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- Bäck, Tom, 1964, et al.
(författare)
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Targeted alpha therapy with astatine-211-labeled anti-PSCA A11 minibody shows antitumor efficacy in prostate cancer xenografts and bone microtumors
- 2020
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Ingår i: Ejnmmi Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Targeted alpha therapy (TAT) is a promising treatment for micrometastatic and minimal residual cancer. We evaluated systemic alpha-radioimmunotherapy (alpha-RIT) of metastatic castration-resistant prostate cancer (mCRPC) using the alpha-particle emitter At-211-labeled to the anti-PSCA A11 minibody. A11 is specific for prostate stem cell antigen (PSCA), a cell surface glycoprotein which is overexpressed in more than 90% of both localized prostate cancer and bone metastases. Methods PC3-PSCA cells were implanted subcutaneously (s.c.) and intratibially (i.t) in nude mice. Efficacy of alpha-RIT (two fractions-14-day interval) was studied on s.c. macrotumors (0, 1.5 and 1.9 MBq) and on i.t. microtumors (100-200 mu m; 0, 0.8 or 1.5 MBq) by tumor-volume measurements. The injected activities for therapies were estimated from separate biodistribution and myelotoxicity studies. Results Tumor targeting of At-211-A11 was efficient and the effect on s.c. macrotumors was strong and dose-dependent. At 6 weeks, the mean tumor volumes for the treated groups, compared with controls, were reduced by approximately 85%. The separate myelotoxicity study following one single fraction showed reduced white blood cells (WBC) for all treated groups on day 6 after treatment. For the 0.8 and 1.5 MBq, the WBC reductions were transient and followed by recovery at day 13. For 2.4 MBq, a clear toxicity was observed and the mice were sacrificed on day 7. In the long-term follow-up of the 0.8 and 1.5 MBq-groups, blood counts on day 252 were normal and no signs of radiotoxicity observed. Efficacy on i.t. microtumors was evaluated in two experiments. In experiment 1, the tumor-free fraction (TFF) was 95% for both treated groups and significantly different (p < 0.05) from the controls at a TFF of 66%). In experiment 2, the difference in TFF was smaller, 32% for the treated group versus 20% for the controls. However, the difference in microtumor volume in experiment 2 was highly significant, 0.010 +/- 0.003 mm(3) versus 3.79 +/- 1.24 mm(3) (treated versus controls, respectively), i.e., a 99.7% reduction (p < 0.001). The different outcome in experiment 1 and 2 is most likely due to differences in microtumor sizes at therapy, or higher tumor-take in experiment 2 (where more cells were implanted). Conclusion Evaluating fractionated alpha-RIT with At-211-labeled anti-PSCA A11 minibody, we found clear growth inhibition on both macrotumors and intratibial microtumors. For mice treated with multiple fractions, we also observed radiotoxicity manifested by progressive loss in body weight at 30 to 90 days after treatment. Our findings are conceptually promising for a systemic TAT of mCRPC and warrant further investigations of At-211-labeled PSCA-directed vectors. Such studies should include methods to improve the therapeutic window, e.g., by implementing a pretargeted regimen of alpha-RIT or by altering the size of the targeting vector.
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| 2. |
- Westerberg, M., et al.
(författare)
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Temporal changes in survival in men with de novo metastatic prostate cancer: nationwide population-based study
- 2020
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 59:1, s. 106-111
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Tidskriftsartikel (refereegranskat)abstract
- Background: There have been large changes in the pattern of detection, work-up and treatment of men with prostate cancer during the last two decades. Therefore, we aimed to investigate temporal changes in survival in men with metastatic prostate cancer. Methods: Population-based cohort study in Prostate Cancer data Base Sweden of 13,709 men with de novo metastatic prostate cancer diagnosed between 1998 and 2015. Overall survival in four calendar periods were compared by the use of Kaplan-Meier analyses and Cox regression models including age at diagnosis, T stage and serum levels of prostate-specific antigen (PSA). Results: Between 1998-2001 and 2010-2015, median survival increased with 6 months for all men. The largest increase in survival was 14 months in men age 60-69 at diagnosis and in multivariable analysis risk of death decreased for men diagnosed in 2010-2015 compared to 1998-2001, hazard ratio (HR) 0.77 (95% CI: 0.68-0.86). The median PSA at date of diagnosis decreased with 46% from 181 ng/mL in 1998 to 98 ng/mL in 2015. Conclusions: There was an increase in survival among men with de novo metastatic prostate cancer in Sweden between 1998 and 2015. This increase was due to a decreased cancer extent indicated by lower PSA levels with ensuing longer lead times and speculatively also due to an increased use of chemotherapy in the latest time period. Given the increasing use of systemic treatment for advanced prostate cancer, our results are likely heralding larger increases in survival in men with metastatic prostate cancer in the near future.
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