Chapter 29 Cancer
AETIOLOGY
Cancer is a multifactorial disease that is still not completely understood. Many theories exist as to what may cause cancer and only a few cancers have definitive risk factors (for example, cigarette smoking and lung cancer,1 or human papilloma (HPV) and cervical cancer).2 However, even with these connections, not everyone who smokes gets lung cancer and not everyone with HPV gets cervical cancer. Table 29.1 shows some possible general theories incorporating medical and naturopathic causes of cancer.
Table 29.1 Theorised causative factors in cancer
| POSSIBLE CAUSE | EXPLANATION |
|---|---|
| Genetics | Certain cancers, such as breast, prostate and colon cancer, have been found to have hereditary links. There are certain genetic markers that the medical fraternity can test for to check if someone has the genetic markers for that cancer, e.g. the BRCA gene for breast cancer.3 |
| Viruses and infection | Viruses such as the HPV have been linked with the development of certain cancers. Examples of these include human papillomavirus (cervical cancer);2 Epstein-Barr virus (non-Hodgkin’s lymphoma);4 HIV (Kaposi’s sarcoma, primary central nervous system lymphoma, invasive cervical cancer and non-Hodgkin’s lymphoma);5 hepatitis B virus (hepatocellular carcinomas);6 retroviruses (adult T-cell leukaemia);7 Helicobacter pylori (gastric cancer in people with certain polymorphisms);8 simian virus 40 (non-Hodgkin’s lymphoma)9 |
| Mitochondrial dysfunction | Cancer progression has been linked with mitochondrial dysfunction. This can be a result of mitochondrial DNA (mtDNA) mutations and/or depletion. These mutations or mitochondrial depletions have also been linked with an increase of drug resistance within cells. This mitochondrial dysfunction has been found in certain cancers such as prostate cancer.10 |
| Environmental influences | Over the years, an increase in cancer in the Western world has been found.11 Epidemiological studies have found an association with this increase and the exposure to environmental toxins such as organochlorides and synthetic pesticides.12 Further research is being conducted but it seems at this stage that fetuses, infants, children and young adults are most at risk.12 There are specific cancers, such as mesothelioma, which have been directly linked with exposure to asbestos.13 |
| Immune system | It has been postulated that a lowered immune system may increase the chance of cancer developing. The natural killer cells are the main surveillance system of the body, protecting against cancer formation and infection. These natural killer cells are a main part of the innate immune system and, if they are not functioning correctly, can allow tumours to develop through abnormal cell development.14 |
| Cell cycle mitosis malfunction | In cell replication certain checkpoints and cellular activity maintain the health of the cell. If these checkpoints, such as p53, have mutations15 or there are abnormal centrosomes in a cell, cancer cells may develop.16 The elderly in particular are prone to malignant tumours that are related to the accumulation of damaged DNA from malfunctioning cell mitosis.17 |
| Oxidative damage | There are several schools of thoughts that oxidative damage, especially to DNA and cellular components, can be attributed to the development of cancer. Reactive species such as ROS (reactive oxygen species) and RNS (reactive nitrogen species) are a natural by-product of normal biochemical and physiological reactions in the body. These reactive species can cause damage to the DNA, cellular membrane and cellular organelles, and can interfere with cellular regulators if there is not enough antioxidants to counteract reactive species damaging effect.18 |
| Mind–body connection | A different way of looking at cancer is the psychological aspect. There are theories on a connection between the mind and the development of certain cancers, but this has not been confirmed. However, there is good evidence that mind–body medicine should be taken into consideration when addressing cancer.19 |
| Polymorphisms | There are numerous studies on polymorphisms and genetic mutations increasing the risk of nearly all cancers. As this is a relatively new area of research, more studies will emerge on new polymorphisms that can be linked with certain cancers, and testing procedures will become more accessible and less expensive.20–22 |
| Epigenetics | The increase of scientific knowledge on how chromatin organisation modulates gene transcriptions has highlighted how epigenetic mechanisms are involved in the initiation and progression of human cancer. These epigenetic changes have been found to affect nearly every step in tumour progression, especially the aberrant promoter hypermethylation that is associated with gene silencing.23 |
Certain cancers have been linked with certain dietary and lifestyle choices (see Table 29.2).
