Shifting Paradigms in the Surgical and Systemic Management of RCC

In an interview with CancerNetwork®, Patrick A. Kenney, MD, and David A. Braun, MD, PhD, came together to discuss keen insights into the surgical and systemic management of renal cell carcinoma (RCC), particularly covering key topics such as selection parameters for cytoreductive surgery, the use of heat shock gene signatures and TGF-beta-driven resistance circuits to inform neoadjuvant treatment, and considerations for use of minimally-invasive procedures in locally advanced disease.

Regarding selection parameters for cytoreductive surgery, Kenney explained that it may be more of a matter of which patients would not draw benefit from cytoreductive therapy, highlighting ongoing trials such as the phase 3 PROBE/SWOG S1931 trial (NCT04510597) and the phase 3 NORDIC-SUN trial (NCT03977571), which will help inform selection criteria for patients.^1,2 Moreover, he highlighted prior research from the phase 3 CARMENA trial (NCT00930033), which suggested that close to 20% of patients who underwent a cytoreductive nephrectomy did not continue to systemic therapy, and highlighted that clinical factors elucidating this occurrence are poorly defined and require further analysis.³

For heat shock gene signatures and TGF-beta-driven resistance circuits, Braun explained that a biologic rationale for their use may reside in the metastatic setting, wherein the former correlated with more favorable responses, but without clarity on whether it was an association or a driver of the response. By contrast, he identified a correlation between TGF-beta activity and poorer responses, which is prompting the development of targeted therapeutics.

Finally, regarding minimally invasive techniques, Kenney explained that although robotic and open surgeries tend to correlate with similar efficacy outcomes, he employs robotic approaches to mitigate hospitalization visits, blood loss, infection risk, and recovery times. Furthermore, he expressed that emergent immune-related adverse effects (AEs) from prior systemic therapy frequently impacts surgical practice, highlighting high rates of detectable adhesions and patients actively on steroids for immune-mediated adrenal insufficiency, which can create questions regarding appropriate procedures and increase complication rates.

CancerNetwork: With the PROBE trial evaluating the benefit of cytoreductive nephrectomy after a period of systemic immunotherapy, what specific radiographic or molecular signals are you utilizing to identify patients who are more likely to derive a survival benefit from delayed surgery?

Kenney: We are still very largely using a combination of clinical parameters to decide around cytoreductive nephrectomy. What we are thinking about is defining biology by the activity of the tumor and how a patient is responding to therapy over time. We are not yet at a point where we are able to definitively select someone for cytoreduction.

An important question is: who should not get cytoreduction? The PROBE trial and NORDIC-SUN, among others, are going to add important information around how to select patients. All of us still have trepidation around cytoreduction, especially when it comes to a patient's ability to receive the systemic therapy that we know they need. Looking back at CARMENA, one of the most important lessons moving forward is that nearly 20% of patients had cytoreductive nephrectomy and were not able to go on to their systemic therapy.

I am comfortable with the idea of patients having systemic therapy first and then looking at clinical factors––a combination of radiographic factors, changing performance status, and pace of disease––to select the people who would be at risk for not doing well after cytoreduction. To me, that is still largely a clinical decision that is somewhat poorly defined. That is the target for the future: can we be more scientific, more rigorous, and more reproducible about selecting patients who would benefit from cytoreduction and selecting those for whom surgery would be a bad idea?

Braun: I agree 100%. When we think about the biological benefits of cytoreduction, there is a lot to consider. There is both eliminating a reservoir of tumor clones that have the potential to be resistant––we have learned over the years that many metastatic clones initially seed from that primary––and removing the negative systemic immune effects of having that primary tumor in place. All of that points to a biological rationale for supporting cytoreductive nephrectomy. The key is systemic therapy.

Systemic disease ultimately needs systemic therapy. If performing a cytoreductive nephrectomy sacrifices the ability to give systemic therapy, that is going to be difficult. In the clinic, we think about exactly that calculus. It is less of a biological argument and much more of a clinical one: based on pace of disease and aggressiveness, do we think we can successfully and safely incorporate this into the treatment while not sacrificing systemic therapy, but augmenting it?

Kenney: I couldn't agree more. We have to have an understanding that cytoreductive nephrectomy is going to favorably alter the trajectory of disease. One of the risks of upfront cytoreduction is that it may unfavorably alter that trajectory. For patients who have systemic disease, systemic therapy is essential.

How might heat shock gene signatures and TGF-beta-driven resistance circuits in T-cells eventually dictate the use of neoadjuvant therapy?

