The following research was published in the March 2006 issue of Integrative Cancer Therapies, a peer-reviewed journal.

Download a full, free copy of this study by clicking here: PDF [104kb]

Precisión del diagnostico de Detección Canina a través del olfato en las fases tempranas y terminales del cáncer de mama y de pulmón: PDF [258kb]

ABOUT THIS RESEARCH, BRIEFLY
Lung cancer, when symptoms arise, is usually diagnosed at Stage III or IV, when the prognosis is rarely good. Treatment is significantly more effective at early stages (I or II) when the tumor is smaller and has not yet spread. Detecting lung cancer in its early stages is difficult, so therefore developing a feasible and effective early detection method is the subject of a considerable amount of research around the world. In terms of breast cancer, while detection at early stages is comparatively easier, finding methods to detect it even earlier are worthwhile.

In an international collaboration, the Pine Street Foundation conceived of and obtained grant support for a rigorously designed diagnostic study aimed at accurate early detection of lung and breast cancers. We invited scientist Professor Tadeusz Jezierski, ScD, of the Polish Academy of Sciences, to serve as principal investigator for this study.

A dog’s nose, considered by both dog trainers and chemists alike to be one of the world’s most powerful olfactory sensor, was the “medical device” used in this research. In a study of 86 people (55 with lung cancer and 31 with breast cancer), five professionally trained scent dogs accurately distinguished between breath samples from diseased patients and those from 83 healthy controls. The dogs’ ability to correctly identify or rule-out lung and breast cancer, at both early and late stages, was around 90%. A more exact and specific discussion of the sensitivity and specificity of the dogs’ abilities is available in the full study.

This work is based on the hypothesis that cancer cells emit different metabolic waste products than normal cells. The differences between these metabolic products are apparently so great that they can be detected by a dog’s keen sense of smell, even in the early stages of disease.

In carefully controlled conditions, the dogs were presented with breath samples of both cancer patients and healthy controls. The dogs were trained by professional dog behaviorist Kirk Turner and the methods used in the field research were developed by Professor Jezierski. Not only did the dogs perform exceptionally well, they did so consistently over a lengthy four month investigation of 12,295 separate scent trials – each one documented on videotape.

What is important about this study is that (1) ordinary dogs, with no prior scent discrimination training, could be rapidly trained to identify lung and breast cancer patients by smelling samples of their breath, when compared to blank unused sample tubes; (2) dogs could accurately and reliably distinguish breath samples of lung and breast cancer patients from those of healthy controls; and (3) the dog’s diagnostic performance was not affected by disease stage of cancer patients, age, smoking, or most recently eaten meal among either cancer patients or controls.

NEXT STEPS
We are actively seeking funding to launch new studies that will build upon this research. This pilot work using canine scent detection demonstrates the validity of using a biological system to examine exhaled breath in the diagnostic identification of lung and breast cancers. Future work will closely examine the chemistry of exhaled breath to identify which chemical compounds can most accurately identify the presence of cancer. A prospective cohort study, comparing both biological (canine scent detection) and chemical methods to conventional diagnosis within a given set of individuals, should help answer the question of whether these approaches can lead to changes in how cancer in diagnosed in clinical practice.

Another goal is to study canine scent detection of ovarian cancer, a disease that is currently very difficult to detect at its earliest stages.

INFORMED CONSENT & ANIMAL SAFETY
All subjects provided written informed consent and our protocol and patient recruitment materials were approved by an independent Institutional Review Board (Independent Review Consulting, Corte Madera, Calif.). Additionally, our animal training and handling methods were designed in consultation with two veterinarians, an independent dog trainer, and the dog owners themselves, all of whom approved our methods. We used food reward-based positive reinforcement training, also known as clicker training; no compulsion training methods were ever used. None of the animals were ever harmed, either physically or psychologically, in the course of this research; the health, safety, and happiness of all the animals involved was always our first priority. We did not provide any compensation to subjects for providing breath samples or to dog owners for volunteering use of their dogs in the study.

GRANT SUPPORT
This research was made possible through the generous support of the MACH Foundation (Fairfax, Calif.) and Frank and Carol Rosenmayr (Kentfield, Calif.). Their support allowed us to invite Dr. Jezierski to work with us for four months and to provide our team of trainers and volunteers with methodical guidance and close supervision. Study sponsors had no role in study design, data collection, data analysis, data interpretation, manuscript preparation, or the decision to publish. We would also like to acknowledge Guide Dogs for the Blind (San Rafael, Calif.) for their help in making dogs available for this study.

HOW YOU CAN GET INVOLVED
There are many ways you can help us to further research in this emerging field:
» Funding. Support from individuals is incredibly important. If you are interested in continuing this research, please make a donation. 92% of our funding comes from individuals like you. Additionally, should you know of any foundations or individuals who might also be interested in supporting us, please pass the word along.
» Replicate Our Study. For researchers, we actively encourage you to learn more about our current study and to build and improve upon it through new research.
» Get the Word Out. The more people who know about this work, the better. Please share us with your friends and colleagues.

FREQUENTLY ASKED QUESTIONS
Was this research published in a peer-reviewed journal?
Yes. Our research was rigorously peer-reviewed prior to publication in Integrative Cancer Therapies, which is a peer-reviewed journal indexed in MEDLINE.

Are the dogs smelling cancer or just people?
Dogs and patients did not meet directly. We gathered breath samples in specially designed tubes and then, at a separate location, presented those tubes to the dogs for training and testing. Additionally, during the entire double-blinded testing phase, upon which our data is based, all breath samples sniffed by dogs, for both cases and controls, were from completely different subjects not previously encountered by the dogs during training or single-blinded testing.

What about the smells of smoking?
Smokers were present in both lung cancer patients and the control groups. The strong results we found remained even after accounting for confounding by smoking in our analysis.

What about the effect of chemotherapy on body odor?
Breath samples were taken before starting conventional treatment.

Weren’t the cases and controls very different from each other?
Yes. This is correct and a valid criticism of our study. In the long course of developing a new diagnostic method, the first step is to see if the method can distinguish known cases from controls. This preliminary step is then followed by testing in which the new method is compared head-to-head with existing diagnostic methods and then examining people whose true health status is not known at the time of the study.

Do you really expect dogs to be used in hospitals to detect cancer?
Our study provides compelling evidence that cancers hidden deep within the body can be detected simply by examining the odors of a person’s breath. The fact that it was dogs who did this does not detract from the novelty of our findings. The dog’s brain and nose is currently one of the most sophisticated odor detection devices on the planet…technology now has to rise to meet that challenge and it remains to be seen whether chemical analysis can meet the level of the dogs.

What are the next steps?
The direction our research is taking, and should take, is toward the development of an “electronic nose”. This sort of device would be much more likely to be incorporated into clinical practice. In the end, diagnostic breath analysis deserves further rigorous study, both through additional work with dogs and through chemical analysis towards the goal of understanding precisely what compounds it is that the dogs are detecting by scent. These are the questions our next generation trial will address, and for which we are currently seeking funding.

