Grenville Oades

Safety and Efficacy of Pazopanib Therapy Prior to Planned Nephrectomy in Metastatic Clear Cell Renal Cancer

Importance The role of cytoreductive nephrectomy in patients with metastatic renal cancer in the era of targeted therapy is uncertain. Objective To establish the safety and efficacy of upfront pazopanib therapy prior to cytoreductive nephrectomy in previously untreated patients with metastatic clear cell renal cancer. Design, Setting, and Participants Single-arm phase 2 study of 104 previously untreated patients with metastatic clear cell renal cancer recruited between June 2008 and October 2012 at cancer treatment centers with access to nephrectomy services. The minimum follow-up was 30 months. Interventions Patients received 12 to 14 weeks of preoperative pazopanib therapy prior to planned cytoreductive nephrectomy and continued pazopanib therapy after surgery. Treatment was stopped at disease progression. Main Outcomes and Measures The primary end point was clinical benefit (using Response Evaluation Criteria in Solid Tumors, version 1.1) prior to surgery (at 12-14 weeks). Secondary end points included surgical complications, progression-free survival (PFS), overall survival (OS), and biomarker analysis. Results Of 104 patients recruited, 100 patients were assessable for clinical benefit prior to planned nephrectomy; 80 of 104 (76.9%) were men; median [interquartile range] age, 64 [56-71] years). Overall, 84 of 100 (84% [95% CI, 75%-91%]) gained clinical benefit before planned nephrectomy. The median reduction in the size of the primary tumor was 14.4% (interquartile range, 1.4%-21.1%). No patients were unable to undergo surgery as a result of local progression of disease. Nephrectomy was performed in 63 (61%) of patients; 14 (22%) reported surgical complications. The 2 most common reasons for not undergoing surgery were progression of disease (n = 13) and patient choice (n = 9). There was 1 postoperative surgical death. The median PFS and OS for the whole cohort were 7.1 (95% CI, 6.0-9.2) and 22.7 (95% CI, 14.3-not estimable) months, respectively. Patients with MSKCC poor-risk disease or progressive disease prior to surgery had a poor outcome (median OS, 5.7 [95% CI, 2.6-10.8] and 3.9 [95% CI, 0.5-9.1] months, respectively). Surgical complications were observed in 14 (22%) of the nephrectomies. Biomarker analysis from sequential tissue samples revealed a decrease in CD8 expression (20.00 vs 13.75; P = .05) and significant reduction in expression of von Hippel-Lindau tumor suppressor (100 vs 40; P < .001) and C-MET (300 vs 100; P < .001) and increased programmed cell death ligand 1 expression (0 vs 1.5; P < .001) in the immune component. No on-treatment biomarker correlated with response. Conclusions and Relevance Nephrectomy after upfront pazopanib therapy could be performed safely and was associated with good outcomes in patients with intermediate-risk metastatic clear cell renal cancer.

Cytoreductive Nephrectomy in the Tyrosine Kinase Inhibitor Era: A Question That May Never Be Answered

Despite great interest, two randomised controlled trials (RCTs) of cytoreductive nephrectomy in the tyrosine kinase inhibitor setting in metastatic renal cell carcinoma have either closed early (SURTIME) or are recruiting very slowly (CARMENA) after 7 yr. Challenges in RCT delivery in uro-oncologic surgery are many. Multiple steps are needed to ensure strong recruitment to trials addressing important urologic cancer questions. Feasibility/pilot studies are key stepping stones towards successful delivery of surgical RCTs.

The Epidemiology and Risk Factors for Renal Cancer

Background: Renal cancer is a frequently occurring malignancy with over 270,000 new cases diagnosed and it being responsible for 110,000 deaths annually on a global basis. Incidence rates have gradually increased whilst mortality rates are starting to plateau. Objective: To review epidemiology and risk factors for renal cancer. Methods: The current data is based on a thorough review of available original and review articles on epidemiology and risk factors for renal cancer with a systemic literature search utilising Medline. Results: The prevalence of associated risk factors such as genetic susceptibility, smoking, hypertension and obesity are changing and could account for the changes in incidence whilst the role of diet and occupational exposure to carcinogens requires further investigation. Conclusion: Despite the evidence of various associated risk factors, further work is required from well designed studies to gain a greater understanding of the etiology of renal cancer.

Reclassification of the Fuhrman grading system in renal cell carcinoma-does it make a difference?

PurposeThe aim of this study was to determine whether reclassifying the Fuhrman grading system provides further prognostic information.Materials and methodsWe studied the pathological features and cancer specific survival of 237 patients with clear cell cancer undergoing surgery between 1997–2007 in a single centre. The original Fuhrman grading system was investigated as well as various simplified models utilising the original Fuhrman grade.ResultsThe median follow up was 69 months. On univariate analysis, the conventional Fuhrman grading system as well various simplified models were predicative of cancer specific survival. On multivariate analysis, only the three tiered modified model in which grades 1 and 2 were combined whilst grades 3 and 4 were kept separate was an independent predictor of cancer specific survival (p=0.001, HR 2.17, 95% CI 1.37-3.43). Furthermore this simplified model demonstrated a stronger relationship to recurrence than the conventional 4 tiered Fuhrman grading system.ConclusionsA modified, three-tiered Fuhrman grading system has been demonstrated to be an independent predictor of cancer specific survival.

