Machine learning predicts conventional imaging metastasis-free survival (MFS) for oligometastatic castration-sensitive prostate cancer (omCSPC) using prostate-specific membrane antigen (PSMA) PET radiomics.

PURPOSE: This study investigated imaging biomarkers derived from PSMA-PET acquired pre- and post-metastasis-directed therapy (MDT) to predict 2-year metastasis-free survival (MFS), which provides valuable early response assessment to improve patient outcomes. MATERIALS/METHODS: An international cohort of 117 oligometastatic castration-sensitive prostate cancer (omCSPC) patients, comprising 34 from John Hopkins Hospital (JHH) and 83 from Baskent University (BU), were treated with stereotactic ablative radiation therapy (SABR) MDT with both pre- and post-MDT PSMA-PET/CT scans acquired. PET radiomic features were analyzed from a CT-PET fusion defined gross tumor volume ((GTV) or zone 1), and a 5 mm expansion ring area outside the GTV (zone 2). A total of 1748 PET radiomic features were extracted from these zones. The six most significant features selected using the Chi2 method, along with five clinical parameters (age, Gleason score, number of total lesions, untreated lesions, and pre-MDT prostate-specific antigen (PSA)) were extracted as inputs to the models. Various machine learning models, including Random Forest, Decision Tree, Support Vector Machine, and Naïve Bayesian, were employed for 2-year MFS prediction and tested using leave-one-out and cross-institution validation. RESULTS: Six radiomic features, including Total Energy, Entropy, and Standard Deviation from pre-PSMA-PET zone 1, Total Energy and Contrast from post-PSMA-PET zone 1, and Entropy from pre-PSMA-PET zone 2, along with five clinical parameters were selected for predicting 2-year MFS. In a leave-one-out test with all the patients, random forest achieved an accuracy of 80 % and an AUC of 0.82 in predicting 2-year MFS. In cross-institution validation, the model correctly predicted 2-year MFS events with an accuracy of 75 % and an AUC of 0.77 for patients from JHH, and an accuracy of 78 % and an AUC of 0.80 for BU patients, respectively. CONCLUSION: Our study demonstrated the promise of using pre- and post-MDT PSMA-PET-based imaging biomarkers for MFS prediction for omCSPC patients.

Genomic Determinants Associated with Modes of Progression and Patterns of Failure in Metachronous Oligometastatic Castration-sensitive Prostate Cancer.

BACKGROUND AND OBJECTIVE: Oligometastatic castration-sensitive prostate cancer (omCSPC) represents an early state in the progression of metastatic disease for which patients experience better outcomes in comparison to those with higher disease burden. Despite the generally more indolent nature, there is still much heterogeneity, with some patients experiencing a more aggressive clinical course unexplained by clinical features alone. Our aim was to investigate correlation of tumor genomics with the mode of progression (MOP) and pattern of failure (POF) following first treatment (metastasis-directed and/or systemic therapy) for omCSPC. METHODS: We performed an international multi-institutional retrospective study of men treated for metachronous omCSPC who underwent tumor next-generation sequencing with at least 1 yr of follow-up after their first treatment. Descriptive MOP and POF results are reported with respect to the presence of genomic alterations in pathways of interest. MOP was defined as class I, long-term control (LTC; no radiographic progression at last follow-up), class II, oligoprogression (1-3 lesions), or class III, polyprogression (≥4 lesions). POF included the location of lesions at first failure. Genomic pathways of interest included TP53, ATM, RB1, BRCA1/2, SPOP, and WNT (APC, CTNNB1, RNF43). Genomic associations with MOP/POF were compared using χ2 tests. Exploratory analyses revealed that the COSMIC mutational signature and differential gene expression were also correlated with MOP/POF. Overall survival (OS) was calculated via the Kaplan-Meier method from the time of first failure. KEY FINDINGS AND CLINICAL IMPLICATIONS: We included 267 patients in our analysis; the majority had either one (47%) or two (30%) metastatic lesions at oligometastasis. The 3-yr OS rate was significantly associated with MOP (71% for polyprogression vs 91% for oligoprogression; p = 0.005). TP53 mutation was associated with a significantly lower LTC rate (27.6% vs 42.3%; p = 0.04) and RB1 mutation was associated with a high rate of polyprogression (50% vs 19.9%; p = 0.022). Regarding POF, bone failure was significantly more common with tumors harboring TP53 mutations (44.8% vs25.9%; p = 0.005) and less common with SPOP mutations (7.1% vs 31.4%; p = 0.007). Visceral failure was more common with tumors harboring either WNT pathway mutations (17.2% vs 6.8%, p = 0.05) or SPOP mutations (17.9% vs 6.3%; p = 0.04). Finally, visceral and bone failures were associated with distinct gene-expression profiles. CONCLUSIONS AND CLINICAL IMPLICATIONS: Tumor genomics provides novel insight into MOP and POF following treatment for metachronous omCSPC. Patients with TP53 and RB1 mutations have a higher likelihood of progression, and TP53, SPOP, and WNT pathway mutations may have a role in metastatic organotropism. PATIENT SUMMARY: We evaluated cancer progression after a first treatment for metastatic prostate cancer with up to five metastases. We found that mutations in certain genes were associated with the location and extent of further metastasis in these patients.

