Enhancing NSCLC recurrence prediction with PET/CT habitat imaging, ctDNA, and integrative radiogenomics-blood insights.

While we recognize the prognostic importance of clinicopathological measures and circulating tumor DNA (ctDNA), the independent contribution of quantitative image markers to prognosis in non-small cell lung cancer (NSCLC) remains underexplored. In our multi-institutional study of 394 NSCLC patients, we utilize pre-treatment computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to establish a habitat imaging framework for assessing regional heterogeneity within individual tumors. This framework identifies three PET/CT subtypes, which maintain prognostic value after adjusting for clinicopathologic risk factors including tumor volume. Additionally, these subtypes complement ctDNA in predicting disease recurrence. Radiogenomics analysis unveil the molecular underpinnings of these imaging subtypes, highlighting downregulation in interferon alpha and gamma pathways in the high-risk subtype. In summary, our study demonstrates that these habitat imaging subtypes effectively stratify NSCLC patients based on their risk levels for disease recurrence after initial curative surgery or radiotherapy, providing valuable insights for personalized treatment approaches.

Clinical Benefit from Docetaxel +/- Ramucirumab Is Not Associated with Mutation Status in Metastatic Non-Small-Cell Lung Cancer Patients Who Progressed on Platinum Doublets and Immunotherapy.

Docetaxel +/- ramucirumab remains the standard-of-care therapy for patients with metastatic non-small-cell lung cancer (NSCLC) after progression on platinum doublets and immune checkpoint inhibitors (ICIs). The aim of our study was to investigate whether the cancer gene mutation status was associated with clinical benefits from docetaxel +/- ramucirumab. We also investigated whether platinum/taxane-based regimens offered a better clinical benefit in this patient population. A total of 454 patients were analyzed (docetaxel +/- ramucirumab n=381; platinum/taxane-based regimens n=73). Progression-free survival (PFS) and overall survival (OS) were compared among different subpopulations with different cancer gene mutations and between patients who received docetaxel +/- ramucirumab versus platinum/taxane-based regimens. Among patients who received docetaxel +/- ramucirumab, the top mutated cancer genes included TP53 (n=167), KRAS (n=127), EGFR (n=65), STK11 (n=32), ERBB2 (HER2) (n=26), etc. None of these cancer gene mutations or PD-L1 expression was associated with PFS or OS. Platinum/taxane-based regimens were associated with a significantly longer mQS (13.00 m, 95% Cl: 11.20-14.80 m versus 8.40 m, 95% Cl: 7.12-9.68 m, LogRank P=0.019) than docetaxel +/- ramcirumab. Key prognostic factors including age, histology, and performance status were not different between these two groups. In conclusion, in patients with metastatic NSCLC who have progressed on platinum doublets and ICIs, the clinical benefit from docetaxel +/- ramucirumab is not associated with the cancer gene mutation status. Platinum/taxane-based regimens may offer a superior clinical benefit over docetaxel +/- ramucirumab in this patient population.

The Future of MR-Guided Radiation Therapy.

Magnetic resonance image guided radiation therapy (MRIgRT) is a relatively new technology that has already shown outcomes benefits but that has not yet reached its clinical potential. The improved soft-tissue contrast provided with MR, coupled with the immediacy of image acquisition with respect to the treatment, enables expansion of on-table adaptive protocols, currently at a cost of increased treatment complexity, use of human resources, and longer treatment slot times, which translate to decreased throughput. Many approaches are being investigated to meet these challenges, including the development of artificial intelligence (AI) algorithms to accelerate and automate much of the workflow and improved technology that parallelizes workflow tasks, as well as improvements in image acquisition speed and quality. This article summarizes limitations of current available integrated MRIgRT systems and gives an outlook about scientific developments to further expand the use of MRIgRT.

Harnessing progress in radiotherapy for global cancer control.

