Vitamin C and cancer: what can we conclude--1,609 patients and 33 years later: comment on the article by Cabanillas.
Article Type: Letter to the editor
Subject: Vitamin C (Health aspects)
Medical research (Health aspects)
Medicine, Experimental (Health aspects)
Cancer (Care and treatment)
Cancer (Health aspects)
Authors: Gonzalez, Michael J.
Miranda-Massari, Jorge R.
Duconge, Jorge
Pub Date: 12/01/2010
Publication: Name: Puerto Rico Health Sciences Journal Publisher: Universidad de Puerto Rico, Recinto de Ciencias Medicas Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 Universidad de Puerto Rico, Recinto de Ciencias Medicas ISSN: 0738-0658
Issue: Date: Dec, 2010 Source Volume: 29 Source Issue: 4
Product: Product Code: 8000200 Medical Research; 9105220 Health Research Programs; 8000240 Epilepsy & Muscle Disease R&D; 8000432 Cancer Therapy NAICS Code: 54171 Research and Development in the Physical, Engineering, and Life Sciences; 92312 Administration of Public Health Programs; 621 Ambulatory Health Care Services SIC Code: 2833 Medicinals and botanicals
Accession Number: 244280056
Full Text: To the Editor:

Our group (RECNAC 2) has been at the forefront of the Vitamin C and Cancer research for the past decade and many of our papers have been published in this journal including in-vitro, animal and clinical studies (1-7). In addition, we authored a review paper on Vitamin C and Cancer published in 2005 (8) which is currently the third most cited article in the peer reviewed journal Integrative Cancer Therapies. We would like to respond to the review on the topic by Dr. Cabanillas.

We would like to point out and discuss certain misleading statements written in this review. The first inaccurate statement is in the title, it is not only 1,609 cancer patients that have been treated with IV Vitamin C. The Center for the Improvement of Human Functioning (now Riordan Clinic) has treated at least 1,500 Cancer patients with IV Vitamin C (9). In addition, The Cancer Treatment Centers of America have treated Cancer patients with IV Vitamin C and many physicians in many countries have also used this therapy for years. In a recent publication (10) it was documented that thousands of cancer patients have been treated each year with intravenous vitamin C in USA (1379 in 2006 and 1509 in 2008).

In order to clarify the facts, in the 1976 Cameron-Pauling Study (on prolongation of survival times with supplemental Vitamin C) the actual protocol was 10g/day by intravenous infusion for 10 days and orally thereafter. The study was criticized because of the use of historic controls. Dr. Cabanillas claims that the experimental group (Vitamin C) was declared terminally ill much sooner than the control group to create a longer survival time. There is absolutely no credible data to support this claim. Dr. Cabanillas cites as a source for this claim, a non peered review publication (Your Patient and Cancer) in which the author "reasoned" that to obtain these results the experimental group must have been declared terminally ill sooner. The third double-blind study cited was not a published paper but an abstract presented in 1983. The discrepancy between the findings of these studies and the Cameron -Pauling studies, may be due mainly to the route of administration of ascorbate. The Cameron -Pauling group administered Vitamin C both orally and intravenously while the Mayo Clinic group gave it exclusively by the oral route.

The first Phase I study done with Vitamin C and terminally ill cancer patients is the Riordan study (6). As all Phase I studies, it was done to establish safety, pharmacokinetics and dose ranging; it was not designed to assess response to treatment. Nevertheless Dr. Cabanillas claims that nobody responded to ascorbate but it is documented that at least one patient had stable disease and continued treatment for 48 weeks.

There is published information on the plasma level of Vitamin C that can reduce tumor growth. Doses of 50-100 g given intravenously may result in plasma concentrations of about 14,000 micromol/L. At concentrations above 1000 micromol/L, vitamin C is toxic to cancer cells but not to normal cells in vitro. Infusions of 60 g of Vitamin C produced peak plasma concentrations exceeding 20 mM with an area under the curve (24 h) of 76 mM per hour. Thus, tumoricidal concentrations of Vitamin C may be achievable in vivo. However, it is important that when referring to the plasma concentrations necessary to achieve antineoplastic activity there are other numerous factors involved that will affect the specific response. Some of these include sensitivity of tumor, hypoxia inducible factor, intracellular RedOx signal transduction and gene expression, apoptosis, autoschizis, effect of collagen on tumor encapsulation and others.

Despite its remarkable safety profile, adverse effects can occur with intravenous vitamin C. But when compared to chemotherapy, these negative effects are extremely rare and occur basically in people with previous specific medical problems. In a recent publication (10) of a total 20,109 patients very few renal side effects were reported. In 11,233 patients in 2006, there were a total of two kidney stone reports and no renal failure was reported. In 2008 of a total of 8,876 patients, two kidney stones were reported (one oxalate and one urate) and one renal failure in a patient with previous renal problems that had a partial renal failure and was suffering of metastases to kidneys.

