With New Technology Comes Great Responsibility: Prostate-Specific Membrane Antigen Imaging in Recurrent Prostate Cancer.
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ABSTRACT:
SUBMITTER: Madan RA
PROVIDER: S-EPMC9851688 | biostudies-literature | 2022 Sep
REPOSITORIES: biostudies-literature
Publications
With New Technology Comes Great Responsibility: Prostate-Specific Membrane Antigen Imaging in Recurrent Prostate Cancer.
Madan Ravi A RA Mena Esther E Lindenberg Liza L Choyke Peter L PL
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20220603 26
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Project description:ImportanceAlthough prostate-specific membrane antigen positron emission tomography (PSMA-PET) has shown improved sensitivity and specificity compared with conventional imaging for the detection of biochemical recurrent (BCR) prostate cancer, the long-term outcomes of a widespread shift in imaging are unknown.ObjectiveTo estimate long-term outcomes of integrating PSMA-PET into the staging pathway for recurrent prostate cancer.Design, setting, and participantsThis decision analytic modeling study simulated outcomes for patients with BCR following initial definitive local therapy. Inputs used were from the literature and a retrospective cohort study conducted at 2 institutions. The base case analysis assumed modest benefits of earlier detection and treatment, and scenario analyses considered prostate-specific antigen (PSA) level at imaging and different outcomes of earlier vs delayed treatment. The analysis was performed between April 1, 2023, and May 1, 2024.Exposures(1) Immediate PSMA-PET imaging, (2) conventional imaging (computed tomography and bone scan [CTBS]) followed by PSMA-PET if CTBS findings were negative or equivocal, and (3) CTBS alone.Main outcomes and measuresThe main outcomes were detection of metastases, deaths from prostate cancer, and life-years and quality-adjusted life-years (QALYs) gained.ResultsThe model estimated that per 1000 simulated patients with BCR (assumed median age, 66 years), PSMA-PET is expected to diagnose 611 (95% uncertainty interval [UI], 565-656) patients with metastasis compared with 630 (95% UI, 586-675) patients diagnosed using CTBS followed by PSMA-PET and 297 (95% UI, 202-410) patients diagnosed using CTBS alone. Moreover, the estimated number of prostate cancer deaths was 512 (95% UI, 472-552 deaths) with PSMA-PET, 520 (95% UI, 480-559 deaths) with CTBS followed by PSMA-PET, and 587 (95% UI, 538-632 deaths) with CTBS alone. Imaging with PSMA-PET yielded the highest number of QALYs, which were 824 (95% UI, 698-885) higher than CTBS. These results differed by PSA level at the time of testing, with the highest incremental life-years and QALYs and lowest number of deaths from prostate cancer among patients with PSA levels of at least 5.0 ng/mL. Finally, the estimates were sensitive to the expected benefit of initiating therapy for recurrent prostate cancer earlier in the disease course.Conclusions and relevanceThe results of this decision-analytic model suggest that upfront PSMA-PET imaging for the evaluation of BCR is expected to be associated with reduced cancer mortality and gains in life-years and QALYs compared with the conventional imaging strategy, assuming modest benefits of earlier detection and treatment.
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Project description:ContextMen with biochemically relapsed prostate cancer face a clinical conundrum. Depending on the detected distribution of disease, treatment goals may range from cure with focal therapy to palliative with systemic therapy to expectant observation. Retrospective studies of prostate-specific membrane antigen (PSMA)-based imaging demonstrate higher disease detection rates than conventional imaging.ObjectiveThis review focuses on available prospective evidence for diagnostic use of PSMA-based imaging to accurately restage recurrent prostate cancer and explores the potential clinical impact, near future uses, and challenges for PSMA-based imaging in this setting.Evidence acquisitionPubMed and EMBASE databases were searched for prospective studies with primary, secondary, or exploratory endpoints evaluating PSMA-based imaging for patients with recurrent prostate cancer published in English in the past 10 yrs.Evidence synthesisWe reviewed 48 prospective studies evaluating the role of PSMA positron emission tomography (PET) in recurrent prostate cancer. These studies establish the diagnostic accuracy and safety of PSMA PET using the 68Ga-PSMA-11 and 18F-DCFPyL radiotracers even at lower prostate-specific antigen (PSA) levels (0.5 ≤ PSA < 1.0 ng/m: disease detection rate 51-78%). The use of PSMA PET has been shown to result in changes in management in up to two-thirds of patients.ConclusionsThere is now higher-level regulatory-quality prospective evidence for PSMA-based imaging for the detection of recurrent prostate cancer. There is prospective evidence of superiority over cross-sectional imaging and bone scintigraphy, as well as for the alterations in disease management as a result of PSMA-based imaging.Patient summaryWhen the prostate-specific antigen (PSA) level is rising after primary therapy, prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is excellent at detecting and localizing prostate cancer, even at low PSA levels. Those who benefit best from treatment modifications based on PSMA PET findings are yet to be defined.