Recent advances and impending challenges for the radiopharmaceutical sciences in oncology.

This paper is the first of a Series on theranostics that summarises the current landscape of the radiopharmaceutical sciences as they pertain to oncology. In this Series paper, we describe exciting developments in radiochemistry and the production of radionuclides, the development and translation of theranostics, and the application of artificial intelligence to our field. These developments are catalysing growth in the use of radiopharmaceuticals to the benefit of patients worldwide. We also highlight some of the key issues to be addressed in the coming years to realise the full potential of radiopharmaceuticals to treat cancer.

Prostate-Specific Membrane Antigen PET Response Associates with Metastasis-Free Survival After Stereotactic Ablative Radiation in Oligometastatic Prostate Cancer.

Purpose: Emerging data suggest that metastasis-directed therapy (MDT) improves outcomes in patients with oligometastatic castration-sensitive prostate cancer (omCSPC). Prostate-specific membrane antigen positron emission tomography (PSMA-PET) can detect occult metastatic disease, and PSMA response has been proposed as a biomarker for treatment response. Herein, we identify and validate a PSMA-PET biomarker for metastasis-free survival (MFS) following MDT in omCSPC. Methods and Materials: We performed an international multi-institutional retrospective study of patients with omCSPC, defined as ≤3 lesions, treated with metastasis-directed stereotactic ablative radiation who underwent PSMA-PET/computed tomography (CT) before and after (median, 6.2 months; range, 2.4-10.9 months) treatment. Pre- and post-MDT PSMA-PET/CT maximum standardized uptake value (SUVmax) was measured for all lesions, and PSMA response was defined as the percent change in SUVmax of the least responsive lesion. PSMA response was both evaluated as a continuous variable and dichotomized into PSMA responders, with a complete/partial response (at least a 30% reduction in SUVmax), and PSMA nonresponders, with stable/progressive disease (less than a 30% reduction in SUVmax). PSMA response was correlated with conventional imaging-defined metastasis-free survival (MFS) via Kaplan-Meier and Cox regression analysis. Results: A total of 131 patients with 261 treated metastases were included in the analysis, with a median follow-up of 29 months (IQR, 18.5-41.3 months). After stereotactic ablative radiation, 70.2% of patients were classified as PSMA responders. Multivariable analysis demonstrated that PSMA response as a continuous variable was associated with a significantly worse MFS (hazard ratio = 1.003; 95% CI, 1.001-1.006; P = .016). Patients classified as PSMA responders were found to have a significantly improved median MFS of 39.9 versus 12 months (P = .001) compared with PSMA nonresponders. Our study is limited as it is a retrospective review of a heterogenous population. Conclusions: After stereotactic ablative radiation, PSMA-PET response appears to be a radiographic biomarker that correlates with MFS in omCSPC. This approach holds promise for guiding clinical management of omCSPC and should be validated in a prospective setting.

