ESOU 2019: Cytoreductive Nephrectomy: What are the Current Recommendations?

Prague, Czech Republic ( Dr. Arnaud Méjean, the primary investigator and senior author the CARMENA study, was invited to review the current recommendations for cytoreductive nephrectomy. He had first presented the CARMENA results at ASCO 2018.

Cytoreductive nephrectomy (CN) is defined as the surgical removal of the primary RCC lesion before initiation of systemic therapy. CN has been a mainstay of therapy for decades. In the IL-2/immunomodulator era, Flanigan et al. (NEJM 2001, JUrol 2004) and Mickisch et al. (Lancet 2001) demonstrated that removal of the kidney was associated with improved overall survival (OS). As a result, it has become an established paradigm in the management of mRCC, and patients who are surgically fit, are often recommended for cytoreductive nephrectomy prior to systemic therapy. However, he emphasized that it is limited to patients with ECOG Performance Status of 0-1 based on those prior studies. More recent retrospective series and meta-analyses have continued to demonstrate a survival benefit to CNx in the setting of mRCC in the targeted therapy age. (Heng et al. EU 2014, Bhindi et al. J Urol 2018) However, this has primarily been in IMDC favorable or intermediate risk patients (IMDC 1-3 risk factors).

He briefly reviewed the 2 current risk classification systems for mRCC, as there were some questions regarding it in the past. The 2 are summarized below:

UroToday ESOU19 Cytoreductive Nephrectomy CARMENA Mejean 1

Both have prognostic implications. But his main emphasis here was that, in both classification systems, patients with synchronous mRCC are, by definition, the intermediate risk at the very least. Hence, patients cannot be good risk. They chose to use the MSKCC classification for one simple reason – the Heng IMDC criteria had not yet been published.

CARMENA is a French randomized clinical trial comparing patients who were randomized to either CNx and sunitinib versus sunitinib alone without CNx; patients were recruited primarily from France, but also the UK.

It had difficulty accruing patients – they expected sample size of 576 patients (and 456 events) to demonstrate noninferiority hypothesis, with 80% power at a 1-sided significance level of 5%. Yet, ultimately, only 450 patients were included – so it should be kept in mind that the study is underpowered.

There were 2 planned interim analysis: after 152 events and 302 events. The study was stopped after the 2nd interim analysis as the independent DSMB felt the primary objective had been met. Inclusion criteria for patients was: Patients (pts) with synchronous mRCC, amenable to CN, had confirmation of clear cell histology on biopsy, ECOG PS 0-1, an absence of symptomatic brain metastasis (patients with treated brain mets were included), acceptable organ function and eligible for sunitinib therapy. Based on these inclusion criteria, 450 pts were included from September 2009 to September 2017 (8 years), 226 and 224 patients in arm A and B, respectively.

Demographics of the cohort(s) are as follows:
Median age was 62
ECOG-PS was 0 in 56% and 1 in 44%
MSKCC risk groups were intermediate/poor in 55.6/44.4% (arm A) and in 58.5/41.5% (arm B)
Median primary tumor size ~8 cm, median total tumor burden ~14 cm in both arms
Study design: Pts were randomized 1:1 to either CN followed by sunitinib (arm A) or sunitinib alone (arm B), and stratified by MSKCC risk groups. Sunitinib was given at 50 mg/d, 4/6wk with dose adaptation to routine practice. In arm A, sunitinib had to start 4 to 6 weeks after surgery.

The study protocol is detailed below:

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The primary endpoint was overall survival (OS). Secondary outcomes were: PFS, ORR, Clinical benefit, Safety.
In terms of adherence to trial protocol, in arm A, 6.7% did not have CN and 22.5% never received sunitinib; in arm B, 4.9 % never received sunitinib and 17% had secondary nephrectomy (delayed nephrectomy).
The breakdown of the population is seen below:

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At the time of the analysis, 326 deaths have been observed with a median follow-up of 50.9 months. In terms of OS for the ITT population, median OS for arm A was 13.9 months and for Arm B was 18.4 months (HR 0.89, 95%CI 0.89-1.10, non-inferior). No difference in response rate and PFS (HR 0.82, CI 0.67-1.00) was observed. However, he did note that “clinical benefit”, or disease control beyond 12 weeks, was significantly better in Arm B than in Arm A (47.9% vs. 36.6%, respectively, p = 0.022).

When looking at the subpopulations:
  1. Median OS – HR similar to ITT population, but wider confidence intervals
  2. PFS - HR similar to ITT population, but wider confidence intervals
Adverse event profile was as expected for sunitinib. Mortality for nephrectomy was minimal (4 deaths, 2%). Most complications were Clavian-Dindo Grade 1-2. 16% were Grade 3-4. Secondary nephrectomy in Arm B – 38 patients (17%) had secondary nephrectomy. Of these, 7 (18.9%) were due to symptoms and considered emergent. However, in 30 patients who had a strong response to systemic therapy, they underwent elective nephrectomy. Median 11.1 months from time of randomization.

Following all this, he made a point to again emphasize that CARMENA was not meant for all mRCC patients. Specifically, he accepts that patients with solitary metastases / oligometastases (that can be completed resected) with large primary tumor OR patients with poor performance status and large metastatic burden were never meant to be the target population. For sure, the patient with oligomets, large primary tumor, and good PS should get nephrectomy – and indeed, these patients were never even referred for the study. Patients with poor PS and large metastatic burden should not get CN – even before CARMENA was presented. However, this study does suggest for patients with moderate metastatic disease burden who are surgical candidates may not warrant upfront CN – especially when systemic therapy is indicated.

Taking into account the SURTIME study results as well, his conclusions were:
UroToday ESOU19 Cytoreductive Nephrectomy CARMENA Mejean 4

Cytoreductive Nephrectomy is not dead!

Presented by: Arnaud Méjean, MD, Ph.D., Professor of Urology, HEGP, Hopital Necker, APHP, Paris Descartes University, Head of the AFU Cancer Committee Director of the AFU, Paris, France

Written by: Thenappan Chandrasekar, MD. Clinical Instructor, Thomas Jefferson University, Twitter: @tchandra_uromd, @TjuUrology, at the 16th Meeting of the European Section of Oncological Urology, #ESOU19, January 18-20, 2019, Prague, Czech Republic