The antioxidant controversy in cancer care.
Subject: Antioxidants (Health aspects)
Antioxidants (Analysis)
Cancer (Risk factors)
Cancer (Care and treatment)
Cancer (Analysis)
Author: Ashewood, Shauna
Pub Date: 06/22/2007
Publication: Name: Australian Journal of Medical Herbalism Publisher: National Herbalists Association of Australia Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2007 National Herbalists Association of Australia ISSN: 1033-8330
Issue: Date: Summer, 2007 Source Volume: 19 Source Issue: 2
Geographic: Geographic Scope: Australia Geographic Code: 8AUST Australia
Accession Number: 174818475
Full Text: The question of the safety and efficacy and indeed the therapeutic applicability of antioxidants has emerged over the last decade. As naturopaths and western herbal medicine practitioners, we need to be well informed about these antioxidant issues as we are faced with confused clients who are hearing conflicting information. This paper specifically addresses the antioxidant controversy in cancer and particularly looks at antioxidants and the potential interactions with chemotherapy and radiotherapy.

Introduction

The questions at the core of this debate are whether antioxidants enhance or inhibit chemotherapy and/or radiotherapy, whether antioxidants influence the side effects of these treatments, and whether the antioxidants have any intrinsic anticancer effect themselves.

The question of antioxidants and cancer treatments has been reviewed by previous authors such as Kenneth Conklin (2000, 2004), Kedar Prasad (2001, 2002, 2004), John Boik (2001), Ralph Moss (2006) and Davis Lamson (1999) amongst others. Some authors have taken a molecular view to understanding the controversy; others have reviewed the extensive laboratory and in vivo experiments on antioxidants. These need to be read for a comprehensive understanding of the basis of the debate.

Perhaps of greater interest to clinicians is the evidence that is arising from clinical trials on humans. Here we look to the work of Kedar Prasad (2002, 2004), Jeanne Drisko (2003), Kumar Pathak (2005) and Isabelle Bairati (2005) (again, amongst others) for insights and evidence of the impact of antioxidants on humans undergoing chemotherapy or radiotherapy.

To understand something of this controversy we need to understand that the action of antioxidants in the human body is part of a dynamic cellular interchange known as the redox reaction. The redox reaction is essentially the transformation of chemical energy to electrical energy by donation of electrons. However electron donors (typically antioxidants) need to be recycled otherwise they become the highly reactive free radicals themselves. So in a natural cellular system there is constant recycling of electron donors and acceptors across intra and extra cellular space.

Whilst antioxidants may be seen as the good guys, they are only so if they have a buddy to rescue them from their oxidised state once they have lost an electron. It's a dependant system in one way since single antioxidants are reliant on 'other' antioxidants to recycle them. Hence for example vitamin C donates to vitamin E and vitamin E donates to coenzyme Q10.

Some of the bad press antioxidants receive is because of the misunderstanding of this basic principle. Hence some studies that used high doses of a single antioxidant, with either no or only low dose additional antioxidant supplementation, showed adverse effects on cancer rates. This was likely to be one of the significant contributing factors to the adverse findings in the ATBC lung cancer prevention trials (Prasad 2004b).

The concern about antioxidants during cancer treatments rests on the premise that cancer treatments rely on free radical damage from oxidative stress to damage the cancer cells and that antioxidants may therefore interfere with their mechanism of action.

It would be fair to say that this is too simple a view of the complex interplay of differing and combined antioxidants with cancer cells which also demonstrate different susceptibility to the oxidative environment compared to normal cells. Other variables are the different types of antioxidants (not all antioxidants are the same); different actions at low and high doses, and the individual intrinsic anticancer effect of particular antioxidants.

It is also reasonable to assert that chemotherapy exerts its action through a number of different mechanisms not solely free radical damage

Here we mainly address the antioxidant vitamins A and beta-carotene, vitamins E and C as well as coenzyme Q10. Selenium, glutathione, alpha lipoic acid, melatonin and resveratrol are other antioxidants of much interest to those working with the cancer patient and will be the subject of future reviews.

John Boik (2001) has a hypothesis that cancer cell proliferation is greatest in a mildly, not highly, oxidative environment. It is thought then that antioxidants are beneficial because they reduce the degree of oxidative stress to a level that favours higher turnover of cells. This therefore leaves the cancer cell more susceptible to the chemotherapeutic agents which rely on intervention in an actively dividing cell.

