THE CUTTING EDGE
EVIDENCE BASED INFORMATION

CONSTANTINE KANIKLIDIS
DIRECTOR, MEDICAL RESEARCH

• memory impairment [Tsolaki 2016], as well as
• Alzheimer's Disease and Dementia) [Akhondzadeh 2010a] [Akhondzadeh 2010b], and these outcomes are backed by high, Level I, evidence (randomized controlled trials (RCTs), and systematic reviews and meta-analysis. Saffron has even matched the efficacy of the prescription Alzheimer's/Dementia agents donepezil, as well as memantine [Farokhnia 2014] [Akhondzadeh 2010a]. In addition, a systematic review of 12 trials [Hausenblas 2015] of the effectiveness of saffron (Crocus sativus L.) on psychological and behavioral outcomes, concluded for the efficacy of saffron as compared to placebo in improving the following conditions:
• depressive symptoms (compared to both conventional anti-depressants and placebo, and matching the efficacy of fluoxetine (Prozac), but minus any significant side effects [Noorbala 2005];
• premenstrual symptoms;
• sexual dysfunction (both for males, for erectile dysfunction [Mohammadzadeh 2015], and females, for female sexual dysfunction (FSD), on symptoms of arousal, lubrication, and pain [Kashani 2013];
• reduction of excessive snacking behavior.

• It is not "YOU" if you are struggling with and suffering under weight control efforts if you're a cancer patient or a cancer survivor: many dysfunctions exist that add far more barriers and burdens to effective weight loss. AND
• That said, nonetheless, because in fact of these very dysfunctions, which can be pathological drivers of cancer, the importance of weight control is proportionately greater, although admittedly harder, and the benefits far more critical to your health, remission and freedom for recurrence.

Edge-CAM Regimen [Version 3.7 - 8/3/2011]

Curcuminoids + EGCG + Melatonin + HD-D3 + Parthenolide

• Selenium has been found to induce p53 redox modification which has the  potential for at least partial restoration of p53 function to mutant p53.  This is important for TNBC tumors because the vast majority of TNBCs express a mutant p53, and such failure of p53 signaling is associated with chemoresistance of tumors to therapy, especially to DNA-damaging oncotherapy (see below). 
• Therefore therapies directed toward restoring p53 function / signaling to the highly accumulated mutant p53 seen in most TNBC tumors can yield substantial benefit by improving the outcome of these oncotherapy for TNBC tumors in which p53 is prevalently mutated. 
• A Tulane University study reported at SABCS 2009 demonstrated that selenium greatly increase the growth-inhibitory potency of genotoxic (DNA-damaging) chemotherapy (doxorubicin) in TNBC cell lines expressing mutant p53 and this represents a safe and highly effective approach for increasing the efficacy of genotoxic oncotherapies in the treatment of TNBC. 
• The form of selenium used in the study (methylseleninic acid, aka MSA) is not readily commercially available, but the best approximation is Super Selenium Complex from LEF; dosing is optimized at 200 mcg (micrograms) daily - single capsule - taken with a meal. 
• Guidance: 
  Anyone with TNBC who is on or anticipating genotoxic (DNA-damaging) oncotherapy, such as:

• • anthracyclines
• • platinum agents  (cisplatin or carboplatin) 
• • cyclophosphamide (Cytoxan)  (as in AC, TAC and CMF regimens)
• • radiation therapy 
• • PARP inhibitor therapy

• Parthenolide (Feverfew extract)
• DHA for metastatic breast cancer (MBC)
• Higher Dosing Limit for Curcumin (6000mg/d)
• Piperine antitumor activity

• 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

• VHD-D3 for AI-Induced Disability [new coverage]
• Provisional: Polyphenol Complex / Quercetin
• Reishi Mushroom Extract [for IBC only]

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

• 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.
• 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 in: (1) advanced disease and metastatic settings, or in, (2) elevated risk contexts. A new study from Mathilde Bayet-Robert at the Centre Jean Perrin has established although the MTD (maximum tolerated dose) of curcumin is 8000 mg/daily, the recommended dosing for near-optimal clinical benefit in human trial of women with advanced or metastatic breast cancer is 6000 mg/daily.
• Take curcumin towards to end of a large meal, preferably in three divided doses. 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) TNBC, (2) IBC, (3) MBC, and (4) HER2+ disease as contexts of elevated risks, in which cases optimize at 6000 mg/d.
• Evidence suggests that piperine itself has antitumor activity of its own.
• New evidence reported (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, the first ever demonstration of the specific TNBC-potential activity of curcumin, showing curcumin-induced promotion of apoptosis and prevention of growth and migration of TNBC cells.