What sorts of dogs did you use in this study? What were your selection criteria?
Five dogs, ages 7-18 months, were chosen out of a total of 13: three Labrador retrievers (two males and one female) and two Portuguese water dogs (one male and one female). Dogs were provided by local dog owners and by Guide Dogs for the Blind in San Rafael, Calif. Our selection criteria called for dogs over six months old with basic obedience training typically given to household pets, as defined by the American Kennel Club, who were judged by the experimenters to be eager to sniff objects and respond to commands.

What were the names of the dogs?
Kobi: Labrador retriever (yellow)
Isabelle: Portuguese water dog
Court: Labrador retriever (black)
Estelle: Labrador retriever (yellow)
Django: Portuguese water dog

How can I get my dog involved in your research?
Should we receive funding to continue research in this field, we will likely be recruiting additional dogs from the San Francisco Bay Area. An announcement will be made through our newsletter, so be sure to sign up to receive email updates. Additionally, the Pine Street Foundation is available to discuss this research with individuals or groups who may be interested in pursuing a collaboration leading toward grant-funded clinical research.

Can I have your dogs screen me to see if I have cancer?
Unfortunately, it is not currently possible to be “screened” by the dogs involved in our research. At this time, it is also not recommended that dogs be used as a primary screening method for cancer. It is our hope, however, that the concepts explored in our research may help develop more accurate cancer screening methods in the future. Nevertheless, numerous anecdotal reports have been published and televised documenting individual cases in which dogs began to display persistent and animated behavior around specific body locations on their owners. These behaviors, on subsequent medical evaluation, proved to be accurate, and in some cases life-saving, early warning signs of cancers such as those of the breast and skin (melanoma). Therefore, should your dog display such behavior, we do recommend medical follow-up.

How can I train my dog to detect cancer?
The methods used in our study are similar to how you might train your dog to sit or roll over. We specifically used “clicker training”, a reward-based method of teaching in which the dog is given food treats for offering the desired behavior. What is more difficult is obtaining breath samples from cancer patients; there are various state and federal requirements regarding medical research that must be followed. There are also important ethical and scientific issues that must be addressed before engaging in this type of training. For example, what would a person do with the dog after training is complete? Would the dog be used to screen people for cancer? How would the dogs’ accuracy and consistency be determined? What would a person who is screened then do with the information gleaned from the dogs? Could or should the results be trusted? Worse than a false positive (where a dog indicates there is cancer present when no disease actually exists) would be a false negative (where the dog indicates no cancer is present when in fact there is disease). Because of the various logistical and ethical considerations associated with this type of research, it is recommended that individuals engaging in this type of training follow appropriate scientific and ethical guidelines such as those documented in our study. Additionally, the Pine Street Foundation is available to discuss this research with individuals or groups who may be interested in pursuing a collaboration leading toward grant-funded clinical research.

QUESTIONS AND COMMENTS
Have comments or additional questions? Please contact us.

Currently, chemotherapy is a vital part of allopathic breast cancer treatment, for both primary and metastatic disease. As advances in chemotherapy are thoroughly covered in other publications, I will instead focus on non-chemotherapy advances in this article.

This year, I have seen new research giving us more information about which herbs, supplements, and other alternative/complementary approaches can minimize treatment side effects and possibly even reduce the risk of breast cancer recurrence. Other progress has improved our ability to determine the full extent of a primary breast cancer, making possible better surgical planning. Finally, I have seen broader acceptance of tests allowing women less likely to benefit from chemotherapy to forgo it with confidence.

ANTIOXIDANTS & CHEMOTHERAPY
An excellent article by Dr. Keith Block reviewed 845 studies, discarding all those that were not randomized or controlled.1 The remaining 19 studies showed that antioxidants such as glutathione, melatonin, vitamin A, vitamin E, vitamin C, ellagic acid (from raspberries, strawberries, and cranberries), and N-acetyl cysteine did not adversely affect the outcome of patients who were also on chemotherapy. In fact, these patients had improvements in their survival time, tumor responses, or both.

As more highquality studies are published, I hope to see more oncologists using antioxidants with chemotherapy.

BOSWELLIA USE IN BRAIN METASTASES
Last year, Dr. Dana Flavin at the Foundation for Collaborative Medicine and Research in Greenwich, CT, reported on a remarkable case of a woman with breast cancer whose multiple brain metastases showed no improvement after two weeks of Xeloda and brain radiation.2 She was then started on boswellia 800 mg three times a day. (Boswellia, also known as Indian frankincense, is an herbal supplement with anti-inflammatory properties and is generally available through retail and online health food stores.) Ten weeks later, a repeat brain CT showed complete resolution of the brain metastases. Impressively, she has been maintained on boswellia for the past four years with no recurrent brain metastasis.

Subsequently, Dr. Flavin has had two more women with brain metastases greatly improve using the same regimen. Reportedly, Harvard’s Dana Farber Cancer Center is seeking approval for a clinical trial to study boswellia use in this setting.

NUTRITION CONTROVERSIES
The December 2006 San Antonio Breast Cancer Symposium (SABCS) saw the unveiling of the Women’s Intervention Nutrition Study (WINS), a large randomized, controlled trial that compared breast cancer patients on high-fat and low-fat diets.3 This study was a joint effort by several institutions including Beth Israel Deaconess Hospital, Memorial Sloan-Kettering Cancer Center, and the University of California, Los Angeles. They found a substantial survival benefit in the low-fat group, especially for those with estrogen receptor-negative cancer.

In contrast, the Women’s Healthy Eating and Living (WHEL) study published recently by the University of California at San Diego showed no survival advantage of a high vegetable/fruit, low-fat, and high-fiber diet.4 Although this trial was also large, randomized, and controlled, it had two key differences from WINS: first, the low-fat group in the WHEL study had, on average, a much higher daily fat intake than those in WINS (45 grams versus 33 grams). Second, the women in the WHEL study gained weight as opposed to those in WINS who shed pounds. Since a Mayo Clinic study showed that breast cancer survivors who gain weight have reduced survival, it is quite possible that whatever benefit the WHEL participants derived from the relatively low-fat and high vegetable/fruit intake was neutralized by their weight gain.5

Interestingly, the same group who published the WHEL study joined Stanford, the Northern California Kaiser Permanente group, and others in a large multi-institutional clinical trial. They found that when women with breast cancer combine higher vegetable-fruit consumption with increased physical activity, their chances of surviving increased by nearly 50%, regardless of their level of obesity.6

PSYCHOSPIRITUAL ASPECT OF BREAST CANCER
An interesting study out of Baylor College of Medicine noted that women who blamed themselves for their breast cancer and lacked self-forgiveness reported more mood disturbances and a lower quality of life.7

Another report in the Journal of the National Cancer Institute showed that breast cancer survivors, particularly African-Americans, have a higher rate of suicide than the rest of the population.8

These studies point to the importance of psychological health and reinforce the fact that a proactive approach to emotional issues is a key part of an integrative breast cancer treatment program.

