It is critical to keep in mind, especially in this chapter that multiple lifestyle options exists that can improve or actually not improve and even exacerbate side effects from cancer treatments. And there are many integrative medicines, especially dietary supplements that can improve, have no impact or actually cause a side effect from cancer treatment to become worse! The purpose of this chapter just like the rest of this book is to cover all of those integrative medicines that work, have no effect or are worthless for multiple cancer treatment side effects. When applicable prescription drug treatments are mentioned and reviewed. Still, this chapter and the book is not intended to provide a summary or exhaustive list of the conventional prescription treatment options for these side effects from A to Z because it would not only create an unreadable voluminous text, but this also would not serve the purpose of this text—to simply provide a non-biased and objective review of the medical research in the area of breast cancer and integrative medicines, especially in regard to lifestyle changes and dietary supplements. This is the area of oncology that appears to have arguably the greatest current needs for more objective and educational attention to this issue.

In prostate cancer when a man receives hormone suppressive treatment then a mild asymptomatic normochromic normocytic anemia can occur in 90 % of patients (acutely or chronically) and it is usually asymptomatic [1, 2]. This is due to testosterone being reduced to almost undetectable levels and this hormone is needed for red blood cell production. Thus, these cancer patients do not usually need iron, B12 or folic acid to improve anemia because it is not macrocytic or microcytic. It should be mentioned that the shape and size of the cells being pro duced are normal but the rate at which these cells are being produced is not maximum or normal. I often give the example of a factory producing widgets and the factory is producing or creating them correctly but it is not able to produce enough of them without some testosterone. And again, few dietary supplements are able to correct anemia in cancer patients unless it is more overt and caused by some rare situation of deficiency or because of a medication induced deficiency (e.g., acid reflux or metformin medications and B12 deficiency) [3].

In women with breast cancer on aromatase inhibitors these drugs prevent the conversion of androstenedione and testosterone to estrogen, and there is arguably a chance of erythrocytosis/polycythemia (similar to that observed with exogenous androgens), albeit small, that has been described in some case studies that resolved with drug cessation [4]. And there is a concern with erythrocytosis when aromatase inhibitors are utilized in other medical settings [5].

Patients and health care professionals often inquire about the need for dietary supplements to ameliorate anemia associated with breast cancer treatments. However, similar to what was mentioned earlier a supplement can rarely provide a benefit for these treatment-based anemias unless a deficiency was caused by medication or another lucid situation. For example, a breast cancer patient on a chronic proton pump inhibitor (PPI) could theoretically incre ase the risk of vitamin B12 deficiency and/or iron absorption issues [6]. The drug metformin can also cause vitamin B12 deficiency [3]. Additionally, weight gain and obesity are associated with a reduction in iron from the generalized inflammatory reaction caused by adipose tissue and an increased hepcidin concentration, which can impair duodenal iron absorption [7]. Chronic use of high-dose zinc can also create a copper deficiency that can result in a sideroblastic anemia and neutropenia [8]. And it is not unusual today for some cancer patients to be ingesting high-doses of zinc (along with other standardized compounds) as part of their macular degeneration supplement because this regimen has shown an ability to prevent vision loss in randomized controlled trials (AREDS), but patients should also seek a product with 2 mg of copper in these eye health products to prevent this issue.

Thus, despite a paucity of data to ingest dietary supplements when experiencing anemia from cancer treatment itself and occasional small publication can invoke enormous interest among patients and alternative medicine enthusiasts. For example a pilot study of 60 cc (2 fluid ounces) of wheat grass (Triticum aestivum) juice daily versus a control group in br east cancer patients during the first three cycles of chemotherapy showed some promise [9]. This was based on a significantly lower rate (p = 0.01) of 5 “censoring events” (premature termination of chemotherapy, dose reduction or initiating GCSF or epoetin) versus 15 in the control arm. The effect of wheat grass appeared to have a greater impact on reducing hematologic toxicity (17 % versus 37 %, p = 0.04) with reductions in neutropenic fever events or neutropenic infections. The authors suggested “apigenin” (bioflavonoid) might inhibit the adhesion of white blood cells to endothelial cells. Another theory is “chlorophyll” (highly concentrated in wheat grass) resembles hemoglobin and has antioxidant activity, as well as other nutrients in wheat grass, which could provide some benefits. Although 73 % of the patients (22 out of 30) in the wheat grass arm had difficulty ingesting the juice because the pungent grassy taste and six patients had worsening nausea. A total of 20 % of the patients could not complete 9 weeks of wheat grass ingestion due to progressive nausea. And this increased incidence of nausea has been reported in another study of patients with inflammatory bowel disease [10]. Thus, wheat grass juice itself is not benign in cancer patients and the statistical clinical outcome difference, which has not received further publications in the past decade may be partially explained by the lack of a placebo group so there was no true blinding. Additionally, wheat grass juice has somewhat of a mini-multivitamin or liquid nutritional support feature to it. Again, it contains chlorophyll (majority of the solid content), but also 18 amino acids and the following vitamins and minerals and dosage per 100 ml or 100 cc:

An older observational stu dy of wheat grass juice also displayed some potential benefits for a lower rate of transfusion, which some experts again credit to chlorophyll having a structural similarity to heme so that production of hemoglobin can occur at a faster rate [11, 12]. There is also some mixed evidence with thalassemia major that wheat grass (tablets in some cases) may reduce transfusions [12–14], but in a 1-year study no clinically significant benefit was documented [13]. The preliminary research sounds interesting but again little has been done recently on this alternative medicine and the mechanism of action has not been thoroughly explored. If a patient wanted to consume 60–90 cc (2–3 ounces) of wheat grass juice the nutrient profile is diverse and low enough in its inherent concentration that it would be somewhat similar to ingesting a children’s multivitamin. It should be kept in mind that wheat grass allergies are also not uncommon and if nausea is already an issue this should be completely avoided. Regardless, diet and dietary supplements have a minimal role in preventing anemia or neutropenia caused by conventional breast cancer treatment and this should be explained to patients to save them time, effort, money and increase safety.

Arthralgia , which is defined as pain and/or stiffness in the joints, is experienced by 50 % of breast cancer patients treated with aromatase inhibitors (AIs), and it is the number one reason for poor compliance on these medications [15].

It appears that estrogen deprivation ap pears to be the cause of arthralgia, but there is also a notably higher risk of general joint issues with aging. It is theorized and plausible that exercise increases perf usion to tissues and increase maximum oxygen utilization, reduces fatigue, and improves mood and range of motion [16–18]. And the preliminary impact of exercise on AIA is profound. For example a randomized 1-year trial of 121 breast cancer survivors were assigned to exercise or 150 min per week of aerobic exercise and supervised resistance training twice a week or usual care [16]. This was one of the first such trials to address this issue in terms of physical activity and it was known as the HOPE (Hormones and Physical Exercise) study. Worst pain scores were reduced by 29 % (1.6 points) at 1-year with exercise versus a 3 % increase (3 %) among those with usual care (p < 0.001). Pain severity and interference and Disabilities of the Arm, Shoulder and Hand (DASH) and the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index were also reduced significantly in the exercise group versus usual care (all p < 0.001). On average, pain scores in women were reduced from moderate at baseline to mild at the end of the exercise program and additional benefits included an increase in fitness, upper- and lower-body strength and weight loss. Interestingly, some benefit was found after 3 months but maximum benefit was observed after 1-year and these patients did have a past history of inactivity. The aerobic exercise intervention involved primarily brisk walking or similar intensity exercises such as stationary bicycling. Exercise was initiated at 50 % of maximal heart rate and increased over the first month to 60–80 % of maximal heart rate for the rest of the study. The resistance protocol consisted of six exercises (8–12 repetitions for three sets and if an individual could lift the same weight 12 times during each set then the weight was increased to the next smallest increment) including three upper- and three lower body activities:

Several other clinical studies and even home-based programs continue to demonstrate benefit against arthralgia including a simple 5-day a week 30 min a day walking program [17, 18]. Since weight gain or obesity has the potential to exacerbate joint pain, another benefit of exercise is simply weight loss, which reduces stress on the joint itself. Regar dless, numerous other types of exercise including yoga and tai chi are also promising [19]. One trial of acupuncture demonstrated a 50 % reduction in pain versus no change in the sham arm [20], but more trials are needed because other studies demonstrating no benefit have also been published [21] and most studies include only a small number of evaluable patients. Thus, a large multicenter randomized trial is being conducted by SWOG to provide more clarity on the impact of acupuncture in this setting.

