The Use of Vitamin C with Chemotherapy in Cancer Treatment: An Annotated Bibliography – 2

JOM Archives – Volume 19, Number 4, 2004

Continued from ‘The Use of Vitamin C with Chemotherapy in Cancer Treatment: An Annotated Bibliography – 1’

 

Positive Reviews (Table 2)

 

Review 1. 1993
Hoffer A: Orthomolecular Oncology. In Quillin P; Williams RW (eds.). Adjuvant Nutrition in Cancer Treatment, 1992 Symposium Proceedings, Cancer Treatment Research Foundation, Arlington Heights, Illinois, USA, 1993.

Summary

Hoffer wrote: “Orthomolecular oncology is the treatment of cancer by the pro- vision of the optimal molecular environment for the body, especially the optimal concentrations of substances normally present in the human body. This does not mean that this treatment is an alternative or is antagonistic to standard therapy using toxic drugs in sublethal doses (xenobiotics). In my opinion, the optimum treatment for cancer today, imperfect as it is, is orthomolecular therapy combined with xenobiotic therapy.”

In this article, Hoffer reported on the 1990 Hoffer and Pauling study mentioned in the above section. Following that study, as a result of a possible concern by “critics” regarding “validity”, another study was conducted for comparison. (The writer does not know the date of the study as it was not mentioned before. However, it may be 1990 or shortly thereafter as the results were known before 1992 as per below.) That study comprised the 101 original treated patients and 19 untreated patients from the original 33 controls (14 of whom had died).

With regard to survival time, the result of this comparison study showed: “The difference in outcome between these two groups [remained] large. In the first year, 75% of the group not on the orthomolecular program died, and at the end of five years only 5% were alive. From the orthomolecular group, 25% died by the end of the first year, and at the end of the 5th year 39% were alive. By January 1, 1992, 41 patients were still alive. The average duration of life from the time I first saw them until this date was 49 months, compared with 15 months for the group treated with xenobiotic therapy only.”
These results supported the investigators’ “conclusion that orthomolecular treatment combined with xenobiotic treatment is much superior to xenobiotic therapy alone.” However, Hoffer stated: “As a clinician who has worked with patients for 42 years, I still think the original control group [of 33] is the sounder one to use scientifically.” The author continued: “Twenty patients out of 59 (34%) survived 8 years. They were first seen between 1978 and 1984. From the remaining 75, seen between 1985 and 1988, 22 (29%) survived 4 years. This suggests that over the four years this group will also yield a 25% 8-year survival.”

Finally, with regard to quality of life, the results of the 1990 study showed that the mineral-vitamin treatment enhanced the life of the patients. Here, Hoffer elaborated on that enhancement. He stated: “It is difficult to measure quality of life, but it is relatively easy to find out whether the patients and their families were more comfortable, suffered less pain, and remained more functional…. I have not had a single complaint from my patients that they suffered more pain and discomfort. This contrasts strongly with xenobiotic therapy, which is characterized by severe discomfort of many kinds, nausea, fatigue of long duration, loss of hair, etc. Orthomolecular therapy tends to decrease the discomfort caused by xenobiotic therapy. This is also difficult to quantify, but I believe my patients were telling me what really happened when they reported that they were able to tolerate radiation and chemotherapy better.” Hoffer added: “Their surgeons often were surprised by their rapid recovery from surgery.” He noted: “They were discharged very quickly from the hospital.”

 

Review 2. 1995
Moss RW: Questioning Chemotherapy. Equinox Press, New York, 1995, chapter 9.

Summary

One of the topics examined by this book is the quality of life that results from the use of chemotherapy and non-toxic substances alone or in combination. Antioxidants, including vitamin C, used in conjunction with chemotherapy have been found to enhance the life of cancer patients.

Moss cited two studies which showed vitamin C’s effectiveness:

(1) “vitamin C increased the cell-killing ability of chemotherapy [Block 1991].” (2) vitamin C “blocked heart damage associated with the drugs doxorubicin (Adriamycin) and interleukin – 2 [Skimpo 1991]” – seen elsewhere in this presentation as well.
Moss quotes Linus Pauling [1987]: ‘Vitamin C … controls to a considerable extent the disagreeable side effects of the cytotoxic chemotherapeutic agents, such as nausea and loss of hair, and that benefit seems to add its value to that of the chemotherapeutic agent.’

Finally, with regard to the concern of some doctors that “by reducing toxic side effects one may inadvertently decrease the effectiveness of cytotoxic drugs”, Moss cited Simone (1994). The latter reported that there are “dozens of studies suggesting an enhanced killing of cancer cells by adding vitamin supplements, especially antioxidants to chemotherapy.”
Review 3. 1999
Prasad KN, Kumar A, Kochupillai V, Cole WC: High Doses of Multiple Antioxidant Vitamins: Essential Ingredients in Improving the Efficacy of Standard Cancer Therapy. Journal of the American College of Nutrition, 1999; 18/1: 13-25.

Summary

Prasad et al. wrote: “Numerous articles and several reviews have been published on the role of antioxidants, and diet and lifestyle modifications in cancer prevention. However, the potential role of these factors in the management of human cancer have been largely ignored.”

The authors also stated: “The efficacy of standard tumor therapy (…chemo- therapy…) has reached a plateau.” They continued by noting: “The lack of enthusiasm among clinical oncologists for using high doses of antioxidant vitamins in combination with … chemotherapy is primarily based on fear that antioxidant vitamins may protect both normal and cancer cells against free radicals which are generated by … most chemotherapeutic agents. Several in vitro and some in vivo studies suggest that such concerns are not valid.”

Prasad et al. continued: “Based on results of our studies and others, we proposed a hypothesis that supplementation with high doses of multiple antioxidant vitamins, together with diet modification and lifestyle changes may improve the efficacy of standard … cancer therapies by reducing their toxicity on normal cells and by enhancing their growth-inhibitory effects (…) on cancer cells.” The authors continued: “This review will discuss whether or not the above hypothesis can be supported by published … clinical results.”

With regard to the use of multiple antioxidants with chemotherapy, the authors stated: “Several in vitro studies have revealed that vitamin C [as reported by many investigators] … enhance[s] the growth inhibitory effect of most of the currently used chemotherapeutic agents on some cancer cells.” An example was cited with sodium ascorbate and 5-Fluorouracil which showed that the vitamin enhanced the anti-tumor effect of the chemotherapy. The authors noted: “The extent of [the] enhancement depends on the dose and form of vitamin, the dose and type of chemotherapeutic agent and the type of tumor cells.”

Prasad et al. also noted: “The effect of individual antioxidant vitamins in combination with … chemotherapeutic agents has not been tested in human tumors in vivo in a systematic manner.” The authors continued: “Most standard therapeutic agents mediate their effects, in part, by generating free radicals which damage both normal and cancer cells. Therefore, clinical oncologists fear that the use of high doses of antioxidant vitamins during standard cancer therapy might be harmful since they might protect both normal and cancer cells against free radical damage produced by tumor therapeutic agents. The available experimental data suggest that such fear has no scientific basis.”

The authors cited examples including that of vitamin C above that demonstrated clearly: “ … antioxidants do not protect cancer cells against free radical and growth- inhibitory effects of standard therapy. On the contrary, they enhance its growth-inhibitory effects on tumor cells, but protect normal cells against its adverse effects.” The study by Prasad et al. (1994) with combined vitamins and chemotherapy was also noted.

With reference to toxicity, Prasad et al. stated: “The second part of our proposed hypothesis is that antioxidant vitamins in combination with standard therapeutic agents may reduce the toxicity of these agents on normal cells. Several studies using animal models (…) support this hypothesis”- vitamin C is among them. For example, the authors cited a study of vitamin C plus adriamycin (similar to Skimpo 1991) which showed that the vitamin reduced “the adverse effects of adriamycin on normal animal cells.” While in combination with other vitamins, it reduced “bleomycin-induced chromosomal breakage” as reported by other investigators.

“Based on the data … and safety issues,” Prasad et al. recommended certain combined supplements for use “during and after standard therapy”. The formula consisted of the following: “Multiple antioxidant vitamins including B-vitamins and appropriate minerals but without iron, copper and manganese, since these three minerals interact with vitamin C to produce free radicals”.