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Project description:Background and objectiveMeta-analysis and meta-regression are often highly cited and may influence practice. Unfortunately, statistical errors in meta-analyses are widespread and can lead to flawed conclusions. The purpose of this article was to review common statistical errors in meta-analyses and to document their frequency in highly cited meta-analyses from strength and conditioning research.MethodsWe identified five errors in one highly cited meta-regression from strength and conditioning research: implausible outliers; overestimated effect sizes that arise from confusing standard deviation with standard error; failure to account for correlated observations; failure to account for within-study variance; and a focus on within-group rather than between-group results. We then quantified the frequency of these errors in 20 of the most highly cited meta-analyses in the field of strength and conditioning research from the past 20 years.ResultsWe found that 85% of the 20 most highly cited meta-analyses in strength and conditioning research contained statistical errors. Almost half (45%) contained at least one effect size that was mistakenly calculated using standard error rather than standard deviation. In several cases, this resulted in obviously wrong effect sizes, for example, effect sizes of 11 or 14 standard deviations. Additionally, 45% failed to account for correlated observations despite including numerous effect sizes from the same study and often from the same group within the same study.ConclusionsStatistical errors in meta-analysis and meta-regression are common in strength and conditioning research. We highlight five errors that authors, editors, and readers should check for when preparing or critically reviewing meta-analyses.
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Project description:Focal therapy of prostate cancer (PCa) is currently of great interest, but a metric of success. other than biopsy, is not yet available. In a patient with a repeatedly negative MRI and negative systematic biopsies, a scan employing the radioisotope 68Ga-PSMA-11 PET/CT identified a PSMA-avid hotspot in the prostate. PSMA-guided biopsy confirmed the diagnosis of a clinically-significant PCa. Following ablation of the lesion with high-intensity focused ultrasound (HIFU), the PSMA-avid lesion disappeared and targeted biopsy confirmed a fibrotic scar with no residual cancer. PSMA imaging may have a role in guiding diagnosis, focal ablation, and follow-up of men with PCa.
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Project description:Gallium-68 is a generator-produced radionuclide for positron emission tomography (PET) that is being increasingly used for radiolabeling of tumor-targeting peptides. Compounds [(68)Ga]3 and [(68)Ga]6 are high-affinity urea-based inhibitors of the prostate-specific membrane antigen (PSMA) that were synthesized in decay-uncorrected yields ranging from 60% to 70% and radiochemical purities of more than 99%. Compound [(68)Ga]3 demonstrated 3.78 +/- 0.90% injected dose per gram of tissue (%ID/g) within PSMA+ PIP tumor at 30 min postinjection, while [(68)Ga]6 showed a 2 h PSMA+ PIP tumor uptake value of 3.29 +/- 0.77 %ID/g. Target (PSMA+ PIP) to nontarget (PSMA- flu) ratios were 4.6 and 18.3, respectively, at those time points. Both compounds delineated tumor clearly by small animal PET. The urea series of imaging agents for PSMA can be radiolabeled with (68)Ga, a cyclotron-free isotope useful for clinical PET studies, with maintenance of target specificity.
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Project description:Prostate-specific membrane antigen (PSMA) is a well-recognized target for identification and therapy of a variety of cancers. Here we report five (64)Cu-labeled inhibitors of PSMA, [(64)Cu]3-7, which are based on the lysine-glutamate urea scaffold and utilize a variety of macrocyclic chelators, namely NOTA(3), PCTA(4), Oxo-DO3A(5), CB-TE2A(6), and DOTA(7), in an effort to determine which provides the most suitable pharmacokinetics for in vivo PET imaging. [(64)Cu]3-7 were prepared in high radiochemical yield (60-90%) and purity (>95%). Positron emission tomography (PET) imaging studies of [(64)Cu]3-7 revealed specific accumulation in PSMA-expressing xenografts (PSMA+ PC3 PIP) relative to isogenic control tumor (PSMA- PC3 flu) and background tissue. The favorable kinetics and high image contrast provided by CB-TE2A chelated [(64)Cu]6 suggest it as the most promising among the candidates tested. That could be due to the higher stability of [(64)Cu]CB-TE2A as compared with [(64)Cu]NOTA, [(64)Cu]PCTA, [(64)Cu]Oxo-DO3A, and [(64)Cu]DOTA chelates in vivo.
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Project description:The repertoire of methods for the detection and chemotherapeutic treatment of prostate cancer (PCa) is currently limited. Prostate-specific membrane antigen (PSMA) is overexpressed in PCa tumors and can be exploited for both imaging and drug delivery. We developed and characterized four nanobodies that present tight and specific binding and internalization into PSMA+ cells and that accumulate specifically in PSMA+ tumors. We then conjugated one of these nanobodies to the cytotoxic drug doxorubicin, and we show that the conjugate internalizes specifically into PSMA+ cells, where the drug is released and induces cytotoxic activity. In vivo studies show that the extent of tumor growth inhibition is similar when mice are treated with commercial doxorubicin and with a 42-fold lower amount of the nanobody-conjugated doxorubicin, attesting to the efficacy of the conjugated drug. These data highlight nanobodies as promising agents for the imaging of PCa tumors and for the targeted delivery of chemotherapeutic drugs.
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