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

• Optimal Formulation: No standardization issue with melatonin. Natrol Melatonin delivers 5 mg per capsule.
• Optimal Dosing: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).
• New research from the Institute of Biological Medicine in Milan) has found  that melatonin added to to AI therapy in metastatic BC patients with poor clinical outcome (metastases 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.

• Optimal Formulation: Vitamin D3 (which is the cholecalciferol form), not Vitamin D2 (which is the ergocalciferol form). No standardization issues.
• Optimal Dosing:  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 (or the "25-Hydroxy Vitamin D" test). Aim for a target level for 25(OH)D of at least 66 ng/ml which typically will require at least 3000 - 4000 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
  It is known that 52 ng/ml levels are associated with a 50% reduction in risk of breast cancer, compared to 13 ng/ml (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), with implications 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 66 ng/ml 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: three consecutive monthly readings are  advised to assure optimal 25(OH)D levels (amounts of 10,000 IUs/daily and even above have been found unproblematic).
• 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 that supplementation with VHD-D3 (very high dose Vitamin D3) in the form of injectable 50,000 IU weekly can reduce musculoskeletal symptoms and fatigue in women with suboptimal vitamin D levels.  At baseline, 63% of women exhibited vitamin D deficiency (<20 ng/ml) or insufficiency (20–31 ng/ml).  25(OH)D levels >40 ng/ml were achieved in all women put on 12 weeks of 50,000 IU D3 supplementation with no adverse effects, and after 16 weeks of AI therapy (letrozole (Femara)), more women with median 25(OH)D levels >66 ng/ml reported no disability from joint pain than did women with any levels  below, by an order of 52% versus 19%, respectively.  Thus, very high levels of 25(OH)D, >= 66 ng/ml, are needed to significantly reduce disability and fatigue from AI-induced arthralgias/myalgias and associated fatigue. 
  
• 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: (1) Source Naturals Boswellia Extract, delivering 262 mg of boswellic acids per tablet, and (2) NSI Boswellia Extract, delivering 200 mg of boswellic acids per tablet.
• Optimal Dosing: Certain breast cancer classes have an elevated risk for development of metastases to the brain (CNS metastasis), and this includes (1) TNBC (and probably basal and BRCA1 mutated) and (2) HER2+ 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 yields approx. 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. 
• So for example the Nature's Herb Boswellin delivers 150mg standardized boswellic acids per tablet, while Now Foods Boswellin delivers 162mg per capsule.  The Source Naturals Boswellia Extract product is one of the higher potency formulations, delivering 262mg per tablet.  And 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 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 AKBA 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 AKBA 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. 
• Important Note on Concurrent Food Intake:
  Pharmacokinetic studies have revealed poor bioavailability for the most critical component of boswellic acids, AKBA, which may compromise efficacy.  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 at least 1 - 2 tablespoons or higher of olive oil.

• 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+, observing the caution below.
• Optimal Formulation: One of these pharmaceutical grade formulations:
  (1) Now Foods Natural  Resveratrol  Mega Potency
  (2) Enzymatic Therapy Resveratrol Forte
  (3) NSI Resveratrol Grape Seed & Red  Wine Extract
• Optimal Dosing:  Extrapolating from the evidence base we can advise 100 mg resveratrol content / daily.
• Caution:
  An in press preclinical study of resveratrol from Masuyuki Fukui and colleagues at the University of Kansas found that that resveratrol strongly diminished the susceptibility of certain breast cancer cells, including triple negative (MDA-MB-231 cells)" to paclitaxel-induced cell death in culture, and also in vivo in mice (not observed in non-TNBC MCF-7 cells), and although this has not been demonstrated in the human clinical setting, it suggests caution in co-administration of resveratrol and paclitaxel (Taxol) (and possibly by extrapolation with other taxanes, although these were not studied).