Conklin (2000) details the possible mechanisms by which antioxidants may impact in a positive way on chemotherapeutic effectiveness. The generation of aldehydes by higher levels of oxidative stress induced lipid peroxidation during chemotherapy may affect the cell cycle in specific ways. Slowing cell cycle progression and inducing cell cycle arrest may interfere with the optimal cytotoxic action of the chemotherapy, some of which targets phase specific points in the cell cycle. Examples of these are the anthracyclines, epipodophyllotoxins, antifolates, vinca alkaloids and taxanes. Platinum complexes and alkylating agents also require cell cycle progression for activity.

Additionally the aldehydes generated by the oxidative stress of chemotherapeutic agents may inhibit caspase activity and death receptor activation and thus interfere with drug induced apoptosis. Since antioxidants reduce oxidative stress and therefore the aldehydes, they may leave cells more susceptible to the cytotoxic effects of chemotherapy.

In vitro evidence provides clues but not conclusions for clinical applications. This is especially so for antioxidant experiments since antioxidants by their nature are highly dynamic substances and easily oxidised in the in vitro environment. It is also not unusual to have conflicting results in vitro.

Nevertheless there have been some interesting results of in vitro experiments with single and combined antioxidants and cancer cell lines.

Single antioxidants and their potential for an anticancer effect

Vitamin A is the collective term for the retinoids including retinol and retinyl esters and beta carotene. Retinol and beta carotene are converted to all trans retinoic acid (ATRA) in human tissue. Retinoids have specific anticancer effects: ATRA can induce differentiation in epithelial tissues, induce maturation of cells and slow proliferation in leukemia. These effects have been applied in the use of ATRA as a treatment in leukemia and head and neck cancers. A combination of chemotherapy and ATRA is used as the first line treatment for acute promyelocytic leukemia (De Botton 2004).

Whilst the doses of ATRA are pharmaceutical rather than those used clinically by naturopaths, the ability of retinols to induce differentiation in tissue has been applied to people with pre cancerous oral lesions using beta carotene at clinically applicable doses. A multicentre prospective study using high dose beta carotene at 60 mg/day produced sustained remissions (at least 1 year) in patients with oral leukoplakia (Garewal 1999).

Retinoic acid has also been used as a topical agent in cervical intraepithelial neoplasia (CIN I and CIN II). In a phase I and II and in a randomised clinical trial, RA was found to induce regression (Meyskens 1994).

We are mainly discussing here the effect of antioxidants in combination with conventional chemotherapy and radiotherapy however the results of cancer prevention trials have often been cited as reasons not to use antioxidants in cancer treatments. A prime example of this is the now well known ATBC and CARET trials of vitamin A for the prevention of lung cancer which had a negative effect of treatment with more lung cancers occurring in the antioxidant group.

The ATBC trial in Finland had smokers exposed to either a 20 mg beta carotene supplement, a 50 mg supplement of vitamin E, the combination of both, or a placebo and were followed for a mean of 6.1 years. The trial was stopped prematurely when a 28% increase in lung cancer in the beta carotene supplemented groups became apparent (Alpha tocopherol, Beta Carotene Cancer Prevention Study Group 1994).

In the US CARET trial smokers or asbestos exposed workers who were at high risk of lung cancer were supplemented with 30 mg of beta carotene combined with 25 000 units of retinol (or placebo). Again it was found that supplementation gave rise to a 20% increase in lung cancer incidence (Omenn 1996).

Alternatively the Physicians Health Study (Hennekens 1996), on a broader population group, showed neither a detrimental nor beneficial effect of beta carotene at 50 mg every other day. There has also been modest protective benefit from vitamin E alone in prostate (Chan 1999) and breast cancer (Fleischauer 2003).

These results have been the cause of much investigation as to why high levels of beta carotene in the diet were preventative of lung cancer but supplementation had a negative effect. The first problem is that of synthetic beta carotene which behaves differently from the natural carotene forms (which are now being used clinically and in the trials evaluating mixed antioxidants and cancer). The larger issue is that in high doses a single antioxidant becomes pro oxidant especially in the highly oxidative/carcinogenic environment of damaged lungs. Every antioxidant needs a co antioxidant and the dose of vitamin E at 50 mg in the ATBC trial was too small to counter the pro oxidant effect of the large dose synthetic beta carotene.

