Efficacy and Safety of a Personalized Vitamin D3 Loading Dose Followed by Daily 2000 IU in Colorectal Cancer Patients with Vitamin D Insufficiency: Interim Analysis of a Randomized Controlled Trial.

A personalized vitamin D3 loading dose has not yet been tested in cancer patients. This interim analysis of the randomized, placebo-controlled VICTORIA trial analyzed the first recruited 74 German adults with nonmetastatic colorectal cancer, a tumor surgery within the past year, and 25-hydroxyvitamin D levels (25(OH)D) < 50 nmol/L. Study participants received a loading dose tailored for a baseline 25(OH)D level and BMI in the first 11 days, followed by a maintenance dose of 2000 IU of vitamin D3 daily until end of trial week 12. The mean 25(OH)D levels were 27.6, 31.0, and 34.1 nmol/L in the placebo group and 25.9, 63.1, and 75.5 nmol/L in the verum group during screening, visit 1 (end of loading dose), and visit 2 (end of maintenance dose), respectively. The prevalence of 25(OH)D) ≥ 50 nmol/L at visits 1 and 2 was 3.5% and 17.4% in the placebo group and 80.0% and 100% in the verum group. No events of 25(OH)D > 150 nmol/L or hypercalcemia were observed. Hypercalciuria events at visit 1 (n = 5 in verum and n = 1 in the placebo group; p = 0.209) receded after discontinuation of the study medication. The personalized loading dose effectively and safely increased the 25(OH)D levels, and 2000 IU of vitamin D3 daily sustained the achieved levels.

Protocol of the VICTORIA study: personalized vitamin D supplementation for reducing or preventing fatigue and enhancing quality of life of patients with colorectal tumor - randomized intervention trial.

BACKGROUND: Cancer-related fatigue represents one major cause of reduced quality of life in cancer patients and can seriously affect the physical, emotional, and cognitive functioning impeding coping with the disease. Options for effective treatment of cancer-related fatigue are limited, consisting only of non-pharmacologic interventions like physical activity, psychosocial, and mind-body interventions. Recent evidence suggests that vitamin D3 supplementation might alleviate cancer-related fatigue. However, confirmation in a randomized controlled trial is needed. METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 456 colorectal cancer (CRC) patients aged 18 years and older are being recruited in three German rehabilitation clinics. Study inclusion requires hospitalization of at least 3 weeks at such a clinic, a diagnosis of non-metastatic CRC (stage I-III), surgical removal of the tumor within the past 9 months, and season-adapted vitamin D insufficiency or deficiency. Eligible patients are randomly assigned to a personalized regimen of vitamin D3 or placebo for 12 weeks. In the intervention group, a loading dose of 20,000 or 40,000 IU vitamin D3 will be administered daily during the first 11 days, followed by a maintenance dose of 2000 IU daily. Patients will complete questionnaires for secondary outcomes (fatigue subdomains, quality of life and subdomains, depression, functional well-being, and infection frequency). Blood and urine samples will be collected for analyses of safety parameters (hypervitaminosis D, hypercalcemia, hypercalciuria, and renal impairment) and efficacy biomarkers (25-hydroxyvitamin D, HbA1c, white blood cell count, leukocyte subtype counts, serum C-reactive protein, uric acid, creatinine, triglycerides, total, low- and high-density lipoprotein cholesterol). DISCUSSION: This trial tests whether a personalized vitamin D3 dosing regimen reduces or prevents fatigue among non-metastatic CRC patients by treating the underlying vitamin D deficiency/insufficiency. If efficacy can be confirmed, personalized vitamin D3 supplementation could be used as a tertiary prevention measure in addition to non-pharmacological treatments of cancer-related fatigue in CRC patients. We expect to detect an effect of vitamin D3 supplementation on secondary outcomes like quality of life, depression, functional well-being, infections, inflammatory biomarkers, diabetes mellitus, and dyslipidemia. TRIAL REGISTRATION: European Clinical Trials Database: EudraCT-No: 2019-000502-30, January 21, 2019; German Clinical Trials Register (DRKS): DRKS00019907 , April 30, 2019.

Modelling the genesis and treatment of cancer: the potential role of physiologically based pharmacodynamics.