Translational research will fail without surgical leadership: SCOTRRCC a successful surgeon-led Nationwide translational research infrastructure in renal cancer

BACKGROUND High quality human biosamples with associated high quality clinical data are essential for successful translational research. Despite this, the traditional approach is for the surgeon to act as a technician in the tissue collection act. Biomarker research presents multiple challenges and the field is littered with failures. Tissue quality, poor clinical information, small sample numbers and lack of validation cohorts are just a few reasons for failure. It is clear that the surgeon involved in tissue acquisition must be fully engaged in the process of biosampling for a specific condition, as this will negate many of the issues for translational research failure due to an inadequate bioresource. APPROACH In this Matter for Debate paper, the Scottish Collaboration On Translational Research into Renal Cell Cancer (SCOTRRCC) is discussed as an example of a urological surgery lead bioresource which has resulted in a National collection of renal cancer tissue and blood (from over 900 patients to date), negating all of the traditional issues with biobanks because of close enagagement and acknowledgement of urologists and uropathologists from seven centres around Scotland. SCOTRRCC has leveraged renal cancer research in Scotland resulting in several high impact publications and providing a springboard for future research in this disease in Scotland and beyond. CONCLUSIONS The SCOTRRCC model presented here can be transferred to other surgical disciplines for success in translational research.

Frozen section during partial nephrectomy: an unreliable test that changes nothing?

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Surveillance versus ablation for incidentally diagnosed small renal tumours: The SURAB feasibility RCT

BACKGROUND There is uncertainty around the appropriate management of small renal tumours. Treatments include partial nephrectomy, ablation and active surveillance. OBJECTIVES To explore the feasibility of a randomised trial of ablation versus active surveillance. DESIGN Two-stage feasibility study: stage 1 - clinician survey and co-design work; and stage 2 - randomised feasibility study with qualitative and economic components. METHODS Stage 1 - survey of radiologists and urologists, and development of patient information materials. Stage 2 - patients identified across eight UK centres with small renal tumours (< 4 cm) were randomised (1 : 1 ratio) to ablation or active surveillance in an unblinded manner. Randomisation was carried out by a central computer system. The primary objective was to determine willingness to participate and to randomise a target of 60 patients. The qualitative and economic data were collected separately. RESULTS The trial was conducted across eight centres, with a site-specific period of recruitment ranging from 3 to 11 months. Of the 154 patients screened, 36 were eligible and were provided with study details. Seven agreed to be randomised and one patient was found ineligible following biopsy results. Six patients (17% of those eligible) were randomised: three patients received ablation and no serious adverse events were recorded. The 3- and 6-month data were collected for four (67%) and three (50%) out of the six patients, respectively. The qualitative substudy identified factors directly impacting on the recruitment of this trial. These included patient and clinician preferences, organisational factors (variation in clinical pathway) and standard treatment not included. The health economic questionnaire was designed and piloted; however, the sample size of recruited patients was insufficient to draw a conclusion on the feasibility of the health economics. CONCLUSIONS The trial did not meet the criteria for progression and the recruitment rate was lower than hypothesised, demonstrating that a full trial is presently not possible. The qualitative study identified factors that led to variation in recruitment across the sites. Implementation of organisational and operational measures can increase recruitment in any future trial. There was insufficient information to conduct a full economic analysis. TRIAL REGISTRATION Current Controlled Trials ISRCTN31161700. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 81. See the NIHR Journals Library website for further project information.

Abstract 14: The effect of Src family kinase inhibitors in non-metastatic clear cell renal cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Approximately 8000 new cases of renal cancer are diagnosed each year, with an estimated five year survival rate of 50%. Treatment options are limited, however a potential target is a family of non-receptor tyrosine kinases, called Src family kinases (SFKs). SFKs have a role in multiple oncogenic processes and are associated with promoting metastases in solid tumours; however, research in renal cancer is limited. Previously, we reported that all eight SFKs were expressed in human renal clear cell carcinoma. Lyn, Blk, Lck, Fyn and Yes showed a significant increase in expression between stages T1 and T2 and a subsequent decrease between T2 and T3, suggesting SFKs increased to promote invasion and migration for metastatic spread. The aim of the current proposal is therefore to investigate if SFKs could be a therapeutic target for renal cancer. The prototypical SFK, Src was investigated for association with clinical outcome measures. High membrane Src expression was associated with improved disease specific survival (p=0.097). However, low expression of phosphorylated cytoplasmic FAK at Y861 a Src specific site, was associated with poor disease specific survival (p=0.001). This suggests that poor prognosis associated with FAK is due to a family member other than Src as all SFKs can phosphorylate this residue. The effect of SFKs inhibition on migration, apoptosis and proliferation in a non-metastatic renal cancer cell line, 786O was examined. Western blot analysis demonstrated that treatment of 786O with the SFK inhibitor, dasatinib, did not affect total levels of Src, but a dose dependent reduction in SFK activation was observed, as shown via Y416 phosphorylation and FAK phosphorylation at Y861. Cells also exhibited a dose dependent reduction in migration accompanied by an increase in apoptosis when treated with dasatinib for 48 hours. However, no effect on proliferation was observed. Treatment with Src siRNA to remove Src from the cells did not significantly influence the effects observed in response to dasatinib suggesting dasatinib acts via another SFK family member. Our data shows that activation measured via phosphorylation of the downstream marker FAK at Y861 was associated with poor prognosis and removing Src from 786O cells did not effect the actions of the Src inhibitor, dasatinib. This combined with our previous observation of SFKs expression increasing from stage T1 to T2 and decreasing from T2 to T3 lead us to conclude that SFKs are important for tumour cells migrating to the outer edge of the organ ready for metastasis then dissipate as the metastasis occurs and that this may be promoted by a SFK family member other than Src. However the specific family member responsible for these actions and the actions of dasatinib is still to be established. Citation Format: Antonia K. Roseweir, Tahir Qayyum, Robert Jones, Grenville Oades, Michael Aitchison, Joanne Edwards. The effect of Src family kinase inhibitors in non-metastatic clear cell renal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 14. doi:10.1158/1538-7445.AM2013-14