AUA 2019: The Role of Cytoreductive Radical Therapy in the Era of Targeted Therapy for Metastatic RCC

Chicago, IL (UroToday.com) In this crossfire debate, the focus was on the role of cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) in the era of targeted therapy. This has been a constant debate since two major trials in this space have come out: CARMENA1 and SURTIME2

Dr. Wood kicked off the session with some background and the index patient. Prior to 2006 and the introduction of targeted therapies, surgery was the mainstay of therapy – mainly due to the absence of effective systemic therapy. In the era of IFN-alpha and IL-2, cytoreduction made sense – as these systemic therapies provided very little survival benefit. Two main studies (SWOG and EORTC) in this era 3,4 and their combined data demonstrated a 5.8 month survival benefit with cytoreductive nephrectomy. Hence, CN became a standard of care.

Yet, the landscape of systemic therapies for mRCC in 2019 is drastically different than it was back then – while targeted therapies remain front line options for good risk patients, immune checkpoint inhibitors (either in combination or with a TKI) have become first line options. So, while systemic therapy has changed – CN has not. Does it still have a role?

The elephant in the room is the CARMENA study, a phase 3 randomized study comparing nephrectomy plus Sunitinib vs. Sunitinib alone in first-line metastatic RCC. They concluded that sunitinib alone was non-inferior to CN followed by sunitinib. 

At this point, Dr. Wood introduced the index patient for this case: a 62 man diagnosed with mRCC during an evaluation for gross hematuria. Importantly, his performance status is 0, he has a locally advanced ccRCC of the right kidney on abdominal imaging, bilateral pulmonary nodules on chest imaging, no other metastatic disease, Hgb 9.8 (anemic), LDH 1000 (elevated), and all other labs normal. Based on these criteria, he falls into different risk groups, depending on the nomogram used (see below) – however, by IMDC or MSKCC (the two most common), he is an intermediate/poor risk mRCC patient.


In the interest of being concise, below I highlight the main points of each of the speakers – but try not to repeat points previously made. 

Dr. Lee was the first to present and argued for CN. The goals of CN, in his eyes, are 3 fold: obtain accurate pathology (to help guide systemic therapy), palliative local symptoms, and to remove large potentially immunosuppressive tumor burden. It should never be done with the intent of inducing spontaneous tumor regression – although this is a real, but rare, event. 

His first main point is that mRCC has highly variable clinical behavior, and prior efforts, even in the TKI era, have been made to help identify patients that would benefit from CN. An MD Anderson Cancer Center, study of 566 patients with mRCC5 identified a subset of patients with lower risk (0-3) factors who did better with CN that those patients who received systemic therapy alone or those with 4+ risk factors. So, clearly, there is a subset that benefits and a subset that does not – the goal is to identify the subset that does benefit. Similar findings in terms of variable response were seen in retrospective database series.

He then touched on the impact of CARMENA. He reviewed the results of the study first, and the main take-home – the non-inferiority of the sunitinib monotherapy. His take-home points from CARMENA:

  • Prospective CN trials are very difficult to accrue and complete – CARMENA only recruited 450 of planned 576 patients. This was over 8 years. In similar time frame, MSKCC completed ~180 CN in a single-center.
  • Ultimately, while the analysis was an ITT, many patients in both arms did NOT get the intended treatment:


  • Patient selection is key to outcomes of CN – 43% of the CARMENA population was poor risk
In the post-TKI immunotherapy era, the new standard of care for poor risk patients are nivo/ipi and pembro/axinitib, along with cabozantinib. 

Based on all of this, he notes that CN in selected patients is likely still necessary – and that CARMENA did not change the story. It adds to the literature, but is no way conclusive. Patient selection and clinical judgment is critical for CN utilization. Close discussion with medical oncology is necessary, as systemic therapy is still required in all patients.

Dr. Campbell provided the first CON argument. He starts first by noting that CARMENA asked whether we should do CN in all patients or no patients – but this black and white picture is not accurate the real-world. Realistically, it’s a “yes for some”, “no for some,” and “maybe for some.”

As has been previously noted, patients with mRCC are placed into risk categories – IMDC and MSKCC being the most commonly used. However, if you look at survival outcomes in the patients in the original CN trials, survival for all 3 risk groups was quite poor – regardless of CN. Yet, with the introduction of targeted therapies, the favorable and intermediate risk patients have seen a dramatic rise in survival outcomes – while only the poor risk have continued to do poorly. This highlights the benefits of newer systemic therapies in the absence of CN. Many of these patients will do well.

He also made a point to highlight the SURTIME data, which is often forgotten. In this study, the question was not yes/no CN. It was immediate vs. deferred CN. Ultimately, they found that deferred CN was non-inferior to immediate CN. Unlike the CARMENA study, most of this study was populated with intermediate risk patients. More importantly, however, this trial demonstrated that by initiating systemic therapy, patients with rapidly progressive disease are selected out. Indeed, the median survival for the patients with primary progressive disease was 3.8 months, which was less than the median survival of the patients with poor risk disease (regardless of treatment arm) of 5.7 months. Therein lies the benefit of delaying CN – immediate CN would be inappropriate and ultimately useless in this population with rapidly progressive disease. 