• Michaela Hoffmeyer at the University of Texas and colleagues recently tested the hypothesis that the immunomodulatory, anti-inflammatory, and anti-cancer effects of  the traditional Chinese medicinal (TCM) agent  Reishi (Ganoderma lucidum) mushroom extract, may be effective against IBC progression and invasion, given accumulating evidence of its ability to inhibit proliferation, adhesion, migration, and invasion of cancer cells via the  triterpenes component which exhibits cytotoxicity against cancer cells at high concentrations, and component polysaccharides that are  immunostimulatory. The Reishi extract effectively inhibited proliferation of the IBC cell line, reducing  cell-cell attachments and decreasing invasion of IBC cells.  Reishi also down-regulated 52% of tumorigenesis genes in the IBC cells treated, and furthermore inhibited the MMP-2  and MMP-9 levels; this suggests that Reishi inhibits IBC progression via cell proliferation reduction, prevention of tumor emboli formation, and inhibition of invasion by reduced matrix MMP levels. So Reishi extract appears to be a natural agent with potential inhibition of IBC progression. (See IBC Watch).
• Optimal Formulation:
  NSI Reishi Mushroom Extract is one optimally standardized (10% polysaccharides) product, delivering 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.  

• Parthenolide, a strongly anti-inflammatory agent, is the primary biologically active agent in Feverfew commonly used for migraine and arthritis, and  the  focus of considerable investigation as a natural oncotherapeutic and cytotoxic agent in several malignancies including breast cancer.
• In endocrine/hormonal disease, Rebecca Riggins and colleagues at Georgetown demonstrated that parthenolide restored fulvestrant (Faslodex)-mediated suppression of cell growth, yielding 4-fold synergistic cell growth reduction and apoptosis enhancement (and this may not be restricted just to fulvestrant, but to other endocrine agents).
• In hormone-negative disease, including and especially TNBC, my  own research in epigenetic reprogramming has uncovered parthenolide to be a natural HDAC inhibitor as well as a DNMT inhibitor, properties similar the investigational epigenetic agent vorinostat (Zolinza), so it too may like vorinostat have potential to change or modulate a challenging breast cancer subtype, TNBC, into a prognostically more favorable phenotype.
• Finally, Yang Liu and colleagues in Peking University demonstrated the activity of parthenolide against cancer stem cells, an activity that curcumin also shares. 
• Dosing and Optimal FormulationThe inclusion of parthenolide into the Edge-CAM regimen is marked provisional solely because we as yet lack decisive dose-finding studies, but extrapolating from the existing preclinical and in vivo data, the target dosing would be hazarded on that basis to be approximately 6 mg of parthenolide content daily.  Source Naturals Feverfew Extract delivers 200 mg of feverfew extract per tablet, standardized at 0.5% parthenolide content, so that yields 1mg/tablet, with optimal schedule being two capsules 3X daily with meals, supplemented with at least 81 (baby) to 325mg (adult) aspirin daily as coadministration with salicylates enhances activity.
• HD-Parthenolide:  High-dose parthenolide in special circumstances - higher anti-inflammatory potency for example in the treatment of peritumoral (cerebral) edema in CNS disease to  reduce reliance on steroid medication - is feasible and safe: studies have shown that parthenolide is essentially non-toxic, so dosing  at levels of 2X  to 3X  the target 6mg/daily  are  plausible to determine if greater relief and benefit are attainable. A high-potency formulation is typically needed. One of the most concentrated in Solaray Migra Gard standardized at 0.7% parthenolide content in 350mg Feverfew capsules, yielding 2.45mg of parthenolide per capsule (in contrast to the Source Naturals product delivering 1mg per tablet).

