However, the introduction of targeted therapies, including tyrosine kinase inhibitors (TKI) and mTOR inhibitors, have drastically changed the outcomes of mRCC patients. While not providing a cure, they are able to provide long-term response in some patients. In doing so, they have significantly extended the survival of patients with mRCC. Unfortunately, with this advancement in systemic therapy, the need for cytoreductive nephrectomy has been called into question.
Then, in 2018, two major studies – CARMENA and SURTIME – reported, and turned the entire field on its head. In CARMENA, the objective was to assess if sunitinib alone was non-inferior to treatment with upfront CNx followed by sunitinib. In SURTIME, the objective was to compare deferred vs upfront CNx.
However, after reviewing CARMENA, she went on to address 5 major limitations that need to be addressed to put the results into context.
1) Accrual – she presented an interesting analysis of accrual. Of course, it is well known that the authors did not meet their accrual requirements despite keeping the trial open for 8+ years. Most of the patients were recruited from France.
In the above, doing some quick math looking at incidence data in the main countries of accrual, she noted that <1% of eligible mRCC patients were actually recruited to the study.
2) Selection – why were patients not enrolled? Likely for a few different reasons including physician preference (lack of equipoise), patient preference (refusal to be randomized), and the fact that CARMENA excluded patients eligible for upfront surveillance / delayed systemic therapy. In the time frame of the study, 55% of patients in Sweden underwent CNx – which is probably mirrored in the other countries – so most patients were still getting CNx.
3) External Validity –The CARMENA patient population is not representative of a general mRCC population.3 Patients on CARMENA were more likely to have higher nodal and visceral metastatic burden and poor risk disease. This is validated by the fact that there was lower OS in CARMENA than in other contemporary studies. This all worked against CNx in the study.
She also noted that on systemic therapy standpoint, external validity failed – because sunitinib (the agent used in CARMENA) was no longer the standard of care in the last few years of the study. As such, they were assessing CNx against an agent that was no longer the norm. Indeed, in looking at the most recent studies of the newest agent combos, most of the patients in those trials had CNx:
4) Off-protocol and Noncompliance: The crossover, noncompliance in the study is summarized below:
As a result, if you look at the results of the study in only patients who actually received the treatment they were randomized to receive, the study did NOT meet its primary endpoint – therefore, based on this study, you cannot conclude that sunitinib alone is non-inferior to CNx followed by sunitinib.
5) Patient selection and Risk stratification – ultimately, this is what killed the study and its impact on management. They used the Motzer criteria, which was meant to predict survival amongst mRCC patients, but not predict response to CNx. They have since been other nomograms specifically assessing that very question. Below, Sarah nicely summarizes all the variables that she was able to identify as predictors – and what she uses in practice:
Hence, as the authors of CARMENA themselves conclude, there is no “one size fits all” approach.
She then briefly discussed the SURTIME trial. Due to very poor accrual (recruited 99 patients instead of expected 458 patients), the primary endpoint was changed from PFS to ITT 28 week PFS. SURTIME suffered from many of the same limitations as CARMENA, including high crossover/noncompliance (12 of the 99 patients did not get the scheduled treatment). Ultimately, they concluded that deferred CNx did not improve the 28-week progression-free rate. But the bigger takeaway is that pretreatment with sunitinib may identify patients with inherent resistance to systemic therapy prior to planned CNx.
At this time, having reviewed the clinical trial data, she reviewed some of the observational data that is relevant to this discussion.
In the absence of randomization, attempted to match patients as best as possible and compared upfront CNx vs upfront systemic therapy.4 After inverse probability of treatment by propensity matching, they found that initial CNx provided a 7 month survival benefit over targeted therapy. More interesting, though, they found that 48% of patients who got upfront CNx went on to get targeted therapy – while only 5% of patients undergoing targeted therapy went on to get CNx.
Utilizing SEER to examine CNx in non-clear cell RCC patients, demonstrating that CNx still provided CSS benefit.5 However, they also noted that the use of CNx was decreasing during that time, from 84% in 2001 to 59% in 2014. Sarah did allude to the fact that CNx is recommended against in patients with sarcomatoid histology in the TKI era, due to poor prognosis – but that recent evidence in the immune checkpoint era, that may change. With Ipi/Nivo, objective response rates exceeded 50% in patients with sarcomatoid histology.6
A systematic review of all studies through June 2018, including CARMENA.7 Below, it is clear that, except for CARMENA, all studies favored CNx in terms of OS benefit:
Granted, all except CARMENA, were observational. Hence, there is naturally some selection bias in these studies.
In 40 patients with multiple sites of metastatic RCC (21 patients had >= 2 sites), the median time to systemic therapy following CNx was 16 months – so CNx may help delay need for systemic therapy in some patients for > 1 year.8
Her last couple points highlighted a few key “other” considerations:
- Patient perspective – ASCO 2019, Abstract 658 – 186 patients were asked, in the context of CARMENA, whether they would still want nephrectomy. 75% responded they would still prefer to undergo CNx. Among patients with primary still in place, 20% wanted CNx.
- Symptomatic primary tumors still warrant surgery – tumor bleeding, pain, paraneoplastic syndromes. These may preclude systemic therapy.
- Patients with tumor thrombus still warrant CNx to address their tumor thrombus
- Patients on systemic therapy with stable/quiescent metastases – but growing primary tumor. These patients perhaps warrant deferred CNx.
I particularly like her breakdown based on risk stratification – and from multiple other speakers, as well as the recent EAU guidelines, this seems to be the best approach at this time.
Presented by: Sarah Psutka, MD, MSc, Depart Department of Urology, University of Washington, Seattle, WA
Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, @tchandra_uromd, @JEFFUrology at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA
References:
- Eggener SE, Rubenstein JN, Smith ND, et al. Renal tumors in young adults. J Urol. 2004 Jan;171(1):106-10.
- 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.
- Arora S, Sood A, Dalela D, et 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.
- Bhindi B, Abel EJ, Albiges L, et al. Systematic Review of the Role of Cytoreductive Nephrectomy in the Targeted Therapy Era and Beyond: An Individualized Approach to Metastatic Renal Cell Carcinoma. Eur Urol. 2019 Jan;75(1):111-128. doi: 10.1016/j.eururo.2018.09.016. Epub 2018 Oct 25.
- Marchioni M, Bandini M, Preisser F, et al. Survival after Cytoreductive Nephrectomy in Metastatic Non-clear Cell Renal Cell Carcinoma Patients: A Population-based Study. Eur Urol Focus. 2017 Dec 8. pii: S2405-4569(17)30268-7. doi: 10.1016/j.euf.2017.11.012. [Epub ahead of print]
- ASCO 2019 Abstract 4513: CheckMate 214 post-hoc analyses of nivolumab plus ipilimumab or sunitinib in IMDC intermediate/poor-risk patients with previously untreated advanced renal cell carcinoma with sarcomatoid features, David F. McDermott
- Bhindi B, Abel EJ, Albiges L, et al. Systematic Review of the Role of Cytoreductive Nephrectomy in the Targeted Therapy Era and Beyond: An Individualized Approach to Metastatic Renal Cell Carcinoma. Eur Urol. 2019 Jan;75(1):111-128. doi: 10.1016/j.eururo.2018.09.016. Epub 2018 Oct 25.
- de Bruijn RE, Kuusk T, Noe AP, et al. Observation After Cytoreductive Nephrectomy in Patients With Synchronous Not Completely Resected Metastases of Renal Cell Carcinoma. Urology. 2017 Nov;109:127-133. doi: 10.1016/j.urology.2017.06.048. Epub 2017 Aug 2.