Surgical Management of Kidney Cancer Impactful but Associated With Unanswered Questions

Surgical resection of the primary tumor and, in some cases, the kidney has long held an important and central role in the treatment of kidney cancer, whether in the metastatic or localized setting. However, therapeutic advances continue to reshape the clinical management of patients with renal cell carcinoma (RCC) and, consequently, the role of surgery.

Specifically, starting with the US Food and Drug Administration approval of the targeted therapies sorafenib and sunitinib in the early 2000s, and subsequently the addition of almost 20 new options—first-line cabozantinib, nivolumab plus cabozantinib, avelumab plus axitinib, nivolumab plus ipilimumab, pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, along with axitinib, everolimus, and tivozanib in refractory settings¹—systemic treatment options for patients have changed, and data that examine the exact role of nephrectomy in the modern era are lacking.

GU Oncology Now recently spoke with several experts in the field and discussed the evolution of nephrectomy as a treatment approach, how it is used today, which patients are best suited for it, and how it figures to exist as a treatment option in coming years.

Surprising Benefit

As far back as the 1950s to the 1980s, cytoreductive nephrectomy served a palliative role in the treatment of metastatic kidney cancer, according to Alexander Kutikov, MD, FACS, chair of the Department of Urology at Fox Chase Cancer Center.

“This procedure was reserved for patients with bleeding and who had bulky, symptomatic disease,” Dr. Kutikov said. “Surgeons went in and took out the kidney. Later they noticed that some patients did well long-term after the tumors were removed.”

In many cases, surgery was used for all patients who could tolerate it because there were not good systemic therapies available.

In the early 2000s, 2 trials were published that had been designed to test the benefit of cytoreductive nephrectomy in metastatic disease. SWOG-8949 randomly assigned patients with RCC to undergo radical nephrectomy followed by interferon alfa-2b or treatment with interferon alfa-2b alone. Patients who underwent surgery had a 3-month overall survival (OS) benefit compared with interferon alone.² A similar trial out of Europe also showed improved progression-free survival (PFS) and OS with radical nephrectomy plus interferon-based therapy.³

“These trials showed if you selected patients appropriately there was a 5- to 6-month survival benefit to cytoreductive nephrectomy, and that became the standard,” Dr. Kutikov said.

Patient selection was key, he said, because when this approach was applied outside of clinical trials there were patients who never made it to systemic therapy—rapid progressors.

“In those early days, the median survival for metastatic kidney cancer was about 10 months, so giving someone 6 additional months was a big deliverable,” Dr. Kutikov said. “The challenge facing surgeons was to make sure we were applying cytoreductive nephrectomy to the right population to achieve that benefit.”

This approach of combining cytoreductive nephrectomy with systemic therapy continued in the era of targeted therapy with sunitinib and sorafenib, according to A. Ari Hakimi, MD, an associate attending surgeon in the Department of Urology at Memorial Sloan Kettering Cancer Center, until the field started re-evaluating the role of surgery.

Challenging the Approach

The role of surgery in the treatment of metastatic kidney cancer was challenged by 2 studies: CARMENA and SURTIME.

With limited level 1 evidence of the benefit of nephrectomy in the era of targeted therapies, CARMENA was designed to compare nephrectomy followed by sunitinib or sunitinib alone in patients with metastatic clear cell RCC. A planned interim analysis showed that sunitinib alone was noninferior to the combined approach. Median OS was 18.4 months with sunitinib alone compared with 13.9 months for nephrectomy plus sunitinib.⁴

SURTIME compared immediate cytoreductive nephrectomy followed by sunitinib versus sunitinib followed by nephrectomy and in the absence of progression followed by sunitinib. Deferred surgery did not improve PFS, but OS results were numerically higher with this approach.⁵

There are acknowledged flaws in the CARMENA study, including lack of accrual and statistical power, patients were not selected based on performance status or other risk criteria, and the inclusion of all-comers.

