Surgical monotherapy appears to fail to cure a significant proportion of “localized” renal cell carcinoma (RCC). In cancer, we just utilize NATt and AT to achieve a variety of outcomes. For RCC in specific, NAT has been used to try to shrink tumors and facilitate surgical intervention. AT is thought to control micrometastatic disease and reduce tumor recurrence risks.
There is mixed evidence as to the efficacy of NAT in the setting of renal tumor thrombus. A number of case series (largest N = 25) have found that approximately 40% of patients change their thrombus size, but very few change thrombus “level.” Indeed, some thrombi continue to grow during NAT, and therapies do not come without their own toxicities.
On the other hand, retrospective series and phase II trials seem to show that NAT helps facilitate more effective surgical resection. Of those receiving NAT, about 25% may appreciate tumor size reduction, and some 50% can then receive a partial nephrectomy. This is a fantastic outcome, though there is clearly a bias when analyzing retrospective data with respect to who is chosen for surgery, etc. The bottom line for NAT is that there is limited, although encouraging, data showing a clinically meaningful effect on renal tumors, but this space is still experimental and requires more data.
The history of AT for RCC has largely been that of failure to achieve clinical impact. Chemotherapy, radiation, and combinations thereof dating back to the 1980s have consistently failed to show improvement in outcomes. The last few years has seen a rags-to-riches story in this area, though; and there are currently a number of adjuvant trials underway with a host of new agents. Highlighting the most high-profile and recently published studies, Dr. Allaf presented data from ASSURE, S-TRAC, and PROTECT.
ASSURE (sunitinib or sorafenib vs. placebo) was negative for overall or disease-free survival. S-TRAC (sunitinib vs. placebo) enrolled a slightly higher-risk patient population, finding that disease-free survival improved by about 1 year with treatment. Overall survival data had not matured by the time of publication. PROTECT (pazopanib vs. placebo) has not been completed, but early data suggest that it, too, will be a negative study.
Does this mean that we continue to have no hope for effective AT in high-risk RCC? Trials in this space are difficult, since accruing enough high-risk patients and following outcomes is challenging in RCC. ASSURE and S-TRAC had several important differences, but patients in both trials also experienced rather significant morbidity. About 60% of individuals in both trials endured Grades 3-4 toxicities, and 40% of patients in the two trials withdrew from the studies. So the bottom line at this stage is that AT is toxic and does not appear to have enough benefit to support clinical application. Several more phase III adjuvant trials are currently underway (SORCE, EVEREST, PROTECT, ATLAS) that may add more clarity to the answer to this question.
Several extremely exciting new immune checkpoint inhibitor trials are now in motion. These include: PROSPER (nivolumab vs. observation), IMmotion10 (atezolizumab vs. placebo), and KEYNOTE (pembrolizumab vs. placebo). Only PROSPER will be evaluated in the neoadjuvant space. Although there are key differences in each of these trial designs, investigators have learned important lessons from the past and we hope to gain clean and actionable data from these ongoing studies.
We should also not forget to push for more studies in the neoadjuvant area. The rationale for NAT is strong because of several key facts. There are most definitely ongoing anti-tumor T-cell responses in tumors. Nephrectomy will remove the vast majority of tumor cells and anti-tumor T-cells. Circulating programmed cell death-1 or PD-1+ cells significantly decrease following nephrectomy. Animal data suggest NAT is better than AT (primary tumor is required for expansion of tumor-specific T-cells). Ultimately, NAT plus AT may have the highest likelihood of successfully reducing tumor recurrence and improving survival in high-risk localized RCC.
This is a rapidly expanding space for research. Circling back to Dr. Allaf’s plea, it is imperative that urologists remain involved and enthusiastically enroll eligible patients into these continuing trials. It is high time that we improve outcomes for high-risk RCC, and we may well be on the cusp of finding a multimodality treatment package that can achieve this dream.
Presented By: Mohammad Allaf, MD, Johns Hopkins
Institutions: Brigham and Women’s Hospital and Dana-Farber Cancer Center
Written By: Shreyas Joshi, MD, Fox Chase Cancer Center, Philadelphia, PA
at the 2017 AUA Annual Meeting - May 12 - 16, 2017 – Boston, Massachusetts, USA