The pace of technological innovation over the past three decades has transformed the field of radiotherapy into one of the most technologically intense disciplines in medicine. However, the global barriers to access this highly effective treatment are complex and extend beyond technological limitations. Here, we review the technological advancement and current status of radiotherapy and discuss the efforts of the global radiation oncology community to formulate a more integrative 'diagonal approach' in which the agendas of science-driven advances in individual outcomes and the sociotechnological task of global cancer control can be aligned to bring the benefit of this proven therapy to patients with cancer everywhere.

Automated Contouring and Planning in Radiation Therapy: What Is 'Clinically Acceptable'?

Developers and users of artificial-intelligence-based tools for automatic contouring and treatment planning in radiotherapy are expected to assess clinical acceptability of these tools. However, what is 'clinical acceptability'? Quantitative and qualitative approaches have been used to assess this ill-defined concept, all of which have advantages and disadvantages or limitations. The approach chosen may depend on the goal of the study as well as on available resources. In this paper, we discuss various aspects of 'clinical acceptability' and how they can move us toward a standard for defining clinical acceptability of new autocontouring and planning tools.

A personal perspective on the development and future of cone-beam CT for image-guided radiotherapy.

The development of cone-beam CT guided radiotherapy has transformed radiation oncology in the 20 years since it was first released commercially. The technological pace of change has spurred a massive transformation in our daily clinical practice, forced us to evolve our approach to multi- and inter-disciplinary collaboration, and enabled new treatment paradigms. Further progress in integrating quantitative CT in these robotic platforms promises to do even more by "burying the complexity" of radiotherapy and leveraging the expanding digital fabric that uses machine learning approaches to bring semi-automated expertise to bear on the issues of expertise and quality. This is the only way we will be able to respond to the massive global shortfall in high-quality radiotherapy services across the globe.

Assessment of intra-fraction motion during frameless image guided Gamma Knife stereotactic radiosurgery.

As frameless stereotactic radiosurgery increase in use, the aim of this study was to evaluate intra-fraction motion through cone-beam CT (CBCT) and high-definition motion management (HDMM) systems. Intra-fraction motion measured between localization, repeat localization and post-treatment CBCTs were correlated to intra-faction motion indicated by the HDMM files using the Pearson coefficient (r). A total of 302 plans were reviewed from 263 patients (114 male, 149 female); 216 pairs of localization-repeat localization, and 260 localization-post-treatment CBCTs were analyzed against HDMM logs. We found the magnitude of intra-fraction motion detected by the HDMM system were larger than the corresponding CBCT results.

Incorporating cross-voxel exchange for the analysis of dynamic contrast-enhanced imaging data: pre-clinical results.

Tumours exhibit abnormal interstitial structures and vasculature function often leading to impaired and heterogeneous drug delivery. The disproportionate spatial accumulation of a drug in the interstitium is determined by several microenvironmental properties (blood vessel distribution and permeability, gradients in the interstitial fluid pressure). Predictions of tumour perfusion are key determinants of drug delivery and responsiveness to therapy. Pharmacokinetic models allow for the quantification of tracer perfusion based on contrast enhancement measured with non-invasive imaging techniques. An advanced cross-voxel exchange model (CVXM) was recently developed to provide a comprehensive description of tracer extravasation as well as advection and diffusion based on cross-voxel tracer kinetics (Sinnoet al2021). Transport parameters were derived from DCE-MRI of twenty TS-415 human cervical carcinoma xenografts by using CVXM. Tracer velocity flows were measured at the tumour periphery (mean 1.78-5.82µm.s-1) pushing the contrast outward towards normal tissue. These elevated velocity measures and extravasation rates explain the heterogeneous distribution of tracer across the tumour and its accumulation at the periphery. Significant values for diffusivity were deduced across the tumours (mean 152-499µm2.s-1). CVXM resulted in generally smaller values for the extravasation parameterKext(mean 0.01-0.04 min-1) and extravascular extracellular volume fractionve(mean 0.05-0.17) compared to the standard Tofts parameters, suggesting that Toft model underestimates the effects of inter-voxel exchange. The ratio of Tofts' extravasation parameters over CVXM's was significantly positively correlated to the cross-voxel diffusivity (P< 0.0001) and velocity (P= 0.0005). Tofts' increasedvemeasurements were explained using Sinnoet al(2021)'s theoretical work. Finally, a scan time of 15 min renders informative estimations of the transport parameters. However, a duration as low as 7.5 min is acceptable to recognize the spatial variation of transport parameters. The results demonstrate the potential of utilizing CVXM for determining metrics characterizing the exchange of tracer between the vasculature and the tumour tissue. Like for many earlier models, additional work is strongly recommended, in terms of validation, to develop more confidence in the results, motivating future laboratory work in this regard.