Glucosamine and chondroitin are both naturally found in human cartilage and both of these compounds are believed to have multiple benefits including local anti-inflammatory effects within joints and even increase production of ot her joint supportive compounds [3]. Glucosamine is a hexosamine sugar (amino acid sugar or aminomonosaccharide) and a basic building block for the production of glycosaminoglycans (GAG) and proteoglycans that are important parts of articular cartilage and synovial fluid. It is naturally produced by the body and widely distributed in connective tissue, including cartilage. Glucosamine supplements are generally derived from crab shells or shells of sea creatures but there are now some sources of glucosamine that are vegetarian friendly that can be derived from corn for example. Patients with a shellfish allergy should avoid taking it unless it comes from a non-shellfish source. It may help with osteoarthritis joint pain and it now also comes in a liquid low-calorie form. Doses of 500–1500 mg/day of glucosamine sulfate versus placebo may be associated with a reduction in pain and an improvement in function versus placebo. Some experts believe that even if glucosamine does not help with pain it may improve cartilage structure. The potential side effects of glucosamine are unknown at this time, but individual reports of blood thinning (do not combine with warfarin), stomach upset and excess gas have been reported in some cases. Check for the amount of sodium in the glucosamine supplement because it is a high source of sodium but even the cheapest glucosamine supplements are able to reduce the amount and many only contain 20–50 mg of sodium per 1–2 capsules.

Chondroitin sulfate (CS) is a GAG found in proteoglycans of articular cartilage or extracellular matrix of connective tissue [3]. It is a complex carbohydrate molecule that helps retain water in cartilage. The supplements are gener ally produced from shark, pig, or cow (bovine) cartilage, but now there are some potential algae or fermentation derived non-animal sources coming to market (the problem in the past and currently is the cost of producing a line of these non-animal based alternatives). It may increase proteoglycan synthesis in the chondrocytes (cells) of articular cartilage. Doses of 800–1200 mg a day have provided some pain relief by itself or when combined with Glucosamine. Some have argued that the dosage should be divided over 2–3 different times during the day but this is controversial. In fact, more recent studies and longer studies of chondroitin sulfate have found the potential for this supplement to reduce cartilage volume loss. Hand and knee pain appear to have more data compared to lower back issues.

Two recent randomized clinical trials (LEGS and MOVES) and a surprising objective extensive analysis need to be reviewed for the reader, and again provides an excellent background to at least extend the testing of these supplements with AIA [22–24]. The first known as “LEGS” (Long-term Evaluation of Glucosamine Sulfate) was a double-blind randomized placebo-controlled trial in over 600 patients reporting chronic knee p ain and evidence of medial tibio-femoral comp artment narrowing [22]. Patients were assigned glucosamine sulfate (source not immediately specified) 1500 mg, chondroitin sulfate 800 mg (bovine-derived), both or placebo over 2 years (product was provided by Sanofi-Aventis Consumer Healthcare). Although there were no statistically significant symptomatic advantages at the end of the trial, the group utilizing glucosamine and chondroitin in combination experienced a significant (p = 0.05) reduction in joint space narrowing after 2 years versus placebo (mean difference 0.10 mm). This would suggest that this supplement combination has the potential of slowing the osteoarthritis process at least from imaging studies. No differences in side effects were observed between the groups.

Additionally, a recent double-blind multicenter randomized trial of over 600 patients found 1500 mg of Glucosamine hydrochloride and 1200 mg of chondroitin sulfate (Droglican, Bioiberica, S.A., Barcelona, Spain) to be of comparable efficacy to prescription 200 mg daily celecoxib in decreasing pain, stiffness, functional limitation and joint effus ion after 6 months in participants with painf ul knee osteoarthritis and with a similar side effect profile (known as the “MOVES” trial or Multicentre Osteoarthritis Intervention trial with SYSADOA) [23].

A recent Cochrane Database review also found adequate support of efficacy for chondroitin in osteoarthritis and a low risk of toxicity after reviewing 43 past randomized clinical trials with over 4900 participants given this supplement versus over 4100 utilizing a placebo or comparison product [24]. Many of these trials were of low quality so the manuscript was a cautionary endorsement of this supplement except more recent higher quality trials such as LEGS and MOVES should add more quality evidence to these objective clin ical reviews. One of the more notable controversial clinical trials of these supplements was the “GAIT” trial (Glucosamine/chondroitin Arthritis Intervention Trial), which reported no impact with these supplements at 24 weeks when the data was analyzed. Howev er, when examining the subgroup of patients with moderate to severe pain at baseline the actual response rate was significantly higher with glucosamine and chondroitin together versus placebo (79.2 % versus 54.3 %, p = 0.002) [25]. Thus, with this as background it appears logical to believe that these agents could have some preliminary efficacy against AIA assuming there are some related mechanisms of action.