ALTERNATIVE APPROACHES
There are various alternative approaches that have shown to be beneficial in recent studies:

» Aromatherapy massage was shown to reduce anxiety and depression.9
» Yoga improved sleep, physical function, and possibly also fatigue in women getting radiation therapy.10
» Reiki, an energy-based healing system from Japan, improved fatigue in cancer patients.11
» Mayo Clinic research suggests that American ginseng at 1000 to 2000 mg per day may be effective for alleviating cancer-related fatigue.12
» A Columbia University study showed that acupuncture can reduce the joint pains caused by aromatase inhibitors such as Femara and Arimidex.13
» Eight weeks of aerobic exercise was shown to improve depression and fatigue as well as improve physical conditioning in breast cancer survivors.14
» I was intrigued by Duke University’s report that women taking calcium supplements had more hot flashes that those who did not. This small study was presented at the ACSO Breast Cancer Symposium two weeks ago. It remains to be seen whether this relationship holds up under larger, more rigorous studies.15

BREAST MRI
Breast MRI continues to be an area of active research. It is well documented that up to 15% of breast cancers are missed by mammogram and breast ultrasound.16 MRI will catch most of these.

Despite this obvious advantage, MRI is not yet ready to replace mammography as our standard screening tool as it does have a significant false-positive rate. In other words, it is very good at finding even tiny breast lumps, but it cannot always distinguish a benign lump from a malignant one.

Nevertheless, one group of women were found to be excellent candidates for MRI breast screening: those with a high risk of developing breast cancer within five years. Women with BRCA gene mutations fall into this category. In addition, women who have a 20% or greater lifetime risk of breast cancer also fall into this group. One easy way to estimate one’s risk is to use the Gail risk model, an interactive computer program where inputting specific information such as age and family history of breast cancer yields an estimate of both 5-year and lifetime risk of breast cancer. It can be accessed at the National Cancer Institute website: www.cancer.gov/bcrisktool.

For those who have already been diagnosed with breast cancer, a breast MRI can add to the information provided by the mammogram to help plan a surgery that will be sure to remove all of the cancer. In fact, researchers have shown that in at least 16% of women, a preoperative MRI found a second cancer that the mammogram had missed and that would probably have escaped the planned lumpectomy.17 In another study, MRI findings resulted in a change in surgical plans in 15% to 30% of cases.18,19

Additionally, a small study from New York University was just presented at the ASCO Breast Cancer Symposium, showing that women who had preoperative MRI not only tended to have a lower rate of re-excision and improved surgical margins, but also had fewer mastectomies.20  I am now beginning to see breast surgeons who routinely incorporate MRI in their pre-operative protocol.

Unfortunately, this research is not mature enough to say definitively whether preoperative breast MRI is beneficial.  In the meantime, those women who would rather risk a negative (i.e. unnecessary) biopsy than a potentially incompletely excised cancer should talk to their breast surgeons about an MRI.

It is important to note that there are currently no national standards for breast MRI imaging as there are for mammograms. Therefore, it makes sense to have your MRI done at a center that uses dedicated breast MRI coils and whose radiologists have at least three years of experience interpreting them.

GENE EXPRESSION PROFILING
I am very happy to report steady advances in the realm of personalized treatment. For many years, women with lymph node-negative, early stage breast cancer were encouraged to undergo chemotherapy even though only 2% of those over 50 years of age, and only 7% of those under 50, would be expected to benefit from it.21 (Although the percentage of women with early stage breast cancer being saved by chemotherapy seems small, when multiplied by the hundreds of thousands of women diagnosed, it actually translates into thousands more women surviving their breast cancer each year.) The problem is that you have to give chemotherapy to many, many women in order to save one. For example, for every 100 women over 50 being treated, 98 would get chemotherapy, with all its side effects but none of its benefit, in order to save two women.

This situation changed dramatically in 2003 when a company called Genomic Health burst on the scene with an elegant test to help decide who would benefit from chemotherapy. They examined DNA from thousands of breast cancer samples from women whose ultimate response (relapse or no relapse) to tamoxifen was known. They found 21 genes that accurately predicted whether a woman with hormone-positive breast cancer taking anti-estrogen therapy would relapse over the next 10 years. The result is OncoType DX, a gene expression profiling test that has now allowed many women to forgo chemotherapy with confidence.

Agendia is another biotech company whose gene profiling test was approved by the FDA this year. Called MammaPrint, it uses a 70-gene profile and has been shown to be as accurate as the Oncotype DX test in predicting breast cancer relapse.

There are differences between the two tests. Oncotype DX requires the breast cancer be lymph node-negative, early stage, and hormone receptor-positive. It can use preserved breast cancer specimens, so even if the cancer was removed years ago, the test can still be done on that tissue sample (pathologists always save tissue specimens). The MammaPrint test requires women to be early stage and lymph node-negative but does not require them to be hormone receptor-positive. However, it does require a fresh tissue sample taken at the time of surgery.

Surprisingly, many oncologists still choose not to discuss these exciting new tests with their patients.

TUMOR MARKERS
A blood test that accurately tracks metastatic cancer activity is a holy grail of sorts in the breast cancer diagnostic world. Armed with the results of this test, one can monitor the effectiveness of the current treatment regimen more quickly. Such a test, called a tumor marker, certainly has advantages over CT, MRI, and PET scans in that it can be done more frequently and without exposure to radiation.

For many years, the only choices were blood tests for CA 15.3 or CA 27.29. Unfortunately, these tumor markers were useful only for some women.

Recently, a new blood test has become available that looks for cancer cells, called circulating tumor cells, in the bloodstream. This test, called Cell Search, uses monoclonal antibodies to find as few as one cancer cell per billion normal cells in a small sample of blood.22 The FDA has approved this test only for women with metastatic breast cancer. It is available from Quest Diagnostics and many other laboratories.

Women with metastatic HER2-positive breast cancer now also have a more accurate tumor marker. Monitoring the HER-2 ECD blood test over time has proved very useful in this regard as noted by several research papers presented at the San Antonio Breast Cancer Symposium (SABCS) and the American Society for Clinical Oncology annual conference (ASCO).23,24 This FDA approved test may be obtained through Specialty Laboratories.

CELEBREX FOR METASTATIC BREAST CANCER
Last year, a group of French researchers published the results of a well-designed study looking at a new drug combination for treating breast cancer.25 They used Celebrex, a COX-2 inhibiting anti-inflammatory medication, and Aromasin, an anti-estrogen drug. This combination was prescribed as the first-line treatment for metastatic breast cancer and was compared to using Aromasin alone. The Celebrex plus Aromasin group had 75% more women whose cancer went into complete or partial remission than did those who took Aromasin alone.

Interestingly, women who took Celebrex plus Aromasin had significantly less pain, joint aches, fatigue, and insomnia. But more of these women experienced edema (about 8% versus 2% in the Aromasin alone group) and hypersensitivity reactions. In fact, anyone who is allergic to Sulfa should not take Celebrex, but should take another COX-2 inhibiting anti-inflammatory agent instead.

Although this study was done with Aromasin, other aromatase-inhibiting anti-estrogens such as Femara and Arimidex may very well work with Celebrex in the same way.