This is of course a separate issue from whether antioxidants are to be used in chemotherapy and radiotherapy. Nevertheless the relevant message from these trials is to combine antioxidants in the appropriate form and dose.

Vitamin E as alpha tocopherol has demonstrated some anticancer effects during in vitro studies. The alpha tocopherol succinate (TS) form is of particular note since in preclinical studies it appears to have a stronger anticancer effect. Alpha TS succinate induced differentiation in melanoma cell lines and induced chromosomal damage in irradiated ovarian and cervical cancer cell lines but not in normal cells. Interestingly alpha TS succinate markedly enhanced radiation induced chromosomal damage in neuroblastoma cells (Prasad 2002).

Vitamin C has been the subject of investigation for its role in the treatment of cancer since the initial reports of Drs Pauling and Cameron in the 1970s. In their original study they reviewed 100 cases of 'terminal' cancer with disease and age matched controls and found the subjects taking the vitamin C protocols lived on average 4 times longer. This was a remarkable finding and of course prospective randomised trials were established to test this. The Mayo centre trials however, could not replicate Pauling's results but these trials have been criticised on the basis of confounding factors between the vitamin C and control groups as well as the lack of intravenous vitamin C administration.

In fact the latter point we now know to be crucial. Vitamin C at intravenous levels (IV) has a cytotoxic effect through a pro oxidant action that is selective to cancer cells. The Mayo trials did not use intravenous dosing. In vitro and in vivo research, along with well documented case studies, confirms the activity of IV vitamin C against cancer cells (Riordan 2005, Padayatty 2006).

The documented clinical results of IV vitamin C along with a combined antioxidant regime are very promising. Riordan and colleagues (2004) have reported on clinical cases using IV vitamin C, as has Drisko (2003), the latter being described in more detail later.

Riordan and colleagues have also conducted experiments on the dose response curves of a number of cell lines when exposed to ascorbic acid. Different cell lines behave differently with sarcoma and melanoma cell lines immediately responding with cell death to even low levels of vitamin C. A biphasic effect is observed with pancreatic and colon cancer cell lines with an increase in cell proliferation at low levels of vitamin C followed by a rapid decline in cell numbers as the concentration of vitamin C increases. All the cell lines studied declined at intravenous doses of vitamin C.

It is interesting to note that for the colon and pancreatic cell lines proliferation occurs at dietary or low level supplementation doses. While it is clear that IV levels of vitamin C have a positive effect on reducing cancer cell numbers, less can be concluded from the reactions of lower doses where the vitamin C is acting as an antioxidant not a pro oxidant. These experiments simply highlight the complexity and dynamic interrelationship of antioxidants.

Padayatty and colleagues (2006), using the NCI Best Case series requirements, report on 3 cases of advanced cancer that had unexpectedly long survival times after receiving high dose intravenous vitamin C therapy. One case involved a 66 year old woman with B cell lymphoma who refused chemotherapy but proceeded with localised radiotherapy to the largest of the lumps. She undertook a course of IV vitamin C that continued at a maintenance dose for about 18 months, along with a range of nutritional supplements and herbs. Despite a poor prognosis she remained disease free at the time of publication 10 years later.

There is also a comprehensive review by Gonzales (2005) on Ascorbic acid and cancer 25 years later that reviews the pharmacokinetics in vitro and some of the clinical evidence about vitamin C, elucidating some of the possible mechanisms of action.

The use of IV vitamin C is currently not available direct to naturopaths in Australia but we are well placed to refer to the Holistic Medical Practitioners who use this treatment. Meanwhile we need to be aware of supporting our clients with the appropriate co-antioxidant supplementation that includes vitamins C, A and E as well as vitamin B12 and alpha lipoic acid (Riordan 2005).

Clinical trials using mixed antioxidants

There are no reported randomised clinical trials using a mixed antioxidant protocol on its own as a treatment for cancer. Such a protocol is not advocated as a sole treatment and indeed it would be unlikely to be acceptable to any clinical trial ethics committee. However there is data available from uncontrolled clinical trials for people who have undergone conventional treatments and are in remission or have residual tumours or metastases.

