High-dose-rate brachytherapy boost in prostate cancer: clinical outcomes, late rectal toxicity and uncertainties in organ at risk delineation
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Prostate cancer is one of the most commonly diagnosed cancers in the developed world, having caused 293,000 deaths in 2013 (Global Burden of Disease Cancer, et al., 2013). According to the Spanish Network of Cancer Registries (REDECAN), 33,370 new cases were diagnosed in 2015 in Spain. In 2014, prostate cancer was ranked fifth in terms of cancer deaths among Spanish men (Instituto de Salud Carlos III, 2014). High-risk prostate cancer is an aggressive form of the disease with a higher risk of distant metastasis and mortality. This classification represents a significant portion of the nearly 28,000 prostate cancer deaths per year in the United States and the 5,855 deaths in Spain (American Cancer Society 2015; Instituto de Salud Carlos III, 2014). There are different treatment options for locally advanced prostate cancer, such as active surveillance, radical prostatectomy, and radiotherapy. The use of radiotherapy in the radical treatment of intermediate- and high-risk prostate cancer has been well studied in several prospective randomized trials (Zelefsky et al., 2008; Coen et al., 2002). This option can be administered through EBRT, BT, and either HDRBT or LDRBT given alone or combined with EBRT. HDRBT is a brachytherapy technique, and when combined with EBRT, it allows for dose escalation, administration of the complete dose to the target (the prostate), and minimisation of the dose received by the surrounding normal tissues. Current international treatment guidelines recommend the use of HDRBT combined with EBRT, which is also known as “HDRBT boost”. According to the ABS, GEC/ESTRO, and ESTRO/EUA/EORTC, this treatment modality improves local control compared with monotherapy, as well as the outcomes in certain patients with intermediate- and high-risk disease (Zaorsky et al., 2017). There are no specific recommendations about the best dose fractionation scheme for HDRBT boost. Several studies have reported various treatment schemes, which has made it difficult to compare the results of acute and late toxicity. In recent years, there has been a transition in the number of fractions delivered. Initially, as many as four boost fractions were used, but currently, the evidence supports large boost fractions with a single HDRBT boost (Morton et al., 2013). This trend has been accompanied by important biological effects, as well as practical and cost-saving advantages. Furthermore, virtually all-geometric uncertainty is eliminated, as there is no risk of inter-fraction variability. For these reasons, there has been much interest in this technique, which has also been adopted by several centres for high-risk patients. This thesis is motivated by the need for clinical outcomes, including improvements in prevention and decrease of rectal toxicity. The purpose of this thesis was threefold. Firstly, to determine the clinical outcomes of a cohort of patients diagnosed with prostate cancer and treated with HDRBT boost using real-time TRUS based planning in combination with EBRT (see Chapter IV, Paper I). Secondly, determining the occurrence of late rectal toxicity in our patients’ cohort and evaluating its potential relationship with D2cc parameter. This was based in the rectal constraint recommended by GEC/ESTRO, given the absence of another rectal dose constraints from similar studies of HDRBT combined with EBRT for prostate cancer (see Chapter IV, Paper I). Thirdly, we proposed to evaluate the D 2cc robustness in HDRBT for prostate cancer using the interobserver variability in the rectum contouring. A first pilot study was performed with a limited number of patients and physicians of the same center (see Chapter IV, Paper II). Lastly, in order to evaluate the outcomes from the pilot study, a multicentre prospective study was performed (see Chapter IV, Paper III). Below is a summary of the information contained in each of the papers of this thesis. Chapter I provides a summary describing the findings of the research that were carried out by the doctoral candidate. Chapter II provides a general introduction and justification of the thesis. Chapter III contains the general aim, specific objectives and the study design of the thesis. In Chapter IV (Paper I), we review our institution´s experience with HDRBT boost for localized prostate cancer. The first purpose of this study was to analyse the clinical outcomes, particularly local control, overall survival, and late rectal toxicity. The second purpose was to determine the significance of dose-volume histogram parameters for predicting LRT after single-fraction HDRBT boost and EBRT in prostate cancer patients. A cohort of 300 patients diagnosed with locally advanced prostate cancer and treated with HDRBT boost plus EBRT were followed prospectively. The patient data were used for both purposes. The treatment comprised a single-fraction HDRBT boost of 15 Gy plus EBRT ...