ER-NEGATIVE BREAST CANCER MAY RESPOND TO ANTI-ESTROGEN THERAPY AFTER ALL
At the December San Antonio Breast Cancer Symposium, much excitement surrounded a multinational study of the effect of aromatase inhibitors on estrogen receptor-negative breast cancer.26 In short, they tested the truism that estrogen receptor-negative cancers do not respond to anti-estrogen therapy.

This elegant study gathered the initial breast cancer samples of 116 women and noted their estrogen receptor status. Some had their cancers progress and, despite being estrogen-negative, were treated with aromatase-inhibiting anti-estrogens. It turned out that a notable 18% of these women had their cancer shrink when they took either Femara or Arimidex.

These results may mean that currently accepted methods do not always detect estrogen receptor-positivity accurately enough. In fact, recent research shows that looking for estrogen-related genes is a much more accurate way of determining estrogen receptor status than the current standard that relies on estrogen receptor dyes.27

The bottom line: when a post-menopausal estrogen receptor-negative cancer is resistant to standard treatment, it makes sense to consider trying Femara or Arimidex.

HER-2 POSITIVE METASTATIC BREAST CANCER
A recent flurry of studies have shown that women whose cancers grew while on Herceptin but continued the Herceptin treatment anyway, lived up to twice as long as those who did not.28,29,30,31

CURRENT HER-2 TESTING PROTOCOLS MAY BE INADEQUATE
A well-respected breast cancer research group called the National Surgical Adjuvant Breast and Bowel Project caused a stir at the ASCO meeting this year. They showed that the IHC and FISH protocols currently used for determining HER-2 status do not predict which women will respond to Herceptin.32 In fact, women who were IHC 2+ or less, or who were FISH-negative but received Herceptin anyway, had a 50% to 80% lower breast cancer recurrence rate than those who did not receive it.

Of course, the top researchers in the breast cancer treatment world, including the authors of this study, hastened to say that this is a preliminary study and oncologists should not be giving Herceptin to women unless they are FISH-positive or IHC 3+ positive for HER-2. While this may be sound public health policy, in an individual case that is resistant to standard treatment, it makes sense to consider trying Herceptin if it has not been tried yet.

In a related study, Italian researchers gave Herceptin to women whose cancers were HER-2 negative according to the standard protocol but were found to have the HER-2 protein in their blood (according to the serum HER ECD blood test).33 These women had more cancer shrinkage when given Herceptin than those who did not receive Herceptin.

HELP FOR “CHEMOBRAIN”
Provigil improved memory and attention in a randomized, controlled trial of women who had chemotherapy for their breast cancer. Of note, scientists from Cephalon, the pharmaceutical company that manufactures Provigil, participated in this study.34

ON THE HORIZON
I am optimistic about the continued advancement of cancer vaccines. The underlying science has been more difficult to conquer than many had envisioned. Nevertheless, the latest round of vaccines in clinical trials has shown some promise.

Vaccines for HER-2 Positive Breast Cancer
Every year sees more anti-HER-2 vaccines introduced into clinical trials. Currently, there are at least five such vaccines being tested. A particularly promising one, E75, was given to women who were at high risk for cancer relapse after receiving the standard treatment.35 There were about 60% fewer relapses at two years compared with those who did not receive E75. A Phase III trial is currently in the planning stage.

Vaccines for Metastatic Breast Cancer (HER-2 Positive and Negative)
The National Cancer Institute presented its latest data on PANVAC at the ASCO Breast Cancer Symposium. PANVAC is a fascinating vaccine that uses a virus to deliver potent immune-activating substances directly to the cancer site. It is hoped that PANVAC will mobilize the immune system to seek out and destroy every breast cancer cell in a woman’s body. While it showed some activity when used as a single agent, the recent NCI study using it in combination with the chemotherapy agent Taxotere showed promising prolonged partial remissions in the two patients who have tried it so far.37

Crying for Better Breast Cancer Screening
The most paradigm-shifting research presented at the ASCO Breast Cancer Symposium was a small study that analyzed the tears of women with breast lumps using a special machine called a mass spectrometer.38 They were able to tell who had breast cancer and who did not based on the results of a protein “fingerprint” of the tears. If these results are corroborated in further research, women may eventually be able to say goodbye to their annual mammogram.

Antiviral Therapy for Metstatic Breast Cancer
In recent years, there is accumulating evidence of a strong link between the human mammary tumor virus and the occurrence of breast cancer. Researchers at the National Cancer Institute are testing this hypothesis. They showed that nelfinavir (Viracept), a protease-inhibiting antiviral drug commonly prescribed for HIV, caused breast cancer cells to die in laboratory conditions.39 I hope it will not be long before a human clinical trial is done to answer this important question more conclusively.

Gwendolyn Stritter, MD, is a clinical advocate for those with difficult or life-threatening health problems. Her practice is focused especially on those with breast cancer. She is a member of the American Society of Breast Disease, the Society for Integrative Oncology, the American Society of Clinical Oncology, and the American Pain Society. Dr. Stritter would like to thank Michael McCulloch and Autumn Stanley for their editorial assistance. She would also like to thank Carl Stritter and Ann Baldwin for reviewing the manuscript. Visit her online at www.strittermed.org.

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Scientific evidence suggests that combining certain chemotherapy treatments with certain antioxidants at specific dosages can help improve drug effectiveness or reduce the severity of side effects.

This issue is important because it has long been the opinion of many practicing oncologists that antioxidants should simply not be used concurrently with chemotherapy because it was believed that the combination might inhibit chemotherapy effectiveness. This reluctance stems, in part, from the fact that some chemotherapy drugs work by strongly promoting oxidation. This is especially the case for the class of chemotherapy drugs called anthracyclines (Adriamycin and epirubicin), the alkylating agents (chlorambucil, cyclophosphamide, thiotepa, and busulfan) and the platinum drugs (cisplatin and carboplatin). Antioxidants, by definition, inhibit oxidation, so it was believed that antioxidants would prevent these chemotherapy drugs from working properly.

Chemotherapy drugs that cause high levels of oxidative stress are thought to rely, in part, on using this stress mechanism to kill cancer cells. But oxidative stress might actually reduce the overall effectiveness of chemotherapy. Oxidative stress slows the process of cell replication, but it is during cell replication that chemotherapy actually kills cancer cells (Conklin, 2004), so slower cell replication can mean lower effectiveness of chemotherapy. One approach to addressing this problem is the addition of certain antioxidants at specific dosages to lessen oxidative stress, thus making the chemotherapy treatment more effective (Perumal and Shanthi, 2005).

The interaction between chemotherapy and antioxidants is more complex than simply promoting and inhibiting oxidative stress, however. There are several mechanisms by which chemotherapy functions and antioxidants also have a number of different effects on the body. Each antioxidant has a different interaction with chemotherapy and this effect can even change based upon the dosage used.

Today, the question may in fact not be whether antioxidants should be used in combination with chemotherapy but rather which should be used and at what dosages.