Moreover, in another published phase I trial of high dose intravenous vitamin C in advanced malignancy, adverse effects were minimal at all dose levels. In a study to assess the risk of oxalate crystallization in the urinary space, it was found that less than 0.5% of a very large intravenous dose of ascorbic acid is recovered as urinary oxalic acid in people with normal renal function.

Research in vitamin C and cancer has increased substantially in the past five years and the preponderance of the evidence demonstrates its effectiveness inhibiting and killing a wide variety of tumor cell lines. In addition, it has been shown to improve quality of life in Cancer patients. In light of the safety of high dose intravenous vitamin C, its antitumor activity and its multiple physiological benefits, it seems a fair option in the treatment of cancer patients, especially when dealing with cases that do not respond to chemotherapy while producing serious toxic effects. In light of the evidence that the use of vitamin C and other nutrients can reduce the toxicity of chemotherapy and might even improved tumor response and survival, a more open and earnest discussion (and research) is warranted.

We agree with Dr. Cabanillas that vitamin C has not received a fair and adequate trial and that more studies are needed. There is no absolutely reliable cure for cancer. Conventional chemotherapy contributes only 2.1% to the five year cancer survival in the USA. For the past 50 years there has been practically no change in Cancer mortality rates. These are the main reasons we pursue a non-toxic protocol for Cancer Treatment. Based on the available published evidence i.v. Vitamin C is a step forward in achieving this goal.

Michael J. Gonzalez, PhD; Jorge R. Miranda-Massari, PhD; & Jorge Duconge, PhD

RECNAC II Project, University of Puerto Rico Medical Sciences Campus

San Juan, Puerto Rico

References

(1.) Gonzalez MJ, Mora EM, Miranda-Massari JR, et al. Inhibition of Human Breast Carcinoma Cell proliferation by Ascorbate and Copper. PR Health Sci J 2002;21:21-23.

(2.) Gonzalez MJ, Miranda-Massari JR, Mora EM, et al. Orthomolecular Oncology: a Mechanistic View of Intravenous Ascorbate Chemotherapeutic Activity. PR Health Sci J 2002;21: 39-41.

(3.) Riordan HD, Hunninghake RB, Riordan NH, et al. Intravenous Ascorbic Acid: Protocol for its Application and Use. PR Health Sci J 2003;22: 225-232.

(4.) Riordan HD, Riordan NH, Jackson JJ, et al. Intravenous Vitamin C as a Chemotherapy Agent: A report on Clinical Cases. PR Health Sci J 2004;23:115-8.

(5.) Casciari JJ, Riordan HD, Miranda-Massari JR and Gonzalez MJ. Effects of High Dose Ascorbate Administration on L-10 Tumor Growth in Guinea Pigs. PR Health Sci J 2005;24:145-150.

(6.) Riordan HD, Casciari JJ, Gonzalez MJ, Riordan NH, Miranda -Massari JR, Taylor P and Jackson JA. A pilot clinical study of continuous intravenous ascorbate in terminal cancer patients. PR Health Sci J 2005;24:269-276.

(7.) Duconge J, Miranda-Massari JR, Gonzalez MJ, Riordan N and Warnock W. Pharmacokinetics of Vitamin C: Insights into the Oral and Intravenous Administration of Ascorbate. PR Health Sci J 2008;27:7-19.

(8.) Gonzalez MJ, Miranda-Massari JR, Mora EM, Guzman A, Riordan NH, Riordan HD, Casciari JJ, Jackson JA, Roman-Franco A. Nutritional Oncology Review: Ascorbic Acid and Cancer: 25 years later. Integr Cancer Ther 2005;4:32-44.

(9.) Personal Communication, Dr. Ron Hunninghake, Riordan Clinic, Wichita, Kansas.

(10.) Padayatty SJ, Sun AY, Chen Q, Espey MG, Drisko J, Levine M. Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS One 2010;5:e11414.

Reply

To the Editor:

Although not a Vitamin C expert, as an experienced investigator and board certified oncologist, I feel qualified to pass judgment and assess the value of cancer clinical trials with this agent.

Both Dr. Saul and Gonzalez bring up the Cameron-Pauling study (1) which I criticized in my article because of its three major flaws:

1. The study was totally retrospective in nature.

2. They failed to provide any data to demonstrate that the patients in the control and Vitamin C groups were matched by tumor stage, performance status, and other important prognostic variables. We teach our fellows in hematology-oncology early on during their training the importance of obtaining a balanced distribution of prognostic factors in both the control and experimental groups. This is a fundamental and critical principle behind any legitimate research study. I am astonished that Gonzalez et al are willing to accept Cameron's and Pauling's conclusions without proof that the Vitamin C and control groups were balanced in their distribution of prognostic features.