“Additional 8 grams of vitamin C in the form of calcium ascorbate”, as the use of “10 g or more have been used in human cancer treatment without toxicity” as has been reported. Extra vitamin E and B-carotene made up the formula.

The authors explained that calcium ascorbate was selected over sodium ascorbate because the latter at high doses has been reported to have particular side effects. They also explained the reasons for selecting the other nutrients and their particular doses, and they described the treatment procedure.

In addition, Prasad and coworkers point out: “A low fat (…) and high fiber (…) diet should be continued during and after standard treatment.”

To conclude, Prasad et al. stated: “The proposed recommendations … will test our hypothesis that vitamin supplements, diet, and lifestyle modifications may markedly improve the efficacy of standard … therapies by enhancing their growth-inhibitory effects selectively on tumor cells, and by reducing their toxicity to normal cells.” The authors added: “The proposed recommendation … may also reduce the risk of second malignancies, which are being detected at increased rates among survivors of standard cancer treatment.”

 

Review 4. 1999
Simone CB, Simone NL, Simone II CB: Nutrients and Cancer Treatment. International Journal of Integrative Medicine, 1999; 1: 20-24.

Summary

Simone et al. noted: “Cellular studies, animal studies, and human studies demonstrate that vitamins A, E, C, and K, beta-carotene, and selenium, as single agents or in combination, all protect against the toxicity of adriamycin and enhance its cancer-killing effects.”

With regard to cellular and animal studies, the authors continued: “In vitro cellular studies and animal studies have used vitamins C [and other nutrients] – as single agents or in combination – given concomitantly with chemotherapy, or tamoxifen, or interferon alpha-2b, or radiation, or combinations of these modalities. They all show the same effect: Increased tumor killing and increased protection of normal tissues.”

In reference to the effectiveness of antioxidants as anti-cancer agents, Simone et al. stated: “Antioxidants protect normal cells and other tissues by fighting free radicals and the oxidative reaction that free radicals cause.” Vitamin C is among these antioxidants.

Finally, the authors, as their contribution to cancer treatment, recommend a program consisting of 22 vitamins, minerals and other nutrients – “Dr. Simone’s Recommended Nutrients/Dosages.”

 

Review 5. 1999
Moss RW: Cancer Therapy: The Independent Consumer’s Guide to Non-Toxic Treatment and Prevention. Equinox Press, New York, 1999.

Summary

The purpose of Moss’ book is two-fold: (1) “to provide the person with cancer [and future cancer patients] with useful information on cancer alternatives”, and (2) “to aid the patient to better exercise freedom of choice in medical care.” To this end, the author presented “nearly 100 non-toxic and less-toxic treatments for cancer” and their “effectiveness and safety” as cited in “nearly 1000 references” from international scientific journals. Treatment with vitamin C alone or in combination with chemotherapy is among the methods used.

The following treatments using vitamin C alone or in combination were shown to work “well in conjunction with conventional treatments, by either enhancing their cell-killing power or decreasing toxic side effects.”

Moss cited studies by Hoffer and Pauling 1990 and 1993 re: combined vitamin-mineral treatment and survival time, Meadows et al. 1991 re: vitamin C and cell- killing and side effects and Skimpo et. al. 1991 re: vitamin C and toxicity of adriamycin. All the cited studies are reviewed elsewhere in this publication.

To conclude, Moss acknowledged the toxicity of high dose vitamin C “under certain circumstances” but noted that by reducing the dosage or changing to another form, the “symptoms can be relieved”. Therefore, he continued, “vitamin C appears to be a very non-toxic substance, which most people can take in large amounts for long periods of time without harm.”

 

Review 6. 1999
Lamson DW, Brignall MS: Antioxidants in Cancer Therapy: Their Actions and Inter- actions with Oncologic Therapies. Alternative Medicine Review, 1999; 4/5: 304-329.

Summary

In this review, Lamson and Brignall presented summaries of the use of antioxidants alone in cancer therapy and as an adjunct to chemotherapy. The authors acknowledged the concern of investigators that antioxidants might “decrease the effectiveness” of chemotherapeutic agents. However, they noted that it had been demonstrated – with a few exceptions – that certain antioxidants including vitamin C were effective with chemotherapy. The review also provided an extensive bibliography.

Lamson and Brignall reported on the following studies: Taper et al. 1987 re: vitamin C plus vitamin K3 given before chemotherapy which showed that the combined vitamin treatment “increased survival and the effect of several chemotherapeutic agents (…) in a murine ascitic liver tumor model.” It was shown that the C+K3 treatment “did not increase the toxicity of these agents to healthy tissue.” A certain characteristic of the models showed the antioxidants to be more effective than that of the “cytotoxic treatment alone, suggesting an immune-stimulating action of the vitamins.”

Skimpo et al. 1991 re: vitamin C plus doxorubicin (adriamycin) which showed that the combination “led to a reduction in the toxicity seen with doxorubicin alone in mice and guinea pigs”

Chiang et al. 1994 re: vitamin C plus vincristine whereby the vitamin was “shown to increase the drug accumulation and decrease resistance to [it] in human non-small-cell lung cancer cells in vitro. An ascorbic acid-sensitive uptake mechanism was theorized to explain these results.”

Wells et al. 1995 re: enhancement by vitamin C in “doxorubicin resistance in human breast cancer cell lines already known to be resistant” as opposed to those that are not.

Kurbacher et al. 1996 re: three chemotherapeutic agents and vitamin C in which the vitamin “at non-cytotoxic concentrations (…) increased the activity of doxorubicin, cisplatin, and paclitaxel in human breast carcinoma cells in vitro.” Doxorubicin had the greatest activity. Lamson and Brignall noted that from these results, the study’s authors noted “that since vitamin C has already shown an ability to reduce the cardiotoxicity of doxorubicin, ascorbic acid and doxorubicin are an attractive future treatment for breast cancer.”

In conclusion, Lamson and Brignall recommended that the time has come “to research the role of [antioxidants] in conventional oncologic treatment, rather than dismiss them as a class based on theoretical concerns.”

 

Review 7. 2000
Conklin KA: Dietary Antioxidants During Cancer Chemotherapy: Impact on Chemotherapeutic Effectiveness and Development of Side Effects. Nutrition and Cancer, 2000; 37/1: 1-18.

Summary

Conklin wrote: “Chemotherapy has long been a cornerstone of cancer therapy. Although extensive research is done on the development of more effective and less toxic antineoplastic agents, much less attention has been paid to factors that may enhance the effectiveness of existing drugs. Nutritional factors may hold a key to enhancing the anticancer effects of chemo- therapy and to reducing or preventing certain chemotherapy-induced side effects.”

The author noted: “Administration of antineoplastic agents results in oxidative stress, i.e., the production of free radicals and other reactive oxygen species (ROS). Oxidative stress reduces the rate of cell proliferation, and that occurring during chemotherapy may interfere with the cytotoxic effects of antineoplastic drugs, which depend on rapid proliferation of cancer cells for optimal activity. Antioxidants detoxify ROS and may enhance the anticancer effects of chemotherapy.”

The author added: “ROS also contribute to side effects that occur only with individual agents, such as doxorubicin-induced cardio- toxicity, cisplatin-induced nephrotoxicity, and bleomycin-induced pulmonary fibrosis. Antioxidants can reduce or prevent many of these side effects, and for some supplements the protective effect results from activities other than their antioxidant properties.”

“This review considers a limited number of dietary supplements that have antioxidant properties or influence cellular antioxidant systems. The emphasis of the review is on those antioxidant supplements that have been most studied with respect to effects on antineoplastic responsiveness or reduction of chemotherapy-induced side effects.” Vitamin C is among these supplements.

In reference to vitamin C and chemotherapy, Conklin reported on several studies, most of them described in this publication.