In this evidence-based review article, we discuss the results of current research showing how antioxidants may enhance or, in some cases, inhibit the therapeutic action of specific chemotherapy drugs used in the treatment of breast cancer. Some of these antioxidants may also reduce chemotherapy side effects or inhibit chemotherapy resistance in breast cancer cells. Finally, some of these antioxidants have been found to be useful for restoring the natural antioxidants in the body, which are often depleted after the completion of chemotherapy.

We searched for clinical or laboratory data published in peer-reviewed medical journals, conducted by cancer researchers in universities and medical research facilities around the world, from MD Anderson Cancer Center in Houston to Peking University in Beijing and dozens of institutions in between. These studies were published in prestigious, peer-reviewed journals such as Anticancer Research, Breast Cancer Research and Treatment, and the Journal of the National Cancer Institute. Some of these studies are still in early stages and include only laboratory data, while others have advanced to include animal or human patients.

We then organized all this data into the major categories of specific chemotherapy drugs. Within each section for a specific drug are found the research on combinations of that drug with various antioxidants, grouped by the name of the antioxidant in question and then by alphabetical order. We also point out specifically which studies were conducted in a laboratory (i.e. using cancer cell cultures), which were conducted using animals, and which were conducted with human volunteers. The dosages given are not necessarily appropriate for all patients and should be individualized with practitioner guidance.

Studies On Single-agent Chemotherapy

DOXORUBICIN/ADRIAMYCIN IN COMBINATION WITH ANTIOXIDANTS

Biochanin A & Silymarin
Biochanin A is a flavonoid found in legumes (the family leguminaceae) and in red clover (Trifolium pratense). Silymarin is extracted from the blessed milk thistle plant (Silybum marianum) which is a member of the sunflower family (Compositae). A laboratory study found that estrogen receptor-positive and multidrug-resistant breast cancer cells that are P-glycoprotein positive became more sensitive to Adriamycin treatment when treated in combination with biochanin A and silymarin (Zhang and Morris, 2003). P-glycoprotein is a protein complex believed to play a role in the resistance of cancer cells to chemotherapy (Rudas and Filipits, 2003). When cancer cells become more sensitive to a chemotherapy drug this means that they can more easily be destroyed by the drug.

» Red Clover Tea (good source of Biochanin A): Typical dosage for a tea is 3 cups per day. In capsules and tablets, 2g to 4g, 3 times per day. In tincture, 2 ml to 4 ml, 3 times per day.

» Silymarin: Typical dosages range from 100 mg to 900 mg daily. An example of a good product is one containing 900 mg, standardized to 80% silymarin (720 mg), 30% silibinin (270 mg) and 4.5% isosilybin B complex (40.5 mg). Silibinin is the most biologically active constituent found in silymarin and isosilybin B complex is the most efficient constituent of silymarin in maintaining healthy cell division.

Rutin & Other Flavonoids
Flavonoids are beneficial antioxidants found in fruits and vegetables, especially red grape juice, green tea, soy, and many other legumes. One potential useful example of a beneficial flavonoid is monoHER, one of the most powerfully active antioxidants in flavonoid products, such as Venoruton, which is used to treat varicose veins (van Acker and Boven, 1997). MonoHER is a derivative of the flavonoid rutin, obtained from many sources, such as buckwheat and the buds of the Chinese herb Saphora japonica. It is also found in propolis. The ability of flavonoids to protect the integrity of blood vessels may, in part, explain how they protect the heart.

Adriamycin can cause cardiomyopathy, a disease of the heart muscle that impairs the heart’s ability to pump blood and deliver it to the rest of the body. Three studies found that flavonoids have a beneficial effect in protecting the heart against Adriamycininduced heart damage. The toxicity of Adriamycin to the heart is thought to be caused by oxidative stress. Flavonoids reduce oxidative stress, which may explain how they protect the heart. The studies, conducted in the Netherlands, found that the flavonoid monoHER almost completely protected the heart without influencing the antitumor effect of Adriamycin treatment against estrogen receptor-positive breast cancer cells (Bast and Kaiserová, 2007; Hüsken and de Jong 1995; van Acker and Boven 1997.)

» Rutin: Typical dosages range from 500 mg to 1,000 mg daily.

Genistein
Genistein is an isoflavone found in legumes, especially soybeans. Isoflavones are antioxidants that counteract the damaging effects of free radicals in body tissues.

Genistein has structural similarity to estradiol and therefore competes with estradiol for estrogen receptor binding. This blocks estradiol from stimulating cell growth (Sarkar and Adsule, 2006).

Isoflavones, such as genistein, also have antiangiogenic effects, blocking the formation of new blood vessels needed to support the growth of tumors.

Genistein sensitizes cancer cells to apoptosis induced by chemotherapeutic agents including Taxotere, gemcitabine, and cisplatin. Apoptosis is the “cellular programming” in the DNA which instructs cells to self-destruct when they have reached the end of their intended life cycle. Apoptosis is a natural and desirable part of cellular growth, and cancer cells “forget” when they are supposed to stop growing, thus contributing to uncontrolled cell growth. Some chemotherapy drugs can help induce apoptosis in cancer cells.

Genistein also directly inhibits breast cancer cell growth both in cell culture and animals (Sarkar & Adsule, 2006).

A laboratory study from Japan showed genistein made estrogen receptor-negative breast cancer cells more responsive to Adriamycin treatment, thus increasing effectiveness. In contrast, no effect or even decreased drug effectiveness was noted in estrogen receptor-positive breast cancer cells (Lim and Kim, 2006).

Another laboratory study from Japan showed that HER2/neu-positive breast cancer cells (which contributes to malignant transformation of cancer cells) were more sensitive to treatment when the combination of genistein and Adriamycin was used (Satoh and Nishikawa, 2003). A laboratory study conducted in Italy found that genistein increases the treatment effect of Adriamycin in both estrogen receptor-positive and estrogen receptor-negative breast cancer cells. This effect was even stronger in Adriamycin resistant breast cancer cells (Monti and Sinha, 1994). When cancer cells become resistant to a chemotherapy drug, this lowers the drug’s effectiveness. An important goal of cancer research is to identify compounds which can reduce chemotherapy resistance, and thus perhaps increase chemotherapy effectiveness.

» Genistein: A good product will use organic non-GMO genistein. Typical dosages range from 40 mg to 60 mg daily. One cup of soy milk will contain on average about 45 mg of genistein and the other related isoflavones.

Glutathione
Adriamycin can cause cardiomyopathy (damage to heart muscle). This injury may happen through oxidation. In one study, dietary glutathione and Adriamycin administered to rats showed that this combination can diminish Adriamycin-induced oxidative damage to the heart muscle (Cao and Kennedy, 1999).

» Glutathione: Typical dosage ranges between 50 mg and 600 mg daily. N-acetyl cysteine is the pre-cursor of glutathione and is more efficiently absorbed. When taking Glutathione or N-acetyl cysteine, combine with three times as much vitamin C. Vitamin C prevents these amino acids from being oxidized in the body and ensures their ability to act as antioxidants.

