Tumour ReviewExtreme hypofractionation for early prostate cancer: Biology meets technology
Introduction
Prostate cancer (PC) is the most common male malignancy in the Western countries and the second most frequently diagnosed cancer among males worldwide [1], [2]. Approximately 80% of men with newly diagnosed PC will have organ-confined disease. Evidence-based and scientifically approved conventional treatment options for prostate-confined cancer include radical prostatectomy, external beam radiotherapy (EBRT), brachytherapy (BT) and active surveillance [1], [3]. Since head-to-head comparison of different options is not available, the choice is based on the tumour stage and characteristics, patient general conditions and preferences and the centre expertise [1], [4], [5]. Radiation therapy (RT) is one of the well-established treatment approaches in localized PC [1], [3].
During the last decades, tremendous advances in pre-treatment imaging, treatment-planning, delivery and verification, combined with mature results from moderately hypofractionated randomized controlled trials [6], [7], [8], [9], [10], [11], reassuring on the sensitivity of PC to larger fraction sizes, have implemented the opportunity of using fewer large dose per fraction delivered in a short treatment duration. Beyond the obvious advantages in terms of patient convenience and health economics, the unique radiobiology of PC [12], [13], [14], [15], along with the evidence that dose-escalation yields better outcomes [16], [17], [18], [19], [20], seems to favour this strategy, widely known as stereotactic body radiation therapy (SBRT).
The aim of this article is to summarize the radiobiological, technical and clinical data available in the literature about SBRT in PC patients. According to the Italian Association of Radiation Oncology (AIRO), the current review could serve as a guide for clinical implementation of extreme hypofractionation programs in well-equipped RT facilities with appropriate clinical and physics expertise. Such approach can be considered in strictly selected organ-confined PC [104], [105].
Section snippets
Radiobiological rationale
The linear-quadratic model represents the basis for predicting the clinical effects of alternative fractionation schemes in RT. In this model, the tissue response to altered fractionation (i.e. different from the standard 2 Gy/fraction) is determined by the tissue α/β ratio. A tissue with a high α/β ratio is less sensitive to a high dose per fraction or hypofractionated RT compared to a tissue with a low α/β ratio. In clinical practice, most tumours have a high α/β ratio (about 10 Gy); therefore,
Technical aspects
SBRT consists in delivering few, highly focused fractions of high doses of RT. Initially introduced for the treatment of brain tumours by Leksell et al. [34], it has known a larger diffusion in the treatment of extra-cranial targets in the last 20 years [35]. The adoption of these highly hypofractionated treatments in the therapeutic approach to PC has been possible thanks to a better knowledge of the tumour biology, but also to several technological improvements allowing a precise localization
Planning and dosimetric considerations
Dosimetrically, the large dose, and accordingly the high monitor unit (MU) numbers, for each fraction associated with the intensity-modulated SBRT delivery might often be different from the conventionally fractionated IMRT. Therefore, SBRT delivery implies additional efforts in the treatment planning process, due to the need of keeping more beams and more intensity segments within the machine constraints of delivering (1–2 MU/segment). This optimisation process allows the safe delivery of high
Clinical outcomes
Table 1 summarizes data about the clinical outcomes and the toxicity rates of the analysed studies [47], [69], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89]. In the majority of these trials, low/intermediate-risk PC patients who underwent experimental schedules of fraction sizes ranging between 6.7 and 10 Gy were the target population. The majority of clinical evidence of prostate SBRT comes from trials using the non-coplanar
Ongoing clinical trials and future directions
We searched in https://clinicaltrials.gov/ [101] for specific keywords to identify studies related to extreme hypofractionation in PC. In particular, five researches were performed on the 1st February 2016, including: “Prostate SBRT”, “Prostate focal radiotherapy”, “Prostate hypofractionation”, “Prostate dominant lesion” and “Prostate monotherapy”, thus obtaining 252 results. They were evaluated for adequacy to the scope of this review, selecting non-repeating results and excluding studies
Conclusions
The use of SBRT as primary PC treatment is steadily increasing. In the United States, 8.8% of low-risk patients treated at academic programs in 2012 received SBRT, with respect to <1% of patients treated with SBRT in 2004 across all risk groups [103]. Several prospective and retrospective trials of extreme hypofractionation have already been published, although only three randomized studies comparing prostate SBRT with a standard of care are currently ongoing. Thereby, no definitive conclusions
Author contributions
All authors actively contributed to the review of the literature, analysis of relevant studies and preparation of the manuscript. All authors read and approved the final version before submission. Barbara A. Jereczek-Fossa served as scientific supervisor.
Conflict of interest
None to be declared.
Acknowledgment
This study was partially supported by AIRC – Associazione Italiana per la Ricerca sul Cancro (IG-13218).
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