Extended Results and Independent Validation of a Phase 2 Trial of Metastasis-Directed Therapy for Molecularly Defined Oligometastatic Prostate Cancer.

PURPOSE: The role of metastasis-directed therapy (MDT) in molecularly defined oligorecurrent prostate cancer (PCa) remains irresolute. We present extended follow-up and an independent validation cohort of a prospective trial. METHODS AND MATERIALS: This study consists of 2 sequential single-arm phase-2 trials of patients with biochemical recurrence (prostate specific antigen [PSA] 0.4-3.0 ng/mL) and negative conventional imaging after radical prostatectomy and postoperative radiation therapy. All patients underwent [18F]DCFPyL positron emission tomography/computed tomography. Patients with molecularly defined oligorecurrent prostate cancer underwent MDT with stereotactic body radiation therapy or surgery, without androgen deprivation therapy (ADT). The primary end point was biochemical response (≥50% PSA decline from baseline). Secondary end points included PSA progression-free survival and ADT-free survival. The sample size of 37 MDT patients was determined based on a Simon's 2-stage design with biochemical response rate >20%, and this design was also applied for the subsequent independent validation cohort. RESULTS: Seventy-four patients underwent MDT: 37 each in the initial and validation cohorts. Both cohorts met the prespecified biochemical response rate and completed the planned 2-stages of accrual. For the pooled cohort, the median number of prostate specific membrane antigen positron emission tomography avid lesions was 2 and most (87%) recurrences were nodal. Sixty-four (87%) had stereotactic body radiation therapy and 10 (13%) had surgery. Median follow-up (interquartile range [IQR]) for the initial, validation and combined cohorts were 41 (35-46) months, 14 months (7-21), and 24 months (14-41), respectively. The biochemical response rates for the initial, validation and combined cohorts were 59%, 43%, and 51%, respectively. For the combined cohort, median biochemical progression-free survival was 21 months (95% confidence interval, 13-not reached), and median ADT-free survival was 45 months (95% confidence interval, 31-not reached). CONCLUSIONS: Half of patients treated with MDT for molecularly defined-only oligorecurrent prostate cancer exhibited a biochemical response. This study provides necessary and validated evidence to support randomized trials aiming to determine whether MDT (alone or with systemic therapy) can affect clinically meaningful end points.

Noise-Based Image Harmonization Significantly Increases Repeatability and Reproducibility of Radiomics Features in PET Images: A Phantom Study.

For multicenter clinical studies, characterizing the robustness of image-derived radiomics features is essential. Features calculated on PET images have been shown to be very sensitive to image noise. The purpose of this work was to investigate the efficacy of a relatively simple harmonization strategy on feature robustness and agreement. A purpose-built texture pattern phantom was scanned on 10 different PET scanners in 7 institutions with various different image acquisition and reconstruction protocols. An image harmonization technique based on equalizing a contrast-to-noise ratio was employed to generate a "harmonized" alongside a "standard" dataset for a reproducibility study. In addition, a repeatability study was performed with images from a single PET scanner of variable image noise, varying the binning time of the reconstruction. Feature agreement was measured using the intraclass correlation coefficient (ICC). In the repeatability study, 81/93 features had a lower ICC on the images with the highest image noise as compared to the images with the lowest image noise. Using the harmonized dataset significantly improved the feature agreement for five of the six investigated feature classes over the standard dataset. For three feature classes, high feature agreement corresponded with higher sensitivity to the different patterns, suggesting a way to select suitable features for predictive models.

