Abstract
Preclinical evidence led to the development of clinical trials that are examining supraphysiologic concentrations of 1,25-dihydroxyvitamin D for the treatment of cancer. Restriction of dietary calcium intake may reduce the dose-dependent hypercalcemia and hypercalcuria expected with such regimens. Conventional methods for monitoring dietary calcium intake require substantial effort by study participants and are ill-suited for patients with advanced malignancies. An easy-to-use 7-day food frequency questionnaire was developed, validated, and tested in a cancer clinical trial of high dose calcitriol. The questionnaire identified with a sensitivity of 88% patients whose daily calcium intake exceeded the goal of 500 mg. The acceptability of dietary calcium restriction was evaluated using selected questions from the previously published Nutritional Health Perceptions Scale and Nutritional Hassles Questionnaire. No change in the nutrition health perceptions score or the irritability score was observed with the introduction of a calcium restricted diet.
CALCITRIOL (1[alpha],25-dihydroxycholecalciferol; 1,25-dihydroxyvitamin D3) is the natural ligand for the vitamin D receptor (VDR) and the principal biologically active form of vitamin D. Recognition that in addition to regulating calcium homeostasis, calcitriol and its synthetic analogues regulate cell proliferation and differentiation led to increasing interest in developing ways to harness this activity for cancer treatment. 1
Vitamin D receptors are expressed ubiquitously among human neoplasms. Antiproliferative activity of VDR ligands has been reported in a variety of malignancies. 2-17 These studies demonstrate that supraphysiologic levels of calcitriol are required for significant inhibition of cancer growth.
Progress in developing calcitriol as an anticancer agent has been hindered by hypercalcemia when calcitriol is dosed above physiologic replacement doses. This predictable adverse effect was dose limiting in all previously published trials of calcitriol treatment of cancer. 18-22 Mechanisms by which supraphysiologic levels of calcitriol may cause hypercalcemia include increased intestinal absorption of calcium, stimulation of osteoclast-mediated calcium reabsorption from bones, and increased renal reabsorption of calcium. Reduced calcium intake in mice receiving supraphysiologic doses of calcitriol reduces the severity of hypercalcemia. 23 Furthermore, short-term treatment with supraphysiologic doses of calcitriol (4 days) did not cause elevations in urinary hydroxyproline, suggesting that short-term exposure may not fully activate osteoclasts. 24
A phase I clinical trial for patients with refractory malignancies was developed to study whether calcitriol's therapeutic index could be improved by introducing a reduced calcium diet while dosing calcitriol intermittently. This trial demonstrated that substantial dose escalation of calcitriol is feasible with weekly dosing and a reduced calcium diet. 25 The standard 3-day dietary record methodology for monitoring dietary calcium intake was thought to be too time-consuming and cumbersome to use routinely and frequently in patients with advanced cancer. We therefore developed and validated a brief dietary calcium assessment instrument (DCAI) designed to routinely monitor compliance with dietary calcium restriction. The acceptability of the diet in this patient population was also evaluated with a brief quality of life questionnaire.