Grape Seed Polyphenol
Grape seed polyphenol increased effectiveness of Adriamycin against estrogen receptor-positive breast cancer cells and also reversed Adriamycin resistance in an animal study from China (Zhang and Zhou, 2004).

Grape Seed extract strongly increases the treatment effect of Adriamycin in both estrogen receptor-positive and -negative breast cancer cells according to a US study (Sharma and Tyagi, 2004).

» Grape Seed Polyphenol (Grape Seed Extract): Sometimes products may combine grape seed extract with the extract called Resveratrol, the “red wine antioxidant” from the red pigment of grape skins. Typical dosages range between 50 mg and 200 mg daily.

Green Tea Polyphenols
Epigallocatechin-3-gallate (EGCG) is the principal polyphenol found in green tea.

In a laboratory study from China, it was demonstrated that green tea polyphenol improved effectiveness of Adriamycin in estrogen receptor-positive breast cancer cells that had become resistant to adriamycin treatment (Zhu and Wang, 2001).

» Green Tea Polyphenols (EGCG): One cup of green tea contains between 10 and 400 mg of polyphenols depending on the source, amount of leaves used, and time the tea steeps. EGCG may be conveniently obtained from extracts. A good product contains 725 mg, standardized to 98% polyphenols, 45% of which is EGCG.

Melatonin
Melatonin protects hematopoietic stem cells from Adriamycin treatment according to a Japanese study (Greish and Sanada, 2005). Hematopoietic stem cells produce the different components of blood, including red and white blood cells and, if damaged by chemotherapy, may lead to anemia or immune deficiency.

Also, an animal and laboratory study from Korea showed that the addition of melatonin to treatment with Adriamycin decreased mortality in rats by 20%. This treatment also reduced Adriamycin-induced side effects, such as weight loss and problems with the blood pressure or blood flow output of the heart. These researchers also found that when melatonin was given together with Adriamycin, a lower dose of chemotherapy could achieve the same efficacy as a higher dose of Adriamycin treatment alone (Kim and Kim 2005).

In an Italian study, 77 advanced breast cancer patients received chemotherapy alone or a combination of chemotherapy and melatonin. Patients treated with melatonin had significantly higher 1-year survival rates and tumor regression rates. In addition, melatonin treated patients had less thrombocytopenia. (Thrombocytopenia is a reduction in platelets, which are cells in the blood that help blood to clot. Thrombocytopenia is sometimes associated with abnormal bleeding.) Patients receiving melatonin also experienced reduced neurotoxicity (damage to the nerves including weakness or numbness, memory loss, headache, cognitive and behavioral problems and sexual dysfunction), cardiotoxicity (toxicity that effects the heart), stomatitis (inflammation of the mouth), and asthenia (loss of strength and energy). This study concluded that in advanced breast cancer patients with poor clinical status, melatonin may reduce toxicity and increase efficacy of treatment (Lissoni and Barni, 1999).

» Melatonin: Typical dosages range from 1 mg to 20 mg. If aiming for a high dosage, one should start with 1 mg and increase the dosage slowly by 1 mg every 3-7 days. The ideal is to achieve peak blood levels of melatonin at about 2am. To do so one can take the melatonin half an hour before bedtime between 9 and 10pm. For
more discussion about the healing value of sleep, click here.

Micronized Zeolite
Zeolites (from the Greek “zein,” meaning “to boil”, and “lithos,” meaning “stone”) are minerals with a porous structure. A Croatian study found that combined treatment of zeolite and Adriamycin in mice and dogs with cancer lead to a reduction in pulmonary metastasis (Zarkovic and Zarkovic, 2003).

» Micronized Zeolite: Usually this is available in a liquid form and dosages range from 5 drops twice a day to 10 drops 3 times a day.

Fish Oil Concentrate (Omega-3, EPA, & DHA)
Mice with estrogen receptor-negative breast cancer were treated with Adriamycin and fed fish oil concentrate. The control group was treated with Adriamycin and given standard food. Mice that were given food supplemented with fish oil concentrate had significantly less tumor growth than the control group (Hardman and Munoz, 2002).

In another animal study of mice with induced breast cancer, one group was given feed containing 5% corn oil and the other was given 3% fish oil concentrate and 2% corn oil. The group fed with added fish oil concentrate responded better to treatment with Adriamycin without increased toxicity (Hardman and Avula, 2001).

A third animal study from India of mice with estrogen receptor-negative breast cancer showed that the incidence of lung metastases and tumor growth rate was significantly less in mice whose diet was supplemented with fish oil concentrate versus mice fed a diet high in corn oil (Rose and Connolly, 1993). This demonstrated that the fish oil helped reduce the ability of breast cancer cells to grow, and to spread to the lungs.

» Omega 3 Polyunsaturated Fatty Acids (PUFA, from fish oil): Typical dosage range is from 1,000 mg to 10,000 mg daily.

Quercetin
Quercetin is a flavonoid found in capers, apples, tea, onions, red grapes, citrus fruits, leafy green vegetables, cherries, and raspberries. Quercetin has anti-inflammatory activity, inhibits allergic and inflammatory reactions, and has strong antioxidant activity.

An Italian laboratory study found that quercetin greatly increases the treatment effect of Adriamycin in estrogen receptor-positive Adriamycin-resistant breast cancer cells (Scambia and Ranelletti, 1994).

» Quercetin: Typical dosages range from 200 mg to 1,200 mg daily.

All-Trans Retinoic Acid (ATRA )
Retinoic acid is the acidified form of vitamin A (Retinol), the animal form of vitamin A. Retinol is a fat-soluble, antioxidant vitamin important in bone growth and vision. Retinol is ingested in a precursor form from animal foods (liver and eggs) and plants (carrots and spinach). In a laboratory study from Poland, researchers found that the antitumor activity of Adriamycin against estrogen receptor-positive breast cancer cells is increased when ATRA is added. Interestingly, the combination of ATRA and Adriamycin significantly outperformed the combination of Adriamycin and tamoxifen (Czeczuga-Semeniuk and Wo?czyski, 2004).

From Italy, a laboratory study testing estrogen receptorpositive breast cancer cells found that the combination of ATRA and Adriamycin inhibited cell growth more than either treatment alone (Toma and Maselli, 1997).

From the United States, a laboratory study found that ATRA makes estrogen receptor-positive and -negative cells more vulnerable to Adriamycin treatment (Wang and Yang, 2000).

A fourth study, from France, found that in multidrugresistant estrogen receptor-positive breast cancer cells, which are highly invasive, ATRA decreases their ability to metastasize (Affoué and Akeli, 1999). Tretinoin is the generic name and Vesanoid is one of the trade names for this prescription drug.

Selenium
Two laboratory studies demonstrated selenium enhanced the treatment effect of Adriamycin in estrogen receptor-positive breast cancer cells (Li and Zhou, 2007; Vadgama and Wu, 2000).

» Selenium (mineral): The US adult Tolerable Upper Intake Level (UL) is 400 mcg a day and the Lowest Observed Adverse Effects Level (LOAEL) for adults is about 900 mcg daily. Selenium is best used in its highly absorbable amino acid forms, such as Lselenocysteine and L-selenomethionine.

