Edge-CAM Regimen [Version 2.6 - 09/06/2009]

What's New (08/27/09)

• VHD-D3 for AI-Induced Disability [new coverage]
• Provisional: Polyphenol Complex / Quercetin
• Reishi Mushroom Extract [for IBC only]
• Some expanded coverage of Lifestyle / Dietary Issues
• New (brief) section on "How to Think About Environmental Tumorigenic Exposure Reduction"
• Some stylistic and structural reorganization for clarity and accessibility

What's New  (09/06/09)

• Melatonin: enhancement of AI  therapy  in metastatic breast cancer
• Melatonin: potential stimulation of ER receptor expression in ER-negative disease
• Curcumin: first evidence of triple negative-specific activity

The Edge-CAM Regimen targets high antitumor / anti-recurrence / anti-metastatic potential founded on the best evidence to date, and includes a CAM intervention, and a Lifestyle Modality (see below). The CAM intervention component:

Curcuminoids + EGCG + Melatonin + HD-D3

+ CoQ10-RN [endocrine-responsive BC]

+ Boswellic Acids + Resveratrol [elevated risk BC]

CoQ10-RN
(90 - 100 mg CoQ10) + riboflavin (Vitamin B12 / 10 mg) + niacin (30 mg)

• Primarily for endocrine disease, and especially during tamoxifen therapy.
• Potential benefit in other forms of breast cancer requires further data.
• No standardization issue.

Curcuminoids

• Optimal Formulation: Standardized to deliver at least 90%+ curcuminoids (the antitumor component) content, and Sabinsa-certified (the pharmaceutical grade formulation used in the studies). One leading pharmaceutical grade product comes from the Doctor's Best brand, as the product Best Curcumin (from Vitacost).
• Optimal Dosing: Minimal effective dosing is 500mg / daily of curcuminoid component (one capsule daily), but this can be escalated to up to at least 1500 to 2000 mg / daily (typically three to four capsules daily) in: (1) advanced disease and metastatic settings, or in, (2) elevated risk contexts (doses up to 12,0000 mg / daily have been tested and found wholly without harm).
• It is best to take curcumin towards to end of a large meal, in at least three divided doses. (Any degree of gastrointestinal (GI) upset, although relatively rare, is likely be due to the piperine (Bioperine) content which is used to enhance bioavailability). When using a piperine (Bioperine) bioavailability-enhanced curcumin formulation, be aware that the piperine ingredient may enhance (but fortunately not decrease) the efficacy of other agents consumed approximately concurrently, so if at all possible, separate co-consumption by at least one hour.
• I consider: (1) triple negative breast cancer (TNBC), (2) inflammatory breast cancer (IBC), (3) metastatic breast cancer (MBC), and (4) HER2-positive disease (HER2+) as contexts of elevated risks.
• In such cases, extrapolation from the evidence supports potential benefit up to but not beyond a maximum of 8000 mg / daily.
• Note: This was formerly set to 3600mg/d in early versions of the Edge-CAM regimen, but we now have a scientific warrant founded on human clinical data for 8 grams of curcuminoids over 18 months with no toxicities observed, and this was in pancreatic cancer, one of the most lethal of all cancers; in this study, two patients had clinically meaningful responses and remained stable for 8 and 22+ months, respectively, while another had a brief but dramatic response (73% reduction in tumor size), and despite not using a bioavailability enhanced formulation (via piperine (Bioperine)). 
• New evidence  just reported this month (9/09) from researchers at the Winship Cancer Institute and Emory University suggests that curcumin may be genotoxic (DNA-damaging), of particular  benefit to triple negative and BRCA1 deficient patients, and this represents the first ever demonstration of the potential triple negative specific activity of curcumin, showing curcumin-induced promotion of apoptosis and prevention of growth and migration of TNBC cells.

EGCG/Green Tea Extract

• Optimal Formulation: This needs to be standardized to > 97% polyphenols, with approx 45% or higher of the active ECGC component.
  Vitacost has a requisitely standardized formulation as NSI Green Tea Extract. 
• Optimal Dosing: Optimal EGCG content should be 250 - 500mg / daily, so 2 capsules daily, taken with meals, would be required (delivering 450mg/daily EGCG content. Some people are sensitive to the modest caffeine content, in which case, full daily dose should be completed before 5PM, or one can use an alternative caffeine-free formulation.