For example the author cited in vitro studies which showed that vitamin C (1) enhanced “the cytotoxic activity of doxorubicin, cisplatin, paclitaxel, dacarbazine, and bleomycin.” (2) increased “drug accumulation” and “partially [reversed] vincristine resistance of human non-small-cell lung cancer cells.” (3) the author also noted: “Animal studies have shown that vitamin C at 500 mg/kg and 1,000 mg/kg [enhanced] the chemotherapeutic effect of cy-clophosphamide, vinblastine, 5-FU, procarbazine, … (BCNU), and doxorubicin, although other studies found that vitamin C was without effect on the activity of doxorubicin when vitamin C was administered at 2 g/kg/day to mice or 835 mg/kg/ day to guinea pigs.” (4) “In mice and guinea pigs, 2,000 mg/kg/day of vitamin C prevented doxorubicin-induced lipid peroxidation and reduced the acute cardiotoxic effect of doxorubicin.” (5) “Protection against chemotherapy-induced mutagenesis by vitamin C has been demonstrated in cultured human lymphoblastoid cell lines and peripheral blood lymphocytes and after intraperitoneal administration of 3, 5, and 7 g/kg of vitamin C in mitomycin C- treated mice.”

The author also reported on a clinical study that compared treatment with 100 mg or 1,000 mg of vitamin C as follows: “Protection against chemotherapy-induced mutagenesis has been found by Pohl and Reddy [1989] after oral administration of vitamin C to human volunteers. These investigators cultured lymphocytes from 10 volunteers two weeks before and two weeks after daily administration of 100 or 1,000 mg of vitamin C and assessed bleomycin-induced chromosomal damage in each of the cultures. Supplementation with 1,000 mg of vitamin C significantly reduced the chromosomal damage, suggesting that vitamin C may reduce the risk of chemotherapy-induced carcinogenesis. Although supplementation with 100 mg of vitamin C reduced chromosomal damage, the difference did not reach statistical significance.”

In conclusion, Conklin stated: “Dietary supplementation with antioxidants may provide a safe and effective means of enhancing the response to cancer chemo- therapy.” The author continued: “Vitamin E may prove to be an important nutrient for enhancing antineoplastic activity because of its role in preventing lipid peroxidation, thus maintaining the rapid rate of proliferation of cancer cells. Other antioxidants may be important because of their antioxidant properties”. With regard to vitamin C, the author did not mention it specifically, but as reported in the studies above, it seems to fit into the “other” category because of its protection “against lipid peroxidation” and its enhancing and reduction of toxicity activities as reported in the studies above.

Conklin also noted the probable improved quality of life with dietary supplements after chemotherapy. The author wrote: “Quality of life of patients after chemo- therapy may be improved by dietary supplementation with antioxidants that reduce or prevent chemotherapy-induced side effects.” He continued: “Although approved cytoprotectants are available” as reported by another investigator, “these agents are not without adverse effects.” He continued: “In contrast, certain dietary antioxidants, in doses that are without adverse effects, can ameliorate some side effects of cancer chemotherapy.” Only coenzyme Q10 in reference to “cardiotoxicity” was mentioned for this activity.

Conklin ended by stating that “much more work is needed to establish a clear role for the use of dietary supplements as an adjunct to cancer chemotherapy.”

 

Review 8 . 2000
Hoffer A: Vitamin C and Cancer. Quarry Press Inc., Kingston, ON, 2000.

Summary

Hoffer wrote that this book “is a collaborative work with Linus Pauling” who originated it, “because of his great interest in vitamin C and cancer”. However, the author stated:

“In spite of his immense prestige, Linus Pauling could not find a publisher who would publish our book.” He continued: “We should have anticipated this response because the Proceedings of the National Academy of Science[s] …, had rejected our first paper.”

The reason that Linus Pauling’s name was not given as co-author is that, as Dr. Hoffer stated, by the time a publisher was found “it was too late to have Dr Pauling participate in the final editing of the book, for he died soon after. After he died I assumed that I could still co-author this book with him, but certain complications made this impossible.”

The purpose of this book is to detail the results of the 1990 Hoffer and Pauling study by “offering the reader the complete case histories” of that study. The author also elaborated on the quality of life of his cancer patients. It is this latter that is summarized here.

The main parts of the presentation are set out under the following chapter headings: New Hope for Cancer Patients; Clinical Nutrition for Treating and Preventing Cancer; Clinical Studies of the Value of Orthomolecular Treatment; Case Histories.

Hoffer, in recognising “the fears of some critics,” stated that “this book is not an attack on the medical profession and the use of the standard methods for treating cancer, which include surgery, radiation, and chemotherapy. Rather, we have attempted to redress the imbalance that exists today between these xenobiotic or drug treatments and nutritional or orthomolecular therapy.” He continued: “It is necessary to let the public know that complementary treatment is available and to alert the press that they should pay as much attention to the newer developments in this field as they do to the standard approaches. It is an attempt to bring nutrition back into medicine, restoring the role it played for hundred of years.”

The new hope is in the survival and quality of life of cancer patients through the use of megavitamins including vitamin C alone, or in combination “as an adjunct to appropriate conventional therapy.” Hoffer pointed out: “An important word in this statement is the adjective ‘appropriate’. If there is good evidence that the proposed conventional therapy has been found to be sufficiently effective in the treatment of other patients with the same kind of cancer to outbalance the disagreeable side effects of the treatment, then the patient should give serious consideration to the possibility of accepting the treatment, but if there is no such evidence, then the patient should reject the proposed therapy.”

Orthomolecular treatment as a complement to chemotherapy has been shown to increase survival time and reduce the side effects of some drugs for certain cancers. The Hoffer regimen was outlined in the 1993 Hoffer and Pauling study as described elsewhere in this document. Hoffer also pointed out: “Oncologists are beginning to emphasize the importance of considering duration and quality of life in measuring response to treatment. Tumor shrinkage alone is no longer considered an adequate measure” and he quoted a Toronto oncologist who agreed with this view.
The author further expounded on the quality of life as seen in his patients by detailing an example. Finally, he reiterated the benefits of orthomolecular treatment with regard to quality of life, side effects from chemotherapy and the program’s palatability. He noted that only those patients who were suffering from severe side effects of chemotherapy, or other associated condition could not follow the regimen.

In conclusion, Hoffer stated: “Orthomolecular therapy provides a step forward in the battle against cancer which must be fully explored. There can be no logical reason today why most of the research funds should go only toward the examination of more chemotherapy and more ways of giving radiation. There must be a major expansion into the use of orthomolecular therapy to sort out the variables and to determine how to improve the therapeutic outcome of treatment.”

In Hoffer’s overall conclusion to the chapter (Clinical Studies of the Value of Orthomolecular Treatment), the last word was for his friend, colleague and collaborator, Dr. Linus Pauling, when he wrote: “Enterprising medical schools should establish chairs in Orthomolecular Oncology, perhaps called the Linus Pauling Chair of Orthomolecular Oncology.”

 

Review 9. 2000
Lamson DW, Brignall MS: Antioxidants and Cancer Therapy II: Quick Reference Guide. Alternative Medicine Review, 2000, Vol. 5, No. 2, pp. 152-163.

Summary

Lamson and Brignall explained: “This guide is meant to be a companion to [their] previous review on effects of antioxidant supplementation during cancer therapy. Widespread use of antioxidant compounds make this an area of increasing interest to oncologists as well as other physicians; hence, the attempt to reduce the findings of a lengthy report to a manageable guide.”

The authors continued: “Reducing complicated interactions to a single sentence can be an oversimplification. In may instances the effect of an antioxidant compound with a certain therapeutic agent may be specific to a particular tumor type, or may vary with dosage of both antioxidant and chemotherapy. This guide is best used as a means of quickly identifying which antioxidants are likely to be indicated or contraindicated with a particular therapeutic agent.”

Lastly, the authors summarized in tables a number of studies, some of which are seen elsewhere in this presentation.

Lamson and Brignall reported on six studies for vitamin C alone or in combination with other vitamins in conjunction with chemotherapy: five studies were positive and one study was negative. The results were as follows:

Positive

(1) Vitamin C in combination “increased [the] therapeutic effect” of cyclophosphamide, doxorubicin, 5-fluorouracil and vincristine (Taper et al. 1987).