Regardless, “these results called into question the potential oncologic benefit of surgery,” said Sarah P. Psutka, MD, an associate professor of urology in the Department of Urology at the University of Washington and Fred Hutchinson Cancer Center. “Fast forward another couple of years to the era of combination modalities and, to date, there are no randomized trial data to support or refute the benefit of nephrectomy.”

Who and When?

Treatment of kidney cancer is now firmly in the era of combination modalities, whether that be combining 2 immunotherapy treatments or combining immunotherapy with tyrosine kinase inhibitors (TKIs).

“These combinations are truly lifesaving and game-changing for patients with kidney cancer,” Dr. Kutikov said. However, with no randomized data, clinicians are left with retrospective data and clinical judgement to decide the best management approach.

“The 2 critical questions are timing of surgery and selection criteria of patients who are most likely to derive benefit from having the primary tumor removed,” Dr. Psutka said.

Although the CARMENA data did not support the use of surgery plus systemic therapy, data from the trial have provided clinicians with insight in terms of patient selection. The trial supported using upfront systemic therapy in most patients with high-volume, poor-risk disease and many patients with intermediate-risk disease. In both intermediate- and poor-risk groups in CARMENA, the median OS was significantly longer with sunitinib monotherapy versus the combination approach.⁴ With longer follow-up the OS benefit of sunitinib alone remained in these patient groups (31.2 vs 17.6 months; P=.03). In contrast, patients with only 1 International Metastatic RCC Database Consortium (IMDC) risk factor had a longer OS after nephrectomy (31.4 vs 25.2 months).⁶

Defining patients who would benefit from upfront nephrectomy is challenging and requires multidisciplinary discussion between urologists and medical oncologists, said Tian Zhang, MD, an associate professor in the Department of Internal Medicine at UT Southwestern Medical Center.

“If the tumor in the primary takes up 90% of the tumor burden within the person, those are the people who we might think about nephrectomy first followed by systemic treatment for metastatic burden,” Dr. Zhang said. “These are people with big primaries and maybe 1 or 2 lung nodules or 1 bone spot. These are situations where we think systemic treatment can wait until after nephrectomy.”

A patient’s response to upfront systemic therapy may also help to identify who may benefit from a deferred or consolidative nephrectomy.

“Delayed nephrectomy could be considered in a patient with limited metastatic burden or where metastatic burden has responded well to systemic agents, but the primary is growing,” Dr. Psutka said. Surgery may also be recommended for patients who remain symptomatic despite response to therapy.

Retrospective data looking at the use of sunitinib showed that carefully selected patients who underwent a deferred procedure after systemic therapy achieved longer OS compared with systemic therapy alone or upfront nephrectomy followed by systemic therapy.⁷

A meta-analysis of studies evaluating the timing of nephrectomy and its use compared with systemic therapy alone showed that the deferred approach significantly improved OS compared with upfront nephrectomy (hazard ratio [HR], 0.56; 95% CI, 0.45-0.69) and systemic therapy alone (HR, 0.45; 95% CI, 0.38-0.53).⁸

Further retrospective data looking at deferred nephrectomy in the era of immunotherapy combinations also signaled a delay in the need for further chemotherapy and survival advantage for deferred cytoreductive nephrectomy compared with systemic therapy alone in selected patients.^9–11

Dr. Psutka was part of a multicenter retrospective study of 367 patients with metastatic RCC that found that cytoreductive nephrectomy was independently associated with a longer OS in patients treated with immune checkpoint inhibitor therapy compared with systemic therapy alone (median OS, 56.3 vs 19.1 months).¹¹

The appropriate timing of a consolidative nephrectomy is still a moving target, according to Dr. Hakimi.

“As a group we have done about 70 or 80 of these surgeries now and performed them as early as 3 months after systemic therapy or as long as 2 to 3 years afterward,” Dr. Hakimi said. “Overall, we have seen good outcomes for these patients, and the procedures are quite safe when done [by] experienced hands.”