• DHA is a lipid of marine origin, and is one of the two principal components of omega-3 fatty acids (OFAs), with preliminary studies showing both chemosensitization and radiosensitization activities, the enhancement of sensitivity appearing to apply preferentially to aggressive tumor cells.
• Phillippe Bougnoux and colleagues reported results of a phase II clinical trial in which DHA was added during a 7 - 10 day loading period before anthracycline-based chemotherapy (FEC) and then continued for the 5 months of chemotherapy, in a population of metastatic BC patients with compromised prognosis (68% had liver metastases in addition to other metastatic sites) with rapidly progressing visceral metastases (17 liver, 9 lung patients), along with 15 patients with bone metastasis, 5 with skin metastasis, and one with brain metastasis. The ORR (overall response rate) was 44% with one complete response (CR) and 10 partial responses (PR), and given that there were 11 stable disease SD cases, the clinical benefit rate (CBR) was 88%, with median overall survival (OS) significantly greater in the sub-population of patients with the highest plasma DHA.
• This clinical trial therefore confirms previous positive findings, and demonstrates that DHA + chemotherapy may improve the outcome of metastatic BC patients, with DHA chemosensitizing tumors.
• Dose at 1.8 grams/d.  Consult Consumerlab.com for high-quality approved products.
• Warning: Alpha-tocopherol (Vitamin E) appears to abolish the DHA-induced sensitization (chemo- and radio-) of tumor cells, so avoid co-consumption with Vitamin E.

Edge-CAM Regimen [Version 3.6 - 7/4/2010]

Curcuminoids + EGCG + Melatonin + HD-D3 + Parthenolide

• Selenium has been found to induce p53 redox modification which has the  potential for at least partial restoration of p53 function to mutant p53.  This is important for TNBC tumors because the vast majority of TNBCs express a mutant p53, and such failure of p53 signaling is associated with chemoresistance of tumors to therapy, especially to DNA-damaging oncotherapy (see below). 
• Therefore therapies directed toward restoring p53 function / signaling to the highly accumulated mutant p53 seen in most TNBC tumors can yield substantial benefit by improving the outcome of these oncotherapy for TNBC tumors in which p53 is prevalently mutated. 
• A Tulane University study reported at SABCS 2009 demonstrated that selenium greatly increase the growth-inhibitory potency of genotoxic (DNA-damaging) chemotherapy (doxorubicin) in TNBC cell lines expressing mutant p53 and this represents a safe and highly effective approach for increasing the efficacy of genotoxic oncotherapies in the treatment of TNBC. 
• The form of selenium used in the study (methylseleninic acid, aka MSA) is not readily commercially available, but the best approximation is Super Selenium Complex from LEF; dosing is optimized at 200 mcg (micrograms) daily - single capsule - taken with a meal. 
• Guidance: 
  Anyone with TNBC who is on or anticipating genotoxic (DNA-damaging) oncotherapy, such as:

• • anthracyclines
• • platinum agents  (cisplatin or carboplatin) 
• • cyclophosphamide (Cytoxan)  (as in AC, TAC and CMF regimens)
• • radiation therapy 
• • PARP inhibitor therapy

• Parthenolide (Feverfew extract)
• DHA for metastatic breast cancer (MBC)
• Higher Dosing Limit for Curcumin (6000mg/d)
• Piperine antitumor activity

• 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

• VHD-D3 for AI-Induced Disability [new coverage]
• Provisional: Polyphenol Complex / Quercetin
• Reishi Mushroom Extract [for IBC only]

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

• 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.
• 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 in: (1) advanced disease and metastatic settings, or in, (2) elevated risk contexts. A new study from Mathilde Bayet-Robert at the Centre Jean Perrin has established although the MTD (maximum tolerated dose) of curcumin is 8000 mg/daily, the recommended dosing for near-optimal clinical benefit in human trial of women with advanced or metastatic breast cancer is 6000 mg/daily.
• Take curcumin towards to end of a large meal, preferably in three divided doses. 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) TNBC, (2) IBC, (3) MBC, and (4) HER2+ disease as contexts of elevated risks, in which cases optimize at 6000 mg/d.
• Evidence suggests that piperine itself has antitumor activity of its own.
• New evidence reported (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, the first ever demonstration of the specific TNBC-potential activity of curcumin, showing curcumin-induced promotion of apoptosis and prevention of growth and migration of TNBC cells.

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

• Optimal Formulation: No standardization issue with melatonin. Natrol Melatonin delivers 5 mg per capsule.
• Optimal Dosing: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).
• New research from the Institute of Biological Medicine in Milan) has found  that melatonin added to to AI therapy in metastatic BC patients with poor clinical outcome (metastases 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.

