Another look at treatment choices for metastatic renal cell carcinoma, "Beyond the Abstract," by Ghieth A. Kazkaz, et al.

BERKELEY, CA ( - Almost a decade ago, systemic treatment options for metastatic renal cell carcinoma (mRCC) were limited to cytokine therapy (interleukin and interferon). Those treatments had modest benefit, albeit, significant toxicities.[1, 2]

Recent years have witnessed a significant emergence of many therapeutic options. Tyrosine kinase inhibitors (TKIs) had proven effective in various malignancies. Imatinib was the first to be introduced into oncology practice, followed by a cascade of new agents targeting different tyrosine kinases.[3] Prompted by better understanding of the role of von Hippel Lindau tumor suppressor gene and its relation to RCC carcinogenesis, researchers investigated agents that target the vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathways as newer candidates.[4] Sorafenib was the first agent to get FDA approval in late 2005, followed by sunitinib, temsirolimus, everolimus, pazopanib, and axitinib in early 2012.[5] Moreover, there are ongoing trials that also investigate agents that are linked to newer targets.[6]

“As the number of options increases, the effort required to make a good decision escalates as well, which is one of the reasons that choice can be transformed from a blessing into a burden.” Barry Schwartz - The Paradox of Choice

Adding bevacizumab (plus interferon) and high-dose interleukin to this list, oncologists today counsel mRCC patients with as much as 8 systemic treatment options in hand,[7] and with very little evidence about superiority/suitability of one over another. Those treatments cannot be equally effective; we simply do not know yet the biomarkers that help individualizing therapy. Our knowledge in this regard is far below certainty, especially with the scarcity of data from direct comparisons between currently used agents other than interferon.[8, 9, 10]

We believe that the safety profile of each of those agents is of an important consideration for decision-making. While there are distinct adverse events (AEs) for each of those TKIs, a lot are common, but the incidence rates (IRs) and the severity vary.[3]

In cancer management, one can accept the risk of serious therapy-associated AEs if and only when there is a clear survival benefit. On the other hand, in the palliative care setting, low-tolerance for AEs is needed where the quality of life (QOL) is an essential goal of therapy. Needless to say, symptoms like fatigue, loss of appetite, and mucositis adversely affect QOL. Moreover, as the etiology and the risk factors associated with those TKI-associated AEs remain unclear, their prevention and management will remain unsatisfactory.

In our meta-analysis we included 5 658 patients in 12 clinical trials. We provided an adequate estimate of sunitinib-associated AEs that would be similar to that to be expected from the use of sunitinib in unselected patients with mRCC. We also showed that the variable rate of reported IRs between studies was mainly attributable to variability in study size.

We discussed, as well, limitations of our study. Only 3 of the included studies were randomized and 2 of them had sunitinib in both arms. Other limitations are inherent to studies that report on AEs: The uncertainty in distinguishing drug-related AEs versus disease-related symptoms, differences in reporting methods between studies, and the nocebo phenomenon, which refers to the AEs reported on a placebo arm.

The best option for first-line treatment and the best combination or sequencing of agents will probably remain unclear and might even be more perplexing with the introduction of newer agents. Efforts to identify biomarkers for response are needed. Moreover, future research to explain, quantify, and specify risk factors for AEs is equally needed.


  1. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 1995;13:688-96.
  2. McDermott DF, Regan MM, Clark JI, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol 2005;23:133-41.
  3. Hartmann JT, Haap M, Kopp HG, Lipp HP. Tyrosine kinase inhibitors - a review on pharmacology, metabolism and side effects. Curr Drug Metab 2009;10:470-81.
  4. Milella M, Felici A. Biology of metastatic renal cell carcinoma. J Cancer 2011;2:369-73.
  5. Drugs Approved for Kidney (Renal Cell) Cancer. (Accessed 24 Jun, 2013, at
  6. Bukowski RM. Third generation tyrosine kinase inhibitors and their development in advanced renal cell carcinoma. Front Oncol 2012;2:13.
  7. NCCN Clinical Practise Guidelines in Oncology.Kidney Cancer:KID-3.
  8. Motzer RJ, Hutson TE, Reeves J, et al. Randomized, open label, phase III trial of pazopanib versus sunitinib in first-line treatment of patients with metastatic renal cell carcinoma (mRCC); Results of the COMPARZ trial. Annals of Oncology 2012;23:ixe13.
  9. Motzer RJ, Escudier B, Tomczak P, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol 2013;14:552-62.
  10. Motzer RJ, Eisen T, Hutson TE, et al. Overall survival results from a phase III study of tivozanib hydrochloride versus sorafenib in patients with renal cell carcinoma. ASCO Meeting Abstracts 2013;31:350.

Written by:
Ghieth A. Kazkaz,a* Ali M. Bayer,a Mohamed T. Albirair,a and Ezzeldin M. Ibrahima as part of Beyond the Abstract on 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.

* Correspondence:
aOncology Center of Excellence, International Medical Center, PO Box 2172, Jeddah 21451, Saudi Arabia

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