(2) Vitamin C “decreased [the] toxicity” of doxorubicin (Skimpo et al. 1991). The authors noted that ‘decreased toxicity ’ referred “to effect on healthy tissue.”

(3) Vitamin C “increased [the] cytotoxic effect” of paclitaxel and cisplatin, as well as in human breast CA [carcinoma] cells of doxorubicin (Kurbacher et al. 1996).

(4) Vitamin C “increased [the] cytotoxic effect” of vincristine (Chiang et al. 1994).

(5) Vitamins C in combination “increased [the] cytotoxic effect” of tamoxifen (Prasad et al. 1994).

Negative

(1) Vitamin C – “ascorbic acid 2-phosphate found no change in drug-sensitive cells and decreased effect in resistant lines of doxorubicin (adriamycin)” (Wells et al. 1995).

Lamson and Brignall concluded by stating: “There are only three presently known examples in which an agent classifiable as an antioxidant has been shown to decrease effectiveness of … chemotherapy in vivo. The vast majority of both in vivo and in vitro studies have shown enhanced effectiveness of standard cancer therapies or a neutral effect on drug action.”

 

Review 10. 2003
Drisko JA, Chapman J, Hunter VJ: The Use of Antioxidant Therapies During Chemotherapy. Gynecologic Oncology, March 2003, Vol. 88, Issue 3, pp. 434-439.

Summary

Drisko et al. wrote: “At the present time, many cancer patients combine some form of complementary and alternative medicine therapies with their conventional therapies. The most common choice of these therapies is the use of antioxidants.”

This article is a review of four antioxidants including vitamin C. The authors noted: “While it is accepted that antioxidants are useful in the reduction of adverse effects of chemotherapy, the prevailing opinion is that antioxidants reduce the effectiveness of chemotherapy and radiation therapy’s neoplastic toxicity [five sources]. However, there is evidence that antioxidants may also be a choice for therapeutic intervention alongside chemotherapy with demonstrated benefit in tumor size reduction and/increased longevity [twelve sources].”

They continued: “Despite the theoretical concern that antioxidant therapies interfere with chemotherapy … by lowering oxidative damage, evidence supporting this mechanism is currently lacking [one source]. In fact, antioxidants act as therapeutic biologic response modifiers and are able to directly induce apoptosis in already established neoplastic cells [five sources]. There is also supportive evidence that antioxidants enhance antitumor effects of chemotherapy in vitro and in vivo [five sources].” Lastly, the authors noted: “It is now recognized that chemotherapy kills tumor cells not by damaging essential biological functions but by initiating programmed cellular responses” and that “mutations that interfere with apoptosis may produce tumor chemotherapy resistance [two sources].”

In reference to vitamin C, Drisko et al. reported from 24 references on the vitamin which showed both positive and negative results of vitamin C alone, or in combination with other vitamins used with chemotherapy, among other descriptions. Three of the studies are reviewed elsewhere in this document.

Drisko et al. concluded: “Currently, evidence is growing that antioxidants may provide some benefit when combined with certain types of chemotherapy. Because of the potential for positive benefits, a randomized controlled trial evaluating the safety and efficacy of adding antioxidants to chemotherapy in newly diagnosed ovarian cancer is underway at the University of Kansas Medical Center.”

 

Review 11, 2003
Tamayo C, Richardson MA: Vitamin C as a Cancer Treatment: State of the Science and Recommendations for Research. Alternative Therapies, 2003; May/June/9/3: 94- 102.

Summary

Tamayo and Richardson stated: “The rise in the use of dietary supplements and herbal medications by patients makes it imperative to reevaluate the past findings of clinical studies. Among unconventional approaches, high-dose vitamin C is one of the most widely used and studied, yet controversial approaches.”

The authors continued: “High doses of vitamin C and other naturally occurring substances are used in orthomolecular medicine as described by the renowned chemist Linus Pauling.” They continued, according to one of the main proponents of orthomolecular medicine: “The primary aim of this approach is to establish an optimal molecular environment, yet the benefits remain unproven and the approach discouraged” by other authors.

“This paper summarizes the evidence for the anti-tumor activity of vitamin C and reviews the biological plausibility supporting the use of high dose vitamin C as a cancer treatment.” Most of the material for this study came from a 1999 Montreal workshop, at which the objective among others, was to “assess the evidence of megadoses of vitamin C alone or with other agents as a cancer treatment.” The findings of this assessment are described here.

By way of introduction, Tamayo et al. briefly recalled an early work by Ewan Cameron, MD, who “used high doses of vitamin C to treat advanced, untreatable cancer in Scotland.” The authors noted: “In 1971, Dr. Cameron conducted a Phase I-II study in patients with advanced, untreatable malignancies and evaluated fifty consecutive cases for minimal/no response growth retardation, cytostasis, tumor regression, or tumor hemorrhage/necrosis” as reported in his 1974 study with Linus Pauling.

Tamayo and Richardson continued: “Approximately 4% of patients had been previously treated with chemotherapy and considered unlikely to respond to standard treatment” as reported in a 1993 book by Cameron and Pauling. This book also outlined positive effects including “reduced tumor progression”.

The present authors continued: “The clinical responses in Scotland suggested a biological basis for further investigation in several cancers. Subsequently, two retrospective studies [1978 and l979 – Cameron and Pauling] compared survival for patients with vitamin C with that of patients treated with conventional treatment and who were matched on gender, age, tumor diagnosis, and clinical stage. Both studies demonstrated significantly improved survival with vitamin C.” Thereafter, Tamayo and Richardson continued: “Increased interest in vitamin C resulted in two randomized, double-blind controlled trials of high dose oral vitamin C that were conducted at the Mayo Clinic. The 1979 study included patients with a variety of advanced cancers [Creagan et al.] and a 1985 trial included patients with advanced colon cancer [Moertel et al.]. Neither found vitamin C beneficial.” However, it was stated by the original investigators (Cameron and Pauling) that the two aforementioned studies were not identical to theirs. Following this controversy, “rational guidelines for testing biological agents such as vitamin C have been developed, and new information has emerged [ten sources].”

Finally, by way of introduction and with regard to safety and toxicity, Tamayo and Richardson noted: “Although data about the effect of high vitamin C concentrations in modifying or enhancing biochemical or molecular function in human tissues is limited, it seems that high doses are safe and lack deleterious toxic effects.” Two authors reported that very high doses – in excess of 2,000 mg “may result in nausea and diarrhea.”

Tamayo and Richardson summarized the findings of the evidence of high dose vitamin C used alone or in combination with chemotherapy in point form. The material for the latter is presented in like manner.

The suggested “mechanisms of action for vitamin C … with conventional chemotherapy” based on several studies were as follows: Enhanced cytotoxicity of conventional chemotherapy [seven sources] Potentiation of chemotherapy … with vitamin K3 [four sources]

[Modulation] and potentiation when combined with [other vitamins] of cytostatic agents (…) [one source]
Increased cisplatin-induced apoptosis [one source]

Reduction of toxicity for select chemotherapy (…) [three sources]
Prevention of adriamycin cardiotoxicity in mice, [one source] and idarubicin genotoxicity and induction of secondary malignancies [two sources]

Reversal of cellular resistance to chemotherapeutic agents [two sources] in MCF-7 breast [one source] and melanoma cells [one source] Many of the above studies are seen elsewhere in this presentation.

Finally, Tamayo and Richardson cited the 1990 Hoffer and Pauling study using orthomolecular medicine, which is also detailed in this presentation, as appearing “to enhance the effectiveness of the conventional treatment [one source].”

To conclude, Tamayo and Richardson stated: “The value of vitamin C as a cancer treatment, alone or in combination with other nutrients, will only be established with scientific studies to determine effectiveness, if any, and appropriate clinical indications and dosages.” The authors continued: Phase I and II studies as well as Phase III investigations are necessary given the plausible evidence from case reports, basic research, and the limitations of prior Phase III research. The types of clinical studies and mechanism of action studies” to be investigated was then described.

 

Review 12, 2003
Houston R: Two Anticancer Mechanisms of Vitamins in Humans: A Review. Townsend Letter for Doctors & Patients, 2003; June/239: 104-106.