Factors Impacting Provider Treatment Decision-Making in Early Glottic Cancer.

OBJECTIVES: Transoral laser microsurgery (TLMS) and radiotherapy (XRT) are mainstays of treatment for early glottic carcinoma (EGC). Here, we investigated case-dependent provider treatment preferences and identify factors which impact decision-making in EGC. METHODS: This cross-sectional survey of laryngologists, head-and-neck surgeons, and radiation oncologists presented five diagrammatic cases of progressively advanced EGC (T1/2, N0). Respondents indicated preference for TLMS or XRT and ranked factors which influenced their recommendation for each case. Analysis utilized descriptive statistics, Fischer's exact tests, and Kruskal-Wallis tests for nonparametric data. RESULTS: A total of 141 complete responses (69.5% laryngologists) were received. Most respondents practiced in academic settings (93.5%) and within multidisciplinary teams (94.0%). Anterior commissure involvement was the most important a priori tumor factor for case-independent treatment recommendation (Likert Scale: 4.22/5), followed by Laterality (Likert Scale: 4.02/5). Across all specialties, TLMS was recommended for unilateral T1a lesions. Laryngologists continued recommending TLMS in T2 lesions (41.0%) more than head-and-neck surgeons (5.0%) and radiation oncologists (0.0%). Across all cases, survival and voice outcomes were the most important clinical factors impacting treatment decisions. Radiation oncologists weighed voice more heavily than laryngologists in more complex presentations of EGC (rank: 1.6 vs. 2.7, Kruskall-Wallis: p < 0.05). CONCLUSIONS: In more complex clinical presentations of EGC, preference for TLMS compared to XRT differed across specialists, despite similar rankings of factors driving these treatment recommendations. This may be driven by differing experiences and viewpoints on case-dependent voice outcomes following TLMS versus XRT, suggesting a need for increased understanding of how tumor location and depth impact voice outcomes. LEVEL OF EVIDENCE: 5 Laryngoscope, 134:3686-3694, 2024.

Multi-institutional Analysis of Metastasis-directed Therapy with or Without Androgen Deprivation Therapy in Oligometastatic Castration-sensitive Prostate Cancer.

BACKGROUND: Metastasis-directed therapy (MDT) is increasingly being used in oligometastatic castration-sensitive prostate cancer (omCSPC). However, it is currently unclear how to optimally integrate MDT with the standard of care of systemic hormonal therapy. OBJECTIVE: To report long-term outcomes of MDT alone versus MDT and a defined course of androgen deprivation therapy (ADT) in omCSPC. DESIGN, SETTING, AND PARTICIPANTS: Here, a multicenter, international retrospective cohort of omCSPC as defined by conventional imaging was reported. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biochemical progression-free survival (bPFS), distant progression-free survival (dPFS), and combined biochemical or distant progression-free survival (cPFS) were evaluated with Kaplan-Meier and multivariable Cox proportional hazard regression models. RESULTS AND LIMITATIONS: A total of 263 patients were included, 105 with MDT + ADT and 158 with MDT alone. The majority of patients had metachronous disease (90.5%). Five-year bPFS, dPFS, and cPFS were, respectively, 24%, 41%, and 19% in patients treated with MDT + ADT and 11% (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.36-0.64), 29% (HR 0.56, 95% CI 0.40-0.78), and 9% (HR 0.50, 95% CI 0.38-0.67) in patients treated with MDT alone. On a multivariable analysis adjusting for pretreatment variables, the use of ADT was associated with improved bPFS (HR 0.43, p < 0.001), dPFS (HR 0.45, p = 0.002), and cPFS (HR 0.44, p < 0.001). CONCLUSIONS: In this large multi-institutional report, the addition of concurrent ADT to MDT appears to improve time to prostate-specific antigen progression and distant recurrence, noting that about 10% patients had durable control with MDT alone. Ongoing phase 3 studies will help further define treatment options for omCSPC. PATIENT SUMMARY: Here, we report a large retrospective review evaluating the outcomes of metastasis-directed therapy with or without a limited course of androgen deprivation for patients with oligometastatic castration-sensitive prostate cancer. This international multi-institutional review demonstrates that the addition of androgen deprivation therapy to metastasis-directed therapy (MDT) improves progression-free survival. While a proportion of patients appear to have long-term disease control with MDT alone, further work in biomarker discovery is required to better identify which patients would be appropriate for de-escalated therapy.