Glucosamine sulfate (1500 mg/day from a shellfish source) and chondroitin sulfate (1200 mg/day from a bovine source; both supplements from Thorne Research-Sandpoint, ID) utilized for 24 weeks in postmenopausal women expe riencing pain from AI partici pated in a single-arm, open-label phase 2 study [26]. This group demonstrated a significant (p < 0.05) improvement in pain and function, and 50 % of the patients experienced 20 % or more improvement in pain, stiffness, and function. Additionally, statistical and clinical improvements in arthralgias and myalgias were reported at 12 and 24 weeks (all p < 0.05). There were no changes in estradiol levels and the most common side effects were headache (28 %), dyspepsia (15 %), and nausea (17 %). However, at baseline 47 % of the participants used pain medications and there were no reported differences in medication use from baseline to 12 or week 24. There was a 30 % dropout rate partially due to the high number of capsules needed for daily use (six capsules per day, each containing 250 mg of glucosamine and 200 mg chondroitin). Patients could use a glucosamine/chondroitin liquid that could replace pills/capsules, but comparative attention should be paid to the caloric content and cost of these newer liquid options. Other novel options include powders or packets that are portable and can be mixed with water produced by numerous companies (Emergen-C^® Joint Health …). Pill count is indeed an issue from my experience with glucosamine and chondroitin as well as omega-3 fatty acids that could be resolved with the latitude in delivery methods now available in the supplement industry.

Omega-3 fatty acids, especially EPA and DHA have preliminary evidence to suggest they may help patients with AIA [27, 28]. For example, mechanistically they can block the conversion of arac hidonic acid to prostaglandin and leukotrienes, which can cause decreases in inflammation. It is of interest that perhaps even an autoimmune-like component or etiology of AIA is plausible based on animal models where aromatase is eliminated and symptoms similar to Sjogrens syndrome occurs. And the preliminary research for omega-3 and even -6 products to reduce dry eye (not dry mouth) for example is intriguing [3]. An older meta-analysis found significant changes in pain, stiffness, painful/tender joints, and NSAID usage with omega-3 supplementation for inflammatory joint pain (not AIA specific but of interest) [27].

A well-done 24-week randomized multicenter placebo-controlled trial (known as “SWOG S0927”) of 240 patients found a 50 % reduction in pain/stiffness in both the 3360 mg/day omega-3 fatty acid group as well as the placebo group (soybean/corn oil) [29]. Triglyceride levels were significantly reduced (−22.1 mg/dl) in the omega-3 group versus no change in the placebo arm (p = 0.01). Patients utilized six capsules per day and each omega-3 capsule contained 560 mg of EPA plus DHA in a 40-to-20 ratio (Ocean Nutrition, Dartmouth, Nova Scotia, Canada). However, why no difference could be found may also have to do with the choice of a potential anti-inflammatory placebo or simply lack of efficacy of omega-3. Regardless, the question needs to be raised that a 50 % improvement may still be an option with these supplements but the choice of six capsules a day appears excessive in my opinion and patients could use a children’s flavored omega-3 liquid that only requires multiple teaspoons a day or 1–2 tablespoons and no pills/capsules. Again, it would be of interest for future clinical trials to utilize more realistic and easier to ingest delivery systems in the future since they are available to the consumer and clinician now.

