Kidney Cancer

Locally advanced and metastatic renal cell carcinoma (RCC) is associated with poor survival outcomes. The integration of presurgical systemic therapy with targeted molecular agents prior to surgical resection of RCC tumors has been utilized to improve on these outcomes. These agents may be associated with an increased risk of perioperative complications due to their action on angiogenesis and cell proliferation.

To examine the evidence for the incidence and severity of perioperative complications following presurgical targeted therapy for locally advanced or metastatic RCC.

We performed a systematic review of retrospective studies, prospective clinical trials, and meta-analyses using key search terms in PubMed and Medline. Studies were screened for eligibility and data were extracted by the authors. A qualitative analysis was performed and the complications for available targeted agents was reported.

Retrospective analyses and small prospective trials indicate varying complication rates and types based on presurgical therapies. While some studies indicate a possible increase in wound-related complications, other studies did not show similar results. Additional unique complications reported include an increase in surgical adhesions. There was not any significant difference in overall or bleeding complications.

Overall, these studies demonstrate an acceptable level of surgical complications that should not discourage the clinician considering presurgical therapy. The results of pending trials looking at presurgical therapies will provide further information.

Papillary renal cell carcinoma (pRCC) is associated with EGFR expression and activation of MET signaling pathway. A randomized multicenter parallel two-stage phase II trial of MET inhibitor tivantinib alone or in combination with EGFR inhibitor erlotinib was conducted in patients with pRCC.

Patients with advanced pRCC and 0-1 prior systemic therapy were randomly assigned to tivantinib 360 mg BID (Arm 1) or tivantinib 360 mg BID plus erlotinib 150 mg daily (Arm 2). Target max accrual was 70 patients (35 per arm) with interim analysis planned after enrollment of 20 patients per arm.

Six % of patients had type 1 pRCC, 42% had type 2, and 52% had no subtype assigned. The study was closed after the first stage when both arms yielded RR of 0%. Median progression free survival (PFS) was 2.0 and 3.9 months, and OS was 10.3 and 11.3 months in Arms 1 and 2 respectively. Treatment was well tolerated. Exome of tumor tissue from 16 patients were successfully sequenced using Agilent SureSelect probes. Only 1 of 16 samples harbored MET mutation. Other mutations associated primarily with type 2 pRCC were noted and included CDKN2A, PBRM1, SETD2, KDM6A, FAT1 and NF2.

Tivantinib - either alone or in combination with erlotinib has no clinical activity in patients with advanced pRCC. The S1107 cohort had a low proportion of patients with MET alterations. MET remains a reasonable therapeutic target in pRCC, but selection of patient subsets exhibiting MET activation may be required to better benefit from therapy with MET inhibitors.

Checkpoint inhibitors (CPI) have now been established as standard agents in the management of patients with metastatic renal cell carcinoma (mRCC). Given the unique toxicity profiles of CPIs, a detailed understanding of their incidence rate and characteristics is critical.

To perform a systematic review for the analysis of the incidence rate and characteristics of toxicities in mRCC patients treated with CPIs in published clinical trials.

A systematic search of EMBASE (Ovid) and MEDLINE (Ovid) was conducted as per PRISMA guidelines to identify prospective clinical trials of checkpoint inhibitors in mRCC. The search method involved querying for the terms renal cell carcinoma or kidney carcinoma with any of the following: programmed cell death 1, PD-1, programmed cell death ligand 1, PD-L1, cytotoxic T-lymphocyte antigen 4, CTLA-4, immunotherapy, checkpoint inhibitor, anti-PD-1, or anti-PD-L1. Only prospective clinical trials were included.

The systematic review yielded 9,722 records through the MEDLINE (Ovid) and EMBASE (Ovid) databases. Ultimately, five prospective clinical trials with 722 patients were selected for inclusion. The rates of any grade adverse event (AE) and grade (G) 3-4 AEs were 79.9% and 20.9%, respectively. Regarding immune-related AEs (irAEs), the most common system affected by any grade irAE was the skin (30.89%) and the most common grade 3-4 irAE was related to the hepatic system (8.23%). Rates of AEs were similar across the CPI monotherapy clinical trials.

The rates of AEs in mRCC patients treated with CPI is similar to rates in other cancers. AEs in mRCC are fairly consistent among monotherapy trials with PD-1 and PD-L1 inhibitors and as one would expect higher when CTLA-4 and PD-1 inhibitors are offered in combination.

To evaluate immunohistochemical erythropoietin (EPO) expression in clear cell renal cell carcinoma (ccRCC), its association with major clinicopathological variables and its prognostic impact.

A total of 220 patients with renal cell carcinoma (RCC) surgically treated between 1989 and 2009 were evaluated in this multi-institutional study. All the cases were reviewed by a single pathologist and the immunohistochemical reactivity to EPO was analysed using tissue microarray.

A total of 176 patients with ccRCC were considered, with an average of 48 months of follow-up. Of the tumours evaluated, 47 (26.7%) were negative for EPO expression, and 129 (73.3%) were positive. EPO expression was associated with incidental tumour (p = 0.016), tumour size (p = 0.015), Karnofsky Performance Score (KPS) (p = 0.016), blood transfusion (p = 0.009) and adrenal involvement (p = 0.038). The median ages of the patients with positive and negative EPO expression were 56.2 years and 66.6 years. Immunohistochemical EPO expression affected overall survival (OS) and disease-specific survival (DSS) rates. The DSS rates of the patients whose tissue was positive and negative for EPO expression were 85.3% and 76.1%, respectively (p = 0.044). In a multivariate analysis, the absence of EPO expression proved to be a bad prognostic factor and negatively affected the OS (p < 0.001) and DSS (p < 0.001) rates.

The absence of tumour EPO expression is an independent predictive factor with a negative effect on survival rates. The use of EPO as possible marker in the management of ccRCC patients requires further studies and a better understanding of the role of EPO in tumour biology.

We previously published an analysis of clinical trials in renal cell carcinoma (RCC) using the publicly available ClinicalTrials.gov registry. Here we present a 3-year update to understand clinical research current trends in RCC compared to 2013.

The Website’s advanced search function was used to search for RCC trials. The characteristics of the trial were extracted, summarized and compared to 2013 data using Fisher’s exact tests.

We locked our search on May 26, 2016 with 165 trials eligible, compared with 169 trials on Sep 25, 2013. There were more phase I and I/II trials in 2016 compared to 2013 (40.8% vs 24.9%, p = 0.05). More clinical trials in 2016 compared to 2013 used immunotherapy (IT) alone or in combination with other drugs (24.2% vs 10.7%, p = 0.001), and the use of targeted therapy alone (TT) declined (32.9% vs 47.9%, p = 0.005). TT+IT combination trials more than doubled (6.7% vs 2.3%, p = 0.07). The number of trials with treatment in (neo)adjuvant settings in 2016 and 2013 were similar (9.7% vs 10.6%, p = 0.77), respectively. Compared to 2013, the number of trials with non-clear cell histology remained low (n = 10). Many more trials were sponsored by the pharmaceutical industry in 2016 vs 2013 (41.5% vs 16.0%, p = <0.001).

IT-based and industry sponsored clinical trials significantly increased from 2013 to 2016 with a concomitant drop in TT only trials. The increase in industry-sponsored studies may reflect the rapid uptake of expensive IT drugs. There continues to be a paucity of (neo)adjuvant studies and for non-clear cell histologies.