With multiple therapies available for metastatic prostate carcinoma, the unmet need is to devise optimal and precision treatment sequencing in an individualized manner to achieve maximum clinical benefits – the concept well known as personalized and precision medicine. Although available guidelines have proposed treatment sequencing, a treatment plan based on molecular tumor biology has yet to be effectively designed and adopted in clinical practice. Background and rationale Dual-tracer imaging of late, has been clinically accepted globally as a promising tool for dynamic evaluation of tumor biology, and the results have been effectively translated for achieving specifically tailored, optimized, and individualized treatment plans. Chan et al. 1 have proposed a similar scoring system – the neuroendocrine tumor (NET)-PET grading system, a 0–5 scale based on the visual comparison of gallium-68 DOTATATE (somatostatin receptor-PET) and fluorine-18 fluorodeoxyglucose (FDG-PET) scans. In a retrospective study of 62 patients with metastatic NETs, the authors showed the NET-PET score to be a significant predictor of overall survival. In accordance with the concept of dual tracer imaging, we have proposed a six-tier integrated dual tracer PET-computed tomography (PET-CT) image scoring system, the pro-PET score 2. Further, we have proposed and demonstrated its utility in clinical decision making and prognosticating metastatic castration resistant prostate carcinoma theranostics 2. Historically, this concept has been well established in the management of NETs for appropriate patient selection, predicting treatment outcome, and prognostication. Pro-PET score – the concept and design In the prostate cancer setting, prostate-specific membrane antigen (PSMA) PET identifies the expression and distribution of PSMA, overexpressed on prostate cancer cells and on neovasculature. In pro-PET score, the PSMA and FDG uptake in the lesions are combined on two respective PET-CT scans done within 15 days of each other 2 The scans were compared and scores assigned based on relative uptake of respective PET tracers on the two scans on a scale of ‘0 to 5’, where 0 denoted normal scan, 1 reflected purely PSMA avid disease, and 5 indicated exclusively FDG avid disease without any PSMA uptake (Figs. 1 and 2).Fig. 1: Spectrum of the proposed pro-PET scoring system by integrating findings of both PSMA and FDG PET scans in patients of prostate carcinoma. FDG, fluorodeoxyglucose; PSMA, prostate-specific membrane antigen. Reproduced with permission from 2Fig. 2: Maximum intensity projection images arranged according to the proposed pro-PET scoring scheme. Row (a) demonstrates baseline PSMA and FDG PET scans, whereas row (b) demonstrates post-Lu-PSMA therapy PSMA and FDG PET scans. Row (c) demonstrates baseline PSMA and FDG PET scans of a patient with pro-PET score 5 (as the patient was ineligible for Lu-PSMA therapy, posttherapy scans were not available). Pro-PET 1 shows complete resolution, Pro-PET 2 shows partial response, pro-PET 3 stable disease, and pro-PET 4 shows disease progression. Reproduced with permission from 2. FDG, fluorodeoxyglucose; PSMA, prostate-specific membrane antigen.Clinical utility High-grade PSMA uptake in the lesions is the most important objective criteria guiding patient selection for PSMA-based radioligand therapy (RLT) for maximum benefit. The same has been on the inclusion criteria of various trials – Lu-PSMA trial 3, Thera P trial 4, UpFront PSMA trial 5, prospective trial of Ga-PSMA and FDG in patients showing early prostate specific antigen progression postcastration 6. On the other hand, FDG uptake was considered as exclusion criteria for Lu-PSMA therapy in most of these studies. One possible therapeutic approach can be to combine Lu-PSMA RLT with taxane-based chemotherapy (preferably docetaxel) in metastatic prostate carcinoma showing avid uptake on both FDG and PSMA PET-CT scans (pro-PET score 3). This can be a possible avenue for prospective investigative research (Table 1). Table 1 - A listing of few landmark trials and peer-reviewed research work/publications employing dual tracer PET-CT in prostate carcinoma for patient selection and prognostication Authors Name of the journal Name of the study Inference Hofman et al. 3 The Lancet Lu-PSMA trial RLT with Lu-PSMA has high response rates, low toxic effects, and pain reduction in mCRPC who have progressed on conventional treatments Hofman et al. 4 The Lancet TheraP trial Lu-PSMA compared with cabazitaxel in mCRPC has higher response rates with fewer grade 3/4 toxic effects Azad et al. 5 The Lancet Oncology UpFront PSMA trial Lu-PSMA followed by docetaxel improved antitumour activity in patients with de-novo high-volume metastatic hormone-sensitive prostate cancer compared with docetaxel alone, without increased toxic effects Wang et al. 6 Clinical Cancer Research A prospective trial of 68Ga-PSMA and 18F-FDG PET/CT in nonmetastatic prostate cancer patients with an early PSA progression during castration Using 68Ga-PSMA and 18F-FDG