• Optimal Formulation: Vitamin D3 (which is the cholecalciferol form), not Vitamin D2 (which is the ergocalciferol form). No standardization issues.
• Optimal Dosing:  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 (or the "25-Hydroxy Vitamin D" test). Aim for a target level for 25(OH)D of at least 66 ng/ml which typically will require at least 3000 - 4000 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
  It is known that 52 ng/ml levels are associated with a 50% reduction in risk of breast cancer, compared to 13 ng/ml (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), with implications 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 66 ng/ml 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: three consecutive monthly readings are  advised to assure optimal 25(OH)D levels (amounts of 10,000 IUs/daily and even above have been found unproblematic).
• 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 that supplementation with VHD-D3 (very high dose Vitamin D3) in the form of injectable 50,000 IU weekly can reduce musculoskeletal symptoms and fatigue in women with suboptimal vitamin D levels.  At baseline, 63% of women exhibited vitamin D deficiency (<20 ng/ml) or insufficiency (20–31 ng/ml).  25(OH)D levels >40 ng/ml were achieved in all women put on 12 weeks of 50,000 IU D3 supplementation with no adverse effects, and after 16 weeks of AI therapy (letrozole (Femara)), more women with median 25(OH)D levels >66 ng/ml reported no disability from joint pain than did women with any levels  below, by an order of 52% versus 19%, respectively.  Thus, very high levels of 25(OH)D, >= 66 ng/ml, are needed to significantly reduce disability and fatigue from AI-induced arthralgias/myalgias and associated fatigue. 
  
• 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: (1) Source Naturals Boswellia Extract, delivering 262 mg of boswellic acids per tablet, and (2) NSI Boswellia Extract, delivering 200 mg of boswellic acids per tablet.
• Optimal Dosing: Certain breast cancer classes have an elevated risk for development of metastases to the brain (CNS metastasis), and this includes (1) TNBC (and probably basal and BRCA1 mutated) and (2) HER2+ 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 yields approx. 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. 
• So for example the Nature's Herb Boswellin delivers 150mg standardized boswellic acids per tablet, while Now Foods Boswellin delivers 162mg per capsule.  The Source Naturals Boswellia Extract product is one of the higher potency formulations, delivering 262mg per tablet.  And 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 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 AKBA 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 AKBA 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. 
• Important Note on Concurrent Food Intake:
  Pharmacokinetic studies have revealed poor bioavailability for the most critical component of boswellic acids, AKBA, which may compromise efficacy.  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 at least 1 - 2 tablespoons or higher of olive oil.

• 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+, observing the caution below.
• Optimal Formulation: One of these pharmaceutical grade formulations:
  (1) Now Foods Natural  Resveratrol  Mega Potency
  (2) Enzymatic Therapy Resveratrol Forte
  (3) NSI Resveratrol Grape Seed & Red  Wine Extract
• Optimal Dosing:  Extrapolating from the evidence base we can advise 100 mg resveratrol content / daily.
• Caution:
  An in press preclinical study of resveratrol from Masuyuki Fukui and colleagues at the University of Kansas found that that resveratrol strongly diminished the susceptibility of certain breast cancer cells, including triple negative (MDA-MB-231 cells)" to paclitaxel-induced cell death in culture, and also in vivo in mice (not observed in non-TNBC MCF-7 cells), and although this has not been demonstrated in the human clinical setting, it suggests caution in co-administration of resveratrol and paclitaxel (Taxol) (and possibly by extrapolation with other taxanes, although these were not studied).

• Michaela Hoffmeyer at the University of Texas and colleagues recently tested the hypothesis that the immunomodulatory, anti-inflammatory, and anti-cancer effects of  the traditional Chinese medicinal (TCM) agent  Reishi (Ganoderma lucidum) mushroom extract, may be effective against IBC progression and invasion, given accumulating evidence of its ability to inhibit proliferation, adhesion, migration, and invasion of cancer cells via the  triterpenes component which exhibits cytotoxicity against cancer cells at high concentrations, and component polysaccharides that are  immunostimulatory. The Reishi extract effectively inhibited proliferation of the IBC cell line, reducing  cell-cell attachments and decreasing invasion of IBC cells.  Reishi also down-regulated 52% of tumorigenesis genes in the IBC cells treated, and furthermore inhibited the MMP-2  and MMP-9 levels; this suggests that Reishi inhibits IBC progression via cell proliferation reduction, prevention of tumor emboli formation, and inhibition of invasion by reduced matrix MMP levels. So Reishi extract appears to be a natural agent with potential inhibition of IBC progression. (See IBC Watch).
• Optimal Formulation:
  NSI Reishi Mushroom Extract is one optimally standardized (10% polysaccharides) product, delivering 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.  

