59 [89Zr]Zr-DFO-girentuximab and [18F]FDG PET/CT to predict WW in mccRCC patients increases the chance of a non-representative patient-mix, which can affect the generalizability of the sensitivity, specificity, and the negative and positive predictive values we observed. Recently, we reported a higher number of metastatic lesions detected by [18F]FDG PET/CT and [89Zr]Zr-DFO-girentuximab PET/CT plus CT compared to only CT in these patients26. Although the clinical implication of those lesions is to be investigated, the analysis of lesional tracer-uptake was limited to RECIST-measurable lesions thereby excluding potentially clinically relevant lesions (e.g., bone lesions). Additionally, only 60% of all RECIST-measurable lesions was PET-positive. As previous reported, tracer-uptake was influenced by lesion size and to a lesser-extent lesion location26. Lesion size introduces partial volume effects and so tracer-uptake may not be observed as higher than the background. While tracer-uptake on a patient level might be underestimated, including all lesions would not be feasible in daily practice upon clinical implementation. The definition of ‘disease progression warranting systemic treatment’ is subject to interpretation of medical physician and patient which introduces subjectivity. However, it does best illustrate daily practice. Furthermore, due to the limited number of eligible patients and clinical trials offering first line immunotherapy, the current paper is published in an era where first line (combination) immunotherapy is available for all patients with mccRCC which has changed the view on a WW-strategy. The four patients in our study not eligible for systemic treatment upon disease progression also stresses the relevance of optimal patient selection for the WW-strategy. With a median OS of 54.8 months in mccRCC patients with WW as initial strategy in our study, WW should still be seen as a valid option, also in the current treatment landscape of mRCC33,34. So far, variable responses have been reported to new first line treatment strategies35. As illustrated by variable [18F]FDG and [89Zr]Zr-DFO-girentuximab uptake in our imaging results, the diverse tumor phenotypes, might explain the heterogenous responses to first line (combination) immunotherapy. Particularly in patients with a good risk mccRCC with less efficacy of (combination) immunotherapy than intermediate or poor risk mccRCC patients, WW could be an interesting treatment strategy. In our patient selection, the response to angiogenesis inhibitor monotherapy or (combination) immunotherapy after a WW-period was comparable to what was reported in registration studies36-38. WW can be considered as initial treatment strategy in a subgroup of mccRCC patients expected to have indolent disease. We confirmed the predictive value of <2 IMDC risk factors and ≤2 involved organ sites (or “W&W criteria”). Moreover, the current study establishes the potential of baseline [18F]FDG-uptake for predicting WW time beyond these criteria, although this should be confirmed in an independent study. 3
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