ESMO 2017-SEQUENCE OF NEPHRECTOMY IN METASTATIC RENAL CANCER

Treating primary tumours by administering targeted therapy with sunitinib prior to cytoreductive nephrectomy (CN) did not improve the progression-free rate at 28 weeks over a sequence of immediate CN followed by sunitinib in patients with synchronous metastatic renal cell carcinoma (mRCC), according to findings from a randomised trial presented at ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.

Axel Bex, Surgical Oncology-Urology, The Netherlands Cancer Institute in Amsterdam, Netherlands and colleagues investigated whether the outcome after sequential cytoreductive nephrectomy (CN) followed by targeted therapy with sunitinib could be improved with the opposite sequence.

They randomised 99 patients with mRCC to immediate CN followed by sunitinib (n=50) versus three cycles of sunitinib followed by CN plus sunitinib (n=49). The study (EORTC 30073 SURTIME NCT01099423) included patients with histologically confirmed clear-cell subtype, and a resectable asymptomatic primary tumour plus 3 or fewer surgical risk factors per Culp, et al.¹

Due to poor accrual, it was decided to report the progression-free rate (PFR) at week 28 as the primary endpoint, which required 98 patients, instead of median progression-free survival, which required 380 events to detect a 3-month increase (Hazard ratio [HR] = 0.75) with deferred CN with a 2-sided 5% logrank test at 80% power. Overall survival (OS), adverse events (AEs) and post-operative progression in both arms were secondary endpoints.

After 5.7 years the study included 99 patients from 19 institutions. The immediate CN arm had 50 patients and the deferred CN arm had 49 patients. The majority of patients were male in both arms with a median age of 60 compared to 58 years, and MSKCC intermediate risk was reported for 86% versus 87.7% of patients, respectively. In the respective arms, WHO performance status (PS) was 0 and 1 in 72% and 28% versus 63.3 % and 36.7%; 86% versus 93.9% of patients had ≥ 2 measurable metastatic sites and the mean (standard deviation) size of the primary tumour was 93.1 (37.8) mm versus 96.8 (31.3) mm.

Patients in each arm derived different benefit from each sequence

At a median follow-up of 3.3 years, 46 of 50 patients underwent CN in the immediate CN arm and 40 of these patients had received post-CN sunitinib. In the deferred CN arm, 48 of 49 patients had been treated with sunitinib prior to CN; of these patients, 40 underwent CN and 26 also received post-CN sunitinib.

No significant difference between the treatment sequence was observed in PFR, which was 42.0% (95% confidence interval [CI] 28.2, 56.8) versus 42.9% (95% CI 28.8, 57.8) in the immediate and deferred arms, respectively (p > 0.99).

Progression free survival (PFS) and overall survival (OS) in the intention to treat (ITT) analysis of deferred versus immediate CN in all patients.

© Axel Bex. 

However, OS stratified by WHO PS of the intention to treat (ITT) population showed an two-fold advantage favouring deferred versus immediate CN; the overall HR was 0.57 (95% CI 0.34, 0.95; p = 0.032) and the median OS was 32.4 (95% CI 14.5, 65.3) months versus 15.1 (95% CI 9.3, 29.5) months, respectively.

In addition, fewer surgical complication were seen in the deferred arm where complication occurred in 27.5% of patients compared to 43.5% of patients treated with immediate CN.

The rate of progression at 16 weeks was 46% of patients after immediate CN, compared to 32.7% of patients prior to planned CN in the deferred arm. The protocol recommended not to perform deferred CN in patients with progression.

Conclusions

While the sequence of CN and sunitinib did not affect the PFR at 28 weeks, an OS signal was seen for deferred CN.

According to the authors, the sample size precludes definitive conclusions from other endpoints, although CN after sunitinib appears to be safe.

M. Staehler who discussed the study results said that the role of nephrectomy in metastatic RCC remains unclear. It is still lacking information about the effect of nephrectomy on early progression. Delaying cyto-reductive nephrectomy in metastatic RCC is a viable option. The authors should consider including their data in a meta-analysis with other neoadjuvant trials, like Panther, Atlas and Carmena.