Physiologically based modelling of pharmacodynamics/toxicodynamics requires an a priori knowledge on the underlying mechanisms causing toxicity or causing the disease. In the context of cancer, the objective of the expert meeting was to discuss the molecular understanding of the disease, modelling approaches used so far to describe the process, preclinical models of cancer treatment and to evaluate modelling approaches developed based on improved knowledge. Molecular events in cancerogenesis can be detected using 'omics' technology, a tool applied in experimental carcinogenesis, but also for diagnostics and prognosis. The molecular understanding forms the basis for new drugs, for example targeting protein kinases specifically expressed in cancer. At present, empirical preclinical models of tumour growth are in great use as the development of physiological models is cost and resource intensive. Although a major challenge in PKPD modelling in oncology patients is the complexity of the system, based in part on preclinical models, successful models have been constructed describing the mechanism of action and providing a tool to establish levels of biomarker associated with efficacy and assisting in defining biologically effective dose range selection for first dose in man. To follow the concentration in the tumour compartment enables to link kinetics and dynamics. In order to obtain a reliable model of tumour growth dynamics and drug effects, specific aspects of the modelling of the concentration-effect relationship in cancer treatment that need to be accounted for include: the physiological/circadian rhythms of the cell cycle; the treatment with combinations and the need to optimally choose appropriate combinations of the multiple agents to study; and the schedule dependence of the response in the clinical situation.

Reduced hypoxic ventilatory response with preserved blood oxygenation in yoga trainees and Himalayan Buddhist monks at altitude: evidence of a different adaptive strategy?

Yoga induces long-term changes in respiratory function and control. We tested whether it represents a successful strategy for high-altitude adaptation. We compared ventilatory, cardiovascular and hematological parameters in: 12 Caucasian yoga trainees and 12 control sea-level residents, at baseline and after 2-week exposure to high altitude (Pyramid Laboratory, Nepal, 5,050 m), 38 active lifestyle high-altitude natives (Sherpas) and 13 contemplative lifestyle high-altitude natives with practice of yoga-like respiratory exercises (Buddhist monks) studied at 5,050 m. At baseline, hypoxic ventilatory response (HVR), red blood cell count and hematocrit were lower in Caucasian yoga trainees than in controls. After 14 days at altitude, yoga trainees showed similar oxygen saturation, blood pressure, RR interval compared to controls, but lower HVR (-0.44 +/- 0.08 vs. -0.98 +/- 0.21 l/min/m/%SaO(2), P < 0.05), minute ventilation (8.3 +/- 0.9 vs. 10.8 +/- 1.6 l/min, P < 0.05), breathing rate (indicating higher ventilatory efficiency), and lower red blood cell count, hemoglobin, hematocrit, albumin, erythropoietin and soluble transferrin receptors. Hypoxic ventilatory response in monks was lower than in Sherpas (-0.23 +/- 0.05 vs. -0.63 +/- 0.09 l/min/m/%SaO(2), P < 0.05); values were similar to baseline data of yoga trainees and Caucasian controls, respectively. Red blood cell count and hematocrit were lower in monks as compared to Sherpas. In conclusion, Caucasian subjects practicing yoga maintain a satisfactory oxygen transport at high altitude, with minimal increase in ventilation and with reduced hematological changes, resembling Himalayan natives. Respiratory adaptations induced by the practice of yoga may represent an efficient strategy to cope with altitude-induced hypoxia.

Central nervous system prophylaxis with high-dose methotrexate does not give rise to significant electroencephalographic changes in children with acute lymphoblastic leukemia.

Acute, subacute, and chronic neurologic complications have been reported in children treated with high-dose methotrexate for various malignant diseases. It was the aim of this study to monitor central nervous system treatment with high-dose methotrexate in children with acute lymphoblastic leukemia by serial electroencephalographic (EEG) examinations. Electroencephalographic examinations with quantitative computed analysis were performed in 21 children before and on the third day after each of four high-dose methotrexate infusions with leucovorin rescue according to protocol M of trial ALL-BFM 90 of the German Society for Pediatric Haematology and Oncology. Six patients with a medium risk of relapse also received L-asparaginase. In the cohort treated with methotrexate solely, no statistically significant changes of the quantitative EEG parameters could be demonstrated. Only two children with delayed serum methotrexate clearance showed reversible diffuse EEG slowing of a slight to moderate degree. In the group with additional L-asparaginase treatment, slight transient EEG slowing also occurred. Our findings indicate that in patients with a normal methotrexate clearance during central nervous system treatment with high-dose methotrexate according to trial BFM-ALL 90, usually no subacute or cumulative EEG changes have to be expected. If neurologic or psychiatric symptoms or EEG slowing occur, delayed methotrexate clearance must be suspected.