Exploring the Role of Cytoreductive Nephrectomy in RCC

Brian M. Shuch, MD

Although recent studies have failed to establish the relevance of cytoreductive nephrectomy in the treatment of patients with advanced renal cell carcinoma (RCC), a true multidisciplinary approach may be able to help answer this question, said Brian M. Shuch, MD.

For example, the phase III CARMENA trial evaluated the benefit of sunitinib (Sutent) monotherapy versus nephrectomy followed by sunitinib. Data showed that sunitinib alone was noninferior to nephrectomy and sunitinib.¹ Specifically, the median overall survival (OS) for those treated with VEGF TKI therapy alone was 18.4 months compared with 13.9 months for patients who underwent nephrectomy. The same held true for those classified as having intermediate-risk (23.4 months vs 19.0 months) or poor-risk (13.3 months vs 10.2 months) disease.

In another phase III trial, the SURTIME study, patients were randomized to receive immediate cytoreductive nephrectomy followed by sunitinib or 3 cycles of sunitinib followed by nephrectomy in the absence of progression followed by sunitinib. Results showed no statistically significant difference in progression-free survival (PFS) rate at 28 weeks, although an OS analysis indicated that deferred nephrectomy could have an advantage over immediate surgery.²

OncLive: What has been the traditional role of cytoreductive nephrectomy in advanced RCC?

What are the biggest takeaways from the CARMENA trial?

In an interview with OncLive, Shuch, director of the Kidney Cancer Program, Alvin & Carrie Meinhardt Endowed Chair of Kidney Cancer Research, University of California, Los Angeles (UCLA) Institute of Urologic Oncology, highlighted the complex data with cytoreductive nephrectomy in RCC and offered advice on how to navigate the intricate treatment landscape.Shuch: Despite the tumor leaving the kidney and going to other sites of the body, classically, there has been a role of what we call debulking or really removing the “mothership,” as I tell my patients. There have been many studies showing a survival benefit to removing the primary tumor. This was based in different eras of treatment, when we gave therapies like cytokines, interferon alfa, and interleukin-2. We have level 1 evidence showing that there is a benefit when you remove the primary tumor in select patients. [There are] trials that have been published in the last year that have questioned the role of this approach in the new treatment era.In the new treatment era, which started in 2005 with the FDA approval of sorafenib (Nexavar) and sunitinib, we have several drugs that are well tolerated and can cause responses or disease control in a majority of patients. The question is, “Is surgery still relevant in this treatment era?” We have retrospective data suggesting that it is still imperative to remove the primary tumor.

The CARMENA trial was a study conducted in France, which looked at many patients with metastatic RCC. They were very nonselective; they allowed patients who had very advanced disease and very poor disease characteristics, including the International Metastatic Renal Cell Carcinoma Database Consortium risk group. About 44% of patients enrolled in the trial were considered to have poor-risk disease. They randomized patients to receive either upfront systemic therapy [with sunitinib] versus surgery followed by systemic therapy.

Have any recent studies offered more clarity in terms of surgery’s role in RCC?

The goal was to try to figure out whether sunitinib alone would be noninferior to receiving nephrectomy [plus sunitinib]. That study was powered to detect a noninferiority limit of 1.2 or a 20% change in outcome. Results from CARMENA did show that there were similar outcomes with sunitinib alone versus cytoreductive nephrectomy followed by sunitinib. It left a lot of investigators scratching their heads and wondering whether surgery was still relevant in this systemic treatment era—what we call the TKI era. TKIs are actually now becoming more of a second-line therapy.We have several studies that have looked at this; I would say the CARMENA study has a lot of flaws. We have a lot of good data from Thomas Powles, MBBS, MRCP, MD, and colleagues in the United Kingdom, which looked at sunitinib or pazopanib (Votrient) as upfront systemic therapy followed by surgery.

What we have learned from those studies is that you have some patients with poor-risk disease who are not going to do well with surgery. If you give them systemic therapy upfront, about 40% to 50% of patients are going to progress and not make it surgery. Those patients who have poor-risk characteristics and undergo surgery will do very poorly.

There was also the SURTIME study, which was conducted by our friend Axel Bex, MD, PhD, of the Netherlands Cancer Institute. Bex et al had a goal of accruing 450 patients but fell short of that goal. Their study was designed to look at whether there was a difference between upfront surgery and trying to delay surgery. It was immediate surgery followed by sunitinib versus sunitinib followed by surgery [in the absence of progression followed by sunitinib]. They were looking at PFS, but because of the poor accrual, they changed the primary endpoint to look at PFS rate at 28 weeks.