3. According to the authors, patients were started on Vitamin C when they were judged to be untreatable or terminal and their subsequent survival was compared to that of the control patients from the time they had also been labeled as terminal. Because survival was measured from the time the patients were declared terminally ill to the time when they died, if the Vitamin C group was labeled terminal sooner than the control group that would result in an artificially longer survival for those assigned to receive Vitamin C. Gonzalez et al state that "There is absolutely no credible data to support this claim." Allow me to review the reasoning and the data behind my allegation which I credit to Dr. William DeWys, who was chief of the clinical investigations branch of the National Cancer Institute's cancer therapy program (2). Logic tells us that if the Vitamin C and control groups were truly comparable, the average time from the initial diagnosis to terminal status should be similar for both groups, yet according to Dr. DeWys' investigations, they were not. For that reason he deduced that many of the Vitamin C patients had been labeled as terminal earlier in the course of their disease and would therefore be expected to live longer. DeWys also pointed out that more than 20% of the patients in the control group had died within a few days of being declared terminal, while none of the Vitamin C patients died early on. It is highly unlikely that Vitamin C had such a quick positive impact on their survival. This observation also implies that the Vitamin C group had less advanced disease at the time they were labeled terminal. Perhaps Gonzalez et al and Saul have a justification for these inconsistencies but they didn't offer an explanation for them in their letters.

Dr. Saul claims that Cameron's study was confirmed by Murata et al (3). I couldn't obtain that paper published in 1982 in a journal that ceased to exist in 1989. Dr. Saul was kind enough to provide me with a copy of the article. I was equally disappointed to find out that Murata et al, instead of conducting a prospective study to confirm Cameron's hypothesis, performed the same type of retrospective comparison with the same structural problems as the Cameron-Pauling study. Furthermore, in the Murata study the treatment and co ntrol groups received various doses and at different times, which make their conclusions even more dubious.

Dr. Saul states that he knows how effective Vitamin C is against cancer. He sustains that "there are many controlled studies that demonstrate that Vitamin C improves both length and quality of life". Unfortunately he fails to submit those "controlled studies". Certainly the Cameron-Pauling and the Murata studies can't be considered as well controlled studies. Dr. Saul states that "what is dangerous is warning people off the very therapy that may help them". He quotes Dr. Victor Marcial who claims that he has treated 40 patients with advanced cancer and obtained a response rate of 75%. I have personally asked Dr. Marcial if he had an IRB approved protocol to conduct such research and surprisingly his reply was that he did not. To say the least, this is a dangerous, unethical conduct and a serious breach of professional behavior. Furthermore, basing conclusions on a clinical trial conducted without a protocol is unscientific, improper and deplorable. Finally, Dr. Marcial, as a well trained radiation oncologist, should very well know that cancer is an extremely heterogeneous group of disorders. For example, results of treatment for lung cancer are very different to lymphoma. For that reason, serious, self-respecting investigators don't report the results of a broad phase II trial in "advanced cancer" without specifying what type of cancers were treated and which responded. To say that Vitamin C has a 75% response rate in "advanced cancer" is absurd.

Gonzalez et al fill up a lot of space in their letter reviewing pharmacology data. They also mention two phase I studies but fail to mention a single prospective phase II or III clinical trial using high dose intravenous Vitamin C. Unless Gonzalez et al can provide information to the contrary, which they did not in their letter, I stand by my assertion "that we still do not know whether Vitamin C has any clinically significant antitumor activity" (4). I also stand by my statement that "a phase II study using 1.5 g/kg three times weekly would be in order so as to establish if there is any hint of antitumor activity." There are more than enough pharmacology studies on Vitamin C but when are the obligatory prospective phase II-III cancer clinical trials going to be performed with high dose I.V. Vitamin C?

Fernando Cabanillas, MD

Director of Auxilio Mutuo Hospital Cancer Center

San Juan, Puerto Rico

References

(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.

(2.) DeWys W. How to evaluate a new treatment for cancer. Your Patient and Cancer 1982;2:31-6.

(3.) Murata A, Morishige F, Yamaguchi H. Prolongation of survival times of terminal cancer patients by administration of large doses of ascorbate. Int J Vitam Nutr Res Suppl 1982;23:103-13.

(4.) Cabanillas F. Vitamin C and cancer: what can we conclude--1,609 patients and 33 years later? P R Health Sci J 2010;29:215-7.
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