Table 29.2 Links between cancer and lifestyle
| FOOD OR BEVERAGE | IMPLICATED CANCER |
|---|---|
| Smoking | |
| Alcohol | |
| Low fruit and vegetable, fibre intake, high intake of processed meats, nitrosamines, highly salted foods | |
| Obesity |
CANCER PREVENTION
A basic list of areas to consider in the prevention of cancer includes:
CAM TREATMENT OF COMMON SIDE EFFECTS OF CHEMOTHERAPY AND RADIATION
Table 29.3 provides specific evidence pertaining to integrative cancer treatment only; see the relevant chapters for generalised information.
Table 29.3 CAM treatment of common side effects of chemotherapy and radiation
| SIDE EFFECT | CAM THERAPY |
|---|---|
| Mouth ulcers | Calcium phosphate, honey, zinc sulfate39 |
| Diarrhoea | Glutamine40 |
| Constipation | Senna41 |
| Intestinal permeability | Glutamine42 |
| Radiation enteritis or enteropathy | Hyperbaric oxygen chambers,43 probiotics during radiation,44 glutamine during radiation45 |
| Neutrophilia | Vitamin E46 |
| Anaemia | Iron47 |
| Fibrosis | Lipoic acid48 |
| Fatigue | L-carnitine,49 coenzyme Q1050 |
| Memory loss | Egg phosphocholine and low-dose vitamin B1251 |
| Weight loss | Omega-3 fatty acids52 |
| Weight gain | Dietary suggestions to keep BMI in range53 |
| Stress/anxiety | l-theanine54 |
| Peripheral neuropathy | Vitamin B1, B6, B1255 |
| Cardiomyopathy | Coenzyme Q1056 |
POTENTIAL INTERACTIONS
Potential interactions between orthodox and complementary therapies need to be taken into consideration when treating a patient with cancer. As there are many different drugs used for cancer, it is important for the naturopath to address each drug and check for any possible interactions both beneficial and contradictory (see Figure 29.1). Unfortunately, most potential interactions of cancer drugs and complementary medicine still require clinical research as there is little human data (most studies are animal or in vitro based).57 A chart of potential interactions between naturopathic medicines and chemotherapeutics is in the appendices at the back of the book.
Figure 29.1 Risk of interactions associated with different CAM treatment protocols
Source: Seely D, et al58.
There are, however, ways in which the potential risk for interaction with chemotherapy can be moderated. As many naturopathic medicines can protect and support not only the body from deleterious effects of chemotherapy but the cancerous tissue as well, it may be prudent to apply a cautionary approach to CAM prescription.58 In principle it takes five half-lives to reach a steady state and five half-lives to eliminate virtually all of a drug in the body. Knowing both the half-lives of naturopathic medicine and chemotherapy can allow for a dosing regimen that can reduce risk of possible interactions (see Table 29.4).
