58 Chapter 3 DISCUSSION The prospective IMPACT-RCC study investigated the value of [89Zr]Zr-DFO-girentuximab and [18F]FDG PET/CT in patients with good or intermediate risk mccRCC to predict time to WW progression. We demonstrated that patients with low [18F]FDG-uptake have a longer WW-period. [89Zr]Zr-DFO-girentuximab-uptake did not show prognostic value. Moreover, we confirmed that <2 IMDC risk factors and ≤2 involved organ sites (“W&W criteria”) identified patients with a prolonged WW-period compared to other patients. The only other prospective study on WW was published by Rini et al. They identified a patient subgroup with a prolonged WW-period based on the number of organ sites besides IMDC-criteria (“W&W criteria”)9. Based on this study and in order to translate our results into standard clinical use outside studies, we used the number of involved organ sites rather than tumor burden as a marker for disease extent. Our study has a similar sample size, distribution of IMDC risk-factors and disease-extent, which allowed us to validate the “W&W criteria” to select patients for a WW-strategy. Moreover, we highlighted that [18F]FDG SUV max alone improved the selection of patients with indolent disease as compared to “W&W criteria”. While CAIX in response to hypoxia has shown prognostic value across tumor types32, no robust prospective data associated CAIX in ccRCC with prognosis16,18,20. In contrast to other tumor types, the over-expression of CAIX in ccRCC is the result of a mutational loss of the Von Hipple Lindau gene13, as opposed to hypoxic tumor microenvironment. Our data show no clinically meaningful prognostic value of CAIX as visualized by [89Zr]Zr-DFO-girentuximab PET/CT on a patient level in patients with mccRCC. Analyses on lesion level could help to better understand this lack of correlation. For example, we have previously reported that highest SUVmax values were observed in adrenal gland and kidney lesions, compared with lower SUVmax values in lung lesions 26. Based on our data, [18F]FDG PET/CT has the potential to change clinical practice by providing guidance for decision making on WW as initial strategy. All patients with a geometric mean [18F]FDG SUV max <3 or negative [ 18F]FDG PET/CT (representing 30% of all patients) remained on WW at least 12 months. This is in agreement with a previous reported association between high [18F]FDG-uptake and more aggressive disease15. While our analyses should be confirmed in a larger prospective cohort and the optimal way to take [18F]FDG SUV max into account is yet to be established, our results support the potential clinical relevance of baseline [18F]FDG PET/ CT in mccRCC patients considered for observation. To help validating our findings, we have included a formula and score chart to predict the 12-month WW duration based on our internally validated model with [18F]FDG PET/CT, IMDC criteria and the number of organ sites. Such external validation is important as our results were derived from a small cohort of patients which may not only lead to overoptimistic results even after internal validation, but a small cohort also
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