His last point was to again highlight the rapid changes in the approved therapies for mRCC, specifically the replacement of targeted therapies for immunotherapies. Hence, we are no longer even in the targeted therapy era. 

Based on the strength of these arguments, he concludes that immediate CN should be abandoned for the majority of cases of mRCC. The role of CN in the new immunotherapy era is uncertain. Surgical complexity of CN may evolve with immunotherapy combinations. 

Therefore, for the index patient, he would recommend 3-6 months systemic therapy and then consider CN given the patient’s response and residual disease burden.

Dr. Kutikov gave an impassioned rebuttal in support of cytoreductive nephrectomy – especially considering the significant flaws of CARMENA. The basis of his talk was that CARMENA is like the online sales company Carmax – it didn’t really present anything new! 

CARMENA ultimately enrolled patients who we already know wouldn’t benefit from CN, did not include patients we know would most likely benefit, and used outdated systemic therapy. 

  1. Enrolled patients who we already know wouldn’t benefit from CN
    1. 43% of the patients were poor risk, had high metastatic burden, and lower OS than recent clinical trials for the same systemic therapies
    2. CARMENA patients had a higher number of metastatic sites that patients in the NCDB6– 2 vs. 1, including lung and bone mets
    3. OS was also markedly lower in CARMENA than in previously published similar trials and population studies – usually 21-26 months, not 13-18
    4. Unlike the original SWOG/EORTC trials, a significant proportion of the patients didn’t even get the treatment – 17% in the CN arm didn’t get sunitinib and 7% didn’t get nephrectomy! Probably because they were too sick to proceed
  2. Did not include patients we know would most likely benefit
    1. In Fox Chase’s own experience in the late 1990’s, they demonstrated that 30% of patients undergoing CN never went on to systemic therapy – so a proportion benefit from CN alone7
    2. Recent work by Rini and Plimack et al.8demonstrated that some patients after CN can remain off systemic therapy for a median of 15 months
    3. But these are not the patients that were included in CARMENA
  3. Used outdated systemic therapy
    1. This has already been stated by the other speakers, but sunitinib has already been replaced by nivo/ipi, cabonzantinib, and more recently, pembo/axinitib. Hence, the results are not particularly relevant.

His take home message and practice algorithm is seen below:


Dr. Coleman argued that data should drive decision making, not just debates. 

His first argument is that, at this time, CARMENA is the only level 1 evidence out there – and because it doesn’t support surgery, surgeons don’t support it. 

His other main points, which reiterated those of Dr. Campbell, are summarized below:
  • Systemic therapies now are much more effective than those from the cytokine era
  • Patients survive much longer on systemic therapy now
  • They have a different mechanism of action and biologic impact
  • Immune checkpoint inhibitors – the primary tumor may have a biologic role as a vaccine
  • Only prospective randomized controlled trial (CARMENA) – CN does not provide benefit

As is always the case, the answer probably lies somewhere in between. It would appear that everyone agreed that CN does still have an active role in mRCC management as an adjunct to systemic therapy, that it doesn’t need to be immediate, and that is must be considered in select patients after coordination between medical oncology and urology.

Moderator: Christopher Wood, MD, FACS, The University of Texas MD Anderson Cancer Center 

Debators: Chung-Han Lee, MD, Memorial Sloan Kettering Cancer Center, Alexander Kutikov, MD, FACS, Fox Chase Cancer Center. Matthew Campbell, MD, MD Anderson Cancer Center, Jonathan Coleman, MD, Memorial Sloan Kettering Cancer Center


Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University @tchandra_uromd, @JEFFUrology at the American Urological Association's 2019 Annual Meeting (AUA 2019), May 3 – 6, 2019 in Chicago, Illinois

References:

  1. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma. August 2, 2018 N Engl J Med 2018; 379:417-427 DOI: 10.1056/NEJMoa1803675
  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. JAMA Oncol. 2018 Dec 13. doi: 10.1001/jamaoncol.2018.5543
  3. 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 Dec 6;345(23):1655-9.
  4. 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 Sep 22;358(9286):966-70.
  5. Culp SH, Tannir NM, Abel EJ, et al. Can we better select patients with metastatic renal cell carcinoma for cytoreductive nephrectomy? Cancer.2010 Jul 15;116(14):3378-88. doi: 10.1002/cncr.25046.
  6. Arora S, Sood A, Dalela Det al. Cytoreductive Nephrectomy: Assessing the Generalizability of the CARMENA Trial to Real-world National Cancer Data Base Cases. Eur Urol. 2019 Feb;75(2):352-353. doi: 10.1016/j.eururo.2018.10.054. Epub 2018 Nov 9.
  7. Kutikov A, Uzzo R, Caraway A, et al. Utilization of Systemic Therapy and Factors Impacting Survival for Patients Undergoing Cytoreductive Nephrectomy BJU Int. 2010 Jul; 106(2): 218–223.doi: 10.1111/j.1464-410X.2009.09079.x
  8. Rini BI,Dorff TB, Elson Pet al. Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial. Lancet Oncol. 2016 Sep;17(9):1317-24. doi: 10.1016/S1470-2045(16)30196-6. Epub 2016 Aug 3.
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