Is Higher Docetaxel Clearance in Prostate Cancer Patients Explained by Higher CYP3A? An In Vivo Phenotyping Study with Midazolam

Patients with prostate cancer (PCa) have a lower docetaxel exposure for both intravenous (1.8-fold) and oral administration (2.4-fold) than patients with other solid cancers, which could influence efficacy and toxicity. An altered metabolism by cytochrome P450 3A (CYP3A) due to castration status might explain the observed difference in docetaxel pharmacokinetics. In this in vivo phenotyping, pharmacokinetic study, CYP3A activity defined by midazolam clearance (CL) was compared between patients with PCa and male patients with other solid tumors. All patients with solid tumors who did not use CYP3A-modulating drugs were eligible for participation. Patients received 2 mg midazolam orally and 1 mg midazolam intravenously on 2 consecutive days. Plasma concentrations were measured with a validated liquid chromatography–tandem mass spectrometry method. Genotyping was performed for CYP3A4 and CYP3A5. Nine patients were included in each group. Oral midazolam CL was 1.26-fold higher in patients with PCa compared to patients with other solid tumors (geometric mean [coefficient of variation], 94.1 [33.5%] L/h vs 74.4 [39.1%] L/h, respectively; P =.08). Intravenous midazolam CL did not significantly differ between the 2 groups (P =.93). Moreover, the metabolic ratio of midazolam to 1′-hydroxy midazolam did not differ between the 2 groups for both oral administration (P =.67) and intravenous administration (P =.26). CYP3A4 and CYP3A5 genotypes did not influence midazolam pharmacokinetics. The observed difference in docetaxel pharmacokinetics between both patient groups therefore appears to be explained neither by a difference in midazolam CL nor by a difference in metabolic conversion rate of midazolam

Smartphone measurements of physical activity and fitness are associated with early trial discontinuation of patients in (hemato)oncology phase I/II clinical trials

Background: Patients, who discontinue early, do not benefit from phase I/II clinical trials (early-phase clinical trials (EPCT)). In this study, associations between objective smartphone measurements of physical activity and fitness and early trial discontinuation in patients with cancer participating in EPCT were investigated. Methods: Before start of treatment, physical activity (steps/day) and physical fitness (meters walked in 6 min) were measured with a smartphone, and patient-reported physical function (PRO-PF) was assessed (EORTC QLQ-C30-PF). Early trial discontinuation was defined as discontinuation ≤ 28 days. Univariable logistic regression analyses were performed to study associations of physical activity, fitness, and function with early trial discontinuation. Optimal cutoff values of physical activity and fitness were assessed with ROCs, based on positive predictive values (PPV). Results: Median (interquartile range (IQR)) step count was 4263 (2548–6897) steps/day, mean ± standard deviation 6-min walking distance was 477 ± 120 m and median (IQR) PRO-PF score was 83 (67–95) points. Fourteen patients (12%) discontinued the trial early. Smartphone measurements of physical activity in units of 100 steps per day (odds ratio (OR) = 0.96, 95% CI = 0.94–0.99, p = 0.01), physical fitness (OR = 0.99, 95% CI = 0.98–0.99, p < 0.01), and PRO-PF (OR = 0.97, 95% CI = 0.94–1.00, p = 0.03) were associated with early trial discontinuation. Optimal cutoff values were < 900 steps for physical activity and < 285 m for physical fitness. PPV for early trial discontinuation was 100% in patients who walked both < 1500 steps per day and < 300 m in 6 min. Conclusions: Objective smartphone measurements of physical activity and fitness are associated with early trial discontinuation. However, cutoff values should be externally validated in a larger cohort before implementation in clinical practice

Is Higher Docetaxel Clearance in Prostate Cancer Patients Explained by Higher CYP3A? An In Vivo Phenotyping Study with Midazolam