Melatonin

• Optimal Formulation: No standardization issue with melatonin. Natrol Melatonin delivers 5 mg per capsule; from Vitacost.com.
• Optimal Dosing: Optimal melatonin level is 20mg / daily (45 - 60 minutes before sleeptime). Begin with 5mg / daily, and step up an additional 5mg every 3 to 4 days to the 20mg level; note however that any amount at or above 3mg/daily, although not optimal, may still be beneficial and preferable to no melatonin consumption).
• Avoidance of Light at Night
  Recent research has established the importance of avoiding what's come to be called informally "light at night", namely light during sleeptime - it's important for complex reasons of underlying melatonin hormonal pathways to sleep in near-complete darkness; the cancer arm of the World Health Organization (WHO), the International Agency for Research on Cancer (IARC), has added overnight shift work (which by virtue of shift schedules entails sleeping during significant light conditions) as a probable carcinogen (via adverse suppression of melatonin production / synthesis), and based on reviews and letters submitted to it (including my own) I am informed that the American Cancer Society (ACS) will likewise soon follow.
• New research from the Institute of Biological Medicine in Milan (May 2009) has found  that melatonin added to to AI therapy in metastatic breast cancer patients with poor clinical outcome (with metastases including to lung, liver, or bone) achieves an impressively high objective tumor response (complete responses (CR) 14% + partial responses (PR) 43%) of 57%, compared to the norm for AI monotherapy reported in the literature which is generally below 40%, with an  additional 29% stable disease (SD), yielding a disease control rate (DCR: CR + PR + SD) of 86% in a poor outcome metastatic disease population, suggesting the enhancement of AI therapy via melatonin.
• It should be remembered that melatonin's benefits are not restrictive to only endocrine (hormone) positive disease: for example, an NCI team under David Danforth demonstrated experimentally the potential of melatonin-induced stimulation of ER expression in ER-negative breast cancer lines, transforming ER-negative into more prognostically  favorable ER-positive breast cancer.

HD-D3

• Optimal Formulation: Vitamin D3 (which is the cholecalciferol form), not Vitamin D2 (which is the ergocalciferol form). No standardization issues.
• Optimal Dosing: Although 2000 IUs (international units) is now known to be optimal for bone health, 3000 IUs is the dose considered optimal for anti-tumor activity. However, these are only broad rules of thumb, and the best way to determine the optimal level for antitumor benefit is through a simple 25(OH)D (Vitamin D3) assay or laboratory test, also known as a cholecalciferol assay / test (and by most laboratories as "25-Hydroxy Vitamin D" test or assay). Aim for a target level for 25(OH)D of at least 42 ng/ml [or (equivalently) 105 nmol/L] which typically will require at least 3000 IU of Vitamin D/daily, remembering that each 1000 IUs of Vitamin D elevates serum 25(OH)D levels approximately 10 ng/ml above base.
• Benefits of High-Optimal 25(OH)D Levels
  The 42 ng/ml is the minimal threshold for optimal oncotherapeutic and bone-positive activity, but higher levels may provide additional, or specialized, benefit (for example, 52 ng/ml levels are associated with a 50% reduction in risk of breast cancer (compared to 13 ng/ml), as per Cedric Garlands's 2006 APHA review). And there is now compelling human clinical data in a case study presented by John Sievenpiper and Simon Pearce with the Royal Victoria Infirmary of high-dose Vitamin D3 (HD-D3) averaging at 10,000 IU/daily that has induced complete remission of distant metastasis (bone). Given that bone is currently considered the critical microenvironment (a tumor incubator, as it were) for metastatic propagation, I would consider that the implications reach beyond bone metastases.
• Therefore, for (1) patients with active malignancies, and/or (2) those at elevated risk of malignancy, recurrence or metastasis, a target level of at least 50 ng/ml [or (equivalently) 125 nmol/L] would be of greater potential benefit.
• The Special Needs of African-American Women
  In addition, adequate testing and supplementation are even more imperative for postmenopausal African-American women who, as the NHANES III study has demonstrated, have lower serum 25(OH)D concentrations at all ages than do whites, and the research of John Aloia at Winthrop University Hospital has established that this population is relatively resistant to low-dose supplementation, finding that supplementation with 800�1000 IU vitamin D per day for 3 years effected absolutely no raising of 25(OH)D or PTH concentrations , in contrast to other racial/ethnic populations.
• But note that there is considerable interpersonal variation, so retesting is prudent, and I counsel three consecutive monthly readings to assure optimal 25(OH)D levels, and amounts of 10,000 IUs/daily and even above have been found unproblematic.
• Adjunct Calcium : In the event of either bone metastases or low Vitamin D3 levels (or both), calcium phosphate supplementation (via the Posture D product), rather than calcium citrate, may be preferable, because both calcium and phosphate metabolism are compromised by low levels of Vitamin D (as 25(OH)D); 1200 mg /daily should be sufficient under adequate Vitamin D levels (with a modest contribution from diet).
• VHD-D3 for AI-Induced Disability
  It's been recently  established that Vitamin D deficiency and insufficiency may be a, if not the, major contributor to musculoskeletal symptoms and bone loss observed in women taking aromatase inhibitors (AIs): Carol Fabian at the University of Kansas, along with Qamar Khan and their colleagues showed in just published study that supplementation with VHD-D3 (very high dose Vitamin D3) in the form of as 50,000 IU of vitamin D3 weekly (injectable)  can reduce musculoskeletal symptoms and fatigue in women who have suboptimal vitamin D levels.  They found that at baseline, 63% of women in the study exhibited vitamin D deficiency (defined as <20 ng/ml) or insufficiency (defined as 20–31 ng/ml). 25OHD levels >40 ng/ml were achieved in all women put on 12 weeks of 50,000 IU D3 supplementation, with no adverse effects whatsoever, and most  interestingly, after 16 weeks of AI therapy (letrozole (Femara)), more women with median 25OHD levels >66 ng/ml reported no disability from joint pain than did women with any levels  below 66 ng/ml, by an order of 52% versus 19%, respectively.  What's really important about this study is that it appears that very high levels of 25OHD, namely above 66 ng/ml, are needed to significantly reduce disability and fatigue from AI-induced arthralgias/myalgias and associated fatigue, and that about 81% of women -  4 out of every 5 - with D3 levels below this continued to suffer  significant AI-associated disabilities. 
  
