Randomized phase II trial of MRI-guided salvage radiotherapy for prostate cancer in 4 weeks versus 2 weeks (SHORTER)

Prostate cancer is the most common non-cutaneous cancer and the second leading cause of cancer death in men [1]. It is predicted that the number of prostate cancer cases will almost double by the year 2030 [2]. For men with localized prostate cancer, radical prostatectomy is a common definitive treatment modality [3]. After radical prostatectomy, approximately one-third to one-half of men with high-risk features will develop biochemical recurrence (BCR) [4‐7].

Post-operative radiotherapy is the current standard of care for men who develop BCR or are at risk of BCR after radical prostatectomy. Post-operative radiotherapy is a potentially curative treatment after prostatectomy for men with BCR and may avoid or delay the need for chronic, non-curative treatment, such as long-term androgen suppression. Given the increase in both prostate cancer diagnosis and the proportion of men with high-risk disease undergoing radical prostatectomy, the number of men requiring post-operative radiotherapy is likely to increase [8]. As such, optimizing radiotherapy approaches for post-operative management is an important and unanswered question. Minimizing genitourinary (GU) and gastrointestinal (GI) toxicity and maximizing quality of life are critical for men with a high chance of cure and long life-expectancy following salvage treatment [9].

Adjuvant radiotherapy, the administration of immediate post-operative radiotherapy based on adverse pathological features, has been demonstrated to improve biochemical progression free survival (PFS) across multiple prospective randomized trials [10‐12]. More recently, early salvage post-operative radiotherapy has become an accepted paradigm. In this approach, men delay post-operative intervention until the time of BCR or if there is a persistently elevated serum prostate-specific antigen (PSA) level after prostatectomy. In support of this paradigm shift, three recent randomized controlled trials and the harmonized ARTISTIC meta-analysis have demonstrated that adjuvant radiotherapy, as compared with salvage radiotherapy, does not improve event-free survival [4, 5, 7, 13]. Additionally, the salvage approach may also avoid overtreatment in the subset of men that despite high-risk features do not develop BCR. The aforementioned studies have helped clarify the timing of post-operative intervention, however, integration of genomic classifiers, optimal target volumes (including pelvic nodal coverage), and the use and duration of androgen suppression therapy remain controversial. Additional studies are needed to further refine patient selection and improve post-operative management.

Increasingly, there has been a trend toward delivering higher doses of radiation over fewer treatment sessions, termed hypofractionation, as opposed to longer courses of treatment with conventional fractionation (1.8–2 Gy/fraction) [14‐16]. Further, as prostate cancer is believed to have a low α/β ratio relative to other tumor types, the therapeutic ratio may favor hypofractionation over conventional regimens [17‐20]. The preliminary report of the phase III randomized NRG-GU003 study demonstrated that moderately hypofractionated post-operative radiotherapy (62.5 Gy in 25 fractions) does not increase patient-reported GU or GI toxicity over conventional post-operative radiotherapy (66.6 Gy in 37 fractions). At a median of 24 months, change in mean GU and GI scores in the moderate hypofractionation arm and conventional fractionation arm were neither clinically nor statistically significant (mean GU = -5.2 vs mean GU = -0.3, p= 0.81; mean GI = -2.2 vs mean GI = -1.5, p = 0.12). Therefore, moderate hypofractionation is non-inferior to conventional fractionation for post-operative RT in measures of late toxicity [21]. This finding is significant, as hypofractionation provides patients with shorter and more accessible courses of radiotherapy, thereby reducing treatment burden. 

