- Current guidelines for metastatic RCC.
- Rational behind cytoreductive nephrectomy (CN).
- Historical evidence supporting current guidelines
- Discussion on the CARMENA trial.
Ever since 1988, when a small retrospective review analyzing 158 patients with MRCC was published, nephrectomy had clinical benefit only when the fittest and healthiest patients were selected.1 The historic SWOG 2001 trial published in the New England Journal of Medicine2 was a prospective controlled trial of 241 patients with metastatic RCC. Tow arms were compared – CN + interferon vs. interferon alone. The primary endpoint was overall survival (OS) and the secondary endpoint was a response of the tumor to treatment. A clear advantage was shown in favor of the CN arm.
In 2001, the EORTC published a similar study as well, comparing CN +interferon to interferon alone. As expected, the CN arm had a statistically significant survival advantage. Later on, the MSKCC (Motzer) criteria were established. These included no prior nephrectomy, Kranofsky performance status<80, low hemoglobin, high corrected calcium, and high LDH. The number of risk factors was shown to be correlated to patient survival (Figure 1). Later on, the International metastatic RCC consortium criteria (IMDC or Heng criteria) were created as well, shown to correlate to overall survival (figure 2). These criteria were not designed for patients with synchronous metastatic RCC.
Figure 1 – MSKCC criteria for survival differences:
Figure 2 – IMDC criteria for survival differences:
Bratslavsky also mentioned that tumor burden by itself can predict prognosis independently from localization of metastasis and prognostic class, defined by MSKCC criteria.3 Additionally, the percentage of tumor burden removed with debulking nephrectomy affects the survival rate, as can be seen in figure 3.
Figure 3 – Progression-free survival by percentage of tumor removed:
In 2015 a retrospective analysis of the national cancer database (NCDB) analyzing over 15000 MRCC patients between 2006-2013 treated with targeted therapy with or without CN. Approximately a third of the patients underwent CN and the survival benefit was assessed. The results clearly demonstrated a survival advantage for CN. According to Bratslavsky, performing CN depends on the extent of disease and patient comorbidities (figure 4).
Figure 4 – When should cytoreductive nephrectomy be performed?
The last topic discussed was the recently published CARMENA trial.4 This was a prospective randomized controlled non-inferiority trial of 450 patients enrolled between 2009-2017. The primary objective was OS with CN + sunitinib vs. sunitinib alone. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), clinical benefit, and postoperative morbidity and mortality. Approximately 160 patients died in each trial. OS was 18.4 months in the sunitinib alone group vs. 13.9 months in the CN+sunitinib group (Figure 5). When stratified to intermediate risk patients only, the numbers were 23.4 months vs. 19 months, and for the poor risk, they were 13.3 months vs. 10.2 months. The hazard ratio (HR) for death was 0.89 (0.71-1.1). For intermediate risk, the HZ was 0.92 (0.68-1.24) and for the poor risk, it was 0.86 (0.62-1.17). PFS was 8.3 months in the sunitinib alone group vs. 7.2 months in the CN+sunitinib group. Lastly, the clinical benefit was 47.9% vs 36.6%.
The major limitations of the study included:
- Patient enrollment and generalizability – the study did not adhere to the original design, and there was a high proportion of poor prognostic risk patients.
- Another limitation was the non-inferiority design.
Bratslavsky concluded his excellent talk with some additional thoughts. It is important to remember that no statistical method can overcome selection bias or trial accrual. Optimal candidates for CN are those with ECOG 1, and minimal disease. Lastly, the role of CN is even less clear now in the era of immuno-oncology.
Figure 5 – Overall survival in the CARMENA trial:
1. Neves RJ. et al. J Urol 1988
2. Flanigan RC. et al. NEJM 2001
3. Lacoverlli R. et al. BJU 2012
4. Mejean A. et al. NEJM 2018
Presented by: Gennady Bratslavsky, MD, Syracuse, NY, US
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the 2018 FOIU 4th Friends of Israel Urological Symposium, July 3-5. 2018, Tel-Aviv, Israel