Cytoreductive nephrectomy, either deferred or upfront, is controversial in the metastatic renal cell carcinoma (RCC) setting, especially in the age of immunotherapy given a paucity of data to guide decision-making. I had the privilege of speaking with Sarah Psutka, MD, MSc, Associate Professor in the Department of Urology at the University of Washington Medical Center, and recognized leader in the field of kidney cancer.
Can you share the history of cytoreductive nephrectomy, how it has been utilized, and some of the major trials that influenced its prominence?
Dr. Psutka: The idea of integrating cytoreductive nephrectomy in the care for metastatic RCC has been around for a long time. Starting in the early 2000s, a body of retrospective data became available that supported this practice. Two major research initiatives—the ERTC trial and the SWOG study—demonstrated in a randomized control setting a survival benefit associated with cytoreductive nephrectomy in patients with metastatic disease who were previously treated with interferon-alpha-based immunotherapy. These trials demonstrated between a 3- and 10-month survival benefit compared with the usual survival for patients with metastatic kidney cancer of less than 12 months. Subsequently, a meta-analysis of the 2 studies estimated a 6-month survival benefit with cytoreductive nephrectomy. These studies fundamentally changed how experts thought about surgery in the metastatic setting. In the immediate years to follow, standard-of-care became upfront nephrectomy for management of patients with metastatic kidney cancer.
In 2006, another paradigm shift occurred in kidney cancer with the introduction of the targeted agent sunitinib. Suddenly, there was an explosion targeted agents as we made significant strides in understanding the molecular biology of metastatic kidney cancer. As these more effective systemic therapies became available, the role for surgery began to be questioned.
In 2018, the CARMENA trial made waves as a landmark trial. It was a randomized controlled trial that compared sunitinib alone with sunitinib after upfront cytoreductive nephrectomy. Up until this point, cytoreductive nephrectomy was an integral component of guidelines-based care for metastatic RCC. In CARMENA, patients were enrolled over an 8-year period from 2009 to 2017. Researchers found overall survival to be non-inferior for patients who received sunitinib alone compared with those who received sunitinib and cytoreductive nephrectomy. No significant difference was observed in progression-free survival or response rates. The CARMENA trial added a lot of uncertainty to the metastatic kidney cancer field. In the years to follow however, a careful examination of the limitations of the trial has made the discussion even more nuanced.
Today, cytoreductive nephrectomy is optimally used in select patients. The most significant ongoing uncertainty that needs to be addressed is the role of cytoreductive nephrectomy in the age of immunotherapy and immuno-oncology. Should cytoreductive nephrectomy be performed at all? If it is to be considered, what patient factors should be addressed to optimize outcomes and minimize risks?
Can you be more specific about the limitations of the CARMENA trial?
Dr. Psutka: There are a few key limitations that have to be considered when evaluating the results in light of the primary outcome:
- Patient accrual: The target accrual was 576 patients, but only 450 patients were ultimately enrolled and randomized. Enrollment took place in multiple countries over an 8-year period, and the vast majority of patients were from France. The patients accrued constituted a small percentage of the total patients available with metastatic kidney cancer who potentially met eligibility criteria. So why weren’t people getting into the trial? The concern has been raised that surgeons and patients may have questioned the basic assertion that sunitinib alone was non-inferior to cytoreductive nephrectomy plus targeted therapy. If surgeons and patients don’t feel that a trial meets the bar of equipoise, it becomes difficult to enroll patients. Thus, the trial was limited by not only under accrual, but also may have suffered due to selection bias in terms of patients who were offered enrollment.
- Generalizability: Patients enrolled in the study do not necessarily have similar characteristics, which impacts the greater generalizability to the overall patient population. The patients enrolled in the CARMENA trial tended to be higher risk patients than the overall population with metastatic RCC. Thus, the odds were stacked against cytoreductive nephrectomy because the study population was systematically enriched for much higher-risk patients who traditionally weren’t great candidates for cytoreductive nephrectomy. That leaves us with a patient population that is much less likely to have good outcomes overall.
- Advances in therapeutic management of metastatic RCC: Much has changed from 2001 to 2018 in terms of systemic therapies. Sunitinib monotherapy is no longer the standard of care for metastatic kidney cancer. NCCN guidelines are updated multiple times per year, so there are a lot more therapies to choose from.
- Off-protocol treatment/Contamination: About 7% of patients in the sunitinib plus cytoreductive nephrectomy arm did not undergo nephrectomy. About 17% of patients never received sunitinib, and 50% of those patients crossed over to other therapy. The study analyzed using the intention-to-treat analysis to minimize potential bias, but it becomes a potential problem when there is such a significant degree of crossover.
The age of immunotherapy has placed uncertainty in how to contextualize the CARMENA trial going forward. You have been involved in several trials and recent papers investigating the role of cytoreductive nephrectomy in the immunotherapy era. Can you discuss some of the most recent literature?
