Neoadjuvant therapy is evolving as a treatment approach for patients with advanced renal cell carcinoma (RCC), according to Ithaar Derweesh, MD, a clinical professor at UC San Diego Heath.

In a presentation at the 2016 International Kidney Cancer Symposium, Derweesh said that neoadjuvant treatment facilitates cytoreductive nephrectomy and metastasectomy for metastatic disease, complete resection for locoregional advanced disease, and partial nephrectomy for large and complex renal masses with imperative indication for nephron-sparing surgery.

To firmly establish the utility of neoadjuvant therapies—including sunitinib (Sutent), axitinib (Inlyta), and pazopanib (Votrient)&mdash;the objective measures employed include RECIST criteria,

 reduction in tumor diameter, and relevant morphometric scores (RNAL, PADUA, C-index). These scores have been shown to correlate not only with reduction in tumor size, but also with the type of surgical approach, complications, and grade of disease. Additionally, The RENAL Nephrometry Score

 has been shown to correlate with cytoreduction in the neoadjuvant setting.

In developing neoadjuvant therapy, the primary rationale is based on the questions, “Can we do more, and can we do better? Can we predict response earlier that might cause us to change course and not persist in a tumor where the response might be poor?” said Derweesh. To this end, independent markers such as platelet count and MRI, have recently emerged.

Currently, there are no published randomized clinical trials to support neoadjuvant therapy in the setting of metastatic RCC, and its use in locally advanced disease is controversial. However, there are 3 phase II studies in the setting of metastatic disease, along with 2 retrospective analyses; 3 phase II studies and 2 retrospective studies in the area of locoregional disease; and 2 retrospective studies and multiple case reports for thrombi. Most of these studies evaluate presurgical or neoadjuvant sunitinib in the setting of locally advanced disease.

The most promising area is neoadjuvant therapy to downsize renal mass to permit partial nephrectomy in imperative indications, an approach supported by mostly single-center phase II and retrospective studies. These studies report a reduction in tumor size of between 18% and 28%, a RECIST partial response rate of between 19% and 45.8%, and a partial nephrectomy success rate of between 50% and 75%.

“An interesting thing, from a surgical standpoint, that makes axitinib attractive for a surgeon, is the short half-life, and therefore the washout period between axitinib, versus sunitinib or pazopanib, is much shorter,” commented Derweesh.

In discussing the next steps for research and practice, Derweesh said, “Ultimately, we’re still waiting, in terms of the timing or the utility of neoadjuvant therapy for systemic therapy and partial nephrectomy, for the publication of the CARMENA and EORTC studies.”

In addition, recent findings showing that checkpoint inhibitors may be better at eliminating circulating tumor cells and micrometastases than angiogenesis inhibitors raise the question of how checkpoint inhibitors may be used in the presurgical or neoadjuvant setting. There are currently studies underway to address these questions, including the phase II UK ADAPTeR study (NCT02446860) and 2 US studies (NCT02446860; NCT02575222) on nivolumab.

Finally, a phase II trial on prior axitinib as a determinant of outcome of renal surgery (PADRES) seeks to broaden research beyond 1 or 2 centers to “a larger group of centers that are high volume, that deal with a lot of these inherited indications, highly complex and imperative partial surgeries.”

This study will use axitinib, includes a target of 10 institutions, and seeks to enroll 50 patients. For this study, the primary efficacy endpoint is the proportion of patients able to undergo successful partial nephrectomy with negative margins. Other endpoints include reduction in tumor size, change in RENAL Score, and renal function assessment.

Together, these phase II studies have provided a springboard for the development of the larger, multicenter, randomized trials needed to firmly establish the utility of and optimal timing for neoadjuvant therapy in locally advanced and metastatic RCC, concluded Derweesh.

Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 

Kutikov A, Uzzo RG. The R.E.N.A.L. nephrometry score: a comprehensive standardized system for quantitating renal tumor size, location and depth. 

Lane BR, Derweesh IH, Kim HL, et al. Presurgical sunitinib reduces tumor size and may facilitate partial nephrectomy in patients with renal cell carcinoma. 

Rini BI, Plimack ER, Takagi T, et al. A phase II study of pazopanib in patients with localized renal cell carcinoma to optimize preservation of renal parenchyma. 

Karam JA, Devine CE, Urbauer DL, et al. Phase 2 trial of neoadjuvant axitinib in patients with locally advanced nonmetastatic clear cell renal cell carcinoma.

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