Sarah Verhoeff

48 Chapter 3 The ability to discriminate between patients with limited and prolonged WW-time was assessed using Harrell’s C-index for the overall observation period30, and using time-dependent receiver operating characteristic (ROC) curves (for both measures, 0.50 denotes no discriminative value and 1.00 perfect discrimination)31. Here 2000-fold bootstrapping was used to obtain confidence intervals and statistically test for differences in discrimination between models. Bootstrapping (2000-fold) was also used for internal validation of multivariable models to account for over-optimism and to yield predicted WW-time probabilities that are more likely to validate when applied to new patients. The data were analyzed with R 3.2.1 for Mac OS, particularly using coxphf (package coxphf 1.11), and cv.glmnet (package glmnet 2.0-3). Estimates are reported with corresponding 95% confidence intervals (CIs), considering a p-value <0.05 as statistically significant. All tests were two-sided, except for the relation between IMDC and “W&W criteria” with WW-time. These were evaluated one-sidedly focused on confirming the previously reported direction of these associations. RESULTS Between February 2015 and March 2018, 48 patients with good or intermediate risk mccRCC eligible for WW, signed informed consent and were screened for study enrolment (Supplementary Figure S1). Five patients were considered screen failures due to PD on baseline ceCT. Since this PD required systemic treatment before the initiation of the WW-period, they did not meet the inclusion criteria of eligibility for a WW-period of at least 2 months. One other patient withdrew consent for personal reasons before baseline imaging procedures. Two other patients withdrew their consent at the first CT-evaluation without PD. Therefore, 40 patients were evaluable for the primary endpoint. Baseline characteristics In total, 14 of 40 patients (35%) had a good prognosis according to IMDC criteria. Intermediate IMDC-prognosis was primarily due to the diagnosis of metastases <1 years after the primary diagnosis (81%). Most patients entered the study with metastases in one or two organs (75%, Table 1). No patient received prior adjuvant treatment. Baseline imaging detected a variable number of lesions considered RECIST-evaluable on ceCT and quantifiable on PET: 230 of 283 lesions on ceCT, 149 of 233 lesions on [18F]FDG PET/CT, and 163 of 272 on [89Zr]Zr-DFO-girentuximab PET/CT. Overall, 30 patients had lesions with visual [18F]FDG and [89Zr]Zr-DFO-girentuximab accumulation. Two patients had no visual lesions on [18F]FDG and [89Zr]Zr-DFO-girentuximab-PET/CT. Four patients had a visual negative 89[Zr]Zr-DFO-girentuximab-PET/CT, and four other patients had a negative [18F]FDG PET/CT. Tracer accumulation within and between patients was heterogeneous for both [18F]FDG and [89Zr]Zr-DFO-girentuximab (Figure 1A,B).