45 [89Zr]Zr-DFO-girentuximab and [18F]FDG PET/CT to predict WW in mccRCC patients INTRODUCTION Metastatic clear cell renal cell carcinoma (mccRCC) has a variable course1,2. The International Metastatic RCC Database Consortium (IMDC) criteria, initially designed to predict survival of patients on 1st line anti-angiogenic drugs3,4, can be used to identify patients with mccRCC with indolent disease. In those patients, a period of watchful waiting (WW) can be considered5,6. This WW strategy prevents over-treatment, unnecessary side-effects and treatment costs, but the current strategy to select patients for WW leaves room for improvement3,7,8. Therefore, a prospective study was performed to improve the selection of patients for WW9. It was reported that patients with <2 IMDC risk-factors and ≤2 involved organs have a WW period of 22.2 months compared with 8.4 months in patients with ≥2 IMDC risk factors and/or >2 involved organ sites. These criteria, further referred to as “W&W criteria”, have not been externally validated. CcRCC biology has been studied intensively, especially the role of cellular homeostasis, glucose metabolism and carbonic anhydrase IX (CAIX) expression10-13. An increased glucose metabolism, as visualized by positron emitting tomography (PET) with [18F]FDG, has been associated with poor survival14,15. Over-expression of CAIX has been correlated with indolent disease although evidence is contradictory16-20. The radiolabeled monoclonal antibody girentuximab, [89Zr]Zr-DFOgirentuximab, can visualize CAIX-expression using PET/CT, which potentially identifies patients with indolent disease16,21-24. In the IMaging PAtients for Cancer drug SelecTion (IMPACT)-RCC study, we evaluated the predictive value of PET/CT using [18F]FDG and [89Zr]Zr-DFO-girentuximab in patients with mccRCC and a good or intermediate prognosis according to IMDC. The primary objective was to predict time to disease progression warranting systemic treatment. A secondary objective was to validate the “W&W criteria”9. Patients and methods Selection criteria In this prospective multi-center cohort study (ClinicalTrials.gov: NCT02228954), patients aged ≥18 years with histologically proven RCC with a clear cell component, recently (<6 months) diagnosed metastases, and 0-2 IMDC risk-factors were enrolled3. Patients were eligible if a WW-period of at least 2 months was expected. Patients with previous systemic treatment for mccRCC, untreated central nervous system metastases, or symptomatic intra-cerebral metastases were excluded. Since patients did not start treatment upon enrollment in this study, the IMDC-criterion ‘time from diagnosis to treatment <1 year’ was adapted into ‘time from primary diagnosis to first metastatic disease <1 year’. This study was conducted at four Dutch academic medical centers and approved by the institutional review board. All patients provided written informed consent. Studies were conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. 3
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