Patients with prostate cancer (PCa) have a lower docetaxel exposure for both intravenous (1.8-fold) and oral administration (2.4-fold) than patients with other solid cancers, which could influence efficacy and toxicity. An altered metabolism by cytochrome P450 3A (CYP3A) due to castration status might explain the observed difference in docetaxel pharmacokinetics. In this in vivo phenotyping, pharmacokinetic study, CYP3A activity defined by midazolam clearance (CL) was compared between patients with PCa and male patients with other solid tumors. All patients with solid tumors who did not use CYP3A-modulating drugs were eligible for participation. Patients received 2 mg midazolam orally and 1 mg midazolam intravenously on 2 consecutive days. Plasma concentrations were measured with a validated liquid chromatography–tandem mass spectrometry method. Genotyping was performed for CYP3A4 and CYP3A5. Nine patients were included in each group. Oral midazolam CL was 1.26-fold higher in patients with PCa compared to patients with other solid tumors (geometric mean [coefficient of variation], 94.1 [33.5%] L/h vs 74.4 [39.1%] L/h, respectively; P =.08). Intravenous midazolam CL did not significantly differ between the 2 groups (P =.93). Moreover, the metabolic ratio of midazolam to 1′-hydroxy midazolam did not differ between the 2 groups for both oral administration (P =.67) and intravenous administration (P =.26). CYP3A4 and CYP3A5 genotypes did not influence midazolam pharmacokinetics. The observed difference in docetaxel pharmacokinetics between both patient groups therefore appears to be explained neither by a difference in midazolam CL nor by a difference in metabolic conversion rate of midazolam

Physical activity in patients with cancer: self-report versus accelerometer assessments

Purpose: The level of daily physical activity in patients with cancer is frequently assessed by questionnaires, such as the Physical Activity Scale for the Elderly (PASE). Objective assessments, with for example accelerometers, may be a good alternative. The aim of this study was to investigate the agreement between the PASE questionnaire and accelerometer-assessed physical activity in a large group of patients with different types of cancer. Methods: Baseline accelerometer and PASE questionnaire data of 403 participants from the REACT (Resistance and Endurance Exercise After Chemotherapy, n = 227), the EXIST (Exercise Intervention After Stem-Cell Transplantation, n = 74), and NET-QUBIC (NEtherlands QUality of Life And Biomedical Cohort Studies In Cancer, n = 102) studies were available for the current analyses. Physical activity was assessed by the PASE questionnaire (total score) and accelerometers (total minutes per day > 100 counts). Linear mixed models regression analysis was used to assess the agreement between the PASE questionnaire and accelerometer-assessed physical activity. Results: The mean (SD) PASE score was 95.9 (75.1) points and mean (SD) time in physical activity measured with the accelerometer was 256.6 (78.8) min per day. The agreement between the PASE score and the accelerometer data was significant, but poor (standardized regression coefficient (B) = 0.36, 95%CI = 0.27; 0.44, p < 0.01). Conclusion: Agreement between the PASE questionnaire and accelerometer-assessed physical activity was poor. The poor agreement indicates that they measure different physical activity constructs and cannot be used interchangeably to assess the level of daily physical activity in patients with cancer

Hepatic arterial infusion pump chemotherapy combined with systemic chemotherapy for borderline resectable and unresectable colorectal liver metastases:phase II feasibility study

Background: Hepatic arterial infusion pump chemotherapy combined with systemic chemotherapy (HAIP-SYS) for liver-only colorectal liver metastases (CRLMs) has shown promising results but has not been adopted worldwide. This study evaluated the feasibility of HAIP-SYS in the Netherlands. Methods: This was a single-arm phase II study of patients with CRLMs who received HAIP-SYS consisting of floxuridine with concomitant systemic FOLFOX or FOLFIRI. Main inclusion and exclusion criteria were borderline resectable or unresectable liver-only metastases, suitable arterial anatomy and no previous local treatment. Patients underwent laparotomy for pump implantation and primary tumour resection if in situ. Primary end point was feasibility, defined as ≥70% of patients completing two cycles of HAIP-SYS. Sample size calculations led to 31 patients. Secondary outcomes included safety and tumour response. Results: Thirty-one patients with median 13 CRLMs (i.q.r. 6–23) were included. Twenty-eight patients (90%) received two HAIP-SYS cycles. Three patients did not get two cycles due to extrahepatic disease at pump placement, definitive pathology of a recto-sigmoidal squamous cell carcinoma, and progressive disease. Five patients experienced grade 3 surgical or pump device-related complications (16%) and 11 patients experienced grade ≥3 chemotherapy toxicity (38%). At first radiological evaluation, disease control rate was 83% (24/29 patients) and hepatic disease control rate 93% (27/29 patients). At 6 months, 19 patients (66%) had experienced grade ≥3 chemotherapy toxicity and the disease control rate was 79%. Conclusion: HAIP-SYS for borderline resectable and unresectable CRLMs was feasible and safe in the Netherlands. This has led to a successive multicentre phase III randomized trial investigating oncological benefit (EUDRA-CT 2023–506194-35-00).</p