Summary

In this review Houston noted:

“Recent literature explains why vita- min C has been both successful and unsuccessful at extending the life of cancer patients. Vitamin C at 10,000 mg/day was effective in the form of sodium ascorbate but not as dry ascorbic acid. The ascorbate solution oxidizes to dehydroascorbate that readily and preferably enters cancer cells and kills them.” The author continued: “However, Abram Hoffer achieved excellent results with ascorbic acid.”

Houston referred to a publication (2001), by a John Boik, which “lists seven traits that distinguish cancer.” Also listed were “some natural compounds [including vitamin C] that are or probably are therapeutic.”

Houston quoted Boik in reference to Hoffer and Pauling 1990, described in Hoffer 2000: ‘My central thesis is that the most successful cancer therapies will be those that target all of these primary events involved in cancer cell survival’.

The author also noted the clinical trials of Cameron mentioned in Cameron and Pauling’s book (1993) and Morishige et al. (1982) in the use of high dose vitamin C. He also noted studies by Tsao et al. (1988) and Agus et al. (1999) with regard to the sodium ascorbate derivative, dehydroascorbate (DHK), and its activity in cancer cell-killing. “Normal cells can control the intake of vitamin C.” The author also mentioned the criticism by Creagan et al. (1979) and Moertel et al. (1985) of the 1976 Cameron and Pauling study. Lastly, Houston mentioned the positive review of Lamson and Brignall (2000) of the use of vitamin C with chemotherapy. The author reported: “High-dose vitamin C can become an oxidizer and kill cancer by a free radical mechanism. Radiation and chemotherapy kill cancer by the same mechanism but also kill normal cells.” Two of the above studies and the review are presented elsewhere in this publication.

In summary, Houston stated: “The single, non-randomized clinical test by Hoffer is not scientific proof.” However he acknowledged that patients are concerned with usability, safety, contraindication and helpfulness. He added: “Hospitals and HMO’s might investigate the possible savings by vitamin augmentation. The vitamins are exceedingly safe compared to standard cancer therapies. The probability of a more comfortable and longer life is high. Side effects and costs with vitamins are low. Vitamins C in the form of oxidized sodium ascorbate is economical and useful but less effective than the Hoffer regimen.”

To conclude Houston stated: “Current cancer patients can consider using sodium ascorbate solution or Hoffer’s regimen under medical supervision.”

 

Neutral Study (Table 3)

Study 1, 2002
Lesperance ML, Olivotto IA, Forde N, Zhao Y, Speers C, Foster H, Tsao M, MacPherson N, Hoffer A: Mega-Dose Vitamins and Minerals in the Treatment of Non-Metastatic Breast Cancer: An Historical Cohort Study. Breast Cancer Research and Treatment, 2002; 2372-02: 1-7.

Summary

This study by Lesperance et al. is described as “an observational study” and it admits that “other unknown factors” may have influenced its results. These showed that high dose vitamin/mineral treatment in combination with chemotherapy did not provide a greater rate of survival or a lower rate of recurrence for a treated group over a controlled group. The authors therefore suggested “caution” when using high dose vitamin-mineral therapy for breast cancer.

Lesperance et al. described the background to the test as follows: “Subjects were women with unilateral, non-metastatic breast cancer diagnosed between 1989 and 1998 inclusive and referred to the British Columbia Cancer Agency-Vancouver Island Centre (BCCA-VIC)…. The BCAA maintains a medical database containing information for all women diagnosed with breast cancer in B.C; complete diagnostic and treatment data are recorded from 1989 onwards.”

The authors continued: “The vitamin/mineral prescribed patients (cases) were seen by a single physician, not affiliated with the BCAA, who has treated over 900 cancer patients with mega-doses of vitamins and minerals in Victoria, British Columbia. Office records identified 271 patients with breast cancer…. Using the identity number, name, and date of birth, each case was linked to the BCCA medical database, and their record retrieved.” The 90 most recent of the 271 patients, all of whom were on the vitamin/mineral treatment, were matched with the BCCA patients.

“The controls were drawn from 2360 women … referred to the BCCA-VIC over the same time period. The cases were matched to the controls (2:1)” using various criteria. The determinants for the selection of the 90 patients in the treated group and the 180 patients in the controlled group were: “BCSS, the number of days from diagnosis to death from breast cancer;” and “DFS, the number of days from diagnosis to systemic relapse (regional or distant) or death from breast cancer.”

The results showed that both the survival and the recurrence rates of the treated group “were worse” than those of the controls. Lesperance et al. stated: “Overall survival at 5 years was 72% (s.e. 5%) and 81% (s.e. 3%) for the cases and controls, respectively. Ten-year survival was 65% (s.e. 7%) and 76% (s.e. 4%), respectively, for the vitamin/mineral treated cases and the controls.”

The authors explained that the shorter survival time of the treated group was determined after adjustment of certain criteria. They recognised that their “observation [contrasted] with an anticipation of survival enhancements due to mega-doses of vitamins and minerals” in the Hoffer and Pauling 1993 study, seen elsewhere in this presentation. However, they suggested “caution” when using high dose vitamin/mineral treatment as an adjunct to chemotherapy in the treatment of breast cancer.

Their general concern acknowledged: “Some oncologists believe that antioxidants could interfere with the actions of some chemotherapy agents, however, the scientific debate on this subject is still ongoing.”

Lesperance et al. stated: “A limitation of the study, however, was that the ultimate sample size was not large enough to provide adequate power to discern small differences in survival between the two groups.” They continued: “Our initial working hypothesis was that the vitamin/mineral prescribed patients would display a 25-30% increase [as reported by Hoffer and Pauling as above] in BCSS and DFS over the controls.” In addition, the authors noted that “unknown factors” could have accounted for the shorter survival time and unimproved recurrence of the treated group over the controlled group.

In conclusion, Lesperance et al. stated: “The magnitude of the effects on survival observed in this study may be useful information, especially to groups planning to undertake controlled clinical trials of mega-dose vitamin/mineral regimes for the treatment of breast cancer. The results suggest that the vitamin/mineral regime prescribed is not a cure for breast cancer.”

 

Negative Study (Table 3)

Study 1, 1999
Agus DB, Vera JC, Golde DW: Stromal Cell Oxidation: A Mechanism by which Tumors obtain Vitamin C. Cancer Research, 1999; 59: 4555-4558.

Summary

Agus et al. noted as reported by several investigators: “Whereas much is known about vitamin C and vitamin C deficiency states, there is little information regarding the physiology of the vitamin in cancer. Given the well-documented role of vitamin C in the maintenance of normal immune processes and host defense, it is popularly believed that supplemental vita- min C ‘strengthens’ the immune system. Patients with cancer who take vitamin C generally believe that it can enhance immune defense against the cancer. These notions give little attention to the nutritional needs of the cancer itself. Cancer cells readily take up vitamin C in vitro, and studies have demonstrated high vitamin C concentrations in neoplasms compared with the adjacent normal tissue. The mechanism by which cancers accumulate vitamin C in vivo, however, is unknown.” The authors continued: “Certain specialized cells can transport ascorbic acid directly through a sodium ascorbate cotransporter, but in most cells, vitamin C enters through the facilitative glucose transporters (GLUTs) in the form of dehydroascorbic acid, which is then reduced intracellularly and retained as ascorbic acid.”

A test observed: “Mice with xenograft tumors were injected into the tail vein with ascorbic acid, dehydroascorbic acid, or sucrose and sacrificed 1 [minute] after injection. Approximately 4% of the injected dehydroascorbic acid radioactivity (…) was found in the brain of the xenograft groups after 1 [minute], a result consistent with our previous work [1997].” These last square brackets are the writer’s – the earlier ones are those of the authors who continued: “Injected ascorbic acid and sucrose yielded only trace radioactivity in the brain homogenate at 1 min, confirming that ascorbic did not readily pass the blood-brain barrier. Sucrose is not metabolized or transported, and therefore it is used as a marker of plasma volume [according to other investigators]. The xenograft tumors accumulated injected dehydroascorbic acid at [various concentrations with different cancers].” Agus et al. continued: “The results [showed] that the vitamin C accumulated in the tumors was >86% ascorbic acid in animals injected with dehydroascorbic acid as well as those injected with ascorbic acid.”