Table 29.4 Selected antioxidant naturopathic medicines and their half-life58
| NATUROPATHIC INTERVENTION | HALF-LIFE |
|---|---|
| Green tea | 3.4 h ± 0.3 h |
| Curcumin | < 1 h |
| Selenium | 102-252 days |
| Vitamin C | 30 min |
RISK FACTORS
The risk factors vary depending on the type of cancer. These may include diet and lifestyle factors, viruses, genetics, environmental exposure and lowered immune system. Other risk factors include lack of physical exercise,59 high BMI/obesity,59 exposure or lack of exposure to sun (due to low vitamin D),60,61 nutrient deficiencies,62 medication (in some cases medication can increase the risk of other cancers, such as Tamoxifen
COMMON TUMOUR MARKERS
causing endometrial carcinoma),63 country/nationality,64 stress,65 gender (for example, prostate cancer in males and ovarian cancer in females), age17 and occupation.66–68
NATUROPATHIC APPROACHES TO CANCER PATHOPHYSIOLOGY
Cell mitosis
Oncogenes and tumour-suppressor genes
Oncogenic processes have long been associated with cancer development and progression. These genes stimulate the process of cell mitosis and DNA replication and studies have shown that these genes are altered in cancer. The two main genes that are focused on are the proto-oncogenes and tumour-suppressor genes.69
Recent studies have identified a specific small class of RNA molecules called microRNAs (miRNAs). These miRNAs negatively regulate gene expression post-transcriptionally and aid the development of cell identity. These are important as they can affect cellular transformation, carcinogenesis and metastasis because they can act as an oncogene or tumour-suppressor gene.70
According to naturopathic treatment, keeping cellular oncogenes working efficiently without the development of cancer requires both dietary regulation and the maintenance of levels of particular nutrients in the body. Epidemiological and experimental data have found that Western diets that are high in fat and low in calcium and vitamin D can accelerate tumour growth by causing genetic manipulation.71 Maintaining a diet low in detrimental fats and increasing calcium and vitamin D levels may therefore prevent gene alteration.
p53, p21
Abnormalities in the regulatory marker p53 have been found in most cancer cells. Cancer cells may have either mutations of the p53 gene or an accumulation of p53 proteins in the cells.72,73 p21-activated kinases (Paks) aid controlling G(2)/M transition and mitosis and are tumour-suppressor genes regulated by p53. Therefore they are necessary for cell proliferation, mitotic progression and other regulators.74,75
A number of different nutrients can affect the p53 and p21 genes and be of benefit for cancer. Low levels of folate and vitamin B6 can affect p53, increasing the risk of colorectal cancer.76 The mechanism of this deficiency involves the mutation of the p53 gene, therefore changing its expression. It is recommended that people should consume over 400 μg of folate a day to prevent this occurring.
Resveratrol has also been found to modulate p53 to induce apoptosis (programmed cell death that is an integral part of normal biological processes to kill abnormal cell development) as well as knocking out excessive p53, having a beneficial effect in preventing cancer. Resveratrol has also been found to induce apoptosis via modulating other cellular molecules such as cyclin D1, p21, BCL2, BAX, Bcl XL, caspase 9 and p27.77,78
Green tea is another nutrient that has been found to affect p53 and p21. One study has found that green tea enhanced Zizyphus jujuba’s selective cytotoxic activity by causing cell death via up-regulation of p53 and p21 while decreasing cyclin E levels in HepG2 cells.79 Green tea has also been found to inhibit tumour growth and angiogenesis as well as induce apoptosis.80 Genistein has been found to influence p21 transcription by markedly inhibiting proliferative activity and inducing the expression of p21 plus ERbeta.81
Vitamin D also influences p53 and p21. Both p21 and p53 have vitamin D binding sites (VDR).75 If a patient is deficient in vitamin D, both p53 and p21 may be affected, possibly influencing cancer development or progression. Flavonoids—such as quercetin—have also been found to influence p53 in relation to cancer. One study found that quercetin helped to stabilise p53 at both the mRNA and the protein level to reactive p53-dependent cell cycle arrest and apoptosis.82 This was achieved by quercetin inducing p53 phosphorylation and total p53 protein, but not up-regulating p53 mRNA at transcription. It also stimulates p21 expression and suppresses cyclin D1 to activate cell cycle arrest. Quercetin was also found to inhibit p53 mRNA degradation post transcriptionally.
