METHODS: Patients with advanced solid cancers were randomized 1:1 to 3-weekly docetaxel 75 mg/m2, with or without sunitinib 12.5 mg daily for 7 days prior to docetaxel, stratified by primary tumour site. Primary endpoints were objective-response (ORR:CR + PR) and clinical-benefit rate (CBR:CR + PR + SD); secondary endpoints were toxicity and progression-free-survival (PFS).
RESULTS: We enrolled 68 patients from 2 study sites; 33 received docetaxel-sunitinib and 35 docetaxel alone, with 33 breast, 25 lung and 10 patients with other cancers. There was no difference in ORR (30.3% vs 28.6%, p = 0.432, odds-ratio [OR] 1.10, 95% CI 0.38-3.18); CBR was lower in the docetaxel-sunitinib arm (48.5% vs 71.4%, p = 0.027 OR 0.37, 95% CI 0.14-1.01). Median PFS was shorter in the docetaxel-sunitinib arm (2.9 vs 4.9 months, hazard-ratio [HR] 2.00, 95% CI 1.15-3.48, p = 0.014) overall, as well as in breast (4.2 vs 5.6 months, p = 0.048) and other cancers (2.0 vs 5.3 months, p = 0.009), but not in lung cancers (2.9 vs 4.1 months, p = 0.597). Median OS was similar in both arms overall (9.9 vs 10.5 months, HR 0.92, 95% CI 0.51-1.67, p = 0.789), and in the breast (18.9 vs 25.8 months, p = 0.354), lung (7.0 vs 6.7 months, p = 0.970) and other cancers (4.5 vs 8.8 months, p = 0.449) subgroups. Grade 3/4 haematological toxicities were lower with docetaxel-sunitinib (18.2% vs 34.3%, p = 0.132), attributed to greater discretionary use of prophylactic G-CSF (90.9% vs 63.0%, p = 0.024). Grade 3/4 non-haematological toxicities were similar (12.1% vs 14.3%, p = 0.792).
CONCLUSIONS: The addition of sunitinib to docetaxel was well-tolerated but did not improve outcomes. The possible negative impact in metastatic breast cancer patients is contrary to results of adding sunitinib to neoadjuvant AC. These negative results suggest that the intermittent administration of sunitinib in the current dose and schedule with docetaxel in advanced solid tumours, particularly breast cancers, is not beneficial.
TRIAL REGISTRATION: The study was registered ( NCT01803503 ) prospectively on clinicaltrials.gov on 4th March 2013.
OBJECTIVES: We aimed to identify risk factors for allopurinol-induced SCARs and to assess their impact on fatality.
METHODS: Adverse drug reaction (ADR) reports with allopurinol as suspected drug were extracted from the Malaysian pharmacovigilance database from year 2000 to 2018. Multiple logistic regression analysis was used to identify significant predictors of allopurinol-induced SCARs. We further analysed the association between covariates and SCARs-related fatality in a separate model. Level of significance was set at p value
OBJECTIVE: This study aims to explore the main drivers influencing the completeness of Malaysian AE reports in VigiBase over a 15-year period using vigiGrade. A secondary objective was to understand the strategic measures taken by the Malaysian authorities leading to enhanced report completeness across different time frames.
METHODS: We analyzed 132,738 Malaysian reports (2005-2019) recorded in VigiBase up to February 2021 split into historical International Drug Information System (INTDIS; n=63,943, 48.17% in 2005-2016) and newer E2B (n=68,795, 51.83% in 2015-2019) format subsets. For machine learning analyses, we performed a 2-stage feature selection followed by a random forest classifier to identify the top features predicting well-documented reports. We subsequently applied tree Shapley additive explanations to examine the magnitude, prevalence, and direction of feature effects. In addition, we conducted time-series analyses to evaluate chronological trends and potential influences of key interventions on reporting quality.
RESULTS: Among the analyzed reports, 42.84% (56,877/132,738) were well documented, with an increase of 65.37% (53,929/82,497) since 2015. Over two-thirds (46,186/68,795, 67.14%) of the Malaysian E2B reports were well documented compared to INTDIS reports at 16.72% (10,691/63,943). For INTDIS reports, higher pharmacovigilance center staffing was the primary feature positively associated with being well documented. In recent E2B reports, the top positive features included reaction abated upon drug dechallenge, reaction onset or drug use duration of <1 week, dosing interval of <1 day, reports from public specialist hospitals, reports by pharmacists, and reaction duration between 1 and 6 days. In contrast, reports from product registration holders and other health care professionals and reactions involving product substitution issues negatively affected the quality of E2B reports. Multifaceted strategies and interventions comprising policy changes, continuity of education, and human resource development laid the groundwork for AE reporting in Malaysia, whereas advancements in technological infrastructure, pharmacovigilance databases, and reporting tools concurred with increases in both the quantity and quality of AE reports.
CONCLUSIONS: Through interpretable machine learning and time-series analyses, this study identified key features that positively or negatively influence the completeness of Malaysian AE reports and unveiled how Malaysia has developed its pharmacovigilance capacity via multifaceted strategies and interventions. These findings will guide future work in enhancing pharmacovigilance and public health.