolimus is recommended.
Still, the question of whether to use these targeted agents alone or in combination with cytoreductive surgery remains unresolved. There are disadvantages with surgery, including delays in scheduling surgery that then in turn delay starting targeted therapy. Further, radical nephrectomy may be associated with complications such as bleeding and infection that might be especially problematic in patients in the intermediate or poor category. On the other hand, several studies have reported that the addition of cytoreductive surgery to immunotherapy might accord a survival benefit.
A recent paper by Méjean et al. published in the New England Journal of Medicine (NEJM), June 3, 2018,6 reported results from the CARMENA (Cancer du Rein Metastatique Nephrectomie et Antiangiogéniques) trial. This phase 3 non-inferiority study enrolled 450 patients who were randomly assigned to either undergo nephrectomy and sunitinib (standard therapy) or receive sunitinib alone. The design involved stratifying subjects based on their prognostic risk (intermediate or poor) using the Memorial Sloan Kettering Cancer Center prognostic model. The primary end point was overall survival, defined as the time from randomization until death from any cause or until the date of last contact for living patients. The study reported that sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic renal-cell carcinoma who were classified as having intermediate- or poor-risk disease. The implication of the results, at least from the authors, was that sunitinib represents a reasonable alternative to sunitinib plus nephrectomy.
An editorial in NEJM7 accompanying this important paper was less prescriptive, arguing that because of several limitations in the study, the main conclusion that should be drawn is that it is important to tailor the therapeutic strategy around the patient’s risk category. Indeed, the authors argued that there may still be a place for cytoreductive surgery prior to initiation of targeted therapy.
My take on this subject—looked at through the lens of a nephrologist—is that options are now becoming available for patients with mRCC that hitherto had few options and quite a dismal prognosis. The bottom line is that ensuring that careful patient selection used in deciding what patients should be treated with remains as applicable today as it was when William Osler was practicing medicine in the early part of the 20th century.
- Rasmussen F. Metastatic renal cell cancer. Cancer Imaging. 2013;13: 374-380. Accessed June 26, 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3783114/
- Cohen HT, McGovern FJ. (2005). Renal-cell carcinoma. New England Journal of Medicine. 353(23): 2477–2490.
- Conti SL, Thomas IC, Hagedorn JC, et al. Utilization of cytoreductive nephrectomy and patient survival in the targeted therapy era. Int J Cancer. 2014;134:2245-2252.
- Roskoski Jr R. Sunitinib: A VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochemical and Biophysical Research Communications. 356 (2007) 323–328. Accessed June 26, 2018, at http://www.brimr.org/Reprints/136.pdf
- Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018 Jun 3. doi: 10.1056/NEJMoa1803675. [Epub ahead of print] PubMed PMID: 29860937.
- Motzer RJ, Russo R. Cytoreductive nephrectomy—patient selection is key. June 3, 2018. doi: 10.1056/NEJMe1806331 https://www.nejm.org/doi/pdf/10.1056/NEJMe1806331