Silibinin
Silibinin (also called silybin) is an important active compound found in silymarin, extracted from blessed milk thistle (Silybum marianum). In a laboratory study from the United States, silibinin increased the ability of Adriamycin to inhibit growth of estrogen receptor-positive and -negative breast cancer cells (Tyagi and Agarwal 2004).

Silibinin potentiates the effect of Adriamycin in Adriamycin-resistant estrogen receptor-positive breast cancer cells according to a laboratory study from Italy (Scambia and De Vincenzo, 1996).

» Silymarin: Silibinin is the most biologically active constituent found in silymarin and isosilybin B complex is the most efficient constituent of silymarin in maintaining healthy cell division. Typical dosages range from 100 mg to 900 mg daily. An example of a good product is one containing 900 mg, standardized to 80% silymarin (720 mg), 30% silibinin (270 mg) and 4.5% isosilybin B complex (40.5 mg).

Topical 99% Dimethyl Sulfoxide (DMSO)
Dimethyl sulfoxide (DMSO) is a natural substance derived from wood pulp. Two patients undergoing Adriamycin treatment developed grade three palmar-plantar erythrodysesthesia syndrome (more commonly known as hand and foot syndrome). Their symptoms resolved over one to three weeks after receiving topical 99% DMSO four times daily for fourteen days (Lopez and Wallace, 1999).

» Dimethyl sulfoxide (DMSO): This product is used topically in small amounts such as 1/8 teaspoon. Thorough cleaning of the skin prior to use is essential. Drying of the skin can occur. This should be a practitioner-guided approach.

DOCETAXEL (TAXOTERE) IN COMBINATION WITH ANTIOXIDANTS

All Trans Retinoic Acid (ATRA)
ATRA increased effectiveness of Taxotere in a laboratory study when estrogen receptor-positive and -negative breast cancer cells are pretreated with ATRA three days prior to treatment with Taxotere (Wang and Wieder, 2004).

Gamma-Linolenic Acid (GLA)
According to a US study (Menendez and Ropero, 2004), the omega-6 polyunsaturated fatty acid gamma-linolenic acid (GLA) and vitamin E, used in combination, enhance the effectiveness of Taxotere in human breast cancer cells (both estrogen receptor positive and negative).

» Gamma-linolenic Acid (GLA): Available as evening primrose oil, borage seed oil, and black currant seed oil. Typical doses range from about 300 mg to 3,000 g daily, usually with meals.

Garlic
There has been concern that garlic may alter the way drugs are metabolized. In a study conducted at the National Cancer Institute, researchers found that garlic does not significantly affect the way Taxotere circulates through the body, but it may reduce the body’s ability to clear Taxotere (Cox and Low, 2006). This could potentially increase levels of the drug in the blood.

» Garlic (from the garlic plant): Typical dosage is approximately one teaspoonful of fresh garlic or 1,000 mg to 3,000 mg of a standardized extract. Note that the active ingredient, allicin, is inactivated by cooking.

Genistein
Genistein was found to sensitize cancer cells to Taxotere treatment in a laboratory study conducted in the US (Sarkar and Adsule, 2006). Another US laboratory and animal study confirmed that genistein significantly increases Taxotere’s effectiveness in estrogen receptor-negative cancer cells (Li and Ahmed, 2005).

» Genistein: A good product will use organic non-GMO genistein. Typical dosages range from 40 mg to 60 mg daily. One cup of soy milk will contain on average about 45 mg of genistein and the other related isoflavones.

Vitamin E
Palmar-plantar erythrodysesthesia (also known as hand-foot syndrome) is a painful feeling in the palms of the hands and the soles of the feet that can sometimes make the skin to turn a red or dark pink color. The skin can also develop ulcers, blisters, or sores. The chemotherapy drugs most likely to cause hand-foot syndrome are cyclophosphamide, Taxotere, Adriamycin, liposomal Adriamycin, etoposide, fluorouracil, hydroxyurea, mercaptopurine, methotrexate, mitotane, bleomycin, capecitabine, cytarabine, and thiotepa.

In a human clinical study from Turkey, five patients treated with a Taxotere and capecitabine combination developed moderately severe palmar-plantar erythrodysesthesia (hand-foot syndrome). They started vitamin E therapy at 300 mg a day (equivalent to 450 IU) without dose reduction of chemotherapy. After one week of treatment, hand-foot syndrome symptoms began to disappear (Kara and Sahin, 2006).

Note that the usual treatment for hand-foot syndrome is dose reduction of chemotherapy, which may lead to reduced effectiveness. This study is important because patients were able to continue at the therapeutic dose of chemotherapy with the help of adjunctive vitamin E.

» Vitamin E: Avoid synthetic vitamin E, such as alpha-tocopherol or succinate. Seek out the mixed tocopherols, particularly those containing the vitamin E fractions called tocotrienols and gamma-tocopherol. Typical dosage ranges from 50 IU to 800 IU daily.

PACLITAXEL/TAXOL IN COMBINATION WITH ANTIOXIDANTS

Curcumin
Curcumin is an extract of the Indian curry spice plant turmeric. It is a polyphenol and produces the yellow color of turmeric. An animal study showed that curcumin enhances the effectiveness of treatment with Taxol and also prevents lung metastasis (Aggarwal and Shishodia, 2005).

» Curcumin: The best supplements contain curcumin at 75% or higher concentration. Typical doses range from 500 mg to 4,000 mg daily. Take with meals, as they can cause stomach upset when taken on an empty stomach. Bioavailability is increased when combined with piperine, the alkaloid responsible for the pungency of black pepper.

Genistein
In a study from Taiwan, genistein (an isoflavone found in soybeans) significantly decreased the effectiveness of both Taxol and vincristine in treating estrogen receptor-positive and -negative cancer cells (Liao and Pan, 2004). It is not recommended that genistein be combined with Taxol or vincristine.

Green Tea
Epigallocatechin-3-gallate (EGCG) is the principal polyphenol found in green tea. A laboratory study from the US found that EGCG increased the sensitivity of human breast cancer cells to treatment with Taxol. It achieved this effect at concentrations that are similar to those in the blood after an oral dose of EGCG (Masuda and Suzui, 2003).

» Green Tea Extract: One cup of green tea contains between 10 and 400 mg of polyphenols depending on the source, amount of leaves used, and time the tea steeps. EGCG may be conveniently obtained from extracts. A good product contains 725 mg, standardized to 98% polyphenols, 45% of which is EGCG.

Propolis
Propolis is a resinous substance that honey bees collect from tree buds to prevent diseases in the hive. It is used in human health to protect the heart, reduce inflammation, heal skin burns, treat tooth decay and gum disease, and for its antibiotic, antiviral and antifungal properties.

In an animal study from India, the combination of Taxol and propolis protected mice against developing cancer more strongly than did treatment with either Taxol or propolis alone (Padmavathi and Senthilnathan, 2006). The researchers found that in animals given propolis, their bodies were less susceptible to oxidative damage to their fat cells, and they had an increase in activity of antioxidants.