Studies by Folkers (1993) and Lockwood (1994) reported some remarkable regressions of advanced tumours in breast cancer patients. Folkers' study was an open, uncontrolled trial in Denmark following 32 breast cancer patients with non localised disease for 18 months. The treatment protocol was as follows: Q10 90mg, vitamin A 2500 IU, vitamin C 2850 mg, vitamin E 2500 IU, beta carotene 32.5 IU, selenium 387 [micro]g, EFAs 1.2 g GLA, 3.5 g omega 3s.

The outcome was that although 4 patients were expected to die none did. None of the patients had signs of further disease progression and quality of life was improved.

In a follow up study (Lockwood 1994) 6 months later, still no patient had died (6 expected). The coenzyme Q10 dose was increased to 390 mg/day. Two patients on this higher dose of Q10 experienced complete regression of their residual tumours.

In another report by the same investigators, 3 breast cancer patients (with incomplete breast cancer resection) on 390 mg of Q10 were followed for 3-5 years. One patient showed complete remission of liver metastases, another had remission of chest wall metastases and another had no sign of any remaining tumour after mastectomy.

Whilst we await the results of clinical trials using mixed antioxidants with high dose coenzyme Q10, these earlier case studies and uncontrolled trials remain early evidence of possible benefit (certainly no harm) especially with the use of high doses of coenzyme Q10 in cancer.

Coenzyme Q10 has been extensively studied in vitro, in vivo and in clinical trials for its effect on anthracycline cardiotoxicity. Anthracycline toxicity is a dose limiting side effect of anthracycline chemotherapy on the mitochondria of heart muscle. Reviewed comprehensively by Conklin (2005), he concluded that Q10 had a cardioprotective effect against chronic anthracycline induced cardiotoxicity although the duration of that effect could not be established (side effects may appear up to 20 years later). Studies have also indicated no negative interference of Q10 on the cytotoxicity of anthracyline and in fact Q10 may even enhance its chemotherapeutic effect. Of note is the fact that Q10 itself is enhanced by vitamin E.

Overall Q10 appears to be a safe antioxidant used with (anthracycline) chemotherapy that ameliorates a potentially fatal side effect while allowing for higher doses to be used. It also has a positive effect on quality of life in people undergoing chemotherapy and afterwards. It has possible anticancer effects in high doses and we look forward to further clinical trials to test this promising effect indicated by the earlier uncontrolled trials.

Clinical trials using antioxidants with chemotherapy

There are a number of small clinical trials evaluating antioxidants and chemotherapy in terms of efficacy and the reduction of side effects.

Jaakkola and colleagues (1992) published their observation of 18 non randomised patients with advanced small cell lung cancer. Survival is generally poor in advanced small cell lung cancer. The patients were treated with additional antioxidants, trace minerals and fatty acids as well as the conventional chemotherapy. This group was then compared to published survival rates.

The antioxidant group survived longer and better tolerated the chemotherapy. This was especially so for those who started the antioxidants earlier.

Although this trial is small and uncontrolled it hints at the value of additional antioxidants and nutrients in patients with advanced cancer undergoing treatments.

A randomised clinical trial to investigate the effects of antioxidants on cisplatin (chemotherapy) induced toxicities was published in 2004 (Weijl 2004). Cisplatin toxicities can be long term and irreversible and in vitro and in vivo research indicated antioxidants may be useful in ameliorating some of this damage. In this trial 48 patients were randomised to receive antioxidant supplementation. This well designed but small study unfortunately suffered from poor patient compliance since the supplement (and placebo) was in a milky beverage.

The active contained 1000 mg vitamin C, 400 mg vitamin E and 100 [micro]g selenium to be taken twice daily. Although there were no significant differences between the groups in terms of the cisplatin side effects, when plasma antioxidant micronutrient scores were evaluated those with a higher level had less nephrotoxicity and ototoxicity. Considering this and the poor compliance, the authors conclude that a higher dose of supplementation especially prior to and during chemotherapy, may be needed to offset the oxidative damage of the cisplatin.