Centrosomes
These microtubules aid cell mitosis by creating the polar rejection force that pushes the chromosomes away from the spindle poles by wobbling at high frequencies. A rise in intracellular calcium aid the regulation of the polar force at the onset of chromosomal splitting. If this is defective, chromosomal instability (characteristic of most cancers) can occur.83 It has also been found that cells that have dysfunctional p53s have more centrosomes.84
Vitamin A plays a key role in centrosomes and chromosome replication through the retinoblastoma protein, which is a regulating protein of cyclins D and E, cdk 4 and 6, cdk inhibitors p16, p15 and p53.85 A vitamin B12 deficiency has been associated with enlarged, disrupted centrioles in monocytes and neutrophils.86
Proteasomes play an important role in a variety of cellular processes such as cell cycle progression, signal transduction and the immune response, and are important in maintaining rapid turnover of short-lived proteins. They also prevent accumulation of misfolded or damaged proteins. Zinc increases proteasome substrates such as p5 and p21, as well as decreasing the enzyme that degrades these substrates in centrosomes.87
Folate also plays a critical role in the prevention of chromosome breakage and hypomethylation of DNA. A folate deficiency can cause centromere defects that can induce abnormal distribution of replicated chromosomes during mitosis. It has also been found to be a risk factor for chromosomes 17 and 21 aneuploidy, which has been observed in breast cancer and leukaemia.88
Glycolysis and p53
A common theory sometimes postulated in the naturopathic treatment of cancer is that tumours feed on sugar. In part this is true, as cancer cells work differently to other cells biochemically. Research has found that most cancer cells have higher rates of glycolysis than normal cells.73 Research has found that, after a loss of functional p53, there were mitochondrial changes, up-regulation of rate-limiting enzymes and proteins in glycolysis and intracellular pH regulation, hypoxia-induced switching to anaerobic metabolism leading to higher lactic acid levels, and metabolic reprogramming.
Extrapolation of these results has led to various diets being developed to ‘starve’ the cancer. This theory has not yet been proven to work; however, it is still recommended that people with cancer decrease their sugar intake as it has been found that insulin-like growth factor 1 is involved in a number of cancers.89,90 One animal study has shown delayed growth of gastric cancer cells with administration of a ketogenic diet high in omega-3 fats.91
Another theory (the Warburg effect) suggests ‘oxygenating’ the body, as cancer cells use more anaerobic glycolysis than normal cells do and normal cells use the aerobic system of the mitochondria.92 Increasing oxygen availability (for example, through breathing exercises and circulatory stimulants) to cells more generally may aid the normal cells rather than the cancer cells and also aid the removal of toxins and carcinogens.
Inflammation
Inflammation has been linked with a variety of different cancers as inflammatory markers aid tumour progression, promotion and growth. It has been found that a cellular inflammatory microenvironment and an increased level of nitric oxide can stimulate or accelerate tumour development.93 Cyclooxygenase enzymes such as prostaglandins and thromboxanes play an important role in cancer, particularly in gastrointestinal, oesophageal, gastric, liver, pancreatic and colorectal cancers.94
A key approach to cancer is to modulate the inflammatory cascade; this can have a positive effect on cancer initiation, promotion, progression and metastasis. Anti-inflammatory nutrients such as curcumin,95 bromelain,96 quercetin96 and EPA/DHA96 can decrease the progressive effect of the inflammation in cancer. Herbal medicines such as Zingiber officinale, Curcuma longa,95 Withania somnifera97 and Boswellia serrata may also be useful.96
Immunological factors
A functioning immune system appropriately monitors and attacks any foreign cells or pathogenic invaders. A dysregulated immune system can allow cancer cells to develop and spread.98 States that can cause a dysregulated immune system affecting cancer include stress,99,100 diabetes,101 HIV (and other viruses)102 and nutritional deficiencies.103,104
Nutrients and herbs that support immune function can be very important in assisting people with cancer. Those clinical nutritional interventions with particular benefit in cancer include vitamin D,105 antioxidants,106 vitamin C,106 zinc106 and medicinal mushrooms such as shiitake or reishi.107,108 Herbal medicines which may be of benefit include Astragalus membranaceaus,109 Uncaria tomentosa,110 Eleutherococcus senticosus,111 Rhodiola rosacea,111 Schisandra chinensis,111 Panax ginseng112 and Echinacea spp.113
Hormonal factors
Some specific cancers, including breast,114 ovarian, endometrial,115 cervical, prostate and testicular cancers, are well known to have hormonal influences.116 Other cancers, including both gastric and lung cancer, may also have hormonal influences.117,118
Breast cancer can be stimulated by oestrogen and/or progesterone,114 whereas ovarian, endometrial and cervical cancers may be oestrogen-stimulated via receptor sites on the cancer cells.115 Testosterone is the key hormone related to prostate- or male genitalia-based cancers, whereas testicular cancer may be related to either oestrogen or androgens, and approximately 7–11% of males who get testicular cancer have also been found to have gynaecomastia.116
Oestrogen may have protective effects on gastric cancer, as the prevalence of gastric cancer is higher in men and lower in premenopausal women, women on hormone replacement and men undergoing oestrogen therapy.117 The actual mechanism of protection is unclear, but it is thought that oestrogen may increase the expression of trefoil factor proteins, which have been found to protect mucous epithelia or inhibit the expression of c-erb-2 oncogene.