From these results the authors concluded: “The involvement of the GLUTs in vitamin C uptake by the xenografted tumors was demonstrated by competitive initiation with D-glucose but not L-glucose. Because the malignant cells were not capable of directly transporting ascorbic acid, we reasoned that the ascorbic acid was oxidized to dehydroascorbic acid in the tumor microenvironment.”

The authors “hypothesized that ascorbic acid was oxidized in the tumor microenvironment by superoxide anion. To test this concept, we coinjected animals bearing xenografts with ascorbic acid and SOD, catalase, or saline. The animals receiving SOD and radiolabeled ascorbic acid had an ~50% reduction in tumor vitamin C accumulation, whereas there was no change in the tumor accumulation of vitamin C in animals coinjected with dehydroascorbic acid and SOD. There was no effect of co-administration of ascorbic acid and catalase, indicating that peroxide likely did not play a role in oxidizing ascorbic acid to dehydroascorbic acid.”

The authors also “tested the ability of the tumor cells themselves to generate superoxide anion.” They argued that: “Because minced xenograft tumors, distinct from the cell lines, had a prominent ability to generate superoxide anion, we concluded that non-neoplastic cells in the tumor stroma were responsible for the superoxide generation.”

Agus and coworkers, as reported by other investigators, confirmed that: “A sodium ascorbate co-transporter is present in many organs”, but they did not find any “sodium-dependent ascorbic acid uptake in” the test materials of the present study. They continued: “Thus, the uptake of vitamin C in the form of dehydroascorbic acid through the GLUTs appears to be a general mechanism for vitamin C uptake.” They added that “the sodium ascorbate co-transporter may have a role in vitamin C uptake of certain tumors.”

Agus and coauthors concluded by referring to studies that dealt with positive use of vitamin C in anti-tumor therapy: “The increased intracellular concentration of vitamin C may have effects on tumor growth and the tumor’s ability to respond to oxidative stress associated with chemotherapy and radiation therapy.” However, they added: “Although studies evaluating the role of vitamin C supplementation in cancer patients have generally shown no benefit with respect to survival or tumor regression [as reported by investigators], it is not known whether high concentrations of vitamin C in human tumors afford the malignant cells with a metabolic advantage.” As seen in this bibliography, subsequently published research have documented the effectiveness of vitamin C treatment with chemotherapy. In conclusion, Agus and coworkers pointed out: “Our studies show the transport of dehydroascorbic acid by GLUTs is a means by which tumors acquire vitamin C and indicate the oxidation of ascorbic acid by superoxide anion produced by cells in the tumor stroma as a mechanism for generating the transportable form of the vitamin.”

 

Negative Reviews (Table 3)

Review 1, 1999
Labriola D, Livingston R: Possible Interactions between Dietary Antioxidants and Chemotherapy. Oncology, 1999; July: 1003-1008.

Summary

Labriola and Livingston noted: “The popularity of non-conventional therapies, for a myriad of diseases, has increased dramatically. Most patients use some form of alternative therapy, often concurrently with conventional treatment and frequently without advising their conventional health care provider. Relying on media reports, Internet advertising, and industry marketing, many patients believe that non-conventional therapies offer cures for literally every disease, including cancer; that they do not interfere with other treatments; and that they are uniformly free of toxicity at any dosage level” as reported by other investigators. They continued: “Since many patients treat themselves with oral antioxidants during chemotherapy, clinicians need to formulate a credible position on this subject if they are to provide their patients with timely advice about the potential risks.”

Labriola and Livingston continued: “To date, no definitive human studies have demonstrated the long-term effects of combining chemotherapeutic agents and oral antioxidants. Fortunately, the mechanisms of action of both are understood well enough to predict the obvious interactions and to suggest where caution should be exercised with respect to both clinical decisions and study interpretation” as reported by other investigators.

The objective of Labriola and Livingston’s review was to “describe [the above] potential interactions and areas of concern, based on the available data. It … also [suggested] several potential courses of action clinicians may take when patients demonstrate an interest in alternative therapies.”

Labriola and Livingston discussed available information under the following head- ings and sub-headings:

-Cytotoxic Actions of Chemotherapeutic Agents

-Actions of Antioxidant Compounds

-Predictable Mechanisms of Interaction

-Factors that may predict Interactions

-Fraction of Drug Effectiveness that depends on Reactive Oxygen Species

-Nature of the Reactive Oxygen Species generated by the Chemotherapeutic Agent

-Dosage and Concentration of Reactive Oxygen Species

-Nature of the Antioxidant

-Concentration of the Antioxidant

-Temporal Relationship between the Antioxidant and Reactive Oxygen Species

-Implications for Future Research

-Implications for Clinical Practice

-Options for the Patient interested in Non-conventional Therapies

-Suggested Plan for Adjunctive Non-conventional Treatment

-Warning Signs of Possible Interactions

Conclusions

Labriola and Livingston’s review made no specific reference to vitamin C, except to note that “most of the non-conventional treatments recommended for use with oncology patients have antioxidant activity. The most common of these include: vitamins A (including beta-carotene), B6, C, and E….” They stressed that: “One of the objectives of this article is to increase oncologists’ attention to potential interactions by articulating these mechanisms.”

 

Review 2, 1999
Labriola D: Guest Editorial-Antioxidants and Chemotherapy: What You Need to Know Before Combining Them. Townsend Letter for Doctors & Patients, 1999; Nov: 120-121.

Summary

This guest editorial responded to the “considerable attention” which ensued from the 1999 Labriola and Livingston negative review of the use of antioxidants during chemotherapy.

In this editorial Labriola stated: “It is important to note that this paper [as above] does not address efficacy, even though it references a number of studies showing the positive effects of nutritional supplementation during chemotherapy. It does, however, discuss those circumstances when the use of antioxidants may interfere with the tumor killing actions of some chemotherapeutic agents. It also describes strategies for safely using both.” The author then detailed a case which involved the use of alternative treatments, including antioxidants, with chemotherapy to support his theory, and he referred the reader to a published account of this patient’s case history. Lastly, Labriola engaged “providers and patients” through questions and answers on four of what he called: “The most common questions” asked. This publication makes no specific mention of vitamin C.

 

Positive Responses (Table 4)

Response 1, 2000
Reilly P: Dr. Labriola’s Editorial on Antioxidants and Chemotherapy, Townsend Letter for Doctors & Patients, 2000; Feb/ Mar: 90-91.

Summary

This letter to the editor was a response to the 1999 Labriola and Livingston article and Guest Editorial of Labriola (1999) as above. Reilly wrote that these publications have “left many readers confused and scared.”

He continued: “It is important to clarify that Dr. Labriola’s concern is based upon a theory which has been shown to be unfounded when actually tested in clinical trials. Contrary to their statement, there have been numerous studies including in-vitro experiments, animal trials and small human trials which have consistently shown an enhancement of tumor kill and patient survival when antioxidants are combined with conventional oncology care.”

The author then referred the reader to three reviews that support the use of antioxidants with chemotherapy (Cole et al. 1997, Prasad et al. 1999 and Lamson and Brignall 1999). Two of these references appear in this bibliography. Reilly noted: “Many of the references cited in [Labriola and Livingston 1999] are not even relevant to the discussion of combining chemotherapy and antioxidants, but are review articles on the favorable use of antioxidants in the prevention of cancer, or general articles on the topic of complementary therapy and its popularity (or totally irrelevant such as a discussion of antioxidants in myotonic dystrophy). The one reference which did specifically examine the topic showed an enhancement of in-vitro and in-vivo antitumor action of [fluorouracil] and doxorubicin when combined with antioxidants. The conclusion of the referenced article was ‘chemotherapeutic agents administered in the presence of antioxidants may provide a novel therapy for colorectal cancer.’ ”

The author described this article under discussion as “basically a pharmacology essay”, and he stated: “Its conclusion is therefore basically a biochemical theory based upon other biochemical theories.” He continued: “Frankly I am surprised that the authors seem to believe their own conclusions in the face of a large body of actual clinical research which contradicts them.”