Braun: This is something not yet defined in kidney cancer, but there is some biology we can discuss.

Kenney: One clarification that is important for our literature and conversations is the difference between neoadjuvant therapy and pre-surgical therapy. We don’t all use uniform vocabulary, and I wish we would.

I use "neoadjuvant therapy" to mean treatment with systemic therapy––or radiation in some diseases––for clinically localized disease. "Pre-surgical therapy" is systemic therapy prior to planned surgery in the setting of metastatic disease. Those are very different beasts, and the decision-making around them is different. When we talk about deferred cytoreduction, you could think of that initial Ilixadencel [Intuvax] or Ilixadencel plus VEGF receptor TKI as pre-surgical therapy, but it is not neoadjuvant because that person has radiographic evidence of metastatic disease. In the urologic literature, those things get confused, and "neoadjuvant" is sometimes used to describe therapy in the metastatic setting. I think that is a misnomer.

Braun: Biologically, where a lot of this might be coming from is some of the work from our lab recently in the metastatic setting. We looked at patients who did well with immunotherapy and those whose disease progressed to identify biological differences.

We have certainly seen heat shock gene expression, particularly the HSP70 family within immune cells, associated with favorable responses. There is a lot of work trying to figure out if that is just an association or if there is biology driving the response. Conversely, we have seen that those with high TGF-beta activity within the tumor––which basically alters how the T cells function––do not have a response. The T-cells don’t work as well, don’t make cytokines as well, and don’t kill tumor as well. Those are emerging as therapeutic targets. The aspirational hope is to use that information to rationally select which drug we might give and when, but we are probably not there for the coming years.

Looking at minimally invasive techniques and how they continue to evolve, what are the current thresholds for robotic-first approaches in locally advanced disease, and how does the presence of previous immune-related AEs complicate management for patients undergoing high-stakes robotic procedures?

Kenney: "Robotic-first" is an important concept, but I would tend to think of it as "minimally invasive first." There can still be a role for pure laparoscopy, but the robotic approach is certainly helpful for recovery. None of our surgical advances have made a meaningful difference in survival outcomes over time––open vs robotic eventually results in the same outcome––but the robotic approach is better for shorter hospitalization, lower blood loss, lower risk of infection, and faster return to usual activities.

For patients with metastatic disease, I favor the robotic approach with the hope that it will help them recover to get back on systemic therapy without missing treatment. One of the risks of cytoreduction is the 20% to 30% risk of not being able to resume therapy; we want to minimize that. We have expanded what we think of as an appropriate case for a robotic approach. Robotic nephrectomy post-checkpoint inhibition is very common here, including node dissection, adjacent organ resection, and caval tumor thrombus resection with or without reconstruction. There are very few factors that absolutely require open surgery, primarily when there is a massive tumor where there is simply not enough working space for insufflation.

Regarding immune-related AEs and the impact of Ilixadencel on the operating room, the literature supports the idea that there is a lot of inflammation. About two-thirds to 70% of patients will have detectable adhesions in the operating room, which adds operative time and may increase blood loss. We also have to think about systemic immune-related AEs. There are times we are operating on patients who are on steroids for immune-mediated adrenal insufficiency. If we need to do an adjacent bowel resection, does their steroid use make them appropriate for a bowel anastomosis, or will they need fecal diversion? It impacts a lot of our decision-making.

Braun: From the non-surgical side, seeing these patients afterward for consideration of adjuvant therapy or in the metastatic setting, it is incredible to see how they are recovering and getting back to their normal function. From an observer’s standpoint, I have seen the difference.

Kenney: I would emphasize that "robotics-first" may not be the right phrase. It should be whatever the best surgical approach is in the hands of the surgeon. This is very surgeon-dependent and skill-set dependent. Whatever will achieve the best outcome for the patient is the right approach. Here, that is very much a robotics-first approach if we can.

References

1. Comparing the outcome of immunotherapy-based drug combination therapy with or without surgery to remove the kidney in metastatic kidney cancer, the PROBE Trial (PROBE). ClinicalTrials.gov. Updated September 9, 2025. Accessed April 21, 2026. https://tinyurl.com/y5fpswhp
2. Deferred cytoreductive nephrectomy in synchronous metastatic renal cell carcinoma: the NORDIC-SUN-trial (NORDIC-SUN). ClinicalTrials.gov. Updated June 17, 2025. Accessed April 21, 2026. https://tinyurl.com/4kbyvub4
3. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379(5):417-427. doi:10.1056/NEJMoa1803675