Optimization of overall treatment time for whole gland stereotactic body radiotherapy with integrated focal boosting in prostate cancer

Prostate cancer (PCa) is the most frequently diagnosed cancer in males in Europe and is associated with substantial morbidity and mortality. In this project we aim to make progress in the disease management of PCa in terms of both treatment outcome (tumor control and toxicity outcome) and patient comfort including patients’ quality of life (QoL) during and after treatment. External beam radiotherapy (EBRT) is often used to treat primary PCa. When using conventional fractionation schemes (35-40 fractions, 7-8 weeks), dose escalation is achieved by increasing the number of fractions resulting in a longer overall treatment time (OTT). However, longer OTT has been identified in recent studies as a potential adverse factor for treatment outcome in PCa patients who were treated by conventional radiotherapy schedules, suggesting that improvements may be achieved by decreases in OTT. Shortening of the OTT is possible by using (ultra-)hypofractionated treatment schedules, in which fewer fractions with a higher dose/fraction are being delivered. Stereotactic body radiotherapy (SBRT) is a promising EBRT technique to deliver such ultra-hypofractionated treatment schemes (±5 fractions) using precise 3D localization of the target (stereotaxis) by means of image guidance. Moreover, as from a radiobiological point of view, PCa has a high fractionation sensitivity. Therefore (ultra-)hypofractionated regimens could theoretically be used to biologically escalate the dose while maintaining current levels of toxicity in PCa patients. Instead of escalating the dose to the whole prostate gland, increasing the radiation dose only to the intraprostatic tumor nodule(s) (focal boosting) while keeping the exposure of surrounding tissues similar to treatment with a conventional, homogeneous dose to the prostate target volume, could be an additional strategy to improve local disease control as local recurrences mostly occur at the site of the primary tumor location. This approach is being tested in several trials, including the phase III FLAME (35 fractions; 7 weeks) and phase II hypo-FLAME (5 fractions; 29 days) trial in which our institute is participating. However, ultra-hypofractioned radiotherapy schedules allow variation in OTT. In general, the OTT varies between 5 days (daily radiotherapy sessions) and 29 days (weekly radiotherapy sessions), depending on the number of radiation-free days between each fraction for 5-fraction schedules. This variation in OTT could potentially result in different outcome and toxicity rates. So far, the optimal OTT regarding treatment outcome, toxicity and patient comfort for ultra-hypofractionated treatment regimens remains unclear. To this end, a multicenter phase II follow-up study of the hypo-FLAME trial, called hypo-FLAME 2.0, will be initiated in this research project. The aim of this phase II trial is to investigate whether it is feasible and safe to further reduce the OTT of whole gland SBRT with a simultaneous integrated focal boost for PCa from 29 to 15 days. Besides a potential biological advantage, the reduced number of treatment fractions and reduced OTT also offers benefits with respect to patient convenience, resources and costs. The ultimate goal of this project is to optimize the current standard radiation treatment for PCa regarding on the one hand treatment outcome (disease control and risk of normal tissue toxicity) and on the other hand patient comfort.  In addition, immune monitoring of this ultra-hypofractionated treatment schedule in combination with focal boosting will be performed. Immune-monitoring of several important cytokines and chemokines during treatment will be conducted in order to get a better understanding of positive and negative modulators of the immune response and compare these between the different FLAME-schedules (FLAME vs hypo-FLAME vs hypo-FLAME 2.0).