Integration of Newer Strategies Into the Management of RCC

In this issue of ONCOLOGY, Dutcher, Mourad, and Ennis provide a current review of some newer strategies in the surgical and systemic treatment options for localized and advanced renal cell carcinoma (RCC). The authors begin with a brief description of surgical approaches for treatment of the primary tumor, and they focus attention on the ablative approaches. As described, percutaneous cryoablation and radiofrequency ablation have become accepted treatments for the management of small renal masses. While conclusions based on long-term data have yet to be established, intermediate-term oncologic efficacy appears to be adequate, with minimal procedure-related morbidity. Tracy et al evaluated outcomes in 208 patients undergoing renal tumor radiofrequency ablation and reported 5-year recurrence-free and cancer-specific survival of 93% and 95%, respectively.[1] As described in the review, the overall complication rate from percutaneous ablation is 6.6%, with patients often being able to return to their normal activities after 72 hours.[2] While the role of radiotherapy as a palliative treatment option for metastatic disease is well established, Dutcher and colleagues describe preliminary phase I study data with the use of stereotactic body radiotherapy for the treatment of primary renal tumors. Given the sensitivity of RCC to immunotherapy, the authors go on to postulate whether radiotherapy in combination with immune modulation may result in improved treatment responses. Clearly, this may be an area for further study.

Next, the authors describe some recent advances in the development of molecular targeted therapies for metastatic RCC. As they note, since 2005 there have been seven new agents approved for treatment of RCC, with several additional medications currently in clinical trials. These agents primarily act to decrease tumor-related angiogenesis by inhibition of the vascular endothelial growth factor (VEGF) pathway or by inhibition of the mammalian target of rapamycin (mTOR) pathway. The development of these therapeutics resulted from understanding the molecular tumorigenic pathways in clear cell RCC in patients with von Hippel-Lindau (VHL) syndrome. While the efficacy of these targeted therapies in clear cell RCC is well established, there continues to be debate regarding which targeted agent is most appropriate in patients with non–clear cell histology. Perhaps, just as research into the mechanisms of the VHL mutation resulted in treatments for clear cell RCC, a better understanding of molecular mechanisms in non–clear cell tumors will lead to the development of more efficacious targeted therapy. In a recent review, Singer and colleagues from the National Cancer Institute discuss the current understanding of the molecular mechanisms involved in hereditary papillary renal cancer, Birt-Hogg-Dube syndrome, and hereditary leiomyomatosis renal cell carcinoma syndrome.[3] Similar molecular pathways seem to be involved in papillary type 1, papillary type 2, and chromophobe kidney cancers.

With regard to integration of systemic therapy in multimodality approaches, various targeted agents have been used in both the adjuvant and neoadjuvant settings. The ASSURE (Adjuvant Sorafenib or Sunitinib in Unfavorable Renal Cell Carcinoma) trial and the S-TRAC (Sunitinib Treatment of Renal Adjuvant Cancer) trial, which randomized patients with high-risk localized tumors to 1 year of adjuvant anti-VEGF therapies, have completed enrollment and are currently in the follow-up phase. Two additional adjuvant trials using newer agents are now enrolling patients. The results of these trials are not expected for several more years. The data for neoadjuvant treatment are even more limited. The literature is limited to small single-institution retrospective series of patients. Neoadjuvant treatment in advanced RCC has the potential to improve the resectability of locally advanced tumors, to improve the feasibility of partial nephrectomy, and perhaps to better select candidates who are most likely to benefit from cytoreductive nephrectomy. Overall, the current literature describes a mean percent change of 1% to 11% in the size of the primary RCC tumor.[4] Clearly, further research and prospective evaluation are necessary to establish the role of neoadjuvant treatment.

In conclusion, Dutcher and colleagues provide a brief review of some of the newer strategies for integrating multimodal therapy into the treatment of both localized and metastatic RCC. For localized tumors, partial/radical nephrectomy and percutaneous ablation are well-established options, with radiotherapy being a potential future option if it is deemed to be oncologically efficacious. In the treatment of metastatic disease, immunotherapy and molecular targeted therapies continue to evolve and may be integrated into management of earlier stages of disease.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Tracy CR, Raman JD, Donnally C, et al. Durable oncologic outcomes after radiofrequency ablation: experience from treating 243 small renal masses over 7.5 years. Cancer. 2010;116:3135-42.

2. Atwell TD, Carter RE, Schmit GD, et al. Complications following 573 percutaneous renal radiofrequency and cryoablation procedures. J Vasc Interv Radiol. 2012;23:48-54.

3. Singer EA, Bratslavsky G, Linehan WM, Srinivasan R. Targeted therapies for non-clear renal cell carcinoma. Target Oncol. 2010;5:119-29.

4. Kenney PA, Wood CG. Integration of surgery and systemic therapy for renal cell carcinoma. Urol Clin North Am. 2012;39:211-31.