Beyond the Abstract - Metastatic renal cell carcinoma to the phalanx, by Douglas F. Beach, MD and Robert Somer, MD

BERKELEY, CA (UroToday.com) -

The Dawn of a New Age in Treatment of Metastatic Renal Cell Carcinoma

 

Renal cell carcinoma (RCC) is considered the most lethal of all of the cancers of the genitourinary system and frequently metastasizes to the lung, bone, brain, liver, and adrenal gland.(1) It can be seen in unexpected locations as seen with our patient described here.

"That fact that agents are currently being tested in the third-line setting speaks volumes about the progress that has been made in a disease with few options even 5 or 6 years ago."

Historically, the treatment of advanced metastatic renal cell carcinoma (mRCC) has been quite limited. Consisting most of cytokine therapy with interleukin-2, a small subset of patients were able to achieve a complete or durable partial remission to treatment. In the vast majority of patients, though, the treatment was poorly tolerated, and the 5-year survival was exceedingly low at approximately 8%.(2) However, in recent years the paradigm has started to shift with improvements in overall and progression-free survival.

In 2005, one of the first promising agents to be approved in this population was sorafenib Sorafenib is a small molecular inhibitor of multiple kinases including RAF, VEGFR-1, -2, and -3, PDGFR-β, FLT-3, c-KIT, and RET. Sorafenib was compared to IFN-α in a phase II randomized trial in previously untreated patients with clear cell RCC (3). Patients were able to be crossed over to sorafenib after disease progression with IFN-α. The primary endpoint of PFS of sorafenib vs. IFN-α was 90.0% vs. 70.4%, 45.9% vs. 46.5%, and 11.5% vs. 30.4% at 3, 6, and 12 months, respectively.(3) Quality of life measures were superior in the sorafenib group, which helped the drug achieve approval.

Approximately 1 year later, Sunitinib, a multi-kinase inhibitor which targets many receptors such as PDGFR-α and –β, VEGFR, c-KIT, FLT-3, RET, etc. followed suit and received FDA approval. This was based largely on a phase III trial of 750 patients published in 2007 and which randomized patients to receive sunitinib or IFN-α.(4) The investigators showed an overall survival advantage of 26.4 months vs. 21.81 months in the sunitinib group vs the IFN-α, respectively.(5)

A trial using bevacizumab and IFN-α together showed an increased PFS (10.2 vs. 5.4 months) and a non-statistically significant trend toward OS (21.3 vs. 23.3 months).(6) Based on these findings, the FDA approved bevacizumab for use with IFN-α as a first-line treatment in 2009.

Other approved agents in the first-line setting now include temsirolimus approved in 2007, and pazopanib in 2009. Adding to the current drug armamentarium and achieving FDA-approval in the second-line settings were everolimus, and axitinib in 2011 and 2012, respectively.

The newest agent, axitinib,, was brought to the market after a single randomized, open-label, multi-center clinical study of 723 patients was performed comparing it to sorafenib.(7) This study evaluated patients whose disease had progressed on or after treatment with one prior systemic therapy, which could have included sunitinib, bevacizumab plus IFN-α, temsirolimus, or cytokines. Results showed a median PFS of 6.7 months with axitinib compared to 4.7 months with sorafenib.(7)

Next in the pipeline is the drug dovitinib (TKI258) for use in the third-line setting. An abstract regarding a phase II trial establishing efficacy of this drug was presented at the ASCO meeting in 2011.(8) The median PFS and OS were 6.1 and 16 months, respectively.(8) A phase III trial is currently underway comparing this agent sorafenib.

Although much improvement is needed, it is clear that we are venturing into uncharted territory with survivals that were initially thought to be untenable. That fact that agents are currently being tested in the third-line setting speaks volumes about the progress that has been made in a disease with few options even 5-6 years ago. This is both exciting and challenging to the health care providers. Unique clinical presentations such as our case will become more commonplace as patients continue to live longer.

References:

  1. DeVita VT Jr HS, Rosenberg SA. Cancer Principles and Practice of Oncology. (ed 8th ). Philadelphia, PA: Lippincott Williams & Wilkins; 2008.
  2. Negrier S, Maral J, Drevon M, et al. Long-term follow-up of patients with metastatic renal cell carcinoma treated with intravenous recombinant interleukin-2 in Europe. Cancer J Sci Am. 2000 Feb;6 Suppl 1:S93-8.
  3. Escudier B, Szczylik C, Hutson TE, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:1280-1289.
  4. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115- 124.
  5. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:3584-3590.58.
  6. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007;370:2103-2111.
  7. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011;378:1931-1939
  8. E. Angevin, V. Grünwald, A. Ravaud, et al. A phase II study of dovitinib (TKI258), an FGFR- and VEGFR-inhibitor, in patients with advanced or metastatic renal cell cancer (mRCC). J Clin Oncol 29: 2011 (suppl; abstr 4551).

 


Written by: 

Douglas F. Beach, MD and Robert Somer, MD 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. 


 

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