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Journal of Clinical Oncology, Vol 26, No 11 (April 10), 2008: pp. 1900-1901 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.7941
Could the Efficacy of Docetaxel in Prostate Cancer Patients Be Potentiated by Concomitant High-Dose Calcitriol Administration?Oncologia Medica, Dipartimento di Scienze Cliniche e Biologiche Università di Torino at Ospedale San Luigi Gonzaga, Orbassano, Italy
Oncologia Medica, Ospedale San Lorenzo, Carmagnola, Italy
Urologia, Dipartimento di Scienze Cliniche e Biologiche, Università di Torino at Ospedale San Luigi Gonzaga, Orbassano, Italy
Oncologia Medica, Dipartimento di Scienze Cliniche e Biologiche Università di Torino at Ospedale San Luigi Gonzaga, Orbassano, Italy To the Editor: Docetaxel is widely recognized as the most efficacious chemotherapeutic agent in hormone-refractory prostate cancer patients. One important question is how can we improve the efficacy of this drug. Preclinical data have shown that calcitriol [(1,25-dihydroxycholecalciferol, 1,25(OH)2-D3] has a significant antitumor activity and could potentiate chemotherapy efficacy. Beer et al1 recently published a phase III trial, the AIPC Study of Calcitriol Enhancing Taxotere (ASCENT), aiming to show whether the addition of high-dose calcitriol to docetaxel in patients with hormone-refractory metastatic disease could result in a greater activity than docetaxel alone. The results showed that the combination of docetaxel and calcitriol failed to show a greater reduction of prostate-specific antigen (PSA) as opposed to docetaxel alone (primary aim of the study) but significantly prolonged the overall survival. How should we interpret this discrepancy? One possible explanation is that 50% PSA reduction from baseline is not a reliable surrogate parameter of docetaxel efficacy, as recently reported2; alternatively, the absence of correlation between PSA reduction and survival improvement in this trial suggests that calcitriol administration can affect survival independently from docetaxel efficacy. Most patients (85% to 90%) in this trial1 had bone metastases and were at risk of skeletal-related events (SREs). Zoledronic acid was not mandatory but was administered in 85 patients (40 placebo treated; 45 calcitriol treated). Overall, calcitriol administration resulted in a prolongation of skeletal morbidity–free survival that just failed to attain statistical significance. Interestingly, if patients are categorized according to whether or not they received zoledronic acid, the SRE incidence rate in the calcitriol group was lower than in the placebo group in zoledronic acid–treated patients (29% v 40%, respectively), but not in patients not receiving zoledronic acid (31% v 34%). Prostate cancer patients tend to be elderly, so a high incidence of hypovitaminosis D is expected in this setting. Zoledronic acid administration could lead to hypocalcemia and secondary hyperparathyroidism, and the occurrence of this metabolic disturbance is influenced by hypovitaminosis D status.3 Parathyroid hormone(PTH) stimulates osteoclast activity and may potentially impair zoledronic acid efficacy. In an explorative analysis performed in patients randomly assigned onto the registrative trial of zoledronic acid versus placebo,4 patients showing elevated PTH levels after zoledronic acid had a greater incidence of SREs than patients who received placebo, these data support the notion that high-dose calcitriol administration could potentiate the zoledronic acid efficacy.5 Moreover, PTH is similar to PTH-related protein, a potent growth factor, and both hormones bind the same receptor expressed in prostate cancer cells.6 In the registrative zoledronic acid trial, we have observed that patients showing elevated PTH levels after 3 months of zoledronic acid administration had a greater risk of death than those showing serum PTH within the normal range.5 These results suggest that zoledronic acid efficacy in terms of survival benefit could be potentiated by high-dose calcitriol aiming to counteract PTH elevation. On these bases, it would be interesting to explore the ASCENT trial, the time to onset of SRE, and overall survival in patient subsets stratified according to whether they received zoledronic acid or not. These analyses could provide additional insights on mechanisms of survival improvement of calcitriol administration in prostate cancer patients. Finally, on the basis of the results of the ASCENT study, the authors have planned to conduct a new phase III study (ASCENT-2) that compares high-dose calcitriol plus docetaxel regimen to the standard once every 3 weeks regimen of docetaxel therapy. In this forthcoming trial, we suggest measuring calcium, vitamin D, and PTH before and during treatment, and adjusting the final results according to the condition of hypovitaminosis D status and PTH level status. In other words, we believe the authors will convincingly conclude that the addition of calcitriol to docetaxel could result in increased antineoplastic activity if they are able to demonstrate no interaction between survival benefit after calcitriol and either vitamin D status or PTH status. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Alfredo Berruti, Novartis (C); Luigi Dogliotti, Novartis (C) Stock Ownership: None Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
1. Beer TM, Ryan CW, Venner PM, et al: Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: A report from the ASCENT Investigators. J Clin Oncol 25:669-674, 2007 2. Armstrong AJ, Garrett-Mayer E, Ou Yang YC, et al: Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer. J Clin Oncol 25:3965-3970, 2007 3. Breen TL, Shane E: Prolonged hypocalcemia after treatment with zoledronic acid in a patient with prostate cancer and vitamin D deficiency. J Clin Oncol 22:1531-1532, 2004 4. Saad F, Gleason DM, Murray R, et al: A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94:1458-1468, 2002 5. Berruti A, Dogliotti L, Tampellini M, et al: Effect of zoledronic acid treatment based on serum parathyroid hormone levels in patients with malignant bone disease. J Clin Oncol 24:495s, 2006 (suppl; abstr 8610) 6. Pérez-Martínez FC, Alonso V, Sarasa JL, et al: Immunohistochemical analysis of low-grade and high-grade prostate carcinoma: Relative changes of parathyroid hormone-related protein and its parathyroid hormone 1 receptor, osteoprotegerin and receptor activator of nuclear factor-kB ligand. J Clin Pathol 60:290-294, 2007
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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