PET, a high prevalence of nodal and metastatic disease and a significant proportion of PSMA-negative and FDG-positive disease in patients with an early PSA progression during castration were observed Michalski et al. 7 European Journal of Nuclear Medicine Prognostic implications of dual tracer PET/CT: PSMA ligand and 18F FDG PET/CT in patients undergoing 177LuPSMA radioligand therapy FDG-positive/PSMA-negative lesions are a negative predictor of overall survival in mCRPC undergoing RLT Ferdinandus et al. 8 European Journal of Nuclear Medicine Prognostic biomarkers in men with metastatic castration-resistant prostate cancer receiving 177Lu-PSMA-617 In addition to established biomarkers, both PSMA and FDG PET-CT parameters have prognostic significance for survival in patients undergoing Lu-PSMA therapy Basu et al. 9 European Journal of Nuclear Medicine Towards personalizing treatment strategies in mCRPC: can dual-tracer PET-CT provide insights into tumor biology, guide the optimal treatment sequence, and individualize decision-making (between chemotherapy, second-generation antiandrogens, and PSMA-directed radioligand therapy) early in the disease course? Possible deployment of promising and less toxic second-generation antiandrogens and Lu-PSMA therapy early in the disease course Suman et al. 10 British Journal of Radiology Therapeutic efficacy, prognostic variables, and clinical outcome of 177Lu-PSMA-617 PRLT in progressive mCRPC following multiple lines of treatment: prognostic implications of high FDG uptake on dual tracer PET-CT vis-à-vis Gleason score in such cohort High FDG uptake is associated with aggressive disease biology coupled with increasing Gleason score and poor 12-month PFS Adnan and Basu 2 Nuclear Medicine Communications Concept proposal for a six-tier integrated dual tracer PET-CT (68Ga-PSMA and FDG) image scoring system (‘Pro-PET’ score) and examining its potential implications in metastatic castration-resistant prostate carcinoma theranostics and prognosis The ‘Pro-PET’ scoring system, integrating dual tracer PET-CT imaging findings in a single parameter, appeared as a potentially promising prognostic marker that has the potential to enhance the objectivity and scientific basis of prostate carcinoma theranostics and prognostication CT, computed tomography; 18F, fluorine-18; FDG, fluorodeoxyglucose; 68Ga, gallium-68; mCRPC, metastatic castration resistant prostate carcinoma; PFS, progression-free survival; PSA, prostate specific antigen; PSMA, prostate-specific membrane antigen; RLT, radioligand therapy. In the proposed scoring system, we have suggested to select upto pro-PET score 3 (PSMA uptake = FDG uptake) patients for Lu-PSMA therapy, yielding favorable clinical outcomes. The score integrates the findings of both Ga-PSMA and FDG PET-CT scans in a single parameter, thus increasing the objectivity and effective triage. Patients in pro-PET 4 and 5 categories are not candidates for Lu-PSMA RLT, and other alternative therapeutic options, namely, second-line chemotherapy and other mutation-directed targeted agents, can be considered. Prognostic and predictive capabilities Pro-PET score can also potentially predict the course of prostate carcinoma as patients with high FDG uptake and low to no significant PSMA uptake (pro-PET 4 and 5) have an aggressive natural course of disease. It needs to be examined whether prostate carcinomas with high metabolic activity (high FDG uptake) develop castration resistance early in the disease course and are more likely to undergo small cell transformation. Selection and sequencing of available treatment options In accordance with the available data, high FDG uptake in prostate carcinoma lesions is associated with high Gleason score, representing aggressive, undifferentiated disease with high proliferative activity, and such cases are more amenable to treatment with taxane-based chemotherapy 9,10. On the other hand, patients with high PSMA uptake and low or no significant FDG uptake in lesions are more responsive to PSMA-based RLT (Fig. 3).Fig. 3: Proposed algorithm for individualization of treatment strategies in metastatic prostate carcinoma. Adapted with permission from 9. CT, computed tomography; 18F, fluorine-18; FDG, fluorodeoxyglucose; 68Ga, gallium-68; PFS, progression-free survival; PSMA, prostate-specific membrane antigen; PRLT, PSMA receptor targeted radioligand therapy.Standardization/trials The above arguments and the fact that various recent studies and trials have realized the potential of dual tracer PET (FDG and PSMA) in metastatic prostate carcinoma, the pro-PET score holds immense potential, both in clinics and research settings. Conclusion The integration of pro-PET score should be prospectively validated and considered for inclusion in ongoing or future theranostic clinical trials for its widespread clinical utilization in tailoring patient-specific management plans in metastatic prostate carcinoma. Acknowledgements Conflicts of interest There are no conflicts of interest.
Adnan et al. (Mon,) studied this question.