• Clinical Lessons re High Dose Vitamin D3:

Boswellic Acids [For special populations]

• Boswellic acids, derived from Boswellia serrata (Frankincense), are powerful LOX inhibitors, where the LOX-5 pathway has been implicated in the inflammatory component of many cancers including breast cancer, and especially of brain cancer or brain metastasis.
• Optimal Formulation: Two high-quality pharmaceutical-grade standardized preparations are Source Naturals Boswellia Extract, delivering 262 mg of boswellic acids per tablet, available from Vitacost.com,
  and NSI Boswellia Extract, also from the same online source, delivering 200 mg of boswellic acids per tablet.
• Optimal Dosing: It is known that certain breast cancer classes have an elevated risk for development of metastases to the brain (CNS metastasis), and this includes (1) triple negative (and probably basal and BRCA1 mutated) breast cancer and (2) HER2-positive disease, and therefore it may be of prophylactic benefit for these populations to supplement with boswellic acids. Except for active brain carcinoma or metastases, dosing should deliver no less than approximately 500 - 600 mg boswellic acid daily.
• Note on Optimal Dosing / Scheduling and Components: 
  Many clinical trials have used the Sabinsa Boswellin product (under different labels), which depending on the provider yields approximately 150 to 162mg per dose, with the  schedule typically being 3X to 4X daily, for a daily dosing of 450 - 486mg of boswellic acid content (not the extract itself) at the 3X schedule, and 600mg - 648mg daily at the 4X schedule.  Therefore, following a Sabinsa-based schedule,  the range would be from a low of 450mg daily to a high of 648mg daily, the general rough rule being to consume no less than 500 - 600mg daily as an average. 
• Note that some European studies are using up to 1000mg of boswellia extract for active disease, which would typically deliver 650 mg (at 65%) to 950mg daily of boswellic acid content.
• There is a second approach emerging to boswellia standardization: some studies are standardizing on the AKBA component of boswellic acids, known from recent research to be the critical apoptotic, anti-angiogenic and anti-proliferative component, with dosing in the range of 45 - 100mg AKBA content daily.  The NSI 5-Loxin product (from Vitacost.com) is one such AKBA-standardized product, delivering 22.5mg per capsule, hence dosing would between 2 and 4 capsules daily (45mg to 90mg, respectively).
• The ABKA approach, as opposed to the overall boswellic acids (BA) approach, is more targeted, seeking to assure that of all the many boswellic acids, the critical ABKA boswellic acid component is delivered precisely, so although we don't have data to resolve the efficacy comparison of the AKBA and BA approaches, the AKBA approach appears to be of higher assured quality delivery of antitumor activity.  [I should note however that Dr. Dana Flavin, author of one of the seminal boswellic acid studies (discussed in my review of CNS Metastases from Breast Cancer) herself recommends (personal communication) using an Ayurvedic brand of Boswellia with standardization at 85% boswellic acids]. 
• Important Note on Concurrent Food Intake:
  Pharmacokinetic studies have revealed poor bioavailability for the most critical component of boswellic acids, AKBA, which may therefore compromise the efficacy of this CAM intervention.  Therefore optimal administration is dosing with a high-fat meal  which dramatically maximizes bioavailability and hence delivered efficacy; the high fat can be intrinsic to the meal, or realized just by adding 3 - 4 tablespoons of olive oil to any full meal during which boswellic acids are consumed.
• Preventive Strategies Against CNS Disease