More Knowledge Needed

There are a number of ongoing clinical trials that should provide more information about the appropriate use of cytoreductive nephrectomy.

“The PROBE trial being run through [the SWOG Cancer Research Network] is looking at perioperative systemic therapy and the role of surgery in the immunotherapy era,” Dr. Psutka said. “This is being viewed as a ‘contemporary CARMENA’ trial and we are all excited to understand more in a prospective, randomized, controlled setting.”

The phase 3 PROBE trial will study the effect of adding cytoreductive nephrectomy (either radical or partial) to a standard-of-care, immunotherapy-based drug combination compared with the immunotherapy-based combination alone.¹²

NORDIC-SUN is a European study that will compare deferred cytoreductive nephrectomy with no surgery after initial nivolumab in combination with ipilimumab or a TKI combination in patients with intermediate- or poor-risk synchronous metastatic RCC.¹³

“These trials should be somewhat helpful,” Dr. Hakimi said, but they are not without concerns.

One concern is the rapid pace of innovation that is occurring in systemic therapies.

“By the time CARMENA and SURTIME read out, the drugs studied were no longer being used in the first-line setting,” Dr. Hakimi said.

Another concern relates to each trial’s criteria for patient selection.

“We spend so much time as surgeons determining which patients will benefit from surgery,” Dr. Hakimi said. “At Memorial [Sloan Kettering] we look at performance status, if the patient is in shape physically, the metastatic burden, size of the primary tumor, how symptomatic the patient is, IMDC risk, blood parameters and values, and disease histology.”

Dr. Psutka also pointed out the need to assess each patient’s priorities and tolerance of risk versus benefit.

“If one of the patient’s key priorities is not undergoing surgery then cytoreductive nephrectomy is not congruent with their goals,” she said.

With other patients, clinicians have to consider if the surgery itself poses an insurmountable risk. If the tumor involves multiple surrounding organs, requiring removal of the spleen, lymph nodes, and vascular reconstruction, that is a much more intensive operation.

“The patient is exposed to considerably higher risk for surgical complications and a prolonged recovery,” Dr. Psutka said. “That may be too much risk for the patient.”

Favored Approach

In the localized disease setting, surgery is a favored approach for anyone fit enough for the procedure, Dr. Hakimi said. However, there are still caveats related to exactly how to incorporate nephrectomy in this setting.

The first caveat is in the case of small renal masses measuring less than 3 cm. In these patients, active surveillance may be the recommended approach in an attempt to reduce overtreatment and potential morbidity.

“We are not taking out these small tumors if we don’t have to, and many patients are comfortable with an active surveillance approach,” Dr. Psutka said.

Another caveat is whether to incorporate the use of neoadjuvant therapy. Neoadjuvant therapy can potentially downsize more advanced tumors, allowing for easier surgical resection.

Data from the single-arm, phase 2 NeoAvAx trial showed that neoadjuvant avelumab/axitinib elicited a partial response in 30% of patients with nonmetastatic high-risk RCC. The mean baseline tumor size was 10.3 cm; the median tumor downsizing was 20%.¹⁴

The phase 3 PROSPER-RCC trial evaluated perioperative nivolumab versus observation in patients with RCC undergoing nephrectomy. However, data showed that nivolumab did not significantly improve recurrence-free survival (RFS) at a median follow-up of 16 months compared with standard-of-care observation.¹⁵

According to Dr. Hakimi, these results speak to the challenges of doing any neoadjuvant trial in patients without metastatic disease because patients are reluctant to wait to undergo surgery.

“Their willingness to tolerate drugs is also less because they don’t have metastatic disease,” Dr. Hakimi said.

Dr. Kutikov said that, on the whole, neoadjuvant treatment is a complicated topic that is not well studied, and it has little enthusiasm in the field. In certain settings, such as locally advanced disease where the tumor invades the inferior vena cava, however, neoadjuvant treatment may have a role, according to Dr. Zhang. There are ongoing trials for this population with higher surgical risk.