Guiding principles on the education and practice of theranostics.

PURPOSE: The recent development and approval of new diagnostic imaging and therapy approaches in the field of theranostics have revolutionised nuclear medicine practice. To ensure the provision of these new imaging and therapy approaches in a safe and high-quality manner, training of nuclear medicine physicians and qualified specialists is paramount. This is required for trainees who are learning theranostics practice, and for ensuring minimum standards for knowledge and competency in existing practising specialists. METHODS: To address the need for a training curriculum in theranostics that would be utilised at a global level, a Consultancy Meeting was held at the IAEA in May 2023, with participation by experts in radiopharmaceutical therapy and theranostics including representatives of major international organisations relevant to theranostics practice. RESULTS: Through extensive discussions and review of existing curriculum and guidelines, a harmonised training program for theranostics was developed, which aims to ensure safe and high quality theranostics practice in all countries. CONCLUSION: The guiding principles for theranostics training outlined in this paper have immediate relevance for the safe and effective practice of theranostics.

The Potential Contribution of Radiopharmaceutical Therapies in Managing Oligometastatic Disease.

There is a growing understanding of the oligometastatic disease state, characterized by the presence of 5 or fewer lesions. Advanced molecular imaging techniques, such as prostate-specific membrane antigen PET, refines the ability to detect oligometastatic recurrences (oligorecurrences) early. These developments have led to the exploration of metastasis-directed therapy (MDT) in oligorecurrent disease as an alternative to or as a means of delaying systemic therapy. Unfortunately, MDT often does not provide a durable cure, and progression-particularly progression in multiple new areas-remains a concern. Simultaneously, developments in radioligand therapy (RLT) have led to studies showing overall survival benefits with α-emitting and ß-emitting RLT in advanced, high-volume, metastatic castration-resistant prostate cancer. The success of RLT in late-stage disease suggests that earlier use in the disease spectrum may be impactful. Specifically, integration of RLT with MDT might reduce progression, including polymetastatic progression, in the setting of oligorecurrent disease.

Radiotheranostics in advanced prostate cancer: Current and future directions.

The discovery of small molecules that target the extracellular domain of prostate-specific membrane antigen (PSMA) has led to advancements in diagnostic imaging and the development of precision radiopharmaceutical therapies. In this review, we present the available existing data and highlight the key ongoing clinical evaluations of PSMA-based imaging in the management of primary, biochemically recurrent, and metastatic prostate cancer. We also discuss clinical studies that explore the use of PSMA-based radiopharmaceutical therapy (RPT) in metastatic prostate cancer and forthcoming trials that investigate PSMA RPT in earlier disease states. Multidisciplinary collaboration in clinical trial design and therapeutic administration is critical to the continued progress of this evolving radiotheranostics field.

PSMA-targeted therapy for non-prostate cancers.

Radioligand therapy (RLT) agents are demonstrating a crucial role in the clinical approach to aggressive malignancies such as metastatic castrate-resistant prostate cancer (m-CRPC). With the recent FDA approval of prostate-specific membrane antigen (PSMA)-targeted RLT for m-CRPC, the field has broadened its gaze to explore other cancers that express PSMA in the tumor parenchyma or tumor neovasculature. In this review article, we discuss current progress in the clinical use of PSMA RLTs in non-prostate cancers such salivary gland cancers, renal cell carcinoma, high grade glioma, and soft tissue sarcoma. We highlight early reports in small case series and clinical trials indicating promise for PSMA-targeted RLT and highlighting the importance of identifying patient cohorts who may most benefit from these interventions. Further study is indicated in non-prostate cancers investigating PSMA RLT dosimetry, PSMA PET/CT imaging as a biomarker, and assessing PSMA RLT safety and efficacy in these cancers.

