Weekly ascorbic acid infusion in castration-resistant prostate cancer patients: a single-arm phase II trial

Torben K Nielsen, Martin Højgaard, Jon T Andersen, Niklas Rye Jørgensen, Bo Zerahn, Bent Kristensen, Trine Henriksen, Jens Lykkesfeldt, Kári J Mikines, Henrik E Poulsen, Torben K Nielsen, Martin Højgaard, Jon T Andersen, Niklas Rye Jørgensen, Bo Zerahn, Bent Kristensen, Trine Henriksen, Jens Lykkesfeldt, Kári J Mikines, Henrik E Poulsen

Abstract

Background: Ascorbic acid (AA) has in vivo cytotoxic properties at concentrations that can only be achieved through intravenous (IV) administration in humans. Treatment with intravenous AA is widely and increasingly used in complementary medicine despite a lack of clinical evidence for the efficacy of this treatment.

Methods: This non-comparative, single-center, phase II trial included patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer (mCRPC) from an outpatient clinic to evaluate the efficacy and safety of IV AA therapy. Patients received weekly infusions of AA (week 1, 5 g; week 2, 30 g; and weeks 3-12, 60 g) followed by efficacy evaluation at 12 weeks. The primary endpoint for efficacy was a 50% reduction in the prostate-specific antigen (PSA) level. The secondary endpoints included changes in health-related quality of life (HRQoL), biomarkers of bone metabolism, inflammation and bone scans. Clinicaltrials.gov identifier: NCT01080352.

Results: Twenty-three patients were enrolled in this study, and 20 completed the efficacy evaluation at 12 weeks. The mean baseline PSA level was 43 µg/L. No patient achieved a 50% PSA reduction; instead, a median increase in PSA of 17 µg/L was recorded at week 12. Among the secondary endpoints, no signs of disease remission were observed. In total, 53 adverse events (AEs) were recorded. Eleven were graded as "serious". Three AEs were directly related to AA, and all of which were related to fluid load.

Conclusions: Infusion with 60 g of AA did not result in disease remission. This study does not support the use of intravenous AA outside clinical trials.

Keywords: Prostatic neoplasms; ascorbic acid (AA); cancer; complementary medicine; translational medical research.

Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Trial flowchart of enrollment and discontinuation.
Figure 2
Figure 2
Waterfall plot of changes in PSA after 12 weeks of intravenous ascorbic acid. Values were capped at 100%; the maximum increase was +397%. PSA, prostate-specific antigen.