Thus, plain old cheap fish oil (from sardines and anchovies and/or mackerel) with the two active ingredients (EPA and DHA) have preliminary positive data for overall joint health, but so does Krill oil now and even New Zealand Green Lipped Mussel [3]. And all these companies claim that their omega-3 product is somehow different than the competitors but in my opinion this is not based on strong evidence! Omega-3 compounds from anchovies, krill or green-lipped muscle (Perna Canaliculus) are going to be structurally similar and maybe some may require higher or slightly lower dosages or smaller pills. I tell patients to first purchase the lowest cost product and see if it helps. Most companies that sell cheap fish oil have been able to concentrate their pills so all you need is 1–2/day or if you cannot take a fish oil pill buy a flavored children’s liquid supplement as mentioned earlier. In fact, about one teaspoon (5 ml) per day will give you over 1000 mg of the active ingredients (EPA and DHA) in fish oil in many cases. So, fish oil at 1000–2000 mg/day of the active ingredients (EPA and DHA) has preliminary evidence in the veterinary and human world that it may reduce aches and pains in the joints. Higher doses might even work better but this should receive more research. Some Krill oil enthusiasts would argue that one tiny Krill oil pill also has “phospholipids” and some data to suggest that are as bioavailable as a much higher dose of fish oil so the price difference works out to be the same. This sounds interesting but until a head-to-head longer study with relevant clinical endpoints is made, it is more theory compared to fact. If a patient has a shellfish allergy keep in mind that Krill is also a shellfish folks. Prescription omega-3 oil in my opinion is of questionable value compared to over the counter brands. This is due to the general use of tiny fish such as anchovies and sardines that do not live a long life and have plenty of omega-3 then they are going to have little to no mercury and most other contaminants (many of those are water soluble are not carried with the final oil product)! So, in this case the smartest business move for the fish oil business turned to provide an unexpected quality control advantage for the consumer! Additionally, in another area of arthritis known as “rheumatoid arthritis” that is a chronic inflammatory disease of the joints and bones there has been a consistent modest benefit for fish oil on pain and joint swelling, morning stiffness, and the ability to reduce the amount of conventional pain medication usage. It is this kind of track record that has to allow for the benefit of the doubt when it comes to this supplement for arthritic pain and as a potential option for some AI patients. If a patient is experiencing gastrointestinal problems (like nausea, diarrhea, or discomfort) or any skin abnormalities (itching, eruptions, allergies) or easy bleeding then your fish oil dose it either too high and switching to an enteric-coated option (if primarily GI issues) or a different product should be considered.

The vitamin D deficiency theory, or even the potential suggestion that vitamin D could significantly imp rove joint or muscle issued from AIs is intriguing, and has indirect but not consistent direct clinical evidence [28, 30]. Vitamin D deficiency and insufficiency is common in women taking AIs. Proximal muscle strength could improve with vitamin D, estrogen increases the conversion of inactive to active vitamin D and activates the vitamin D receptor. Preliminary research suggests higher blood levels of vitamin D with or without supplementation are associated with a lower risk of joint pain from Ais [30, 31].

And in the still yet to be published (since the publication of this text) randomized VITAL trial (Vitamin D for Arthralgias from Letrozole), 160 postmenopausal women with a blood vitamin D level less than 40 ng/ml received 30,000 IU oral vitamin D3 weekly for 24 weeks or placebo. Approximately 38 % of the women on vitamin D reported an increase in pain compared to 61 % of the controls (p = 0.008) [32]. Still, peer review and more rigorous investigation are needed to prove absolute cause and effect. The good news for patients is that these vitamin D interventions can be attempted to improve AI compliance in some benefits with the benefit exceeding the risk for most.

Vitamin D3 has been suggested as a treatment for AIMSS, but again no rigorous trials of more moderate dosages of vitamin D have been conducted until recently (US study—Minneapolis and Washington, DC) [33]. A total of 113 postmenopausal women ingesting 600 IU D3 (n = 56) or 4000 IU D3 (n = 57) for 6 months was conducted and after this time the 25-OH vitamin D test was 33.8 ng/ml for the low-dose versus 46 ng/ml for the high-dose group. And no difference was found for AIMSS or other measures such as pain or stiffness between groups.

What appeared to be complicating matters are several issues including the potential for 25-OH vitamin D to potentially function as a negative acute phase reactant [34]. A recent systematic review of eight relevant studies found that six demonstrated a drop in blood levels of vitamin D with an initial inflammatory insult and in another study there was a suggestion of hemodilution with no impact on inflammation [35]. Regardless, there is sufficient preliminary data to suggest 25-OH vitamin D can act as a negative acute phase reactant and could also be reduced with multiple other patient parameters such as weight gain. Thus, the question remains—does vitamin D really ameliorate AIA or do individuals with greater health parameters and a higher probability of having a sufficient vitamin D level (with or without supplementation) give the perception that vitamin D is effective when in reality it is the health status of the patient that really determines outcome (not vitamin D supplementation)?! This needs to be addressed and may explain some of the negative findings in other clinical trials outside of breast cancer.