In an earlier study by Pace (2003), 47 patients were randomly assigned to cisplatin or cisplatin plus alpha tocopherol 300 mg/day during treatment and for 3 months after. The primary outcome was to measure the effect of the vitamin E on the neurotoxicty of cisplatin. Peripheral nerve damage incidence and severity was significantly lower in the vitamin E group and no adverse interaction between cisplatin and vitamin E was found.

A Ralph Moss review (2006) of antioxidants also quotes several other studies of vitamin E used with chemotherapy.

Small cell lung cancer was again the subject of a study with multiple antioxidants and chemotherapy published in 2005 by Pathak and colleagues. This study had 136 patients and was randomised and placebo controlled. The antioxidant supplementation was 6100 mg/day ascorbic acid, d-alpha tocopherol 1050 mg/day and beta carotene 60 mg/day. Although there was a trend to better survival in the antioxidant plus chemotherapy arm, it was not statistically significant. The authors note that the results do not support the concern that antioxidants might inhibit chemotherapy.

Drisko (2003) describes the use of a mixed antioxidant protocol and IV vitamin C along with conventional chemotherapy. The first case is a 55 year old woman diagnosed with stage IIIc adenocarcinoma of the ovary. She began an antioxidant protocol prior to her first chemotherapy cycle that included vitamin E 1200 IU, coenzyme Q10 300 mg, vitamin C 9000 mg, beta carotene 25 mg and vitamin A 10000 IU daily.

She had a good early response after one cycle of chemotherapy and after 6 cycles. Before consolidation chemotherapy she elected to begin IV vitamin C at 60 g twice weekly. After 6 more cycles of chemotherapy she reduced the dose to 60 g IV vitamin C once a week. At the time of publication (2003) she was 40 months disease free and still in remission.

A second case is in a slightly older woman with stage IIIc ovarian cancer who refused further conventional treatment after she failed to completely respond to chemotherapy. She elected to continue a mixed antioxidant protocol plus IV vitamin C. Three years after diagnosis she remains stable with a CA-125 of 5.

These very positive cases along with other case studies and in vitro and in vivo supportive evidence of the anticancer effect of antioxidants has led the authors to conduct a randomised clinical trial evaluating the safety and efficacy of antioxidants with chemotherapy in cases of ovarian cancer. We look forward to the results.

Antioxidants and radiotherapy: vitamin A and vitamin E

Prasad and colleagues (2002) have reported on a range of in vitro and in vivo experiments that demonstrate that the combination of natural beta carotene or vitamin A with radiation therapy significantly improves survival in mice with breast cancer.

In a human study published in 1988 beta carotene at 75 mg daily during radiation treatment for advanced squamous cell carcinoma of the mouth significantly reduced the incidence of severe mucositis reactions without causing noticeable side effects. The authors noted that the remission rate was unchanged by beta carotene treatment (Mills 1988).

A 1995 study showed an enhanced effect of radiation on locally advanced cervical cancer using a combination of retinoic acid plus interferon (Lippman 1995).

The results of randomised, double blind, placebo controlled trial using antioxidants to prevent acute adverse effects among 540 head and neck cancer patients treated with radiation therapy was published in 2005 (Bairati). Patients were supplemented with alpha tocopherol (400 IU/d) and beta carotene (30 mg/d) or placebo during radiation therapy and for 3 years thereafter.

During the course of the trial supplementation with beta carotene was discontinued because of ethical concerns after publication of the adverse results of beta carotene on smokers in ATBC trial. Bairati's trial continued with the vitamin E alone arm. There was therefore insufficient statistical power (75.5%) to analyse the beta carotene plus vitamin E group. However for vitamin E alone group an increased rate of second primary cancers was found over the first 3.5 years (Hazard ratio 2.88 CI=1.56-5.31). Interestingly after 8 years the rates of second primary and recurrences were equal in the supplement and placebo groups.

Notably there was also a 62% reduction in severe side effects in antioxidant group. This was statistically significant for combined antioxidants for any site.

Prasad and Cole (2006) have responded to these outcomes questioning the type of vitamin E used as well as the dose and type of beta carotene. Critics note again the problem with dietary versus higher dose levels of antioxidants given alone and the potential for the single high doses to act as a pro oxidant. Prasad and Cole advocate the use of high doses of multiple antioxidants to overcome this problem whilst still gaining the benefit from antioxidant supplementation. They also promote the use of high doses of natural beta carotene which was not used in the Bairati trial (Prasad 2004a,b, 2006).