A roadmap to clinical trials for FLASH.

While FLASH radiation therapy is inspiring enthusiasm to transform the field, it is neither new nor well understood with respect to the radiobiological mechanisms. As FLASH clinical trials are designed, it will be important to ensure we can deliver dose consistently and safely to every patient. Much like hyperthermia and proton therapy, FLASH is a promising new technology that will be complex to implement in the clinic and similarly will require customized credentialing for multi-institutional clinical trials. There is no doubt that FLASH seems promising, but many technologies that we take for granted in conventional radiation oncology, such as rigorous dosimetry, 3D treatment planning, volumetric image guidance, or motion management, may play a major role in defining how to use, or whether to use, FLASH radiotherapy. Given the extended time frame for patients to experience late effects, we recommend moving deliberately but cautiously forward toward clinical trials. In this paper, we review the state of quality assurance and safety systems in FLASH, identify critical pre-clinical data points that need to be defined, and suggest how lessons learned from previous technological advancements will help us close the gaps and build a successful path to evidence-driven FLASH implementation.

Digitally enabled hemovigilance allows real time response to transfusion reactions.

BACKGROUND: Transfusion carries a risk of transfusion reaction that is often underdiagnosed due to reliance on passive reporting. The study investigated the utility of digital methods to identify potential transfusion reactions, thus allowing real-time intervention for affected patients. METHOD: The hemovigilance unit monitored 3856 patients receiving 43,515 transfusions under the hemovigilance program. Retrospective comparison data included 298,498 transfusions. Transfusion medicine physicians designed and validated algorithms in the electronic health record that analyze discrete data, such as vital sign changes, to assign a risk score during each transfusion. Dedicated hemovigilance nurses remotely monitor all patients and perform real-time chart reviews prioritized by risk score. When a reaction is suspected, a hemovigilance trained licensed clinician responds to manage the patient and ensure data collection. Board-certified transfusion medicine physicians reviewed data and classified transfusion reactions under various categories according to the Centers for Disease Control hemovigilance definitions. RESULTS: Transfusion medicine physicians diagnosed 564 transfusion reactions (1.3% of transfusions)-a 524% increase compared to the previous passive reporting. The rapid response provider reached the bedside on average at 12.4 min demonstrating logistic feasibility. While febrile reactions were most diagnosed, recognition of transfusion-associated circulatory overload demonstrated the greatest relative increase. Auditing and education programs further enhanced transfusion reaction awareness. DISCUSSION: The model of digitally-enabled expert real-time review of clinical data that prompts rapid response improved recognition of transfusion reactions. This approach could be applied to other patient deterioration events such as early identification of sepsis.

Predictive Radiation Oncology - A New NCI-DOE Scientific Space and Community.

With a widely attended virtual kickoff event on January 29, 2021, the National Cancer Institute (NCI) and the Department of Energy (DOE) launched a series of 4 interactive, interdisciplinary workshops-and a final concluding "World Café" on March 29, 2021-focused on advancing computational approaches for predictive oncology in the clinical and research domains of radiation oncology. These events reflect 3,870 human hours of virtual engagement with representation from 8 DOE national laboratories and the Frederick National Laboratory for Cancer Research (FNL), 4 research institutes, 5 cancer centers, 17 medical schools and teaching hospitals, 5 companies, 5 federal agencies, 3 research centers, and 27 universities. Here we summarize the workshops by first describing the background for the workshops. Participants identified twelve key questions-and collaborative parallel ideas-as the focus of work going forward to advance the field. These were then used to define short-term and longer-term "Blue Sky" goals. In addition, the group determined key success factors for predictive oncology in the context of radiation oncology, if not the future of all of medicine. These are: cross-discipline collaboration, targeted talent development, development of mechanistic mathematical and computational models and tools, and access to high-quality multiscale data that bridges mechanisms to phenotype. The workshop participants reported feeling energized and highly motivated to pursue next steps together to address the unmet needs in radiation oncology specifically and in cancer research generally and that NCI and DOE project goals align at the convergence of radiation therapy and advanced computing.

