Control of Prostate Cancer Associated With Withdrawal of a Supplement Containing Folic Acid, L-methyltetrahydrofolate and Vitamin B12

A Case Report

Glenn Tisman; April Garcia

Disclosures

J Med Case Reports. 2011;5(413) 

In This Article

Abstract and Introduction

Abstract

Introduction: This is the first report of possible direct stimulation of hormone-resistant prostate cancer or interference of docetaxel cytotoxicity of prostate cancer in a patient with biochemical relapse of prostatic-specific antigen. This observation is of clinical and metabolic importance, especially at a time when more than 80 countries have fortified food supplies with folic acid and some contemplate further fortification with vitamin B12.
Case presentation: Our patient is a 71-year-old Caucasian man who had been diagnosed in 1997 with prostate cancer, stage T1c, and Gleason score 3+4 = 7. His primary treatment included intermittent androgen deprivation therapy including leuprolide + bicalutamide + deutasteride, ketoconazole + hydrocortisone, nilandrone and flutamide to resistance defined as biochemical relapse of PSA. While undergoing docetaxel therapy to treat a continually increasing prostate-specific antigen level, withdrawal of 10 daily doses of a supplement containing 500 μg of vitamin B12 as cyanocobalamin, as well as 400 μg of folic acid as pteroylglutamic acid and 400 μg of L-5-methyltetrahydrofolate for a combined total of 800 μg of mixed folates, was associated with a return to a normal serum prostatic-specific antigen level.
Conclusion: This case report illustrates the importance of the effects of supplements containing large amounts of folic acid, L-5-methyltetrahydrofolate, and cyanocobalamin on the metabolism of prostate cancer cells directly and/or B vitamin interference with docetaxel efficacy. Physicians caring for patients with prostate cancer undergoing watchful waiting, hormone therapy, and/or chemotherapy should consider the possible acceleration of tumor growth and/or metastasis and the development of drug resistance associated with supplement ingestion. We describe several pathways of metabolic and epigenetic interactions that could affect the observed changes in serum levels of prostate-specific antigen.

Introduction

The clinical course of our patient with hormone-refractory or hormone-resistant prostate cancer appears to have been affected by ingestion followed by withdrawal of a vitamin supplement containing a mixture of large amounts of folic acid (FA), L-methyltetrahydrofolate (L-methyl-THF, or folate) and cyanocobalamin (vitamin B12). Prior to supplement withdrawal, the patient had been treated with docetaxel for 18 weeks but had a continuous rise in serum prostatic-specific antigen (PSA) levels. Only after withdrawal of the supplement did the patient's elevated serum PSA level return to normal (from 22 ng/mL to 2.08 ng/mL).

Biological and Clinical Background

In 1946, Lewisohn et al.[1] reported the effects of pteroylglutamic acid (teropterin) and FA (defined as liver Lactobacillus casei factor) on mice with spontaneous breast cancer. Careful examination of their results revealed that the newly discovered FA stimulated, in a dose-dependent fashion, the growth and metastasis of spontaneous murine breast tumors and shortened overall survival. Two years later Heinle and Welch[2] reported FA stimulation of chronic myelogenous leukemia (CML) in three patients so inflicted. In 1948, Farber[3] referred to an "acceleration phenomenon" observed while treating 10 children with leukemia with pteroylglutamic acid (diopterin) and teropterin. In 1950, Skipper et al.[4] reported that large doses of FA alone and in combination with aminopterin modulated the survival of mice with the transplanted acute Ak4 strain of leukemia. He surmised that FA is a rate-controlling factor in Ak4 leukemia. An excess of FA clearly accelerated the leukemic process, causing the animals to die before untreated controls. Acceleration of CML by vitamin B12 in patients with pernicious anemia was reported by Corcino et al. in 1971[5] and Green in 1994.[6] In 2009, Tisman et al.[7] presented evidence for the acceleration of prostate cancer dedifferentiation during vitamin B12 depletion and prostate cancer acceleration in response to vitamin B12 administration in a patient with localized prostate cancer and pernicious anemia. In 2009, Figueiredo et al.[8] reported the results of a large, randomized, controlled clinical trial carried out over 10 years in which a group of men received 1000 μg of oral FA daily. They observed a near tripling of the incidence of prostate cancer compared to controls. Finally, a report by Lawson et al.[9] published in 2007 described a direct relationship between prostate cancer stage and multivitamin use. During that period, most multivitamins contained an additional 400 μg of FA.

Case Presentation

Our patient is a 71-year-old Caucasian man who had been diagnosed in 1997 with prostate cancer. His baseline PSA level was 8 ng/mL. All six biopsy cores contained 90% Gleason scores of 3+4 = 7 adenocarcinoma, and peri-neural invasion was observed. The patient's clinical stage was T1c. He elected therapy with intermittent androgen deprivation (IAD) with flutamide, leuprolide, and finasteride. In 2007, after the third cycle of IAD, his PSA level slowly increased into the 3 ng/mL range and his serum testosterone remained < 20 ng/dl. Sequential anti-androgen withdrawal, ketoconazole, diethylstilbestrol, estramustine, and transdermal β-estradiol, along with a trial of low-dose oral cyclophosphamide and capecitabine, all while he was being treated with leuprolide maintenance therapy, were either transiently effective or unsuccessful.

The patient was restaged, with a bone scan and computed tomography yielding only evidence of biochemical PSA relapse. He then received docetaxel 30 mg/m2 for three of every four weeks while his leuprolide treatment was continued. His PSA level continued to rise exponentially for 18 weeks, thus we assumed docetaxel resistance. The patient revealed that he was ingesting a supplement of 10 daily dose units of Intrinsi B12/folate (Metagenics, San Clemente, CA, USA. Each dose unit contained 20 mg of porcine intrinsic factor and 500 μg of vitamin B12, as well as 400 μg of FA, and 400 μg of L-5-methyltetrahydrofolate (for a total of 800 μg of mixed FAs). On 11 February 2010, his PSA level reached 21.3 ng/mL, and on 25 February 2010, his serum FA level was assayed to be 134 ng/mL (normal range 5 ng/mL to 24 ng/mL), his serum vitamin B12 level was > 1500 pg/mL (normal range 300 pg/mL to 900 pg/mL), his serum testosterone level was < 20 ng/mL (normal range 212 ng/mL to 755 ng/mL), and his total serum homocysteine was 12.0 μmol/L (normal range 7 μmol/L to 12 μmol/L).

The patient discontinued the oral supplement on day 900 (Figure 1), and within two weeks his serum PSA level started to decline. At the time of this writing, his PSA level is 2.08 ng/mL. He continues to receive weekly docetaxel chemotherapy. His last serum FA level was 4.0 ng/mL (borderline deficient), his serum vitamin B12 level was 377 pg/mL, and his total serum homocysteine level was 17.8 μmol/L.

Figure 1.

The clinical course of our patient's prostatic-specific antigen response.

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