The bigger questions in the local setting are the use of partial compared with a radical approach and when to employ adjuvant therapy.

“You can show the same scan and information to a bunch of different surgeons and get different opinions on the appropriate surgical approach,” Dr. Hakimi said. “In general, though, I think we have a mantra that if you can do a partial you should do it … with certain caveats.”

Dr. Kutikov agreed that most experienced surgeons will attempt partial nephrectomy on most tumors.

The caveats are that partial nephrectomy is associated with a higher perioperative risk, especially in elderly patients or patients on anticoagulation therapies.

“The oncologic safety for high-risk, complex tumors is also a bit controversial,” Dr. Kutikov said. “There remains debate about when to deploy partial nephrectomy for complex tumors versus just taking the kidney out, especially in the face of normal kidney function and a normal contralateral kidney.”

Among patients with small renal masses, the phase 3 EORTC trial first tried to compare the effect of partial with radical nephrectomy. At the time of the study, radical nephrectomy was the standard approach in patients with a normal contralateral kidney. Looking at 541 patients from 45 institutions, the use of partial nephrectomy did not compromise renal cancer control and reduced the incidence of at least moderate renal dysfunction.¹⁶

Since then, the Robotic Surgery for Large Renal Mass Collaborative Group published retrospective data showing that a robot-assisted partial nephrectomy in patients with complex renal masses (RENAL [radius, exophytic/endophytic properties, nearness of tumor to the collecting system or sinus in millimeters, anterior/posterior location relative to polar line] scores of 10-12) was not associated with increased risk for complications or worse oncologic outcomes compared with minimally invasive radical nephrectomy.¹⁷ In upstaged pT3a RCC, multicenter retrospective data showed that partial nephrectomy did not adversely affect RFS and provided functional benefit.¹⁸

“There is a lot of enthusiasm for a surgical trial, but patients are going to be hesitant to enroll and often have an opinion about what approach they want,” Dr. Kutikov said. “There has been a lot written about how to make that judgement call, but the decision to use a nephron-sparing approach will often be surgeon-, patient-, and institution-specific.”

The question of benefit associated with adjuvant therapy has also received a lot of attention.

“There are many trials that show no signal,” Dr. Kutikov said. “Sunitinib received approval as an adjuvant therapy but had variable traction in the academic community. People were left to [decide] whether they give a drug that has high rates of side effects for a year, in order to have clean scans for an additional year, but not change the patient’s destiny.”

Results of KEYNOTE-564 showed a disease-free survival benefit with adjuvant pembrolizumab, and updated results with 30 months of follow-up showed that this benefit persisted over time in patients at high- and intermediate-risk.^19,20 However, the data on OS has yet to mature.

“Without proving the OS advantage, there are critics who say that you save [pembrolizumab] for only those patients who do recur and give it later in combination with a TKI where you know it is the optimal therapy,” Dr. Kutikov said. “By giving the single-agent therapy to everybody you are basically overtreating some and undertreating others at a very high cost.”

Dr. Zhang emphasized that in the adjuvant setting, medical oncologists and surgeons are using multidisciplinary approaches to identify the highest-risk patients needing adjuvant immunotherapy. In her practice she uses nomograms like the ASSURE nomogram to help identify patients at highest risk based on clinical and pathologic features.²¹

Surgical management of kidney cancer continues to be one of the most impactful deployments of surgery for the treatment of cancer, Dr. Kutikov said.

“Surgery is top of mind [for] every surgeon, but just because you can do surgery doesn’t mean you should do surgery,” he said. “It remains a very exciting space where there is a lot of innovation taking place and [where] there [also] remain a lot of unanswered questions.”

