Evolution of Hypofractionated Accelerated Radiotherapy for Prostate Cancer – The Sunnybrook Experience

PERSPECTIVE ARTICLE published: 14 November 2014 doi: 10.3389/fonc.2014.00313 Evolution of hypofractionated accelerated radiotherapy for prostate cancer – the Sunnybrook experience Hima Bindu Musunuru 1,2 , Patrick Cheung 1,2 and Andrew Loblaw 1,2,3 * 1 Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada 3 Department of Health Policy, Measurement and Evaluation, University of Toronto, Toronto, ON, Canada 2 Edited by: Alan Jay Katz, Flushing Radiation Oncology, USA Reviewed by: Ronald C. Chen, University of North Carolina at Chapel Hill, USA Alan Jay Katz, Flushing Radiation Oncology, USA *Correspondence: Andrew Loblaw , Rm T2-103, 2075 Bayview Avenue, Sunnybrook Health Sciences Center, Toronto, ON M4N 3M5, Canada e-mail: andrew.loblaw@ sunnybrook.ca Stereotactic ablative body radiotherapy (SABR) is a newer method of ultra hypo fractionated radiotherapy that uses combination of image-guided radiotherapy (IGRT) and intensitymodulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT), to deliver high doses of radiation in a few fractions to a target, at the same time sparing the surrounding organs at risk (OAR). SABR is ideal for treating small volumes of disease and has been introduced in a number of disease sites including brain, lung, liver, spine, and prostate. Given the radiobiological advantages of treating prostate cancer with high doses per fraction, SABR is becoming a standard of care for low and intermediate-risk prostate cancer patients based upon the results from Sunnybrook and also the US-based prostate SABR consortium. This review examines the development of moderate and ultra hypo-fractionation schedules at the Odette Cancer centre, Sunnybrook Health Sciences. Moderate hypo-fractionation protocol was first developed in 2001 for intermediate-risk prostate cancer and from there on different treatment schedules including SABR evolved for all risk groups. Keywords: prostate cancer, image-guided radiotherapy, stereotactic ablative radiotherapy, quality of life INTRODUCTION Prostate cancer is the most prevalent male cancer in the western world with varying management options as per the individual’s risk stratification, functional domain, and preference. There is now convincing evidence that radiotherapy dose escalation is beneficial across all risk groups of prostate cancer patients (1, 2). Dose escalation beyond 81 Gy with conventional radiotherapy techniques has posed problems due to the increase in bowel toxicity (2) despite the use of image guided (IGRT) and intensity-modulated radiotherapy (IMRT). Alternative means of safe radiotherapy dose escalation are low dose rate (LDR) or high-dose rate (HDR) brachytherapy alone or in combination with EBRT. While LDR brachytherapy monotherapy is established for low risk and selective intermediaterisk patients, HDR monotherapy remains experimental (3). HDR boost in combination with EBRT is an excellent example of safe radiotherapy dose escalation (4). Despite this being an appealing option, limitations include patient fitness for anesthetic exposure, urinary morbidity, and limited operating room capacity. One notion that has revolutionized the field of radiotherapy has been the purported low α/β ratio for prostate cancer (5). Miralbell et al. presented the outcomes of 5969 patients, which calculated the α/β to be 1.3, 1.6, and 1.8 for low, intermediate, and high-risk prostate cancers (6). This in association with a higher α/β ratio for acute (10) and late (≈3–4) responding tissues, can theoretically improve the therapeutic ratio of hypofractionated radiotherapy (7). Strategies include either moderate hypo-fractionation (2– 3.5 Gy per fraction) or ultra hypo-fractionation (>3.5 Gy per fraction). www.frontiersin.org These concepts have led to the development of various prostate hypofractionated accelerated radio therapy (pHART) protocols at the Odette Cancer Centre, Sunnybrook Health Sciences. This is the first report describing the evolution of various gantry-based coplanar radiotherapy techniques for hypofractionation, adapted in accordance with the emerging radiotherapy technology. This review also discusses the role of hypo-fractionation in various prostate cancer risk groups and is the first to include a significant number of high-risk patients. MODERATE HYPOFRACTIONATION pHART1 – INTERMEDIATE RISK In 2001, pHART1 was developed to treat 33 intermediate-risk prostate cancer patients. The first phase involved delivering 42 Gy in 21 fractions using three-dimensional conformal radiotherapy (3DCRT) to the prostate and proximal seminal vesicles with a 10-mm planning target volume (PTV) margin. Following CT simulation, patients had digital fluoroscopic imaging of the gold seed fiducials to quantify the respiratory induced prostatic motion. For the first nine fractions, location of the implanted fiducials was captured pre- and post-treatment using electronic portal imaging device (EPID). Based on this data, a patient specific PTV margin was derived and applied to the second phase of treatment, which was an IMRT boost using a dose of 30 Gy in 10 daily fractions with daily online EPID imaging. The calculated mean PTV margin was 3 mm (range 2– 5 mm) in the lateral direction, 3 mm (range 2–7 mm) in the superior–inferior, and 4 mm (range 2–8 mm) in the anterior– posterior directions. Three patients (9.1%) developed acute grade 3 urgency/frequency. This study showed that the intra-fraction November 2014 | Volume 4 | Article 313 | 1 Musunuru et al. prostate movement was generally small, allowing for significant PTV margin reduction if daily online imaging is performed (8). Sunnybrook SABR prostate treatment cohorts (85 vs. 79%, p = 0.065). In the subgroup analysis, patients with PSA ≥20 ng/ml or Gleason 4 + 3 had better bRFS with the hypo-fractionation schedule (15). pHART2 – HIGH RISK pHART4: POST-OPERATIVE RT In 2004, 67 high-risk prostate cancer patients were enrolled into a prospective, phase 1 study (pHART2) delivering 67.5 Gy to the prostate in 25 fractions (2.7 Gy per day), while the pelvic nodes received 45 Gy in 25 fractions over the same period, in conjunction with 3 years of ADT. Patients were treated using a simple four field box technique (4FB) to deliver the pelvic elective nodal irradiation (ENI), while an optimized IMRT plan was used to deliver the concomitant IMRT boost to the prostate. The acute toxicity from this study has been very favorable (9). In the next phase, the same dose-fractionation scheme was employed for the same high-risk group in another 30 additional patients. However, the radiotherapy technique was changed to deliver both ENI and concomitant prostate boost using a single optimized IMRT plan. The toxicity data has been updated for these 97 patients in this phase I–II study with a median follow up of 39 months. The incidence of acute grade 2 gastrointestinal (GI) toxi (...truncated)