Lung cancer has also been found to have an oestrogen connection. Adenocarcinoma is the most common type of lung cancer in non-smokers, and it has been suggested that there is a distinct pattern concerning oestrogen beta receptors.118
A number of nutrients and herbs can have a positive effect in the integrative treatment of hormonal tumours. For oestrogen- and progesterone-stimulated tumours, cruciferous indoles—particularly indole-3-carbonol—aids in a number of different ways: it aids the induction of apoptosis in breast and cervical cancer cells by inducing DNA breakage in the nucleus of the cells,119 and it alters the metabolism of active oestrogen hormones indicated in urinary excretion (16-oestrodiol to 2-oestrodiol).120
Other nutrients that have been found to be of assistance include zinc for testosterone via the enzyme 5 alpha-reductase;121 resveratrol via inhibiting the cytochrome p450 19 enzymes—also called aromatase catalases—which are the rate limiting step of oestrogen synthesis;122 and genistein, which, although controversial and having mixed results, has shown positive results by inhibiting cell proliferation and inducing apoptosis in breast cancer cell lines.123 However, it has also been shown to stimulate growth in oestrogen-dependent human tumour cells, MCF-7, and may negate the inhibitory effect of Tamoxifen.124
Herbs that have shown to be of potential benefit include Serenoa repens for prostate cancer. Serenoa has been found to induce growth arrest of prostate cancer cells as well as increasing p21 and p53 in the prostate cells.125 Cimicifuga racemosa has been found to improve symptoms associated with breast cancer by alleviating vasomotor symptoms associated with the decrease of oestrogen.126
Trifolium pratense has also been found to be of benefit for oestrogen-based cancers. The isoflavone constituent biochanin A has been found to inhibit cytochrome p19 (aromatase) activity and gene expression, therefore decreasing the effect of active oestrogen.127
Mitochondrial function
Mitochondrial dysfunction has been linked with the increased risk of cancer.128 Most of the mitochondrial influence is via its link to apoptosis (p53) and anaerobic glycolysis; however, there may be another area in which mitochondrial function plays an important role. Cancer cells may have impaired mitochondria and mitochondrial activity, which may support Warburg’s theory as to why cancer cells use the anaerobic glycolysis pathway rather than the aerobic system.129 Concentrating on mitochondrial reprogramming and support may therefore assist in addressing cancer. Nutrients that have been found to assist mitochondrial function include coenzyme Q10,130 lipoic acid,131 carnitine132 and B vitamins such as niacin (NAD).133
Angiogenesis
Angiogenesis (developing their own blood supply to aid their proliferation and growth) in tumours is well recognised.128 Many chemotherapeutics currently target this angiogenic process. However, some naturopathic medicines have also been found to possess an anti-angiogenic action. These include intravenous vitamin C,134 Curcuma longa,135,136 Artemisia annua, Viscum album, Scutellaria baicalensis, resveratrol and proanthocyanidins, Magnolia officinalis, Camellia sinensis, Ginkgo biloba, quercetin, Poria cocos, Zingiber officinales, Panax ginseng and Rabdosia rubescens hora.137 Using any number of these naturopathic medicines may aid the reduction of angiogenesis, by virtue of possibly having a positive effect on decreasing tumour initiation, promotion, progression and metastasis.
