Caren van Roekel

200 Chapter 7 Strengths of this study are the homogenous patient population, the standardized methods for tumor delineation, the use of a mixed-effects regression model accounting for clustered data, and the analyses of both safety and efficacy. This study also has several limitations. First, it is a single- center retrospective evaluation and there is a level of subjectivity in identifying the response of existing lesions, possibly leading to inter-operator variations in estimated doses. Second, the sample size was limited and due to the low incidence of toxicity, there was not enough data to draw a strong conclusion on the maximum tolerable parenchymal dose. Furthermore, the discriminatory value of absorbed dose for response estimation is limited and a causal dose- response relationship cannot be claimed based on these observational data. Hence, the reference values obtained should be interpreted with uttermost caution and only be used as a direction. The rigid co-registrations used in this study are likely affected by differences in patient positioning, differences in breath-hold policy and the relatively low resolution of the low-dose CT of the SPECT/CT. The resulting (local) errors are likely to propagate as underestimated tumor doses and (slightly) overestimated parenchymal doses, which contributes to the error in each response category, decreasing statistical power. In future studies on radioembolization in CRC patients, personalized dosimetry should be used. By using dosimetry-based optimized treatment planning, treatment doses can be tailored to the individual patient to acquire a maximum response while minimizing the chance of toxicity. As the incidence of toxicity was low, it is difficult to establish an absolute threshold for a maximum parenchymal dose. At the same time, it is likely that the parenchymal- absorbed dose threshold is different for each individual patient, dependent on many clinical characteristics. We therefore advise a pragmatic and clinically feasible approach, with activity calculation in order to obtain a sufficient tumor-absorbed dose and a parenchymal-absorbed dose of up to 55 Gy, dependent on individual patient characteristics. With a median parenchymal- absorbed dose of 37 Gy and a maximum of 55 Gy, this was proven to be a safe approach, with only one case of REILD. Furthermore, those patients for whom no meaningful mean tumor-absorbed dose (>90 Gy) can be reached at an acceptable parenchymal-absorbed dose threshold should be excluded from radioembolization treatment. On a tumor-level, based on our results, treatment strategy should be adjusted to guarantee a tumor-absorbed dose of at least