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1.
Eur Urol ; 82(5): 512-515, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35688662

RESUMO

The PI3K/AKT/PTEN pathway is frequently deregulated in metastatic castration-resistant prostate cancer (mCRPC). ProCAID was a phase 2 trial assessing addition of the AKT1/2/3 inhibitor capivasertib to docetaxel for patients with mCRPC. We previously reported that capivasertib did not extend a composite progression-free survival primary endpoint but did significantly improve the secondary endpoint of overall survival (OS). Here we present OS data after 66% of events had occurred in the intent-to-treat population (n = 150). Median OS was 25.3 mo for capivasertib plus docetaxel versus 20.3 mo for placebo plus docetaxel (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.47-1.05; nominal p = 0.09). Receipt of subsequent life-extending treatments was balanced between the treatment arms. The OS benefit associated with capivasertib was maintained in a subset of patients previously treated with abiraterone and/or enzalutamide (median OS 25.0 vs 17.6 mo; HR 0.57, 95% CI 0.36-0.91; nominal p = 0.02) but not in abiraterone/enzalutamide-naïve patients (median OS 31.1 mo vs not reached; HR 1.43, 95% CI 0.63-3.23). We conclude that OS may be extended by addition of capivasertib to docetaxel. Exploratory analysis revealed that the OS benefit was maintained in a subset of patients previously exposed to androgen receptor-targeted agents, which should be evaluated in prospective trials. PATIENT SUMMARY: The ProCAID study examined whether adding the AKT inhibitor drug capivasertib to docetaxel chemotherapy improves outcomes for patients with advanced prostate cancer. Initial analysis of the ProCAID results suggested that capivasertib improved overall survival benefit. This follow-up analysis suggests that capivasertib addition may be particularly beneficial for patients whose cancer was previously treated with drugs that target the androgen receptor.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas , Intervalo Livre de Doença , Docetaxel/uso terapêutico , Humanos , Masculino , Nitrilas/uso terapêutico , Feniltioidantoína , Fosfatidilinositol 3-Quinases , Estudos Prospectivos , Neoplasias de Próstata Resistentes à Castração/patologia , Proteínas Proto-Oncogênicas c-akt , Pirimidinas , Pirróis , Receptores Androgênicos , Resultado do Tratamento
2.
Cureus ; 14(2): e21803, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35261829

RESUMO

Background Neodymium-doped yttrium aluminium garnet (Nd:YAG) posterior capsulotomy is a common treatment for posterior capsular opacification. Practice varies regarding routine follow-up. In this study, we reviewed follow-up rates and treatment-related complications from a district general hospital's ophthalmology unit to assess areas for improvement and cost-effectiveness. Methodology We conducted a retrospective review of electronic patient records for all patients treated with Nd:YAG capsulotomy in 2019 at our hospital. Primary outcomes included visual acuity, complications, and follow-up data. Secondary outcomes included medication prescribing and the grade of surgeon. Results In total, 912 eyes of 744 patients were included. Overall, 536 (58.8%) eyes were discharged immediately following their laser. Complication rate was 4.3% (39 eyes). Junior training grades had a higher rate of medication prescribing (40/46 eyes; 87.0%) and follow-up (36/40 eyes; 78.3%). Conclusions Certain selected patients may be safely discharged following capsulotomy with safety-netting advice. This strategy increases the capacity to follow-up patients at higher risk of complications. Higher rates of follow-up among junior ophthalmologists offers potential for training.