Clinical and Genomic Differences Between Advanced Molecular Imaging-detected and Conventional Imaging-detected Metachronous Oligometastatic Castration-sensitive Prostate Cancer.

In metastatic castration-sensitive prostate cancer (mCSPC), disease volume plays an integral role in guiding treatment recommendations, including selection of docetaxel therapy, metastasis-directed therapy, and radiation to the prostate. Although there are multiple definitions of disease volume, they have commonly been studied in the context of metastases detected via conventional imaging (CIM). One such numeric definition of disease volume, termed oligometastasis, is heavily dependent on the sensitivity of the imaging modality. We performed an international multi-institutional retrospective review of men with metachronous oligometastatic CSPC (omCSPC), detected via either advanced molecular imaging alone (AMIM) or CIM. Patients were compared with respect to clinical and genomic features using the Mann-Whitney U test, Pearson's χ2 test, and Kaplan-Meier overall survival (OS) analyses with a log-rank test. A total of 295 patients were included for analysis. Patients with CIM-omCSPC had significantly higher Gleason grade group (p = 0.032), higher prostate-specific antigen at omCSPC diagnosis (8.0 vs 1.7 ng/ml; p < 0.001), more frequent pathogenic TP53 mutations (28% vs 17%; p = 0.030), and worse 10-yr OS (85% vs 100%; p < 0.001). This is the first report of clinical and biological differences between AMIM-detected and CIM-detected omCSPC. Our findings are particularly important for ongoing and planned clinical trials in omCSPC. PATIENT SUMMARY: Metastatic prostate cancer with just a few metastases only detected via newer scanning methods (called molecular imaging) is associated with fewer high-risk DNA mutations and better survival in comparison to metastatic cancer detected via conventional scan methods.

A Multimedia Strategy to Integrate Introductory Broad-Based Radiation Science Education in US Medical Schools.

US physicians in multiple specialties who order or conduct radiological procedures lack formal radiation science education and thus sometimes order procedures of limited benefit or fail to order what is necessary. To this end, a multidisciplinary expert group proposed an introductory broad-based radiation science educational program for US medical schools. Suggested preclinical elements of the curriculum include foundational education on ionizing and nonionizing radiation (eg, definitions, dose metrics, and risk measures) and short- and long-term radiation-related health effects as well as introduction to radiology, radiation therapy, and radiation protection concepts. Recommended clinical elements of the curriculum would impart knowledge and practical experience in radiology, fluoroscopically guided procedures, nuclear medicine, radiation oncology, and identification of patient subgroups requiring special considerations when selecting specific ionizing or nonionizing diagnostic or therapeutic radiation procedures. Critical components of the clinical program would also include educational material and direct experience with patient-centered communication on benefits of, risks of, and shared decision making about ionizing and nonionizing radiation procedures and on health effects and safety requirements for environmental and occupational exposure to ionizing and nonionizing radiation. Overarching is the introduction to evidence-based guidelines for procedures that maximize clinical benefit while limiting unnecessary risk. The content would be further developed, directed, and integrated within the curriculum by local faculties and would address multiple standard elements of the Liaison Committee on Medical Education and Core Entrustable Professional Activities for Entering Residency of the Association of American Medical Colleges.

Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed Therapy Versus Observation in Oligometastatic Prostate Cancer: Analysis of STOMP and ORIOLE Trials.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The initial STOMP and ORIOLE trial reports suggested that metastasis-directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer (omCSPC) was associated with improved treatment outcomes. Here, we present long-term outcomes of MDT in omCSPC by pooling STOMP and ORIOLE and assess the ability of a high-risk mutational signature to risk stratify outcomes after MDT. The primary end point was progression-free survival (PFS) calculated using the Kaplan-Meier method. High-risk mutations were defined as pathogenic somatic mutations within ATM, BRCA1/2, Rb1, or TP53. The median follow-up for the whole group was 52.5 months. Median PFS was prolonged with MDT compared with observation (pooled hazard ratio [HR], 0.44; 95% CI, 0.29 to 0.66; P value < .001), with the largest benefit of MDT in patients with a high-risk mutation (HR high-risk, 0.05; HR no high-risk, 0.42; P value for interaction: .12). Within the MDT cohort, the PFS was 13.4 months in those without a high-risk mutation, compared with 7.5 months in those with a high-risk mutation (HR, 0.53; 95% CI, 0.25 to 1.11; P = .09). Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained clinical benefit to MDT over observation. A high-risk mutational signature may help risk stratify treatment outcomes after MDT.