After noting non-negative examples on side effects in Labriola and Livingston 1999, Reilly reported on six positive examples “published in peer reviewed literature that support the contention that antioxidants not only reduce the side effects of cancer treatments but also enhance tumor kill.”

With reference to vitamin C, the author referred to Prasad et al. 1994, Skimpo et al. 1991 and Kurbacher et al. 1996 which are reviewed elsewhere in this annotated bibliography. The author also noted an article – Hunter et al. 1994 – which described the use of antioxidants with chemotherapy as perhaps being “beneficial”.

Lastly, Reilly stated: “Meta-analysis of chemotherapy shows it to be curative in a few tumor types, but to have much smaller benefit in the most common cancers. If nutrition can reduce the side effects and perhaps even improve tumor kill, as most studies suggest, then the cost benefit equation for use of chemotherapy and radiation begins to favor rational application of these modalities in situations where little else is available. Nutritional support clearly reduces side effects of treatment. This benefit alone allows many patients to complete treatment who would otherwise discontinue due to side effects.”

In conclusion, he stated: “Theory is a starting point for research, but when the evidence contradicts the theory, then we must recognize the primacy of evidence. The evidence at this point strongly favors the use of antioxidants to improve efficacy of treatment, reduce short-term side effects and hopefully reduce the incidence of secondary cancers caused by the treatment. The primary rule of medicine is first do no harm. [Medical practitioners] must look at the harm we cause by ignoring data that does not fit our expectations and denying patients access to protective factors.”

Reilly ended by stating: “The current research does need to be expanded upon with larger studies, both in vitro and in vivo. However to ignore the results of over 200 studies showing benefit based upon the same criteria used to judge other medications is irrational. Using the same logic, taxol could not be approved for use until 20 years had passed in order to prove that the initial benefit was longstanding. The problem with this logic is that cancer patients don’t have 20 years to wait. If 180 articles agree a treatment can be beneficial, then we owe it to our patients to begin utilizing it while continuing to support research to further clarify any potential contraindications.”

 

Response 2, 2000
Gignac MA: Antioxidants and Chemotherapy: What You need to know before following Dr. Labriola’s Advice. Townsend Letter for Doctors & Patients, 2000; Feb/ Mar: 88-89.

Summary

This letter to the editor is a second response to the 1999 Labriola and Livingston article and Guest Editorial of Labriola (1999) as above. Gignac wrote that the former resulted in his “consulting with numerous confused and frightened cancer patients”. He continued: “The original article references 31 papers with no substantive data to support their contention that antioxidants interfere with chemotherapy. What is worse, this ‘scientific’ paper virtually ignores the fact that there are literally hundreds of articles (in vitro, in vivo, and human studies) which support the positive benefits of combination treatments. In light of the obvious bias of this article, one can hardly justify its inclusion in a ‘scientific’ journal.”

Gignac stated that Labriola’s “central premise is that dietary antioxidants most likely undermine the effectiveness of chemotherapy and that when in doubt, do not use any supplements while on chemotherapy!” He continued: “I am growing more and more perplexed as to why a naturopathic physician who purports to be a specialist in the treatment of cancer would ever write an article that is so clearly biased and one-sided. This article, and its aftermath, had done more to harm the patient perception of ‘integrated’ oncology care than anything else that I can think of. How am I to understand Dr. Labriola’s presumed objectivity when he fails to even mention that well over 100 scientific articles refute his contention that antioxidants interfere with chemotherapeutic effectiveness?”

The author then referred the reader to the three reviews mentioned in Reilly above that support the use of antioxidants with chemotherapy (Prasad et al. 1999, Lamson and Brignall 1999 and Cole et al. 1997).

Gignac then turned his attention to the Guest Editorial of Labriola (1999), stating that the editorial was “so full of weak assumptions and faulty conclusions” that he wanted “to address them individually.” The discussion was in five parts including the example of the case involving alternative treatments, among them antioxidants, with chemotherapy.

In conclusion, Gignac stated: “The future of cancer treatment lies in the proper integration of conventional and complementary treatments. Oncologists should not be complacent about the fact that an estimated 40% of cancer patients die of malnutrition. According to Kern [1988] and Ollenschlager [1991], between 40 and 80% of all cancer patients have clinical signs of malnutrition. Many responsible physicians believe that much of the toxicity symptoms from chemotherapy are directly exacerbated by systemic nutrient depletion, secondary to treatment. Some German physicians are now openly recommending ‘high-dose supplementation of essential antioxidants for patients undergoing bone marrow transplantation’ [Clemens 1989]. Until more research is completed, the preponderance of existing data supports the concurrent use of antioxidants with chemotherapy.”

 

Response 3, 2000
Hoffer A: Facts and Factoids: An Information Sheet for Patients, http:// www.doctoryourself.com/hoffer_factoids. html, May 2003; 1-9

Summary

In this article Hoffer described the difference between a fact and a factoid, and he also responded to the 1999 Labriola and Livingston review.

With regard to the discussion on facts and factoids the author wrote: “Fact: Something that has really occurred or is the case: hence a datum of experience, as distinct from conclusions. Loosely defined, something that is alleged to be, or might be a ‘fact.’” “Factoid: A factoid is a fact that never existed before it appeared in print, but has been reprinted ever since. It is truly launched if it first appears in a reputable medical journal like the Journal of the American Medical Association and republished in the New York Times which gives it international stature. A factoid, using simple Anglo Saxon terminology, is a lie, and like many lies and misconceptions, once it has been published develops a life of its own and is reprinted over and over, from textbook to textbook. The best example is the lie (factoid) that vitamin C causes kidney stones.”

Hoffer then elaborated on facts and factoids in general and then under the headings:

-Evidence required to establish Facts in Clinical Medicine

-Evidence required to establish Factoids in Clinical Medicine

In reference to Labriola and Livingston (1999), Hoffer noted the “rebuttals” by “Reilly, Gignac, and Lamson and Brignall”, but he did not report on the “arguments”. He stated however, that “it was evident that Dr. Labriola was not convinced by the points put forward by Reilly and Gignac” and said: “I think the factoid repeated by Dr. Labriola would have a much better chance of becoming a fact if he had considered [certain] points.” These points were outlined in five parts thus: What is the therapeutic value of chemotherapy without any antioxidants? The difference between possibility and probability. If he had not tried to bolster his argument by referring so frequently to the peer reviewed journal in which his paper appeared. Moss points out that oncologists have no objection to using xenobiotic antioxidants during chemotherapy. Dr. Labriola emphasizes that long term studies must be used.

Hoffer stated: “In conclusion, as the proponents of the old paradigm [vitamins- as-prevention] see it, facts are facts only after double-blind controlled experiments conducted by the right investigators from the correct school and published in the correct medical journals. Factoids can be thought up by anyone and immediately become facts in the profession if the factoid attacks the evidence against the new paradigm [vitamins-as-treatment].” He continued: “These factoids are based upon hypotheses. There is no clinical data to support any of them and almost all studies show that they are not true or real. They are not supported by any studies.” He then listed a number of current factoids about megadose vitamin C which included that the vitamin “inhibits chemotherapy” and “prevented Linus Pauling from living longer”.

Finally, Hoffer stated: “The opposite of a factoid is a fact. The good news is that as none of [the] factoids [in the list mentioned above] are true, the opposite is true. This summary statement is based upon literally thousands of published papers in medical literature and hundreds of books that have been published in the past twenty years.” The author said that he could “not provide references to these numerous clinical studies, but readers of the Journal of Orthomolecular Medicine have ready access to the facts and also to the book reviews of over one hundred of these books. The internet contains a large number of excellent discussions of vitamins and, of course, the facts and factoids which are current.”

The author then listed some maladies, conditions and treatments for which vitamin C was used. Under the headings “Alleged Toxicity”, “Factoid (lies)” and “Fact”, he noted what the factoid claims and what the fact is. These included, for the purpose of this bibliography, the use of vitamin C with chemotherapy and the factoid that the combination “Decreases efficacy,” and the fact that it “Increases efficacy.” This list also included Linus Pauling’s use of vitamin C as having “Shortened his life”, to which Hoffer remarked: “A ridiculous claim. He died age 94, fully mentally alert.”