Molecular research shows that CNS (brain and/or spinal) metastases involve critical pathogenic underlying metastatic-cascade molecular pathways, and although no single agent addresses this exceedingly wide spectrum of targets, but the components of my the Edge-CAM regimen collectively target all these major pathogenic highways and byways of breast carcinoma and advanced disease, with some components earmarked especially for TNBC and when relevant, for CNS metastases (especially boswellic acids /AKBA).

Resveratrol [For special populations]

• Even though, as I noted, the potential benefit of resveratrol are not quite as mature as those on curcuminoids, EGCG and melatonin, I consider supplementation sufficiently motivated in these cases: TNBC, IBC, MBC, or HER2+.
• Optimal Formulation: One of these pharmaceutical grade formulations:
  (1) under the Now Foods label as  Natural  Resveratrol  Mega Potency (from Vitacost.com)
  (2) under the Enzymatic Therapy label as Resveratrol Forte (from iHerb.com)
  (3) under the NSI label as NSI Resveratrol Grape Seed & Red  Wine Extract (from Vitacost.com)
• Optimal Dosing:  Extrapolating from the evidence base we can advise 100 mg resveratrol content / daily.
• Provisional: Polyphenol Complex / Quercetin

Just reported preliminary cell-based evidence suggests that combined grape polyphenols at physiologically relevant concentrations are more effective than individual compounds (resveratrol, quercetin, or catechin) at inhibition of breast cancer cell proliferation, cell cycle progression, primary mammary tumor growth and cell migration, and that a polyphenol complex of resveratrol + quercetin + catechin activated apoptosis with potential NF-kF inhibition, and with image analysis of distant organs for metastases demonstrating reduced distant metastasis especially to liver and bone.

• A polyphenol complex of resveratrol + quercetin + catechin only involves adding quercetin to the regimen which already includes resveratrol and a catechin (EGCG.  Obtain single-agent Quercetin (as from Vitacost), like Jarrow Quercetin 500 rather than NSI Quercetin and many other brands which include citrus bioflavonoids); as soon as the data mature a bit further I will, if positive, add quercetin officially to the regimen (and, as with resveratrol, we already have positive human clinical results in other malignancies, including some provisional evidence of activity in the brain).

Reishi (Ganoderma lucidum) Mushroom Extract [for IBC only]

• Michaela Hoffmeyer at the University of Texas and colleagues recently found that  Reishi mushroom extract effectively inhibited proliferation of the IBC cell line, reducing  cell-cell attachments and decreasing invasion of IBC cells, but not the normal mammary epithelial cell line.  Reishi also down-regulated 52% of tumorigenesis genes in the IBC cells treated, suggesting that Reishi inhibits IBC progression via cell proliferation reduction, prevention of tumor emboli formation, and inhibition of invasion by reduced matrix MMP levels. Hence Reishi appears effective in inhibiting IBC progression. (See supporting discussion on my  IBC Watch).
• Optimal Formulation:
  NSI Reishi Mushroom Extract, from Vitacost has an affordable and optimally standardized (10% polysaccharides), which would deliver 50mg of  standardized component per capsules.
• Optimal Dosing:
  The  goal would be  100mg active component daily, so dose at two capsules daily, preferably on an empty or near-empty stomach.  

Summary: Practical Principles of Some Lifestyle-Oriented Breast Cancer Risk Reduction

Dietary Restriction

1. Some Principles
   • Interventions to control the degree of adiposity (amount of body fat) via promotion of both exercise and caloric restriction) are likely to have a greater impact on breast cancer incidence and recurrence than just a reduction in fat intake.

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   • The benefits of dual-reduction of adiposity, that is by both physical activity / exercise AND caloric restriction, are likely to be greater than either single intervention alone (via at least the reduction of circulating levels of estradiol and estrone, as shown by both the research of Anne McTieran with the Fred Hutchinson Cancer Research Center, as well as the WHI-DM trial).

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   • The benefits of dietary restriction is favored by younger age, premenopausal status, and double or triple negative receptor status, although some significant / non-trivial benefits remain for women outside these categories, especially when using the more favored mode of dual-reduction of adiposity (physical activity + caloric restriction).