Impact of PET scanner non-linearity on the estimation of hypoxic fraction in cervical cancer patients.

BACKGROUND: Tumor hypoxia is defined as a low oxygen level in tissue and is associated with poor clinical outcome after chemo-/radiotherapy and surgery in many solid tumor types. Positron Emission Tomography (PET) imaging provides a non-invasive means of measuring local variations in the uptake of hypoxia-targeted agents (e.g. FAZA or FMISO). Accurate quantification of uptake is critically dependent on the PET scanner's linear count rate performance. In the context of cervix cancer, high PET agent accumulation in the bladder, low uptake in the tumor, and their relative proximity makes an accurate quantification of the tumor's hypoxic fraction challenging. The purpose of this study was to estimate the impact of PET scanner non-linearity on PET-based estimation of hypoxic fraction. MATERIAL AND METHODS: The impact of PET scanner non-linearity effect was assessed with a NEMA body phantom, using the cylinder as the "bladder-mimicking" compartment and the water filled background as a surrogate region for the tumor. A simple model of the non-linearity effect was then applied to a set of patient-derived FAZA-PET scans (N = 38) to estimate the impact of the non-linearity on the calculated hypoxic fraction (HF) for each patient. RESULTS: The NEMA body phantom measurements revealed a substantial overestimate of activity outside the injected "bladder mimicking" cylinder compartment. This uptake resulted in an overestimate in activity between 1.9 and 0.3 kBq/cc corresponding to distances from 1.0 - 7.0 cm from the cylinder. In the patient-derived PET images, the bladder-to-tumor distance ranged between 1.0 and 3.0 cm. For the 38 patients analyzed, the HF was demonstrated to decrease by 1.1-75.0 % [median 27.2 %] depending on distance and relative uptake levels. Additionally, the magnitude of the effect of the non-linearity was found to depend on the pre-scanning hydration protocol employed (p = 0.0065). CONCLUSION: Hypoxia imaging of tumors of the cervix is challenging due to patient specific activity accumulation in the bladder and the non-linear response of PET scanner performance. This can result in a substantial overestimate of the calculated hypoxic fraction in cervical tumors. Additional effort needs to be invested to improve the linearity of PET scanners in anatomical regions proximal to the bladder.

Cancer Needs a Robust "Metadata Supply Chain" to Realize the Promise of Artificial Intelligence.

Profound advances in computational methods, including artificial intelligence (AI), present the opportunity to use the exponentially growing volume and complexity of available cancer measurements toward data-driven personalized care. While exciting, this opportunity has highlighted the disconnect between the promise of compute and the supply of high-quality data. The current paradigm of ad-hoc aggregation and curation of data needs to be replaced with a "metadata supply chain" that provides robust data in context with known provenance, that is, lineage and comprehensive data governance that will allow the promise of AI technology to be realized to its full potential in clinical practice.

Flat-panel conebeam CT in the clinic: history and current state.