• Parthenolide, a strongly anti-inflammatory agent, is the primary biologically active agent in Feverfew commonly used for migraine and arthritis, and  the  focus of considerable investigation as a natural oncotherapeutic and cytotoxic agent in several malignancies including breast cancer.
• In endocrine/hormonal disease, Rebecca Riggins and colleagues at Georgetown demonstrated that parthenolide restored fulvestrant (Faslodex)-mediated suppression of cell growth, yielding 4-fold synergistic cell growth reduction and apoptosis enhancement (and this may not be restricted just to fulvestrant, but to other endocrine agents).
• In hormone-negative disease, including and especially TNBC, my  own research in epigenetic reprogramming has uncovered parthenolide to be a natural HDAC inhibitor as well as a DNMT inhibitor, properties similar the investigational epigenetic agent vorinostat (Zolinza), so it too may like vorinostat have potential to change or modulate a challenging breast cancer subtype, TNBC, into a prognostically more favorable phenotype.
• Finally, Yang Liu and colleagues in Peking University demonstrated the activity of parthenolide against cancer stem cells, an activity that curcumin also shares. 
• Dosing and Optimal FormulationThe inclusion of parthenolide into the Edge-CAM regimen is marked provisional solely because we as yet lack decisive dose-finding studies, but extrapolating from the existing preclinical and in vivo data, the target dosing would be hazarded on that basis to be approximately 6 mg of parthenolide content daily.  Source Naturals Feverfew Extract delivers 200 mg of feverfew extract per tablet, standardized at 0.5% parthenolide content, so that yields 1mg/tablet, with optimal schedule being two capsules 3X daily with meals, supplemented with at least 81 (baby) to 325mg (adult) aspirin daily as coadministration with salicylates enhances activity.
• HD-Parthenolide:  High-dose parthenolide in special circumstances - higher anti-inflammatory potency for example in the treatment of peritumoral (cerebral) edema in CNS disease to  reduce reliance on steroid medication - is feasible and safe: studies have shown that parthenolide is essentially non-toxic, so dosing  at levels of 2X  to 3X  the target 6mg/daily  are  plausible to determine if greater relief and benefit are attainable. A high-potency formulation is typically needed. One of the most concentrated in Solaray Migra Gard standardized at 0.7% parthenolide content in 350mg Feverfew capsules, yielding 2.45mg of parthenolide per capsule (in contrast to the Source Naturals product delivering 1mg per tablet).

• DHA is a lipid of marine origin, and is one of the two principal components of omega-3 fatty acids (OFAs), with preliminary studies showing both chemosensitization and radiosensitization activities, the enhancement of sensitivity appearing to apply preferentially to aggressive tumor cells.
• Phillippe Bougnoux and colleagues reported results of a phase II clinical trial in which DHA was added during a 7 - 10 day loading period before anthracycline-based chemotherapy (FEC) and then continued for the 5 months of chemotherapy, in a population of metastatic BC patients with compromised prognosis (68% had liver metastases in addition to other metastatic sites) with rapidly progressing visceral metastases (17 liver, 9 lung patients), along with 15 patients with bone metastasis, 5 with skin metastasis, and one with brain metastasis. The ORR (overall response rate) was 44% with one complete response (CR) and 10 partial responses (PR), and given that there were 11 stable disease SD cases, the clinical benefit rate (CBR) was 88%, with median overall survival (OS) significantly greater in the sub-population of patients with the highest plasma DHA.
• This clinical trial therefore confirms previous positive findings, and demonstrates that DHA + chemotherapy may improve the outcome of metastatic BC patients, with DHA chemosensitizing tumors.
• Dose at 1.8 grams/d.  Consult Consumerlab.com for high-quality approved products.
• Warning: Alpha-tocopherol (Vitamin E) appears to abolish the DHA-induced sensitization (chemo- and radio-) of tumor cells, so avoid co-consumption with Vitamin E.

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