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   • The benefits of dietary restriction are further favored by particular reduction in saturated fats, and by increase in MUFA - mono-unsaturated (especially the oleic acid component derived from olive oil, and also by some extent canola oil - and to a lesser extent, PUFA (polyunsaturated) fatty acids, especially marine origin high in omega-3 EPA / DHA components.

• A Better Way to Diet: Intermittent Energy Restriction (IER)
  • Michelle Harvie at CRUK University in Manchester showed that intermittent energy restriction (IER) is a potential strategy for promoting periods of energy restriction on a long-term basis, with preclinical and human data suggesting that IER may have cancer preventative effects beyond that of chronic energy restriction (CER) and weight loss. Current and emerging data strongly therefore suggest that IER may be a potential strategy for the primary prevention of various cancers. Also in this connection, a recent study conducted by Michael Pollak at General Jewish Hospital in Montreal demonstrated that intermittent energy restriction (IER) at 650 kcal on any 2 days a week and 1800 kcal on remaining 5 days, may be superior to CER at 1500 kcal/daily, with greater insulin serum level reduction with IER, and with greater patient compliance than with CER. Both diets are considered approximately isocaloric (within an accepted margin of 200 calories weekly).

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  • To translate to real life, if one also reduced the constant 5-day caloric intake down from 1800 kcal to 1500 or below, that would provide both improved insulin (gylcemic) control and modest weight loss; you can also adjust the 2-day kcal level to above 650 kcal if that is too spartan for some, as long as the 5-day kcal is reduced in step. So in all, intermittent energy restriction (IER) can positively modulate insulin, assist in weight control, and enhance compliance with dieting. And there is independent evidence from the Cancer Prevention Laboratory at Colorado State suggesting that dietary energy restriction modulates favorably the mTOR intracellular energy sensing pathway in both mammary and liver malignancies, a primitive molecular developmental pathway that is the focal point of translational research into breast cancer curative objectives.
• Insulin Control
  The combined evidence of epidemiological data supports a modest association between insulin dysfunction in type 2 diabetes and risk of breast cancer, more consistently among postmenopausal than among premenopausal women (confirmed in the recent comprehensive meta-analysis of 26 epidemiological studies conducted by Fei Xue and Karin Michels at Harvard's Brigham and Women's Hospital, and also independently by Patrizia Pasanisi and her colleagues team at the National Tumor Institute in Milan), buttressing independent evidence for a fundamental role of underlying insulin pathways on the carcinogenesis, tumorigenesis, and possibly also metastatic development and recurrence of breast carcinoma. Therefore, strict limitation of sweets and carbohydrates is imperative, within a prudent overall diet such as the Mediterranean Diet, along with strict glycemic control (see below).

• Glycemic Control
  As the glycemic markers (gylcemic index and gylcemic load, GI and GL, respectively), they can be viewed as essentially biomarkers of underlying activity of the molecular IGF (insulin growth factor) pathway, and of the insulin demand of the diet, and we know from very recent findings (especially Sabina Sieri's with the National Cancer Institute in Milan) - in agreement with a stratified analysis of 946 breast cancer cases in the Women's Health Study - that high dietary glycemic marker levels, especially GL (glycemic load) but also high dietary glycemic index (GI), are significantly associated with a greater risk of breast cancer, especially in, but not wholly restricted to, premenopausal women, and this strongly signals that the consumption of large quantities of high-GI (glycemic index) foods is linked to the development of breast cancer. This is also in agreement with the ORDET Study cohort findings that breast cancer risk increases significantly with increasing serum concentrations of IGF-1 (insulin-like growth factor 1) and glucose in premenopausal women (possibly via alteration of cell cycle kinetics or apoptosis inhibition, although there may also be adverse contributions via a gonadotropic effect given that insulin stimulates ovarian androgen synthesis, or via metabolic effects on the liver given that insulin inhibits the synthesis of sex hormone binding globulin and IGF-1 binding proteins 1 and 2, thereby increasing the bioavailability of both sex hormones and IGF-1, powerfully stimulative of breast cancer pathogenesis, as well as of several other cancers). Increased dietary amounts of fiber-rich low-glycemic index natural foods, and avoidance or radical consumption reduction of sweets and sugars, especially, but not only, fructose, improves blood glucose control, reduces the number of hypoglycemic events, and can be an aid in lowering IGF-mediated elevated breast cancer risk, and moreover, with comparable benefits for colorectal and thyroid cancer (as demonstrated in the recent findings of Giorgia Randi). The most authoritative source of GI and GL food values is The Glycemic Index, maintained by the University of Sydney.