The Role of Cytoreductive Nephrectomy Remains Uncertain in mRCC

Although some patients with metastatic renal cell carcinoma (mRCC), particularly those who have favorable-risk disease, can benefit from cytoreductive nephrectomy, the overall role of surgery in this space remains uncertain among inconclusive randomized data and newer agents, said Justin T. Matulay, MD.

During a 2020 OncLive^® Institutional Perspectives in Cancer webinar on genitourinary malignancies, Matulay, an assistant professor of urology at the Levine Cancer Institute of Atrium Health, discussed whether there is a role for cytoreductive nephrectomy in mRCC, as well as key data that have helped guide this paradigm.

Cytoreduction Emerges and Remains a Standard Approach for Decades

The earliest data that suggested there was a role for cytoreductive nephrectomy came from non-randomized trials based on decades worth of retrospective knowledge, said Matulay.

“Dating back to the 1960s, cytoreductive nephrectomies for renal cell carcinoma were being performed with the observation that in very few rare patients, surgeons would see a profound reduction in the degree of metastatic burden after removing the primary tumor,” explained Matulay.

In 2001, data from the SWOG 8949 trial showed a marked improvement in median overall survival (OS) with cytoreductive nephrectomy plus interferon alfa-2b (IFN), which was the standard of care at the time, compared with IFN alone.¹ Moreover, patients who had more favorable-risk disease at baseline, based on performance status, derived additional benefit from the addition of surgery. Similar findings were reported from the EORTC 30947 trial.²

“Despite only modest gains in survival, cytoreductive nephrectomy had, at that point, become the standard for patients, especially for those with good performance status and low volume of disease,” said Matulay. “The rationale was that even a small [survival] improvement was desirable in this patient population [because] medical care was virtually the same as no therapy at all or [was] minimally effective.”

In the era of targeted therapy with TKIs and VEGF inhibitors, the median OS for patients in 1999 versus 2009 improved from 10 months to 22 months, respectively, Matulay explained. However, during this time, the surgical paradigm remained largely the same, although interest began to mount regarding the ultimate role of surgery among more effective therapeutics. Additionally, multiple retrospective trials were published showing a benefit with cytoreductive nephrectomy; however, most of the benefit was derived from the favorable-risk population, Matulay said.

“This evidence suggested that rather than there being biological rationale for why cytoreduction was working, we were likely seeing the influence of surgical selection,” Matulay said. “Surgeons are excellent at picking the right patients for surgery, so that was probably what we were seeing in these retrospective trials.”

Randomized Data Add to the Conversation but Raise Additional Questions

Following the retrospective analyses, the role of cytoreductive nephrectomy was evaluated in 2 randomized, phase 3 clinical trials: CARMENA and SURTIME.

Both studies looked at the role of immediate cytoreduction; however, CARMENA compared surgery with systemic therapy with a primary end point of OS, and SURTIME compared surgery with delayed cytoreduction with a primary end point of progression-free survival (PFS).

In the CARMENA trial, 450 patients with intermediate- and poor-risk, surgically resectable, clear cell RCC were randomized to 50 mg of sunitinib (Sutent) or cytoreductive nephrectomy followed by 50 mg of sunitinib.³

In the intention-to-treat population, sunitinib alone was found to be noninferior to cytoreductive nephrectomy plus sunitinib (non-inferior OS, 18.4 months vs 13.9 months, respectively). Ultimately, the trial was stopped early, Matulay said.

Regarding crossover, further analysis from CARMENA showed that 7% of patients from the surgery group did not undergo surgery, and 17% of the patients from the sunitinib group did undergo surgery. Additionally, 18% of patients on the surgery arm did not receive sunitinib. Notably, 43% of patients enrolled on the trial were poor risk.

The SURTIME trial randomized 99 patients with intermediate- and poor-risk, surgically resectable disease to 50 mg of sunitinib for 3 cycles followed by cytoreductive nephrectomy followed by 50 mg of sunitinib or immediate cytoreductive nephrectomy followed by 50 mg of sunitinib.⁴

Findings reported that the primary end point of 28-week PFS was not statistically different between groups (42% with immediate cytoreduction versus 42.9% with deferred cytoreduction). The median OS was 32.4 months in the deferred group compared with 15.1 months in the immediate group (HR, 0.57; 95% CI, 0.34-0.95; P = .03).

In SURTIME, 92% of patients in the immediate group and 71% in the deferred group received their respective surgeries. In the deferred group, 29% of patients progressed on sunitinib and did not undergo surgery. Eighty percent and 98% of patients received sunitinib, respectively. Notably, no difference in surgery-related complications was observed, and the trial enrolled mostly patients with intermediate-risk disease (88%).

Future Surgical Directions Amid Novel Therapies in mRCC

Although data from the CARMENA and SURTIME trials are about 2 years old, the rapidly expanding RCC armamentarium raises some unanswered questions, Matulay said. For example, newer TKIs, such as cabozantinib (Cabometyx), pazopanib (Votrient), and axitinib (Inlyta), have demonstrated superiority over sunitinib in mRCC. Therefore, these agents could potentially be more effective in eliminating the need for cytoreductive nephrectomy.

Additionally, whether there is a biological basis for cytoreduction remains unknown, said Matulay.

“There are certainly compelling arguments on either side for leaving the tumor in as a source of neoantigens versus removing the tumor burden, which may be acting as an immune sink. Perhaps, combining these ideas, the initial period of immune stimulation may be beneficial prior to surgical therapy,” Matulay concluded.

References

1. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell carcinoma. N Eng J Med. 2001;345(23):1655-1659. doi:10.1056/NEJMoa003013
2. Mickisch GH, Garin A, van Poppel H, et al. Radical nephrectomy plus interferon–alfa–based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001;358(9286):966-970. doi:10.1016/S0140-6736(01)06103-7
3. Mèjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Eng J Med. 2018;379(5):417-427. doi:10.1056/NEJMoa1803675
4. Bex A, Mulders P, Jewett M, et al. Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial. JAMA Oncol. 2019;5(2):164-170. doi:10.1001/jamaoncol.2018.5543