References

    1. Bishop FL, Rea A, Lewith H, et al. Complementary medicine use by men with prostate cancer: a systematic review of prevalence studies. Prostate Cancer Prostatic Dis 2011;14:1-13. 10.1038/pcan.2010.38
    1. Padayatty SJ, Sun AY, Chen Q, et al. Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS One 2010;5:e11414. 10.1371/journal.pone.0011414
    1. Creagan ET, Moertel CG, O'Fallon JR, et al. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial. N Engl J Med 1979;301:687-90. 10.1056/NEJM197909273011303
    1. Moertel CG, Fleming TR, Creagan ET, et al. High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison. N Engl J Med 1985;312:137-41. 10.1056/NEJM198501173120301
    1. Cameron E, Campbell A. The orthomolecular treatment of cancer. II. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer. Chem Biol Interact 1974;9:285-315. 10.1016/0009-2797(74)90019-2
    1. Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A 1976;73:3685-9. 10.1073/pnas.73.10.3685
    1. National Institutes of Health, U.S. Department of Health and Human Service. Developmental Therapeutics Program 2014. Available online:
    1. Du J, Cullen JJ, Buettner GR. Ascorbic acid: chemistry, biology and the treatment of cancer. Biochim Biophys Acta 2012;1826:443-57.
    1. Padayatty SJ, Sun H, Wang Y, et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med 2004;140:533-7. 10.7326/0003-4819-140-7-200404060-00010
    1. Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008;26:1148-59. 10.1200/JCO.2007.12.4487
    1. Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 1999;17:3461-7. 10.1200/JCO.1999.17.11.3461
    1. Nielsen TK, Højgaard M, Andersen JT, et al. Elimination of ascorbic acid after high-dose infusion in prostate cancer patients: a pharmacokinetic evaluation. Basic Clin Pharmacol Toxicol 2015;116:343-8. 10.1111/bcpt.12323
    1. Tsao CS, Salimi SL. Evidence of rebound effect with ascorbic acid. Med Hypotheses 1984;13:303-10. 10.1016/0306-9877(84)90163-4
    1. A'Hern RP. Sample size tables for exact single-stage phase II designs. Stat Med 2001;20:859-66. 10.1002/sim.721
    1. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-12. 10.1056/NEJMoa040720
    1. Lykkesfeldt J. Ascorbate and dehydroascorbic acid as reliable biomarkers of oxidative stress: analytical reproducibility and long-term stability of plasma samples subjected to acidic deproteinization. Cancer Epidemiol Biomarkers Prev 2007;16:2513-6. 10.1158/1055-9965.EPI-07-0639
    1. Halabi S, Small EJ, Kantoff PW, et al. Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol 2003;21:1232-7. 10.1200/JCO.2003.06.100
    1. Smaletz O, Scher HI, Small EJ, et al. Nomogram for overall survival of patients with progressive metastatic prostate cancer after castration. J Clin Oncol 2002;20:3972-82. 10.1200/JCO.2002.11.021
    1. Ulmert D, Kaboteh R, Fox JJ, et al. A novel automated platform for quantifying the extent of skeletal tumour involvement in prostate cancer patients using the Bone Scan Index. Eur Urol 2012;62:78-84. 10.1016/j.eururo.2012.01.037
    1. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010;140:883-99. 10.1016/j.cell.2010.01.025
    1. Grivennikov SI, Karin M. Inflammation and oncogenesis: a vicious connection. Curr Opin Genet Dev 2010;20:65-71. 10.1016/j.gde.2009.11.004
    1. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55. 10.1097/00000421-198212000-00014
    1. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365-76. 10.1093/jnci/85.5.365
    1. van Andel G, Bottomley A, Fosså SD, et al. An international field study of the EORTC QLQ-PR25: a questionnaire for assessing the health-related quality of life of patients with prostate cancer. Eur J Cancer 2008;44:2418-24. 10.1016/j.ejca.2008.07.030
    1. National Cancer Institute, U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events v4.0. 2010. Available online:
    1. Jacobs C, Hutton B, Ng T, et al. Is there a role for oral or intravenous ascorbate (vitamin C) in treating patients with cancer? A systematic review. Oncologist 2015;20:210-23. 10.1634/theoncologist.2014-0381
    1. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371:424-33. 10.1056/NEJMoa1405095
    1. 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 2007;25:3965-70. 10.1200/JCO.2007.11.4769
    1. Petrylak DP, Ankerst DP, Jiang CS, et al. Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG 99-16. J Natl Cancer Inst 2006;98:516-21. 10.1093/jnci/djj129
    1. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010;363:411-22. 10.1056/NEJMoa1001294
    1. Huijskens MJ, Walczak M, Sarkar S, et al. Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. Cytotherapy 2015;17:613-20. 10.1016/j.jcyt.2015.01.004
    1. Porkkala-Sarataho E, Salonen JT, Nyyssönen K, et al. Long-term effects of vitamin E, vitamin C, and combined supplementation on urinary 7-hydro-8-oxo-2'-deoxyguanosine, serum cholesterol oxidation products, and oxidation resistance of lipids in nondepleted men. Arterioscler Thromb Vasc Biol 2000;20:2087-93. 10.1161/01.ATV.20.9.2087
    1. Colloca G. Prostate-specific antigen kinetics as a surrogate endpoint in clinical trials of metastatic castration-resistant prostate cancer: a review. Cancer Treat Rev 2012;38:1020-6. 10.1016/j.ctrv.2012.03.008
    1. Scott N, Fayers P, Aaronson NK, et al. EORTC QLQ-C30 reference values. 2008. Available online:
    1. Yeom CH, Jung GC, Song KJ. Changes of terminal cancer patients’ health-related quality of life after high dose vitamin C administration. J Korean Med Sci 2007;22:7-11. 10.3346/jkms.2007.22.1.7
    1. Takahashi H, Mizuno H, Yanagisawa A. High-dose intravenous vitamin C improves quality of life in cancer patients. Per Med Universe 2012;1:49-53. 10.1016/j.pmu.2012.05.008
    1. Stephenson CM, Levin RD, Spector T, et al. Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemother Pharmacol 2013;72:139-46. 10.1007/s00280-013-2179-9
    1. Hoffer LJ, Levine M, Assouline S, et al. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol 2008;19:1969-74. 10.1093/annonc/mdn377
    1. Miller M, Boyer MJ, Butow PN, et al. The use of unproven methods of treatment by cancer patients. Frequency, expectations and cost. Support Care Cancer 1998;6:337-47. 10.1007/s005200050175
    1. Zachariae R, Johannessen H. A Methodological Framework for Evaluating the Evidence for Complementary and Alternative Medicine (CAM) for Cancer. Cancers (Basel) 2011;3:773-88. 10.3390/cancers3010773
    1. Bonacchi A, Toccafondi A, Mambrini A, et al. Complementary needs behind complementary therapies in cancer patients. Psychooncology 2015;24:1124-30. 10.1002/pon.3773
    1. Lee AY, Levine MN. Venous thromboembolism and cancer: risks and outcomes. Circulation 2003;107:I17-21. 10.1161/
    1. Monti DA, Mitchell E, Bazzan AJ, et al. Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. PLoS One 2012;7:e29794. 10.1371/journal.pone.0029794
    1. Kuiper C, Vissers MC, Hicks KO. Pharmacokinetic modeling of ascorbate diffusion through normal and tumor tissue. Free Radic Biol Med 2014;77:340-52. 10.1016/j.freeradbiomed.2014.09.023
    1. Sinnberg T, Noor S, Venturelli S, et al. The ROS-induced cytotoxicity of ascorbate is attenuated by hypoxia and HIF-1alpha in the NCI60 cancer cell lines. J Cell Mol Med 2014;18:530-41. 10.1111/jcmm.12207
    1. Pollard HB, Levine MA, Eidelman O, et al. Pharmacological ascorbic acid suppresses syngeneic tumor growth and metastases in hormone-refractory prostate cancer. In Vivo 2010;24:249-55.
    1. Chen Q, Espey MG, Sun AY, et al. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci U S A 2008;105:11105-9. 10.1073/pnas.0804226105
    1. Verrax J, Calderon PB. Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects. Free Radic Biol Med 2009;47:32-40. 10.1016/j.freeradbiomed.2009.02.016

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