DIET AND CANCER
There have been a number of studies on diet and its effect on cancer. Certain dietary deficiencies have been associated with cancer development. Dietary factors account for approximately 30% of cancer cases in developed countries and 20% in developing nations, and are second only to tobacco as a preventable cause of cancer.138 Other studies have been conducted on specific foods or beverages linked with cancer. There are also a multitude of diets that are promoted as ‘anti-cancer diets’, but most of these have not been studied specifically and are mostly based on broader empirical evidence.
The most common dietary link to cancer is the crude lack of fruit and vegetables.139 An increased intake of fruit and vegetables has been found to be protective against lung,140 oesophageal141 and colon cancer.142 Fruit and vegetable intake has also been suggested to be protective from breast and ovarian cancer although results at this stage state that the lack of fruit and vegetables is not a risk factor for either.143,144
In addition to an increased consumption of fruit and vegetables, a low intake of meat and potatoes has been found to be protective against colorectal and oesophageal cancer.141,142 High meat consumption—particularly through adolescence—has also been found to be a risk factor for premenopausal breast cancer.145 Both high meat consumption and high sugar intake have also been linked as risk factors for pancreatic cancer.146 High poultry intake and high-fat dairy intake are associated with an increased risk of gastric cancer.141 Adherence to a Western-style diet and high alcohol intake are also associated with an increased risk of gastric cancer.147 A high intake of alcohol has been associated with not only gastric cancer but also breast148 and liver cancer.26
Fat intake is another area of concern in relation to cancer. High-fat diets have been linked with numerous cancers, including breast, prostate and colon cancers.149,150 Studies have also found that high fat intake increases the oxidation of DNA and encourages damaged cell proliferation.149 However, specific fats, such as omega-3 fatty acids as found in fish oil, have demonstrated protective effects for breast, prostate and colon cancer.149,150 The current Western diet has a disproportionate ratio of omega-6 fatty acids to omega-3 fatty acids compared to more traditional diets; this may result in increased risk of cancer development.150
Iodine has been studied for a number of cancers, including thyroid cancer and breast cancer. Both a deficiency and an excessive amount of iodine have been associated with an increased risk of thyroid cancer.151,152 For breast cancer, recent studies have suggested that iodine may have a protective effect on breast tissue by inhibiting cancer development via the modulation of the oestrogen pathway.152
Green tea153 has also been extensively studied for cancer with positive results, and black tea154 and coffee155 have also shown convincing beneficial effects. Green tea and black tea have demonstrated benefit across a broad range of cancers; however, coffee seems to be mainly beneficial in protection against liver cancer. The protective effect of coffee seems to be related to moderate intake with studies looking at only one coffee drink a day, or less than 250 mg of caffeine intake a day.155
Studies looking at vegetarian or plant-based diets have also achieved reasonable results, though nothing conclusive has been found at this stage. It seems that a vegetarian or plant-based diet or a macrobiotic diet may be of benefit, particularly for colorectal, prostate and breast cancer.156,157 This may be related not merely to the vegetarian nature of the diet, but also to the increased proportions of fibre, fruit and vegetable intakes often associated with these diets.
INTEGRATIVE MEDICAL CONSIDERATIONS
Acupuncture
There are many studies proving the beneficial effects of acupuncture for cancer, for a variety of different reasons. Studies using acupuncture to treat cancer pain,163 vasomotor and fatigue symptoms of both breast and prostate cancer164,165 show that it boosts the immune system and decrease tumour growth166 and is beneficial for the treatment of nausea and other side effects.167 Acupuncture has had documented success in improving nausea symptoms associated with chemotherapy.168–170 Electroacupuncture seems more effective than manual acupuncture for this purpose. Other studies on acupuncture and specific cancer conditions show benefit, suggesting it may be a beneficial adjuvant treatment.128
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