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2011 Irene Lips

External beam radiotherapy for prostate cancer: the potential for dose escalation

The treatment results for intermediate and high risk prostate cancer are insufficient with five-year biochemical relapse rates of approximately 35%. Previous dose escalation trials found that an increase in dose to the prostate resulted in an improved biochemical disease free survival. Further dose escalation is expected to lead to further improvement. However, dose escalation to the whole prostate is limited due to an unacceptable high risk of toxicity. Recurrences often occur at the location of the macroscopic tumor, so boosting the radiation dose to the macroscopic tumor within the prostate might increase local control. To establish whether this approach is feasible and safe, several questions were answered in this thesis. Firstly, the position uncertainties during treatment were investigated by exploring the effect of interfraction errors on complex dose distributions with an integrated microboost to the macroscopic tumor. The influence of the geometric uncertainties appeared to be minimal with the use of optimal position verification. Only small margin are necessary to account for the remaining interfraction motion. A double-blind placebo-controlled randomized trial revealed that the use of a laxative during external beam radiotherapy is not effective in reducing the intrafraction prostate motion. Also, the use of an antiflatulent diet during treatment did not reduce the intrafraction motion. Therefore, there is no indication to use magnesium oxide or an antiflatulent diet in clinical practice to reduce the intrafraction motion. Evaluation of the treatment-related toxicity of patients treated with a dose of 76 Gy revealed that with the use of advanced radiotherapy techniques, such as intensity-modulated radiotherapy (IMRT) in combination with gold-fiducial marker-based position verification, the grade 3 genitourinary acute toxicity was only 3% and no grade ≥ 3 gastrointestinal acute toxicity was seen. The severe grade ≥ 3 genitourinary and gastrointestinal toxicity rates were 4% and 1%, respectively. The use of IMRT and accurate position verification made it also possible to treat patients with a high dose to the prostate without compromising the patient’s quality of life. The satisfactory QoL and toxicity results after high dose radiotherapy for prostate cancer using IMRT and accurate position verification, suggests that further dose escalation is possible without a clinically relevant deterioration in QoL when the combination of accurate delivery and compliance to current dosimetric constraints for the organs at risk will be used. The findings presented in this thesis made it safe to start the FLAME-trial (Focal Lesion Ablative Microboost in prostatE cancer). This single-blind multicenter randomized phase III trial investigates whether an additional ablative microboost to the macroscopic tumor is indeed beneficial on biochemical control. Furthermore, by localizing the recurrent tumors within the prostate during follow-up and correlating this with the delivered dose, accurate dose-effect information for both the macroscopic tumor and subclinical disease in prostate cancer can be obtained.