The advent of magnetic resonance imaging (MRI)-guided radiotherapy (MRgRT) – enabled through the integration of MRI and linear accelerator (MR-LINAC) technology may facilitate safe delivery of hypofractionated and ultra-hypofractionated regimens. Multi-parametric MR imaging on the MR-LINAC improves target delineation and this feature combined with real-time MR image-guidance and tracking, allows for reduction in planning margins and accounts for inter-fractional changes in anatomy during treatment thereby decreasing dose to adjacent structures, including the bladder and rectum [22]. In addition, the MR-LINAC technology can facilitate online adaptive planning as needed. Taken together, MRgRT may safely allow larger radiation doses to be delivered in fewer fractions in the intact and post-operative setting. The MIRAGE phase III study comparing MRI-guidance versus standard computed tomography (CT)-guidance with stereotactic body radiotherapy (SBRT) for intact prostate cancer demonstrated that acute grade ≥ 2 GU toxicity was significantly reduced among men receiving MRgRT (43.4.1% vs. 24.4%, p = 0.01). Acute grade ≥ 2 GI toxicity was also significantly reduced in men receiving MRgRT (10.5% vs. 0%, p = 0.003) [23]. Similarly, the SCIMITAR phase II study evaluated the safety profile of post-prostatectomy SBRT and incorporated a pre-planned, non-randomized exploratory analysis of toxicity and patient-reported quality-of-life (QoL) outcomes between MRI-guidance versus CT-guidance. Compared with CT-guided post-operative SBRT, MRgRT was associated with significantly lower rates of any-grade acute GI toxicity (41.9% vs. 72.5%, p = 0.0056) per CTCAE version 4.0 criteria, corresponding to an estimated absolute reduction of 30.5%. In terms of late effects, MRgRT was associated with numerically lower any-grade late GI toxicity, however, these differences were not significantly different (37.7% vs. 29%, p = 0.4) when compared with CT-guidance. There were no differences in acute or late GU toxicity in the comparison of patients treated with CT versus MRI-guided SBRT. Overall, three patients experienced grade 3 toxicity (GU, n = 1; GI n = 2), notably no patients treated with MRgRT experienced any grade 3 toxicity or grade ≥ 2 GI toxicity. While additional randomized studies are needed, these findings demonstrate the potential of MRgRT to improve the precision and safety of post-operative radiation delivery [24].

The SHORTER trial (NCT04422132) is designed to evaluate if MR-guided ultra-hypofractionated post-operative radiotherapy (5 fractions in two weeks) has a non-inferior GU and GI toxicity profile as compared with MR-guided moderately-hypofractionated post-operative radiotherapy (20 fractions in four weeks) among prostate cancer patients undergoing salvage radiotherapy. This randomized phase II study lays the foundation to potentially redefine the standard of care for post-prostatectomy patients with BCR to include MRgRT and decrease treatment burden.

With growing acceptance of hypofractionation and the increase of ultra-hypofractionation for definitive radiation treatment of intact prostate cancer, hypofractionated regimens for post-operative management are poised to become a convenient option for patients. Abbreviated radiation schedules may reduce the burden of treatment on patients and treatment centers alike while maintaining clinical efficacy and safety. A primary consideration for patients in need of post-operative radiotherapy is toxicity, manifesting as both acute and late side effects of the bladder and bowel. Such side effects impact quality of life following treatment, highlighting the importance of treatment approaches that minimize toxicity. MRgRT may facilitate higher radiation doses to be delivered in fewer sessions with increased accuracy and precision. The potential advantages of MRgRT include better visualization of the prostatic fossa, the capacity for real-time tracking, and the ability to perform online adaptive radiotherapy that accounts for organ deformation. These factors may decrease the radiation dose received by adjacent structures, thereby minimizing toxicity [23, 24]. The SHORTER trial is the first randomized trial to evaluate whether the theoretical advantages of hypofractionation combined with MRI-guidance translate into the salvage radiotherapy setting from a toxicity standpoint. The SHORTER trial will provide information not only on toxicities, but also well-documented information on time to progression, prostate cancer-specific survival and overall survival. We hope that the data from this trial will elucidate the non-inferiority of ultra-hypofractionated, MRI-guided post-operative radiotherapy.