Research into conebeam CT concepts began as soon as the first clinical single-slice CT scanner was conceived. Early implementations of conebeam CT in the 1980s focused on high-contrast applications where concurrent high resolution ( < 200 µ m ), for visualization of small contrast-filled vessels, bones, or teeth, was an imaging requirement that could not be met by the contemporaneous CT scanners. However, the use of nonlinear imagers, e.g., x-ray image intensifiers, limited the clinical utility of the earliest diagnostic conebeam CT systems. The development of consumer-electronics large-area displays provided a technical foundation that was leveraged in the 1990s to first produce large-area digital x-ray detectors for use in radiography and then compact flat panels suitable for high-resolution and high-frame-rate conebeam CT. In this review, we show the concurrent evolution of digital flat panel (DFP) technology and clinical conebeam CT. We give a brief summary of conebeam CT reconstruction, followed by a brief review of the correction approaches for DFP-specific artifacts. The historical development and current status of flat-panel conebeam CT in four clinical areas-breast, fixed C-arm, image-guided radiation therapy, and extremity/head-is presented. Advances in DFP technology over the past two decades have led to improved visualization of high-contrast, high-resolution clinical tasks, and image quality now approaches the soft-tissue contrast resolution that is the standard in clinical CT. Future technical developments in DFPs will enable an even broader range of clinical applications; research in the arena of flat-panel CT shows no signs of slowing down.

Incorporating cross-voxel exchange into the analysis of dynamic contrast-enhanced imaging data: theory, simulations and experimental results.

Predictions of tumour perfusion are key determinants of drug delivery and responsiveness to therapy. Pharmacokinetic models allow for the estimation of perfusion properties of tumour tissues but many assume no dispersion associated with tracer transport away from the capillaries and through the tissue. At the level of a voxel, this translates to assuming no cross-voxel tracer exchange, often leading to the misinterpretation of derived perfusion parameters. Tofts model (TM), a compartmental model widely used in oncology, also makes this assumption. A more realistic description is required to quantify kinetic properties of tracers, such as convection and diffusion. We propose a Cross-Voxel Exchange Model (CVXM) for analysing cross-voxel tracer kinetics.In silicodatasets quantifying the roles of convection and diffusion in tracer transport (which TM ignores) were employed to investigate the interpretation of Tofts' perfusion parameters compared to CVXM. TM returned inaccurate values ofKtransandvewhere diffusive and convective mechanisms are pronounced (up to 20% and 300% error respectively). A mathematical equation, developed in this work, predicts and gives the correct physiological interpretation of Tofts've.Finally, transport parameters were derived from dynamic contrast enhanced-magnetic resonance imaging of a TS-415 human cervical carcinoma xenograft by using TM and CVXM. The latter deduced lower values ofKtransandvecompared to TM (lower by up to 63% and 76% respectively). It also allowed the detection of a diffusive flux (mean diffusivity 155µm2s-1) in the tumour tissue, as well as an increased convective flow at the periphery (mean velocity 2.3µm s-1detected). The results serve as a proof of concept establishing the feasibility of using CVXM for accurately determining transport metrics that characterize the exchange of tracer between voxels. CVXM needs to be investigated further as its parameters can be linked to the tumour microenvironment properties (permeability, pressure…), potentially leading to enhanced personalized treatment planning.

Evaluating an Image-Guided Operating Room with Cone Beam CT for Skull Base Surgery.

