Expert Explains Clinical Developments With Cytoreductive Nephrectomy in mRCC

Ulka Vaishampayan, MD

Cytoreductive nephrectomy should be considered after systemic therapy, if at all, in the majority of patients with metastatic renal cell carcinoma (mRCC), according to Ulka Vaishampayan, MD, a professor of oncology at Wayne State University.

“If the patient presents with oligometastatic disease that is resectable, we may consider nephrectomy and resection of the metastatic sites. However, the majority of patients have unresectable metastatic disease,” said Vaishampayan. “These patients should start on systemic therapy. Depending on their response and [the amount of] residual disease, [we will] decide whether to [proceed with nephrectomy] or switch to another systemic therapy.”

This rationale is based on findings from the phase III CARMENA trial, in which patients with intermediate- and poor-risk disease had noninferior overall survival (OS) with cytoreductive nephrectomy followed by sunitinib (Sutent) versus sunitinib alone (HR, 0.89; 95% CI, 0.71-1.10).¹ With longer-term follow-up at 61.5 months, the median OS in the intent-to-treat population was 15.6 months with cytoreductive nephrectomy/sunitinib versus 19.8 months with sunitinib alone (HR, 0.97; 95% CI, 0.79-1.19).²

In the longer follow-up, among patients who proceeded to secondary nephrectomy after randomization to sunitinib alone, the median OS was 48.5 months (95% CI, 27.9-64.4) versus 15.7 months (95% CI, 13.3-20.5) in patients who never had surgery (HR, 0.34; 95% CI, 0.22-0.54), suggesting the benefit of delaying nephrectomy in fit patients.

In an interview during the 2019 OncLive State of the Science Summit on Genitourinary Malignancies, Vaishampayan, who is also the chief of the Solid Tumor Program at Barbara Ann Karmanos Cancer Institute, discussed the historical management of patients with mRCC and how advances with systemic therapy have impacted the sequencing of cytoreductive nephrectomy in the treatment paradigm.

OncLive: Historically, how has cytoreductive nephrectomy been used in patients with mRCC?

Vaishampayan: Historically, cytoreductive nephrectomy demonstrated an OS benefit in [patients with] metastatic kidney cancer. [Nephrectomy] was considered the first step in the management of patients who presented with primary and metastatic disease and had good performance status.

Could you speak to the pivotal phase III CARMENA trial? What were the key findings?

The CARMENA trial examined the role of cytoreductive nephrectomy in the context of anti-VEGF therapy. Historically, this was looked at with interferon because that was the only treatment that was available and applicable to the majority of patients at the time. With contemporary anti-VEGF therapy, cytoreductive nephrectomy was not shown to be beneficial, [as we saw] in the CARMENA trial. Because of that, the trial resulted in a paradigm shift of how we approach treatment.

Could you expand on how the role of cytoreductive nephrectomy has shifted in the metastatic setting?

Now, if someone presents with a primary lesion and metastatic disease, we typically give systemic therapy first because the efficacy of systemic therapy has improved remarkably. Then, we consider whether to do cytoreductive nephrectomy or not. We have to stay tuned for a SWOG trial that addresses this question with contemporary immunotherapy up front after which patients will be randomized to cytoreductive nephrectomy or continue on systemic therapy. We would love to have patients consider the clinical trial as it becomes available. 

What are some of the remaining challenges with cytoreductive nephrectomy?

The delay in starting systemic therapy remains a challenge. If you do nephrectomy, you're going to delay the patient from receiving systemic therapy, which [we know is beneficial] to the primary and metastatic sites. The CARMENA trial showed that 20% of patients never made it to systemic therapy and had worse outcomes because of that. To avoid that from happening, we should consider systemic therapy first and defer the nephrectomy to a later date; it makes perfect sense. 

What is your take-home message regarding cytoreductive nephrectomy in mRCC?

You should consider systemic therapy up front for patients with synchronous metastatic disease and then consider whether doing a nephrectomy makes sense. [That decision] should be based on the patient’s response [to treatment], how they're feeling overall, and what kind of performance status they're maintaining.

References

1. Méjean 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.
2. Méjean A, Thezenas S, Chevreau C, et al. Cytoreductive nephrectomy (CN) in metastatic renal cancer (mRCC): update on CARMENA trial with focus on intermediate IMDC-risk population. J Clin Oncol. 2019;37(suppl 15; abstr 4508). doi: 10.1200/JCO.2019.37.15_suppl.4508.