Lutetium-177 Prostate-Specific Membrane Antigen Therapy: A Practical Review.

Prostate-specific membrane antigen is a transmembrane protein found predominately on prostate epithelium and is expressed at high levels in prostate cancer. In this review, we discuss the background, clinical data, patient selection, side effects, and necessary resources to deliver lutetium-177 prostate-specific membrane antigen in the research setting, or as standard of care if approved by the United States Food and Drug Administration. Targeted radionuclide therapeutics require understanding of fundamental principles of radiobiology and physics, and radiation oncologists and medical physicists are well-suited to play an integral role in their delivery and treatment response monitoring as key components of a multidisciplinary care team.

Lutetium-177 DOTATATE: A Practical Review.

Neuroendocrine tumors (NETs) are a heterogeneous group of tumors that originate in endocrine tissues throughout the body. Though most are indolent, clinical outcomes vary greatly based on histologic differentiation and grade. Peptide receptor radionuclide therapy has emerged as a promising treatment for patients with locally advanced and/or metastatic disease refractory to standard of care treatment. The phase III NETTER-1 trial found that [177Lu] Lu-DOTA-[Tyr3]-octreotate improved disease-free survival versus octreotide alone for somatostatin receptor-positive gastroenteropancreatic NETs and had a favorable toxicity profile, leading to Food and Drug Administration approval. [177Lu] Lu-DOTA-[Tyr3]-octreotate is an important new treatment that expands the role of radiation in the treatment of NETs. Several important trials are ongoing to better elucidate the role of this treatment.

ASTRO's Framework for Radiopharmaceutical Therapy Curriculum Development for Trainees.

In 2017, the American Society for Radiation Oncology (ASTRO) board of directors prioritized radiopharmaceutical therapy (RPT) as a leading area for new therapeutic development, and the ASTRO RPT workgroup was created. Herein, the workgroup has developed a framework for RPT curriculum development upon which education leaders can build to integrate this modality into radiation oncology resident education. Through this effort, the workgroup aims to provide a guide to ensure robust training in an emerging therapeutic area within the context of existing radiation oncology training in radiation biology, medical physics, and clinical radiation oncology. The framework first determines the core RPT knowledge required to select patients, prescribe, safely administer, and manage related adverse events. Then, it defines the most important topics for preparing residents for clinical RPT planning and delivery. This framework is designed as a tool to supplement the current training that exists for radiation oncology residents. The final document was approved by the ASTRO board of directors in the fall of 2021.

Head and neck cancer survivorship consensus statement from the American Head and Neck Society.

OBJECTIVES: To provide a consensus statement describing best practices and evidence regarding head and neck cancer survivorship. METHODS: Key topics regarding head and neck cancer survivorship were identified by the multidisciplinary membership of the American Head and Neck Society Survivorship, Supportive Care & Rehabilitation Service. Guidelines were generated by combining expert opinion and a review of the literature and categorized by level of evidence. RESULTS: Several areas regarding survivorship including dysphonia, dysphagia, fatigue, chronic pain, intimacy, the ability to return to work, financial toxicity, lymphedema, psycho-oncology, physical activity, and substance abuse were identified and discussed. Additionally, the group identified and described the role of key clinicians in survivorship including surgical, medical and radiation oncologists; dentists; primary care physicians; psychotherapists; as well as physical, occupational, speech, and respiratory therapists. CONCLUSION: Head and neck cancer survivorship is complex and requires a multidisciplinary approach centered around patients and their caregivers. As survival related to head and neck cancer treatment improves, addressing post-treatment concerns appropriately is critically important to our patient's quality of life. There continues to be a need to define effective and efficient programs that can coordinate this multidisciplinary effort toward survivorship.