» Propolis: Insist on propolis that is tested to avoid heavy metal content. Typical dosage range is from 100 mg to 3,000 mg daily.

All Trans Retinoic Acid (ATRA)
In a laboratory study from Canada, researchers found that ATRA sensitizes estrogen receptor positive cells to Taxol (Pratt and Niu, 2006). Tretinoin is the generic name, and Vesanoid is one of the trade names for this prescription drug.

Vitamin E
A human trial was conducted in Greece with thirty-one patients to evaluate the neuroprotective effect of vitamin E when used together with cisplatin and Taxol chemotherapy treatment. Whereas 73.3% of control patients receiving chemotherapy alone developed neurotoxicity side effects, only 25% of patients who received 600 mg (or 900 IU) per day of vitamin E in combination with chemotherapy developed neuropathy, during and up to three months after chemotherapy (Argyriou and Chroni, 2005).

» Vitamin E: Avoid synthetic vitamin E, such as alpha-tocopherol or succinate. Seek out the mixed tocopherols, particularly those containing the vitamin E fractions called tocotrienols and gamma-tocopherol. Typical dosage ranges from 50 IU to 800 IU daily.

EPIRUBICIN/ELLENCE IN COMBINATION WITH ANTIOXIDANTS

Flavonoids
In a study from Hungary, chemotherapy-resistant estrogen receptor-
negative breast cancer cells became more sensitive to treatment
with epirubicin when treated with flavonoids (Gyémánt and
Tanaka, 2005).

Superoxide Dismutase, Catalase, & Glutathione
A laboratory study from Turkey study showed that the addition of superoxide dismutase, catalase and glutathione, to estrogen receptor positive cancer cells treated with epirubicin, decreased the ability of epirubicin to kill cancer cells (Ozkan and Fiskin, 2006). It is not recommended that these antioxidants be combined with epirubicin.

Melatonin
Fourteen women with metastatic breast cancer were treated with epirubicin. Melatonin at 20 mg a day was started seven days prior to chemotherapy and continued every day through treatment. Twelve patients were evaluable after four cycles of chemotherapy. Nine out of twelve patients had normalization of platelet number and no further decline in platelet number occurred (Lissoni and Tancini, 1999).

» Melatonin: Typical dosages range from 1 mg to 20 mg. If aiming for a high dosage, one should start with 1 mg and increase the dosage slowly by 1 mg every 3-7 days. The ideal is to achieve peak blood levels of melatonin at about 2am. To do so one can take the melatonin half an hour before bedtime between 9 and 10pm.

CYCLOPHOSPHAMIDE/CYTOXAN IN COMBINATION WITH ANTIOXIDANTS

Curcumin
A US study using an animal model of human breast cancer found that supplementation with curcumin inhibited tumor regression and decreased cell death from treatment with cyclophosphamide (Somasundaram and Edmund, 2002).

Coenzyme Q10, Riboflavin, and Niacin
In India, a human study with 78 patients found that co-administration of tamoxifen with 100 mg CoQ10, 10 mg riboflavin, and 50 mg niacin reverted all lipid and lipoprotein abnormalities back to normal within 90 days of combination therapy (Yuvaraj and Premkumar, 2007). Rats with induced breast cancer treated with tamoxifen and CoQ10, riboflavin, and niacin had near normal levels of lipid peroxide and enzymatic and non-enzymatic antioxidants. Furthermore antitumor activity was enhanced. (Perumal and Shanthi, 2005).

» Coenzyme Q10: Oil softgels have higher absorption. Daily doses of CoQ10 range from 30 mg to 300 mg and is best taken with food. About three weeks of daily dosing are necessary to reach maximal serum concentrations of CoQ10. Bioavailability is increased when combined with piperine. The most advanced version of COQ10 is the more highly absorbable version called Ubiquinol.

» Riboflavin (Vitamin B2): Typical doses can range between 100 mg and 200 mg per day.

» Niacin (Vitamin B3): Typical doses can range between 100 mg and 1200 mg per day. Slow dose escalation is essential to acclimate the body to the “niacin flush”. Some people find that the niacinamide version does not cause flush.

Vitamin C & E
Tamoxifen, a hormonal inhibition treatment for breast cancer, can cause lipid abnormalities. A human study in India found that administering 500 mg vitamin C and 400 mg (or 600 IU) of vitamin E for 90 days to postmenopausal breast cancer patients undergoing tamoxifen treatment significantly decreased the lipid abnormalities (Babu and Sundravel, 2000).

» Vitamin C: The LOAEL (Lowest Observed Adverse Effect Level) is 3,000 mg daily. Many people find that doses above 3,000 mg can cause diarrhea. Using buffered Vitamin C can help reduce stomach and intestinal irritation.

» Vitamin E: Avoid synthetic vitamin E, such as alpha-tocopherol or succinate. Seek out the mixed tocopherols, particularly those containing the vitamin E fractions called tocotrienols and gammatocopherol. Typical dosage ranges from 50 IU to 800 IU daily.

Studies on Combination Chemotherapy Protocols

Cyclophosphamide, Methotrexate, 5-Fluorouracil (CMF)
Melatonin (not as supplement)
A study from Poland discovered that the combination treatment CMF induced an increase in the body’s natural melatonin levels in the blood. These melatonin levels did not differ between women who were tested as healthy controls and women prior to chemotherapy treatment. But following CMF treatment, melatonin was significantly increased. The researchers postulated that this increase may actually be an essential component to successful treatment with CMF (Kajdaniuk and Marek, 2001).

CONCLUSION
This review of research, including laboratory, animal, and human studies, found data in most cases supporting the combination of antioxidants with chemotherapy. Much of the evidence available, however, is from laboratory studies rather than randomized, controlled human studies, so if patients and practitioners decide to use antioxidants, they are faced with some uncertainty as to which antioxidants to use and at which dosages. Further research should help to identify optimal dosing schedules and further investigate the wide range of nutritional and herbal therapies that exist for additional treatment candidates.

When a patient decides not to take antioxidants with chemotherapy, they should discontinue all antioxidants two weeks prior to chemotherapy and not resume until two to three weeks after the last session. The risk is that healthy cells may be less protected against chemotherapy and could include serious consequences such as organ damage and impaired immune function and, therefore, prevent the body’s ability to fight cancer. The cancer itself may also be more able to develop resistance to chemotherapy. The benefit could be that the chemotherapy drugs may work better.

When a patient decides to take antioxidants with chemotherapy, they should continue to take antioxidants before, during, or after chemotherapy in consultation with a knowledgeable practitioner. The risk is that antioxidants could interfere with chemotherapy and cancer cells not killed by the first round may become resistant to future treatment. The benefit is that antioxidants may help chemotherapy work better, protect healthy cells against the harmful effects of chemotherapy, and reduce side effects.

While there is still no consensus among medical practitioners on the issue of whether or not to combine antioxidants with chemotherapy, we hope that this discussion will help patients in the process of informed decision making as they work together with their medical team.

Johanna Altgelt is an associate researcher at the Pine Street Foundation.

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