Additionally the differing behaviour of alpha tocopherol versus alpha tocopheryl succinate on cancer cells should be noted. Alpha tocopheryl succinate induces differentiation, apoptosis and growth inhibition in melanoma cell cultures whereas alpha tocopherol does not. It also inhibits growth in human cervical and ovarian cells. In general it appears that tumour cells are more sensitive to alpha tocopheryl succinate although some tumour cells are sensitive to both (Kumar 2002, Prasad 2002).

The authors (Bairati 2005) also note that advanced latent tumours may be promoted by vitamin E alone in high risk groups, a possibility that will be tested by current prevention trials using high dose alpha tocopherol.

A small phase 1 and 2 trial reported at the International Conference on Nutrition and Cancer in 2002 involved 47 women with breast cancer divided into radiation only group and radiation plus antioxidants. The antioxidant protocol was a multi vitamin, calcium ascorbate 8 gm, vitamin E as alpha tocopheryl succinate 800 IU and natural beta carotene 60 mg.

After 22 months there were positive preliminary findings with no cancers in the antioxidant plus radiation group but 2 cancers in the radiation only group. We await further results in the phase 2 and the phase 3 trials (Walker 2002).

Co enzyme Q1O and radiation

A 1998 study warned that CoQ10 reduces the effect of radiotherapy on small cell lung cancer in mice. This trial showed CoQ10 at 40 mg/kg oral dose significantly inhibited radiation induced cell growth delay. This effect was borderline at 20 mg/kg and nil at 10 mg/kg (Lund 1998). According to Lamson and Brignall (1999) this is a dose equivalent to 700 mg in an adult human. They state 'based on this the normal human dose of CoQ10 of 100-400 mg/day probably has little inhibitory effect on concurrent radiotherapy'. It would be interesting to investigate CoQ10 at these doses when combined with vitamin E which recycles Q10 back to the reduced state.

Conclusion

Meanwhile in practice we are reminded that antioxidant supplementation needs to be as close as possible to its form in the human system. At a cellular level antioxidants are part of an interactive, dynamic system that relies on other antioxidants to recycle.

It is important that not only should antioxidants be in their natural form but also they should be given in the appropriate higher doses in combination and at sustaining dose regimes.

Antioxidants have other actions and functions that are anticancer and attention needs to be paid to the form and level of dose to achieve this outcome.

Several authors (Lamson 1999, Prasad 2001), whilst supportive of mixed antioxidant use during chemotherapy and radiotherapy, have expressed reservations about the use of endogenously generated antioxidants. It is possible that cysteamine, glutathione and N-acetylcysteine may protect cancer cells against chemotherapy agents that act via nucleophilic substitution reactions such as the alkylating agents and platinum compounds. Glutathione however has been used in a number of cinical trials to reduce the neurotoxicity of cisplatin without any adverse effect on survival during the trial (Moss 2006). Nevertheless these antioxidants need to be regarded with caution in these particular situations as well as during radiotherapy.

Lamson and Brignall (1999) have another specific concern regarding the use of tangeretin and tamoxifen. 'Except in cases where interactions with specific flavonoids are clearly defined, it seems prudent to avoid treatment with flavonoids in therapeutic doses concurrently with tamoxifen'.

I believe there is an emerging body of evidence that supports the use of mixed antioxidants in chemotherapy and radiotherapy. The safety and indeed possible enhanced action when using antioxidants with chemotherapy seems supported by a range of data from in vitro and in vivo experiments and evidence from human clinical trials.

There is similarly an emerging body of evidence about the use of high doses of antioxidants such as natural beta carotene and alpha tocopherol succinate alongside vitamin C that suggests their concurrent use ameliorates side effects of radiotherapy without compromising its action. What is clear is that the use of single antioxidants with radiotherapy is to be avoided and this is especially so in individuals with a high risk of recurrent disease.

While more research is always needed, I invite you to make your own evaluation of the evidence so far and refer you again to the excellent reviews in the literature. While we await the results of the next generation of clinical trials testing these very questions, we need also act to apply this current level of knowledge in a prudent and beneficial way.