Although it did not show any difference in this endpoint, there was a difference in OS benefit, which served as a secondary endpoint. The patients who had deferred nephrectomy—meaning they had systemic therapy and went on to surgery if they did not have disease progression—experienced an improvement in OS at 32 months compared with 15 months in the immediate nephrectomy group.

When a patient with advanced RCC comes into the clinic, how do you decide whether or not nephrectomy is appropriate?

I do think the study was underpowered to show that delayed nephrectomy is beneficial. However, it shows that with the TKIs, if you have patients who will do poorly with systemic therapy and you're going to put them through upfront surgery, some of those patients are not going to do well. By the time they are ready to receive systemic therapy, they may no longer be a candidate for that approach; they might be too frail. That type of approach—delaying systemic therapy and re-imaging at 3 or 4 months—would potentially “weed out those bad actors,” get them to second-line therapy, and avoid surgery all together. That was the secondary endpoint, and that study had only 99 patients. As to the relevance of these findings in the even newer era—what we call the targeted immunotherapy era—who knows. We are looking forward to studying this further.I would tell you that this needs to be done in a true multidisciplinary setting. At UCLA, we have an integrated program that I lead. I have clinic with our medical oncologist who only does RCC; we meet patients together. It may be financially inefficient to have everyone seeing these types of patients on the same day in the same clinic, but it gives patients better access to all providers. The way I set up our team is that if a patient has a large primary tumor and he/she is asymptomatic with low disease burden, that patient could be a candidate for what we call active surveillance. This is an accepted modality for low-volume disease. It's a no-brainer. If a patient is a good surgical candidate, they will go right to surgery. If you see the need to initiate systemic therapy, it should be because that patient has a disease that needs immediate treatment. You should give systemic therapy and/or local radiation, palliation, ablation, or metastasectomy for that distant disease. If you don't need aggressive management of the metastatic site, you can go down the route of deciding whether or not that primary tumor is very symptomatic. If it's not, and the patient needed treatment for their metastatic disease very recently, give them systemic therapy.

If the patient does need systemic therapy and they have significant symptoms, you could risk-stratify them. If patients have high-risk features and we feel that they would not do well with surgery, and it's going to delay their initiation of systemic therapy, they should receive systemic therapy. If this is the case, and the primary tumor is symptomatic, we would give either an embolization, which is very effective at palliating, or we would do stereotactic radiosurgery for the large tumor.

Now that we are moving toward more of an immunotherapy/TKI regimen, how do you foresee that affecting nephrectomy?

Could you speak to the importance of considering patient preference in terms of surgery?

If the patient has very limited poor-risk characteristics and we feel we can do a quick radical nephrectomy and get them ready for systemic therapy in a couple weeks, there's no reason why we can't do this. We have those 3 or 4 questions and a clinical workflow to evaluate our patients. We do feel that surgery is still relevant, but it needs to be discussed in a multidisciplinary setting.Within our SWOG group, I am the co-leader of the RCC team. Ulka Vaishampayan, MD, and I are putting together a proposal that will be going to the Genitourinary Committee and hopefully it will get approved. It is looking at the role of surgery, and basically, patients would get randomized to receive either ipilimumab (Yervoy) plus nivolumab (Opdivo)—which is the frontline standard of care for clear cell RCC—followed by surgery or the combination alone. We are looking to see if surgery in that setting will improve outcomes. That trial has been redesigned multiple ways, but it's really a 2-arm study that will help answer this question in the new immunotherapy era. Hopefully, this proposal will get approved and it will be something we can have data for soon.There has been great work done by simply asking the patient if they want a cytoreductive nephrectomy knowing that it may not actually improve outcomes. There was a survey asking patients if they had a large primary tumor with metastatic sites coming from it, would they want to get it surgically removed? It was very informative that patients said despite not having much survival benefit, they would still want that tumor removed from their body. There are patients that can definitely be harmed if they are not good candidates, but trying to understand what the patient wants is important.

References

1. Mejean A, Escudier B, Thezenas S, et al. CARMENA: cytoreductive nephrectomy followed by sunitinib versus sunitinib alone in metastatic renal cell carcinoma—results of a phase III noninferiority trial. J Clin Oncol. 2018;36(suppl 18; abstr LBA3). doi: 10.1200/JCO.2018.36.18_suppl.LBA3.
2. 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 [published online December 13, 2018]. JAMA Oncol. doi: 10.1001/jamaoncol.2018.5543.