Dr. Psutka: In contemporary trials, we are seeing better response rates to multiagent systemic therapy and patients are living longer, thankfully. These patients may have undergone multiple lines of multi-agent therapy, which are carefully selected based on risk factors and disease characteristics. In this context, understanding the roles of cytoreductive nephrectomy and metastatectomy becomes increasingly important. In a recent retrospective paper, we partnered with researchers from the Ohio State University to publish a paper that assessed a multicenter cohort of 367 patients, 135 of whom received immunotherapy at some point in their treatment journey. Thirty-two patients underwent cytoreductive nephrectomy and systemic therapy. The surgery was either upfront or delayed. Even after attempting to control for relevant confounders, we found an independent association between cytoreductive nephrectomy and improved OS.1
It’s important to note that we can’t just say “cytoreductive nephrectomy improves overall survival in metastatic kidney cancer” because this was a retrospective study and therefore is subject to those same selection biases mentioned earlier. However, the study does show a potential signal that there is an association between improved survival in carefully selected patients and receipt of cytoreductive nephrectomy, and there are other recent papers with similar findings.
So, how does cytoreductive nephrectomy hold up in the immunotherapy era? Should any patients undergo cytoreductive nephrectomy in the upfront setting? Based on our research and what we’ve seen, there’s a case to be made that patients with low-volume metastatic disease and excellent performance status stand to gain by having their primary tumor, and potentially low volume metastases, surgically removed or treated definitively (e.g., with surgery, thermal ablation, or SBRT, etc.). This strategy has the added benefit of potentially giving patients the opportunity to forego systemic therapy and avoid further unnecessary costs and adverse events altogether.
I think we’re amid a paradigm shift surrounding perioperative and neoadjuvant systemic therapy, with a trend towards attempting to reduce disease burden with systemic therapy and then moving on to surgical consolidation. However, further work is needed to facilitate optimal patient selection and guide decision-making.
What does the literature show regarding upfront versus deferred cytoreductive nephrectomy?
Dr. Psutka: Currently, there isn’t high-level data that supports one versus the other. In the case of intermediate-risk disease, it appears that cytoreductive nephrectomy should only be used in specific situations. I consider upfront cytoreductive nephrectomy as a great option for really healthy patients with excellent performance status who have very low volume/oligometastatic disease. This procedure may help them get to the point where they don’t need or can delay needing systemic therapy.
Conversely, for intermediate-risk disease, upfront systemic therapy is probably not the right first-step at this point, but deferred cytoreductive nephrectomy can also be considered and is being evaluated prospectively in the SWOG PROBE trial. For poor-risk patients, cytoreduction should not be considered standard of care at this time unless there is a clear palliative indication. The findings from CARMENA support this statement.
How do you counsel patients when discussing the role of cytoreductive nephrectomy?
Dr. Psutka: Critical in all of this is the need to discuss the risks and benefits of surgery transparently and clearly. Patients need to understand that if surgery or its complications defer their ability to receive necessary systemic therapy and they have high-volume metastatic disease, that could be highly problematic. On the other hand, if debulking and surgically resecting tumors, lymph nodes, and metastases allows them to substantially decrease their tumor burden, that could be hugely beneficial. Contextualizing cytoreduction for patients in this new environment of systemic therapies is very nuanced. It calls for a fairly granular discussion with patients on risk factors and needs to be personalized to each individual patient.
Given all the risks that go into the surgery, do you believe that cytoreductive nephrectomy is underutilized or overutilized? How can we improve on its utilization or on overall care for patients with metastatic kidney cancer?
Dr. Psutka: Currently, there is data suggesting that cytoreductive nephrectomy is used less frequently than it once was. There is increasing consolidation, appropriately so, of cytoreductive surgery in centers of excellence with multidisciplinary teams leading the decision-making. Gone are the days when surgeons would make decisions on metastatic kidney cancer by themselves. We know that is not appropriate anymore.
Multidisciplinary teams allow medical and surgical oncologists to work side-by-side across different episodes of care. This approach is the optimal way to achieving the best outcomes for patients.
Are there any ongoing clinical trials related to cytoreductive nephrectomy or systemic treatment for patients with metastatic kidney cancer that we should keep an eye on?
Dr. Psutka: We mentioned earlier the SWOG PROBE trial – a phase 3 study evaluating the role of cytoreductive nephrectomy in metastatic RCC.2 There are also numerous multicenter, collaborative efforts to better understand how cytoreductive nephrectomy impacts quality of life and to better define selection criteria. Individuals like Dr. E. Jason Abel at University of Wisconsin and Jose Karam at MD Anderson are leading the charge in this space. These kinds of collaborative efforts really get at the granular patient-specific selection factors that can help us make more appropriate decisions and better counsel patients about their relative risks and the oncologic impact of the surgery.
David Ambinder, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.
- Gross EE, Li M, Yin M, Orcutt D, Hussey D, Trott E, Holt SK, Dwyer ER, Kramer J, Oliva K, Gore JL, Schade GR, Lin DW, Tykodi SS, Hall ET, Thompson JA, Parikh A, Yang Y, Collier KA, Miah A, Mori-Vogt S, Hinkley M, Mortazavi A, Monk P, Folefac E, Clinton SK, Psutka SP. A multicenter study assessing survival in patients with metastatic renal cell carcinoma receiving immune checkpoint inhibitor therapy with and without cytoreductive nephrectomy. Urol Oncol. 2023 Jan;41(1):51. e25-51. e31. doi:10.1016/j.urolonc.2022.08.013. Epub 2022 Oct 26. PMID: 36441070.
- Bell H, Cotta BH, Salami SS, Kim H, Vaishampayan U. “PROBE”ing the Role of Cytoreductive Nephrectomy in Advanced Renal Cancer. Kidney Cancer J. 2022 Mar 15;6(1):3-9. doi:10.3233/kca-210010. PMID: 35310961; PMCID: PMC8929722.