References

1. Benjamin DJ, Xu A, Lythgoe MP, et al. Cancer drug approvals that displaced existing standard-of-care therapies, 2016-2021. JAMA Netw Open. 2022. doi:10.1001/jamanetworkopen.2022.2265
2. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345:1655-1659. doi:10.1056/NEJMoa003013
3. 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
4. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379:417-427. doi:10.1056/NEJMoa1803675
5. 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
6. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy for patients with metastatic renal cell carcinoma: is there still a role for cytoreductive nephrectomy? Eur Urol. 2021;80(4):417-424. doi:10.1016/j.eururo.2021.06.009
7. Bhindi B, Graham J, Well JC, et al. Deferred cytoreductive nephrectomy in patients with newly diagnosed metastatic renal cell carcinoma. Eur Urol. 2020;78(4):615-623. doi:10.1016/j.eururo.2020.04.038
8. Britton CJ, Andrews JR, Wallis CJD, et al. Deferred cytoreductive nephrectomy in the management of metastatic renal cell carcinoma: A systematic review and meta-analysis. Urol Oncol. 2023;41(3):125-136. doi:10.1016/j.urolonc.2022.09.021
9. Shapiro DD, Karam JA, Zemp L, et al. Cytoreductive nephrectomy following immune checkpoint inhibitor therapy is safe and facilitates treatment-free intervals. Eur Urol Open Sci. 2023;50:43-46. doi:10.1016/j.euros.2023.01.016
10. Yochino M, Ishihara H, Nemoto Y, et al. Therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. Jpn J Clin Oncol. 2022;52(10):1208-1214. doi:10.1093/jjco/hyac099
11. Gross EE, Li M, Yun M, et al. 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. doi:10.1016/j.urolonc.2022.08.013
12. U.S. National Library of Medicine. 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 Identifier: NCT04510597. ClinicalTrials.gov. Accessed July 5, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04510597
13. U.S. National Library of Medicine. Deferred cytoreductive nephrectomy in synchronous metastatic renal cell carcinoma: the NORDIC-SUN-trial (NORDIC-SUN). ClinicalTrials.gov Identifier: NCT03977571. ClinicalTrials.gov. Accessed July 5, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03977571
14. Bex A, Abu-Ghanem Y, van Thienen JV, et al. Efficacy, safety, and biomarker analysis of neoadjuvant avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx). J Clin Oncol. 2022;40(no. 6_suppl):289-289. doi:10.1200/JCO.2022.40.6_suppl.289
15. Allaf M, Kim SE, Harshman LC, et al. Phase III randomized study comparing perioperative nivolumab (nivo) versus observation in patients (pts) with renal cell carcinoma (RCC) undergoing nephrectomy (PROSPER, ECOG-ACRIN EA8143), a National Clinical Trials Network trial. Ann Oncol. 2022;33(suppl_7):S808-S869. doi:10.1016/annonc/annonc1089
16. Scosyrev E, Messing EM, Sylvester R, Campbell S, Van Poppel H. Renal function after nephron-sparing surgery versus radical nephrectomy: results from EORTC randomized trial 30904. Eur Urol. 2014;65(2):372-377. doi:10.1016/j.eururo.2013.06.044
17. Cerrato C, Patel D, Autorino R, et al. Partial or radical nephrectomy for complex renal mass: a comparative analysis of oncological outcomes and complications from the ROSULA (Robotic Surgery for Large Renal Mass) Collaborative Group. World J Urol. 2023;41(3):747-755. doi:10.1007/s00345-023-04279-1.
18. Patel SH, Uzzo RG, Larcher A, et al. Oncologic and functional outcomes of radical and partial nephrectomy in pT3a pathologically upstaged renal cell carcinoma: a multi-institutional analysis. Clin Genitourin Cancer. 2020. doi:10.1016/j.clgc.2020.05.002
19. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385:683-694. doi:10.1056/NEJMoa2106391
20. Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab as post nephrectomy adjuvant therapy for patients with renal cell carcinoma. Abstract 290. Presented at the 2022 ASCO Genitourinary Cancers Symposium; February 19, 2022; San Francisco, California.
21. Cancer prediction tools. Assure RCC prognostic nomogram. Fox Chase Cancer Center. Accessed July 5, 2023. https://cancernomograms.com/nomograms/492