Optimizing the therapeutic ratio of PSMA-PET-guided para-aortic radiotherapy for prostate cancer: A systematic review and structured quantitative synthesis.

Abstract

BackgroundThe increasing use of prostate-specific membrane antigen positron emission tomography (PSMA-PET) has transformed the detection of para-aortic lymph node recurrence in prostate cancer, creating new opportunities for metastasis-directed radiotherapy. However, the optimal balance between oncologic benefit and treatment-related toxicity remains uncertain, particularly when comparing focal stereotactic body radiotherapy (SBRT) with elective nodal irradiation (ENI).PurposeTo systematically evaluate the clinical, dosimetric, and radiobiological evidence regarding PSMA-PET-guided para-aortic radiotherapy for prostate cancer and to develop an evidence-informed therapeutic-ratio framework to support patient selection and treatment planning.MethodsA systematic literature search of PubMed, Scopus, and Web of Science identified studies published between January 2014 and January 2025 evaluating PSMA-PET-guided para-aortic radiotherapy in prostate cancer. Following PRISMA 2020 methodology, studies were selected according to predefined eligibility criteria. Owing to substantial clinical and methodological heterogeneity, findings were synthesized using the Synthesis Without Meta-analysis (SWiM) framework. Evidence was interpreted according to study design, consistency of findings, and clinical applicability.ResultsTwenty studies met the inclusion criteria, including one randomized phase II trial, prospective cohorts, retrospective comparative studies, dosimetric investigations, and systematic reviews. PSMA-PET consistently improved detection of occult para-aortic nodal disease and altered radiotherapy target delineation. Randomized and retrospective comparative evidence suggested that ENI combined with short-term androgen deprivation therapy improved regional control and metastasis-free survival compared with focal SBRT in selected patients with metachronous oligorecurrent disease, although overall survival data remain immature. SBRT achieved excellent local control with low toxicity but was associated with frequent adjacent out-of-field nodal relapse. Previous pelvic radiotherapy substantially increased the complexity of re-irradiation, emphasizing the importance of cumulative equivalent dose in 2 Gy fractions (EQD2) assessment. Safe implementation depended on daily image-guided radiotherapy, appropriate motion management, and strict gastrointestinal dose constraints. The available evidence was predominantly retrospective and heterogeneous, limiting definitive comparative conclusions.ConclusionCurrent evidence supports individualized PSMA-PET-guided para-aortic radiotherapy rather than a uniform treatment strategy. Patients with metachronous, low-volume (1-3 node) para-aortic recurrence and a radiation-naïve pelvis appear most likely to benefit from ENI ± simultaneous integrated boost, whereas focal SBRT remains an important option for patients with prior pelvic irradiation or limited tolerance for extended-field treatment. Prospective phase III trials are required to determine whether these approaches improve overall survival and to refine patient selection.Plain language summaryAdvanced imaging can now detect small areas of prostate cancer that have spread to lymph nodes, but the best radiation treatment approach is still unclear. This study reviewed published research on radiation treatment guided by prostate-specific membrane antigen positron emission tomography, a scan that helps find prostate cancer more accurately. This study found that broader lymph node treatment may improve disease control for some people, while focused treatment can control known cancer areas with low side effects but may miss nearby disease. This matters because choosing the right treatment for each person could improve outcomes while reducing unnecessary side effects.