Randomized controlled trial on the effect of 1-hour infusion of vincristine versus push injection on neuropathy in children with cancer (final analysis)

Introduction: Vincristine is an integral component of treatment for children with cancer. Its main dose-limiting side effect is vincristine-induced peripheral neuropathy (VIPN). The VINCA trial was a randomized controlled trial that explored the effect of 1-hour infusion compared with push injection of vincristine on the development of VIPN in children with cancer. The short-term outcomes (median follow-up 9 months) showed that there was no difference in VIPN between the randomization groups. However, 1-hour infusion was less toxic in children who also received azoles. We now report the results of the final analyses (median follow-up 20 months), which includes treatment outcome as a secondary objective (follow-up 3 years). Methods: VIPN was measured 1–7 times per participant using the Common Terminology Criteria for Adverse Events (CTCAE) and the pediatric-modified total neuropathy score. Poisson mixed model and logistic generalized estimating equation analysis for repeated measures were performed.Results: Forty-five participants per randomization group were included. There was no significant effect of 1-hour infusion compared with push injection on VIPN. In participants receiving concurrent azoles, the total CTCAE score was significantly lower in the one-hour group (rate ratio 0.52, 95% confidence interval 0.33–0.80, p = 0.003). Four patients in the one-hour group and one patient in the push group relapsed. Two patients in the one-hour group died. Conclusion:1-hour infusion of vincristine is not protective against VIPN. However, in patients receiving concurrent azoles, 1-hour infusion may be less toxic. The difference in treatment outcome is most likely the result of differences in risk profile.</p

Impact of DNA damage repair defects and aggressive variant features on response to carboplatin-based chemotherapy in metastatic castration-resistant prostate cancer

Platinum-based chemotherapy is not standard of care for unselected or genetically selected metastatic castration-resistant prostate cancer (mCRPC) patients. A retrospective assessment of 71 patients was performed on platinum use in the Netherlands. Genetically unselected patients yielded low response rates. For a predefined subanalysis of all patients with comprehensive next-generation sequencing, 30 patients were grouped based on the presence of pathogenic aberrations in genes associated with DNA damage repair (DDR) or aggressive variant prostate cancer (AVPC). Fourteen patients (47%) were DDR deficient (DDRd), of which seven with inactivated BRCA2 (BRCA2mut). Six patients classified as AVPC. DDRd patients showed beneficial biochemical response to carboplatin, largely driven by all BRCA2mut patients having >50% prostate-speci

Real-world Outcomes of Sequential Androgen-receptor Targeting Therapies with or Without Interposed Life-prolonging Drugs in Metastatic Castration-resistant Prostate Cancer

_Background:_ Cross resistance between androgen-receptor targeting therapies(ARTs) (abiraterone acetate plus prednisone [ABI + P] or enzalutamide [ENZ]) fortreatment of metastatic castration-resistant prostate cancer (mCRPC) may affectresponses to second ART (ART2). _Objective:_ To establish treatment duration and prostate-specific antigen (PSA)response of ART2 in real-world mCRPC patients treated with or without otherlife-prolonging drugs (LPDs; ie, docetaxel, cabazitaxel, or radium-223) betweenART1 and ART2. _Design, setting, and participants:_ Castration-resistant prostate cancer patients,diagnosed between 2010 and 2016 were retrospectively registered in Castra-tion-resistant Prostate Cancer Registry (CAPRI). Patients treated with both ARTswere clustered into two subgroups: ART1 > ART2 or ART1 > LPD > ART2

Health-related Quality of Life and Pain in a Real-world Castration-resistant Prostate Cancer Population: Results From the PRO-CAPRI Study in the Netherlands

Background: The purpose of this study was to determine generic, cancer-specific, and prostate cancer-specific health-related quality of life (HRQoL), pain and changes over time in patients with metastatic castration-resistant prostate cancer (mCRPC) in daily practice. Patients and Methods: PRO-CAPRI is an observational, prospective study in 10 hospitals in the Netherlands. Patients with mCRPC completed the EQ-5D, European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and Brief Pain Inventory-Short Form (BPI-SF) every 3 months and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Prostate Cancer Module (EORTC QLQ-PR25) every 6 months for a maximum of 2 years. Subgroups were identified based on chemotherapy pretreatment. Outcomes were generic, cancer-specific, and prostate cancer-specific HRQoL and self-reported pain. Descriptive statistics were performed including changes over time and minimal important differences (MID) between subgroups. Results: In total, 151 included patients answered 873 questionnaires. The median follow-up from the start of the study was 19.5 months, and 84% were treated with at least 1 life-prolonging agent. Overall, patients were in good clinical condition (Eatern Cooperative Oncology Group performance status 0-1 in 78%) with normal baseline hemoglobin, lactate dehydrogenase, and alkaline phosphatase. At inclusion, generic HRQoL was high with a mean EQ visual analog score of 73.2 out of 100. The lowest scores were reported on role and physical functioning (mean scores of 69 and 76 of 100, respectively), and fatigue, pain, and insomnia were the most impaired domai

Clinical outcomes and molecular profiling of advanced metastatic castration-resistant prostate cancer patients treated with 225Ac-PSMA-617 targeted alpha-radiation therapy

Targeted alpha-radiation therapy (TAT) with 225Ac-labeled prostate-specific membrane antigen (PSMA)-ligands is a promising novel treatment option for metastatic castration-resistant prostate cancer (mCRPC) patients. Limited data is available on efficacy, quality of life (QoL) and pretherapeutic biomarkers. The objective was to evaluate the efficacy of 225Ac-PSMA TAT and impact on QoL in advanced mCRPC, and to explore predictive biomarkers on pre-therapeutic metastatic tissue biopsies. Design, setting and participants: Observational cohort study including consecutive patients treated with 225Ac-PSMA TAT between February 2016 and November 2017. Primary endpoint was overall survival (OS). Furthermore, prostate-specific antigen (PSA) changes, radiological response, safety, QoL and xerostomia were evaluated. Biopsies were analyzed with immunohistochemistry and next-generation sequencing. We used Kaplan-Meier estimates for OS. Thirteen patients were included. Median OS was 8.5 months for the total cohort and 12.6 months for PSMA radioligand therapy-naïve patients. PSA declines of ≥90% and ≥50% were observed in 46% and 69% of patients, respectively. Six patients were radiologically evaluable; 50% showed partial response. All patients showed >90% total tumor volume reduction on PET imaging. Patients experienced large improvement of physical and role functioning and clinically relevant decrease of pain. Xerostomia persisted during follow-up. Patients with high baseline PSMA expression or DNA damage repair alterations tended to have longer OS. The small sample size limits the interpretation of the results. TAT with 225Ac-PSMA resulted in remarkable survival and biochemical responses in advanced mCRPC patients. Patients experienced large QoL improvement, although xerostomia was found to be non-transient. Larger prospective studies on 225Ac-PSMA TAT are warranted, including evaluation of pretherapeutic biomarkers. In this observational study, we examined outcomes of 225Ac-PSMA TAT in end-stage mCRPC patients. Patients experienced decrease of pain and improvement of functioning. Dry mouth symptoms were non-transient at follow-up. These findings warrant further evaluation of 225Ac-PSMA TAT in larger prospective clinical trials.JRC.G.I.5 - Nuclear Science and Application