Case of the month from the Radiotherapy Unit, Department of Medical and Surgical Sciences, University of Bologna, Italy: breaking boundaries beyond five lesions with multifocal stereotactic radiotherapy in prostate cancer

Stereotactic body radiotherapy (SBRT), characterised by its precise and focused delivery of high doses of radiation to well-defined targets, has emerged as an effective treatment modality for oligometastatic prostate cancer (PCa). Traditionally applied to patients with a limited number of metastases (≤5) [1], SBRT offers targeted therapeutic benefits. In this case study, we present an exceptional instance wherein a patient with PCa underwent SBRT for 20 metastatic lesions concurrently. This innovative approach served as a bridge therapy, strategically used in the interim as the patient awaited the availability of the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy lutetium-177 (177Lu-PSMA-617) vipivotide tetraxetan. In June 2022, a 74-year-old castration-resistant PCa patient with a history of several treatments underwent assessment at our centre. His treatment course encompassed radical prostatectomy, adjuvant ADT, postoperative RT, salvage ADT, para-aortic lymphadenectomy, postoperative RT to para-aortic nodes, abiraterone, enzalutamide, docetaxel, and seven sequential SBRTs targeting bone or lymph node metastases. A PSMA-PET showed 20 new or progressing bone/nodal metastases (4/20 previously irradiated), alongside a total PSA of 3.7 ng/mL. While 177Lu-PSMA-617 therapy, which gained approval from the US Food and Drug Administration on 23 March 2022 [2], and authorisation from the European Medicines Agency on 9 December 2022 [3], was recommended following a comprehensive multidisciplinary evaluation, its current lack of reimbursement in Italy for a projected 6–12-month duration prompted the proactive planning of SBRT for all discernible metastases. Variable doses and fractionations (25–40 Gy in five fractions) were determined based on proximity to organs at risk and previous radiation doses (Tables S1 and S2). The patient was treated using frameless SBRT on an Elekta Versa-HD linear accelerator equipped with a micro-multileaf collimator and four-dimensional cone-beam CT. The treatment was delivered using volumetric-modulated arc therapy with 6-MV photon beams. The patient was positioned and immobilised using thermoplastic masks and image guidance was carried out using four-dimensional cone-beam CT. The targets were delineated on the images of the four-dimensional CT, and the PSMA-PET images were used as references. The time required for contouring and planning was 36 h and 9 min. In this case, the D95 was found to be less than 95% for six lesions (specifically, C4, D4, D5, D9, due to their close proximity to the spinal canal, and III left rib and X right rib, due to their proximity to previously irradiated sites) and equal to or greater than 95% for 14 metastases. Figure 3 shows the composite dose distribution from four SBRT sessions in a coronal CT slice of the patient. The timeline of SBRT treatments, isocentres, and delivered monitor units are reported in Table S3. Uninterrupted SBRT was administered without patient-reported side effects within 3 weeks. One month post-SBRT, PSA decreased to 2.6 ng/dL (remaining below pre-treatment levels for the subsequent 6 months). A PSMA-PET at 3 months post-SBRT displayed metabolic partial or complete response at all treated sites. The patient remained asymptomatic and in good condition until May 2023 when 177Lu-PSMA-617 therapy was started, with subsequent PSA reduction from 9.1 to 3.4 ng/dL within 15 days. After two treatment cycles, PSA levels dropped to 0.6 ng/dL, while a subsequent PSMA-PET showed reduced metastatic site numbers and sizes. Historically, the management of multiple bone metastases in PCa has garnered significant interest due to the prevalent impact of skeletal complications on patient quality of life and prognosis. In this therapeutic landscape, treatments such as half-body irradiation [4-7] and strontium therapy [6-9] have emerged as notable alternatives, offering symptomatic relief and potential disease control. Half-body irradiation, characterised by its broad coverage, has been valued for its ability to address widespread skeletal disease, yet its utility is tempered by notable toxicity risks, affecting patient tolerance and overall well-being. On the other hand, strontium therapy, leveraging the bone-seeking properties of radioisotopes, provides a targeted approach to alleviating pain and managing metastatic spread. However, its effectiveness is often circumscribed by limitations in disease modification and the potential for haematological toxicity. These historical modalities underscore the ongoing challenge of balancing therapeutic efficacy against adverse effects, a challenge that has spurred the evolution of more precise and tolerable interventions such as SBRT, which promises focused treatment with reduced side effects. This case report highlights the potential of SBRT as an effective treatment strategy in metastatic PCa, both as initial local intervention and for re-irradiation across a multitude of metastatic sites. Notably, this case study challenges the conventional constraint of limiting SBRT to patients with a strictly defined number of metastases (≤5), emphasising the pivotal role of therapeutic intent in treatment decisions. In our case, the primary goal was to stabilise the disease, allowing for a considerable period to initiate a subsequent line of systemic therapy. Moreover, this case underscores the intriguing observation that SBRT's tolerability and safety extend well beyond the confines of treating a maximum of five sites. The successful irradiation of 20 metastatic lesions within a condensed 3-week timeframe raises further questions regarding the clinical rationale underpinning the numerical threshold. The absence of reported side effects in our patient reaffirms the broader viability of treating a higher