Importance Skull base surgery requires precise preoperative assessment and intraoperative management of the patient. Surgical navigation is routinely used for complex skull base cases; however, the image guidance is commonly based on preoperative scans alone. Objective The primary objective of this study was to assess the image quality of intraoperative cone-beam computed tomography (CBCT) within anatomical landmarks used in sinus and skull base surgery. The secondary objective was to assess the registration error of a surgical navigation system based on intraoperative CBCT. Design Present study is a retrospective case series of image quality after intraoperative cone beam CT. Setting The study was conducted at Toronto General Hospital and Princess Margaret Cancer Centre, University Health Network, Toronto. Participants A total of 46 intraoperative scans (34 patients, 21 skull base, 13 head and neck) were studied. Main Outcome and Measures Thirty anatomical landmarks (vascular, soft tissue, and bony) within the sinuses and anterior skull base were evaluated for general image quality characteristics: (1) bony detail visualization; (2) soft-tissue visualization; (3) vascular visualization; and (4) freedom from artifacts (e.g., metal). Levels of intravenous (IV) contrast enhancement were quantified in Hounsfield's units (HU). Standard paired-point registration between imaging and tracker coordinates was performed using 6 to 8 skin fiducial markers and the corresponding fiducial registration error (FRE) was measured. Results Median score for bony detail on CBCT was 5, remaining at 5 after administration of IV contrast. Median soft-tissue score was 2 for both pre- and postcontrast. Median vascular score was 1 precontrast and 3 postcontrast. Median score for artifacts on CBCT were 2 for both pre-and postcontrast, and metal objects were noted to be the most significant source of artifact. Intraoperative CBCT allowed preresection images and immediate postresection images to be available to the skull base surgeon. There was a significant improvement in mean (standard deviation [SD]) CT intensity in the left carotid artery postcontrast 334 HU (67 HU) ( p < 10 -10 ). The mean FRE was 1.8 mm (0.45 mm). Conclusion Intraoperative CBCT in complex skull base procedures provides high-resolution bony detail allowing immediate assessment of complex resections. The use of IV contrast with CBCT improves the visualization of vasculature. Image-guidance based on CBCT yields registration errors consistent with standard techniques.

Curative-intent Metastasis-directed Therapies for Molecularly-defined Oligorecurrent Prostate Cancer: A Prospective Phase II Trial Testing the Oligometastasis Hypothesis.

BACKGROUND: The hypothesis of a curable oligometastatic prostate cancer (PCa) state remains to be clinically-proven. Conventional imaging often fails to localize early recurrences, hampering the potential for radical approaches. OBJECTIVE: We hypothesize that prostate-specific membrane antigen (PSMA)-targeted PET-MR/CT allows for earlier detection and localization of oligorecurrent-PCa, unveiling a molecularly-defined state amenable to curative-intent metastasis-directed treatment (MDT). DESIGN/SETTING/PARTICIPANTS: Single-institution single-arm phase-two study. Patients with rising PSA (0.4-3.0 ng/mL) after maximal local therapy (radical prostatectomy and post-operative radiotherapy), negative conventional staging, and no prior salvage hormonal therapy (HT) were eligible. INTERVENTIONS: All patients underwent [18F]DCFPyL PET-MR/CT. Patients with molecularly-defined oligorecurrent-PCa had MDT (stereotactic ablative body radiotherapy [SABR] or surgery) without HT. OUTCOME MEASUREMENTS/STATISTICAL ANALYSIS: Primary endpoint was biochemical response (complete, i.e. biochemical 'no evidence of disease' [bNED], or partial response [100% or ≥50% PSA decline from baseline, respectively]) after MDT. Simon's two-stage design was employed (null and alternate hypotheses <5% and >20% response rate, respectively), with α and ß of 0.1. RESULTS: Seventy-two patients were enrolled (May/2017-July/2019). Thirty-eight (53%) had PSMA-detected oligorecurrent-PCa amenable for MDT. Thirty-seven (51%) agreed to MDT: 10 and 27 underwent surgery and SABR, respectively. Median follow-up was 15.9 months (IQR 9.8-19.1). Of patients receiving MDT, the overall response rate was 60%, including 22% rendered bNED. One (2.7%) grade 3 toxicity (intra-operative ureteric injury) was observed. CONCLUSIONS: PSMA-defined oligorecurrent-PCa can be rendered bNED, a necessary step towards cure, in 1 of 5 patients receiving MDT alone. Randomized trials are justified to determine if MDT +/- systemic agents can expand the curative therapeutic armamentarium for PCa. PATIENT SUMMARY: We studied men treated for prostate cancer with rising PSA. We found PSMA imaging detected recurrent cancer in three-quarters of patients, and targeted treatment to these areas significantly decreased PSA in half of patients.