As an overall conclusion, Hoffer stated: “The factoids about vitamins, used in optimum doses when needed, are not true, are not based upon clinical evidence, do not have any studies including double blind controlled clinical data to support them, and are used primarily to attack the new paradigm, the vitamins-as-treatment paradigm. Be wary of factoids whether they are in print, on the internet, in the news media, on radio or on television….” The author ended by stating: “The unfortunate result of these lies is that patients are made fearful, some will stop taking their vitamins, medical costs will increase since patients want to see their doctor again to discuss these matters, and more patients will relapse. The harm done by these factoids is immeasurable, but fortunately is slowly decreasing as the population becomes more knowledgeable and sophisticated about nutrition and nutrients. In the same way that drug companies are not allowed to make false therapeutic claims about their products, we need a system which will neutralize the factoids as they are proposed. And above all we need the public media to become much more intelligent and less subservient to major papers like the New York Times.”

 

Response 4, 2001
Prasad KN, Cole WC, Kumar B, Prasad KC: Scientific Rationale for Using High- Dose Multiple Micronutrients as an Adjunct to Standard and Experimental Cancer Therapies. Journal of the American College of Nutrition, 2001; 20/5: 450S-463S. Summary

This review by Prasad et al. responded to the negative review of Labriola and Livingston (1999).

Prasad et al. wrote: “Two opposing hypotheses regarding the use of antioxidants as an adjunct to standard cancer therapy have recently been proposed. We have suggested that high-dose multiple antioxidant supplements before and during standard or experimental cancer therapy may improve treatment efficacy by increasing tumor response and decreasing toxicity [1999]. An alternative hypothesis is that antioxidant supplements should not be used while treating cancer patients with standard therapy because they would protect both normal and cancer cells against free radicals that are produced by most of the anticancer agents [Labriola and Livingston 1999].”

The authors continued: “These two conflicting hypotheses can be resolved if the following scientific principles are followed: (a) the results of the effects of low-dose (physiological range) antioxidants on cells are not extrapolated to those obtained with high-dose (pharmacologic, but non-toxic dose range) antioxidants; (b) data on the effects of a single antioxidant on cells are not extrapolated to those obtained with multiple antioxidants; (c) results of the effects of antioxidants on cancer cells are not extrapolated to those on normal cells; (d) data obtained on the effects of short treatment duration with antioxidants are not extrapolated to those obtained after long treatment duration; (e) all biological observations on the effects of antioxidants on cells are not related to their action of scavenging free radicals; and (f) all antioxidants do not produce similar effects on cells.”

Prasad et al. stated: “The purpose of this review [was] to analyze each of the above scientific principles to demonstrate that current opinions opposing the use of antioxidants as an adjunct to standard cancer therapy have no scientific basis, and that micronutrient supplementation, including antioxidants, under appropriate conditions may improve the efficacy of the current management of human tumors.”

In reference to vitamin C or vitamin C with other vitamins and chemotherapy, a few examples were cited and explanations given for the principles (Cameron et al. 1979, Patiak et al. unpublished information and Prasad et al. 1979, 1994, 1999) – the last two references also appear in this bibliography.

Lastly, the authors stated: “Another part of [their] proposed hypothesis is that antioxidant vitamins in combination with standard therapeutic agents may reduce the toxicity of these agents on normal cells. Several studies using animal models (…) also support this part of the hypothesis [Prasad et al. 1999].” The authors cited two examples of vitamin C which showed that (1) the vitamin “reduces the adverse effects of some chemotherapeutic agents on normal cells, such as those from adriamycin [Fujita et al. 1982]”, and (2) vitamins C+E+A “reduce bleomycin-induced chromosomal breakage [Trinza et al. 1993].”

In conclusion, Prasad et al. stated: “Substantial laboratory data and limited human studies indicate that supplementation with high-dose multiple micronutrients, including appropriate antioxidants (vitamin C, … ), as an adjunct to standard or experimental therapy (…), may improve their efficacy by increasing tumor response and decreasing toxicity. Clinical trials on this issue are in progress. The responses of tumor cells to antioxidants differ from those of normal cells. Antioxidants, in part, have different mechanisms of action on tumor cells. In addition, some antioxidants, depending upon doses, can produce a bi-phasic effect on certain tumor cells. Additional mechanistic studies on antioxidants alone and in combination with standard tumor therapeutic agents are needed.”

 

Discussion

This annotated bibliography presents research findings that assess the effective- ness of vitamin C alone, or with other vitamins, when used during chemotherapy.

The summaries presented lead to the general conclusion that vitamin C can play a safe and positive role in cancer treatment as an adjunct to chemotherapy. This literature review suggests that the use of vitamin C alone with chemotherapy results in:

-An increase in survival time (Hoffer 1996, Meadows et al. 1991, Sarna et al. 1993, Skimpo et al. 1991)

-Enhancement of chemotherapy (Meadows et al. 1991, Prasad et al. 1994, Sarna et al. 1993)

-Inhibition of tumor growth (Chiang et al. 1994, Meadows et al. 1991)

-A decrease in toxicity (Skimpo et al. 1991)

-Decreased elevated lipid peroxide (Skimpo et al. 1991)
-modulation of genotoxicity of chemotherapy (Blasiak et al. 2002)

-An increase in cell death (Reddy et al. 2001)

-When vitamins C and K3 were used with chemotherapy, results showed that the vitamin “did not increase the general and organ toxicity that accompanies cancer chemotherapy” (Taper et al. 1987)

-The vitamin treatment “produced a distinct chemotherapy-potentiating effect” for certain drugs (Taper et al. 1987) and “selectively potentiated tumor chemotherapy [and] produced sensitization of tumors resistant to some drugs” (Calderon et al. 2002)

-The application resulted “in a synergistic effect on growth inhibition” (Kurbacher et al. 1996)

-The combination was more effective than the chemotherapy alone (De Loecker et al. 1993)

-When vitamin C was given together with other vitamins or during chemotherapy, results showed that the mixture “markedly enhanced the growth inhibitory effect” of the chemotherapy (Prasad et al. 1994)

-“Reduced growth of melanoma cells by about 85%” (Prasad et al. 1994)

-Decreased side effects (Drisko et al. 2003)

-Increased survival time (Hoffer 1990)

-Enhanced quality of life (Hoffer 1990)

-Was “added adjunctively to chemotherapy without adversely affecting outcome of survival” (Drisko et al. 2003)

-That combined treatment with chemotherapy and vitamins was more effective than drug alone (Abdel Rehim et al. 2003)

All but one of the studies and reviews presented in this bibliography support the use of vitamin C with chemotherapy. One neutral study, however, suggests “caution” when using high dose vitamin/mineral therapy for breast cancer. The only negative review warned of “Possible Interactions between Dietary Antioxidants and Chemotherapy.” This stimulated four responses supporting the use.

In conclusion, this annotated bibliography of literature on the effectiveness of vitamin C alone, or with other vitamins, during chemotherapy confirms the conclusions of Prasad and coworkers (1999): “… antioxidants [including vitamin C] do not protect cancer cells against free radical and growth-inhibitory effects of standard therapy. On the contrary, they enhance its growth-inhibitory effects on tumor cells, but protect normal cells against its adverse effects.”

 

Acknowledgements

This work was supported by a research grant from the Lotte and John Hecht Memorial Foundation. The writer is very grateful to Dr. Harold D. Foster of the Department of Geography at the University of Victoria, British Columbia, for his kindly offering the use of his computer and for his very valuable assistance, especially his excellent editing of the document. The writer should also like to thank the office staff of the Department of Geography for helpful computer assistance, the staff of the Greater Victoria Public Library and the University of Victoria’s library for kindly securing interlibrary material and for providing access to other information. Lastly, the writer thanks staff of the Saskatoon Public Library, Saskatoon Board of Education and from the following at the University of Saskatchewan: Department of Geography, Information Technology, Library and Saskatchewan Population Health and Evaluation Research Unit, Inc. for kindly providing computer assistance or access.