References

Bairati I, Meyer F, Gelinas M et al. 2005. Randomized trial of antioxidant vitamins to prevent acute adverse effects of radiation therapy in head and neck cancer patients J Nat Cancer Inst 97:7;481-8.

Boik J. 2001. Natural Compounds in Cancer Therapy. Oregon: Medical Press.

Chan JM, Stampfer MJ, Ma J et al. 1999. Supplemental vitamin E intake and prostate cancer risk in a large cohort of men in the United States. Cancer Epidemiol Biomarkers Prev 8:10;893-9.

Conklin KA. 2000. Dietary antioxidants during cancer chemotherapy: impact on chemotherapeutic effectiveness and development of side effects. Nutrition & Cancer 37:1;1-18.

Conklin KA. 2004. Chemotherapy-associated oxidative stress: impact on chemotherapeutic effectiveness. Integ Cancer Ther 3:4;294-300.

Conklin KA. 2005. Coenzyme Q10 for prevention of anthracycline-induced cardiotoxicity. Integ Cancer Ther 4;110-32.

De Botton S, Coiteux V, Chevret Set al. 2004. Outcome of childhood acute promyelocytic leukemia with all-trans-retinoic acid and chemotherapy. J Clin Oncol 15:22(8);1404-12.

Drisko J, Chapman J, Hunter V. 2003. The use of antioxidants with first-line chemotherapy in two cases of ovarian cancer. J Am Coll Nutrition 22:2;118-23.

Fleischauer AT, Simonsen AT, Arab L. 2003. Antioxidant supplements and risk of breast cancer recurrence and breast cancer-related mortality among postmenopausal women. Nutrition & Cancer 46:1;15-22.

Folkers K, Brown R, Judy W, Morita M. 1993. Survival of cancer patients on therapy with coenzyme Q10. Biochem Biophys Res Comm 192:1;241-5.

Garewal HS, Katz RV, Meyskens F et al. 1999. Betacarotene produces sustained remissions in patients with oral leukoplakia: results of a multicenter prospective trial. Arch Otolaryngol Head Neck Surg 125:12;1305-10 (abstract).

Gonzalez MJ, Miranda-Massari JR, Mora EM, Guzman A, Riordan NH, Riordan HD et al. 2005. Orthomolecular oncology review: ascorbic acid and cancer 25 years later. Integ Cancer Ther 4;32-44.

Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, Belanger C, LaMotte F, Gaziano JM, Ridker PM. 1996. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. New Engl J Med 334:18; 1145-9.

Jaakkola K, Lahteenmaki P, Laakso J, Harju E, Tykka H, Mahlberg K. 1992. Treatment with antioxidant and other nutrients in combination with chemotherapy and irradiation in patients with small-cell lung cancer. Anticancer Res 12:3;599-606.

Kumar B, Jha M, Cole W, Bedford J, Prasad K. 2002. D-alpha tocopheryl succinate enhances radiation induced chromosomal damage levels in human cancer cells, but reduces it in normal cells. J Am Coll Nutrition 21:4;339-43.

Lamson D, Brignall M. 1999. Antioxidants in cancer therapy; their actions and interactions with oncologic therapies. Alt Med Rev 4:5;304-29.

Lippman SM, Parkinson DR, Itri LM et al. 1995. 13 cis retinoic acid plus interferon; highly active systemic therapy for squamous cell carcinoma of the cervix. J Nat Cancer Inst 84;241-5.

Lockwood K. Moesgaard S, Hanioka T, Folkers K. 1994. Apparent partial remission of breast cancer in high risk patients supplemented with nutritional antioxidants, essential fatty acids and coenzyme Q10. Mol Aspects Med 15:s231-40.

Lund EL, Quistorff B, Spang-Thomsen M, Kristjansen PEG. 1998. Effect of radiation therapy on small-cell lung cancer is reduced by ubiquinone intake. Folia Microbiol 43;505-6 in Lamson 1999.

Meyskens FL, Surwit E, Moon TE et al. 1994. Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: a randomized trial. J Nat Cancer Inst 86;539-43.

Meyskens FL, Valanis B, Williams JH. 1996. Effects of a combination of beta carotene and vitamin a on lung cancer and cardiovascular disease. New Engl J Med 334:18;1150-55.

