General introduction and thesis outline 17 markers (fiducials) are inserted into the prostate prior to treatment. These fiducials can be visualised prior to dose delivery. This way, corrections for (large) interfraction shifts can be performed. Hypofractionated radiotherapy Over the years, radiotherapy schemes have changed significantly for prostate cancer patients. Whereas 10 years ago patients received no less than 35 treatment fractions, nowadays low- and intermediate-risk patients are commonly treated with only five fractions.52,53 Although patients are treated with fewer fractions, the dose per fraction has also increased significantly from in general 2.0 Gray (Gy) to ³ 7.0 Gy for some indications. These shifts find their origin in the fact that prostate cancer appears particularly sensitive to radiation and more specifically, to the dose delivered per treatment fraction. Radiosensitivity is often expressed by the alpha/beta ratio (α/β). For prostate cancer, the α/β is estimated to be as low as 1.5 Gy.54 Most cancers actually have a much higher α/β, often around 10 Gy for rapidly proliferating tumours.55 These are more sensitive to a higher overall radiation dose, whereas a low α/β means that the tumour is more sensitive to the radiation dose per treatment fraction and less to the total delivered dose. With hypofractionation, the treatment is delivered in less fractions than with ‘conventional’ fractionation (i.e. 20 compared to 39 fractions for prostate cancer). With terms such as ultra-hypofractionation and extreme hypofractionation, mostly treatment delivery in five or less fractions with a high fractional dose (³ 7.0 Gy) is implied. This is also referred to as stereotactic body radiation therapy (SBRT). Because organs-at-risk (OARs) generally have a higher α/β compared to prostate cancer tissue, it was hypothesised that larger fractional doses might not only improve oncological outcomes, but also increase the therapeutic ratio (the ratio between oncological outcomes and toxicity).54 The vast improvement in accuracy of radiotherapy treatment delivery with modern day techniques, and therefore better sparing of OARs, has created room for ultra-hypofractionated radiotherapy. The last years, results from several trials have been published that directly compared conventional fractionated radiotherapy with five-fraction SBRT for the treatment of localised prostate cancer, including the randomised HYPO-RT-PC and PACE-B trials.56,57 No significant differences were observedwith respect to oncological outcomes, with a 5-year failurefree survival rate of 84% in both treatment groups in the HYPO-RT-PC trial.56 Furthermore, in the HYPO-RT-PC trial weak evidence was found for higher acute grade ³ 2 urinary toxicity in the SBRT group, although this was statistically non-significant (28% for SBRT versus 23% for conventional fractionated radiotherapy in 39 fractions).56 A systematic review and meta-analysis by Jackson et al.58 confirmed the excellent oncological outcomes after SBRT, with an overall 5- and 7-year biochemical recurrence-free survival (bRFS) of 95.3% and 93.7%, respectively. In addition, severe (grade ³ 3) late GU and gastrointestinal (GI) toxicity was estimated to be 2.0% and 1.1%, respectively.58 Not only is SBRT considered effective and safe for the treatment of low- and intermediate-risk prostate cancer, it also positively impacts patient burden and departmental capacity, as patients need to make fewer visits to the hospital compared to conventional hypofractionated therapy.59 However, with increasing fractional doses and fewer fractions to deliver the complete dose, delivery accuracy becomes even more important, especially in the light of intrafraction target and OAR motion.60–62 With higher fractional doses, the overall daily treatment time is prolonged due to longer beam-on times, thus allowing more intrafraction motion and deformations to occur.62 Intrafraction 1
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