Renal Cell Carcinoma Part 3

Renal Cell Carcinoma Part 3 Comprehensive Review Article Prof. Dr. Semir. A. Salim. Al Samarrai Advanced/metastatic RCC: Local therapy of advanced/metastatic RCC Cytoreductive nephrectomy Tumour resection is potentially curative only if all tumour deposits are excised. This includes patients with the primary tumour in place and single- or oligometastatic resectable disease. For most patients with metastatic disease, cytoreductive nephrectomy (CN) is palliative and systemic treatments are necessary. In a combined analysis of two RCTs comparing CN+ IFN-based immunotherapy vs. IFN-based immunotherapy only, increased long-term survival was found in patients treated with CN [1]. However, IFN-based immunotherapy is no longer relevant in contemporary clinical practice. In order to investigate the role and sequence of CN in the era of targeted therapy, a structured literature assessment was performed to identify relevant RCTs and systematic reviews published between July 1st – June 30th 2019. Two RCTs [2,3] and a narrative systematic review were identified [4]. The narrative systematic review included both RCTs and ten non-randomised studies. CARMENA, a phase III non-inferiority RCT investigating immediate CN followed by sunitinib vs. sunitinib alone, showed that sunitinib alone was not inferior to CN followed by sunitinib with regard to OS [5]. The trial included 450 patients with metastatic ccRCC of intermediate- and MSKCC poor-risk of whom 226 were randomised to immediate CN followed by sunitinib and 224 to sunitinib alone. Patients in both arms had a median of two metastatic sites. Patients in both arms had a tumour burden of a median/mean of 140 mL of measurable disease by Response Evaluation Criteria In Solid Tumours (RECIST) 1.1, of which 80 mL accounted for the primary tumour. The study did not reach the full accrual of 576 patients and the Independent Data Monitoring Commission (IDMC) advised the trial steering committee to close the study. In an ITT analysis after a median follow-up of 50.9 months, median OS with CN was 13.9 months vs. 18.4 months with sunitinib alone (HR: 0.89, 95% CI: 0.71–1.10). This was found in both risk groups. For MSKCC intermediate-risk patients (n = 256) median OS was 19.0 months with CN and 23.4 months with sunitinib alone (HR: 0.92, 95% CI: 0.60–1.24) and for MSKCC poor risk (n = 193) 10.2 months and 13.3 months, respectively (HR: 0.86, 95% CI: 0.62–1.17). Non-inferiority was also found in two per-protocol analyses accounting for patients in the CN arm who either did not undergo surgery (n = 16) or did not receive sunitinib (n = 40), and patients in the sunitinib-only arm who did not receive the study drug (n = 11). Median PFS in the ITT population was 7.2 months with CN and 8.3 months with sunitinib alone (HR: 0.82, 95% CI: 0.67–1.00). The clinical benefit rate, defined as disease control beyond twelve weeks was 36.6% with CN and 47.9% with sunitinib alone (p = 0.022). Of note, 38 patients in the sunitinib-only arm required secondary CN due to acute symptoms or for complete or near-complete response. The median time from randomisation to secondary CN was 11.1 months. The randomised EORTC SURTIME study revealed that the sequence of CN and sunitinib did not affect PFS (HR: 0.88, 95% CI: 0.59–1.37, p = 0.569). The trial accrued poorly and therefore results are mainly exploratory. However, in secondary endpoint analysis a strong OS benefit was observed in favour of the deferred CN approach in the ITT population with a median OS of 32.4 (range 14.5–65.3) months in the deferred CN arm vs. 15.0 (9.3–29.5) months in the immediate CN arm (HR: 0.57, 95% CI: 0.34–0.95, p = 0.032). The deferred CN approach appears to select out patients with inherent resistance to systemic therapy [6]. This confirms previous findings from single-arm phase II studies [4,7]. Moreover, deferred CN and surgery appear safe after sunitinib which supports the findings, with some caution, of the only available RCT. In patients with poor PS or IMDC poor risk, small primaries and high metastatic volume and/or a sarcomatoid tumour, CN is not recommended [8]. These data are confirmed by CARMENA [5] and upfront pre-surgical VEGFR-targeted therapy followed by CN seems to be beneficial [9]. Meanwhile first-line therapy recommendations for patients with their primary tumour in place have changed to ICI combination therapy with sunitinib and other VEGFR-TKI monotherapies reserved for those who cannot tolerate ICI combination or have no access to these drugs. High-level evidence regarding CN is not available for ICI combinations but up to 30% of patients with primary metastatic disease, treated with their tumour in place, were included in the pivotal ICI combination trials (Table 1). The subgroup HRs, where available, suggest better outcomes for the ICI combination compared to sunitinib monotherapy. In mRCC patients without a need for immediate drug treatment, a recent systematic review evaluating effects of CN demonstrated an OS advantage of CN [4]. These data were supported by a nation-wide registry study showing that patients selected for primary CN had a significant OS advantage across all age groups [10]. Table 1: Key trials on immune checkpoint inhibitor combinations for primary metastatic disease The results of CARMENA and SURTIME demonstrated that patients who require systemic therapy benefit from immediate drug treatment. While randomised trials to investigate deferred vs. no cytoreductive nephrectomy with ICI and ICI combinations are ongoing, the exploratory results from the ICI combination trials demonstrate that the respective IO+IO or TKI+IO combinations have a superior effect on the primary tumour and metastatic sites when compared to sunitinib alone (Table 1). In accordance with the CARMENA and SURTIME data this suggests that mRCC patients and IMDC intermediate- and poor-risk groups with their primary tumour in place should be treated with upfront IO-based combinations. In patients with a clinical response to IO-based combinations, a subsequent CN may be considered. Embolisation of the primary tumour In patients unfit for surgery or with non-resectable disease, embolisation can control symptoms including visible haematuria or flank pain [11,12,13]. Local therapy of metastases in metastatic RCC A systematic review of the local treatment of metastases from RCC in any organ was