3.
Clin Cancer Res ; 27(7): 1882-1892, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33472913

RESUMO

PURPOSE: Preclinical data indicate that DNA methyltransferase inhibition will circumvent cisplatin resistance in various cancers. PATIENT AND METHODS: SPIRE comprised a dose-escalation phase for incurable metastatic solid cancers, followed by a randomized dose expansion phase for neoadjuvant treatment of T2-4a N0 M0 bladder urothelial carcinoma. The primary objective was a recommended phase II dose (RP2D) for guadecitabine combined with gemcitabine and cisplatin. Treatment comprised 21-day gemcitabine and cisplatin cycles (cisplatin 70 mg/m2, i.v., day 8 and gemcitabine 1,000 mg/m2, i.v., days 8 + 15). Guadecitabine was injected subcutaneously on days 1-5, within escalation phase cohorts, and to half of 20 patients in the expansion phase. Registration ID: ISRCTN 16332228. RESULTS: Within the escalation phase, dose-limiting toxicities related predominantly to myelosuppression requiring G-CSF prophylaxis from cohort 2 (guadecitabine 20 mg/m2, days 1-5). The most common grade ≥3 adverse events in 17 patients in the dose-escalation phase were neutropenia (76.5%), thrombocytopenia (64.7%), leukopenia (29.4%), and anemia (29.4%). Addition of guadecitabine to gemcitabine and cisplatin in the expansion phase resulted in similar rates of severe hematologic adverse events, similar cisplatin dose intensity, but modestly reduced gemcitabine dose intensity. Radical treatment options after chemotherapy were not compromised. Pharmacodynamics evaluations indicated guadecitabine maximal target effect at the point of cisplatin administration. Pharmacokinetics were consistent with prior data. No treatment-related deaths occurred. CONCLUSIONS: The guadecitabine RP2D was 20 mg/m2, days 1-5, in combination with gemcitabine and cisplatin and required GCSF prophylaxis. Gene promoter methylation pharmacodynamics are optimal with this schedule. Addition of guadecitabine to gemcitabine and cisplatin was tolerable, despite some additional myelosuppression, and warrants further investigation to assess efficacy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adulto , Idoso , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Azacitidina/análogos & derivados , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Gencitabina
4.
J Clin Oncol ; 39(3): 190-201, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33326257

RESUMO

PURPOSE: Capivasertib is a pan-AKT inhibitor. Preclinical data indicate activity in metastatic castration-resistant prostate cancer (mCRPC) and synergism with docetaxel. PATIENTS AND METHODS: ProCAID was a placebo controlled randomized phase II trial in mCRPC. Patients received up to ten 21-day cycles of docetaxel (75 mg/m2 intravenous, day 1) and prednisolone (5 mg twice daily, oral, day 1-21) and were randomly assigned (1:1) to oral capivasertib (320 mg twice daily, 4 days on/3 days off, from day 2 each cycle), or placebo, until disease progression. Treatment allocation used minimization factors: bone metastases; visceral metastases; investigational site; and prior abiraterone or enzalutamide. The primary objective, by intention to treat, determined if the addition of capivasertib prolonged a composite progression-free survival (cPFS) end point that included prostate-specific antigen progression events. cPFS and overall survival (OS) were also assessed by composite biomarker subgroup for PI3K/AKT/PTEN pathway activation status. RESULTS: One hundred and fifty patients were enrolled. Median cPFS was 7.03 (95% CI, 6.28 to 8.25) and 6.70 months (95% CI, 5.52 to 7.36) with capivasertib and placebo respectively (hazard ratio [HR], 0.92; 80% CI, 0.73 to 1.16; one-sided P = .32). Median OS was 31.15 (95% CI, 20.07 to not reached) and 20.27 months (95% CI, 17.51 to 24.18), respectively (HR, 0.54; 95% CI, 0.34 to 0.88; two-sided P = .01). cPFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway activation status. Grade III-IV adverse events were equivalent between arms (62.2%). The most common adverse events of any grade deemed related to capivasertib were diarrhea, fatigue, nausea, and rash. CONCLUSION: The addition of capivasertib to chemotherapy did not extend cPFS in mCRPC irrespective of PI3K/AKT/PTEN pathway activation status. The observed OS result (a secondary end point) will require prospective validation in future studies to address potential for bias.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Docetaxel/uso terapêutico , Prednisolona/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Progressão da Doença , Docetaxel/efeitos adversos , Método Duplo-Cego , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prednisolona/efeitos adversos , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/enzimologia , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Fatores de Tempo , Reino Unido
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