Mills E. 1988. The modifying effect of betacarotene on radiation and chemotherapy induced oral mucositis. Brit J Cancer 57;416-17.

Moss R. 2006. Should patients undergoing chemotherapy and radiotherapy be prescribed antioxidants? Integ Cancer Ther 5:1;63-82.

Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A et al. 2003. Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy. J Clin Oncol 21;927-93.

Padayatty SB, Riordan HD, Hewitt SM, Katz A, Hoffer LJ, Levine M. 2006. Intravenously administered vitamin C as cancer therapy: three cases. CMAJ 174:7;942.

Pathak KA, Bhutani M, Guleria R et al. 2005. Chemotherapy alone vs. chemotherapy plus high dose multiple antioxidants in patients with advanced non small cell lung cancer. J Am Coll Nutrition 24:1;16-21.

Prasad KN, Cole WC, Kumar B, Che Prasad K. 2001. Scientific rationale for using high-dose multiple micronutrients as an adjunct to standard and experimental cancer therapies. J Am Coll Nutrition 20:90005;450-63S.

Prasad K, Cole W, Kumar B, Che Prasad K. 2002. Pros and cons of antioxidant use during radiation therapy. Cancer Treat Rev 28:79-91 www.idealibrary.com.au accessed 12 Feb 2005.

Prasad K. 2004a. Rationale for using high dose antioxidants as an adjunct to radiation therapy and chemotherapy. Am Soc Nut Sc J Nut 134;3182S-3183S. www.nutrition.org/cgi/content/full/134/11.3182S accessed 14 Feb 2005.

Prasad K. 2004b. Multiple dietary antioxidants enhance the efficacy of standard and experimental cancer therapies and decrease their toxicity. Integ Cancer Ther 3:4;310-22.

Prasad K, Cole W. 2006. Antioxidants in cancer therapy. J Clin Oncol 24:6;8-9.

Riordan H. 2005. Intravenous ascorbate as a chemotherapeutic and biologic response modifying agent. Accessed March 2005 http://www.canceraction.org.gg/recnac.htm

Riordan HD, Riordan NH, Jackson JA et al. 2004. Intravenous vitamin C as a chemotherapy agent: a report on clinical cases. PR Health Sci J 23; 115-18.

The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. 1994.The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers N Engl J Med 330;1029-35.

Walker EM, Ross D, Peggy J, Devine G, Prasad KN, Kim JH. 2002. Report to the International Conference Nutrition & Cancer. Uruguay.

Weijl NI, Elsendoorn TJ, Lenties EG, Leiden et al. 2004. Supplementation with antioxidant micronutrients and chemotherapy-induced toxicity in cancer patients treated with cisplatin-based chemotherapy: a randomised, double-blind, placebo-controlled study. Eur J Cancer 40:11;1713-23.

Shauna Ashewood BSc DipEd DipHlthCouns DipNat MPH MNHAA

Shauna has been in practice as a Naturopath and Herbalist since 1988 after qualifying from the SA College of Natural Therapies and Botanic Medicine. She has been in clinical practice since then concentrating on cancer and women and children's health. In the last 10 years she has worked more intensively with cancer and feels honoured to work with people during the processes of treatment, recovery and survival as well as end of fife issues. Shauna is qualified with a Bachelor of Science Degree and in 2001 completed a Master of Public Health Degree focusing on Complementary Medicine Research. Shauna has been a member of the Board of the NHAA since October 2003. She is the author of Cancer and herbal medicine practice published in the Australian Journal of Medical Herbalism in 2005 and regularly lectures to health professionals as well as community groups.

Email ashewood@cobweb.com.au Phone (08) 8242 2083
Summary Protocols from clinical trials

                Prasad (2004)      Drisko (2003)    Lockwood (1994)

Vitamin E       800iu a TS         1200 IU           2500 IU
Vitamin A                          10 000 IU         2500 IU
Beta carotene   60mg (natural)     25mg (natural)    32.5 IU
Vitamin C       8000-10000 mg      9000 mg 60 g IV   2850 mg
Q10                                300 mg            390 mg
Selenium                                             387ug
Other           Vit D, B but not                     EPA/DHA
                Fe, Cu, Mn                           Vit B, Mag, Zinc,
                                                     Cu, Mn
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