number of metastatic sites without compromising patient well-being. Despite the promising prospects offered by multifocal SBRT, however, its implementation is not without challenges. Our case study presents a great challenge to radiation oncologist for several reasons. Firstly, the complexity of recalculating treatment plans across eight sequential SBRT cycles, and particularly the re-irradiation plans, demands significant man-hours and resources. Furthermore, the logistical aspect of dedicating a linear accelerator and a treatment bunker exclusively for this patient over a 3-week period underscores the resource-intensive nature of this approach. This highlights a key limitation regarding the feasibility of such an intervention in RT units with a high patient volume. Interestingly, the feasibility of planning and delivering SBRT to treat more than five lesions has been previously documented. A sub-analysis of the SABR-COMET-10 randomised trial conducted by Ashram et al. [10] highlighted that stereotactic ablative RT planning could be achieved effectively without compromising the planning target volume for a majority of patients treated for 4–10 oligometastases. The study found that only a marginal 3% of targets were covered with a D95 value below 95%, with compromises primarily required for vertebral and lymph node targets [10]. In another investigation by Li et al. [11], frameless SBRT based on volumetric-modulated arc therapy successfully treated patients with five and seven lung metastases, respectively, demonstrating favourable tolerability. Similarly, Yang et al. [12] reported a compelling case involving a patient with 15 mediastinal lymph node and hilar region metastases. The patient received CyberKnife-based SBRT, resulting in the complete regression of both the primary tumour and metastatic lesions [12]. Similar findings were reported by Bowden et al., demonstrating that Gamma Knife stereotactic radiosurgery serves as an effective treatment for a large number of brain metastases, especially in patients with breast cancer [13]. As the body of evidence supporting the efficacy of SBRT in oligometastatic patients grows, there remains a scarcity of data concerning its use in polymetastatic scenarios. The ARREST trial, launched in 2020, aims to recruit up to 48 polymetastatic patients (with more than 10 sites) who have opted out of systemic therapies. These patients are to receive SBRT in escalating weekly fractions of 6 Gy. The trial objective is to determine the maximally tolerated dose of SBRT in individuals with polymetastatic disease [14, 15]. However, it must also be recognised that, beyond the clinical and dosimetric feasibility, the possibility of planning and delivering such a complex treatment seems prohibitive in a centre with scarce personnel resources or with waiting list and treatment planning systems or treatment machines problems. In fact, dedicating 36 h of planning and two machine-hours per day to a single patient would be impossible in a very busy RT department. Another interesting aspect of our case is the excellent response to 177Lu-PSMA-617 in our patient, despite several previous treatments, and in particular, despite the previous irradiation and re-irradiation of various bone and nodal sites. 177Lu-PSMA-617 is an emerging and promising approach, addressing the complex landscape of metastatic PCa. This targeted RT leverages the affinity of vipivotide for PSMA, a protein abundantly expressed on PCa cells. By conjugating the radioactive isotope lutetium-177 with vipivotide, the therapy achieves precision in delivering radiation directly to cancerous cells, while sparing surrounding healthy tissues. This innovative modality holds particular significance for patients with advanced PCa, including those with multiple metastases. 177Lu-PSMA-617 therapy exhibits potential in delaying PCa progression and improving patient outcomes, underscoring its role as a novel systemic intervention within the evolving therapeutic armamentarium against PCa [16-18]. Ultimately, our case offers valuable insights into the dynamic realm of advanced PCa management, demonstrating that the selection of treatment modalities should not be tethered solely to numerical thresholds, but rather grounded in therapeutic goals and individual patient characteristics. The success of this case invites further exploration and consideration of multifocal SBRT as an effective strategy within the complex landscape of PCa therapy. None. Elisa Lodi Rizzini reports support for attending meetings and/or travel from NOVARTIS; Paolo Castellucci reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from CURIUM NOVARTIS and support for attending meetings and/or travel; Stefano Fanti reports grants from AMGEN and reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AAA, AMGEN, BAYER, IMMEDICA, JANSSEN, NOVARTIS, TELIX, reports support for attending meetings and/or travel from AAA, NOVARTIS, TELIX, reports participation on a Data Safety Monitoring Board or AdvisoryBoard with NOVARTIS; Alessio G.Morganti reports grants from IGEA, BAYER, ASTELLAS, THEMA SINERGIE, and JANSSEN, and participation on a Data Safety Monitoring Board or Advisory Board with ALFASIGMA and JANSSEN. Erika Galietta, Silvia Strolin, Savino Cilla, Milly Buwenge, Maria Vadalà, Maria Ntreta, and Lidia Strigari report no conflict of interest. E.G., A.G.M. and M.N. had the idea for the article. E.G., S.S., E.L.R., P.C. and M.N. performed the data collection. E.G., M.B., M.D. and A.G.M. drafted the manuscript. All authors critically revised the work. This research received no external funding. The patient provided written informed consent for the use of his clinical data, diagnostic images, and medical history for the purpose of this case report publication. Table S1. Doses and fractionations of irradiated sites. Table S2. Composite DVH of the main Organs at risk. Table S3. Timeline of SBRT treatments and related Monitor units. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.