It is of interest in osteoarthritis that in a 2-year randomized trial of a moderate dosage (2000 IU/day increased serum levels 16 mg/dl) of vitamin D in individuals with a baseline BMI of 30 and 25-OH vitamin D of 22 ng/ml was not helpful [36]. Higher dosages, especially in overtly deficient patients (10 ng/ml or less for example) are needed to resolve some of the issues as to who are the best (if any) candidates for vitamin D supplementation in regards to joint and muscle issues.

There are a plethora of osteoarthritis dietary supplements that theoretically could be tested and utilized for AIA, but have not received adequate attention in this area [3, 37].

Over the counter joint creams or gels such as capsaicin (ingredient from the hot pepper plant that makes it “hot”) see m to work real well for hand arthritis, and for the knee, but not very well on the hip because that joint is too deep in the body to be impacted by the topical cream. In at least five double-blind randomized clinical trials participants used 0.025 % capsaicin four times daily for 4–12 weeks. In other trials 0.015 % capsaicin was applied once per day for 6 weeks and 0.075 % four times daily for 4 weeks. In all of these clinical trials (especially 0.025–0.075 % up to four times a day) capsaicin was found to be significantly more effective in improving pain compared to placebo. It appears that the longer the study, the greater the reduction in pain severity and benefit. Redness and burning sensation are common because of the way this herbal topical works and it should be applied with gloves to the site of concern and that area covered if possible to preventing spreading of this substance to sensitive areas (especially eyes, mouth, …). Capsaicin has also become a well-documented conventional option for painful diabetic peripheral neuropathy [38], and even can be obtained as a higher strength (8 %) prescription patch option that has efficacy against HIV neuropathy and post-herpetic neuralgia [39]. Thus, with all of this background and evidence with over the counter or prescription strength capsaicin where is the research on AIA? There is even some preliminary evidence for topical capsaicin to improve post-mastectomy pain syndrome at a concentration of 0.025–0.075 % [40, 41]. And there appears to be far greater interest in the potential antitumor effects of capsaicin (via apoptosis induction) [42] versus AIS. Capsaicin may have some of its own arom atase inhibitory potential from preliminary basic science research [43]. Still, most AI-related symptoms or arthralgia appear to impact the joints close to the skin such as wrist/hands, ankles/feet, elbows, and knees more often [44], which is precisely where topical capsaicin could provide the most benefit. It would be of interest even if a case study or case series could be published to help resolve this issue and whether it could be helpful or harmful. Unfortunately no initiated or ongoing clinical trials of capsaicin and breast cancer could be found at the clinical trials.gov website. Capsaicin dietary supplement pills are also available now but have no adequate research in the area of arthralgia.

Curcumin (diferuloylmethane) is a yellow coloring agent/pigment that is derived from turmeric (Curcuma longa), and it is a spice comm only found in curry powders, and appears to have been crowned the king or queen of anti-inflammatory agents by so many pseudo experts. What it needs, are more clinical trials ASAP [3]. Of course I am excited about the preliminary data that curcumin can reduce the pain of OA [45, 46], but with such a crowded field of potentially beneficial supplements “you have to earn your way into this crowd” if what I often cite to patients. And very high doses of curcumin in some studies have the ability to create abdominal fullness and pain, and the bioavailability of this supplement is not good and needs assistance (another molecule attached to it for increased absorption) [3]. It is for this reason an even cursory view of the medical literature will suggest that a variety of commercialized highly bioavailable curcumin powders mixed with other ingredients might have efficacy against arthritis or joint issues.

Curcumin has receive d some phase I research as a potential synergistic agent with chemotherapy for breast cancer and it also receives numerous clinical reviews [47, 48], but it is in need of effective clinical trials. Perhaps, most of the interesting work thus far has been published in pancreatic cancer where higher doses have been utilized (8 g) with chemotherapy and no patients, among 18 in one trial, experienced a partial or complete response but it appeared that median survival time could have been increased compared to retrospective controls so more study is needed [49]. Another small study of advanced pancreatic patients (n = 17) needed to lower the 8-g curcumin dose to 4 g because of abdominal complaints and efficacy appeared “modest” with only one potential partial response [50]. Another issue here is simply the sheer number of pills (16 or more) used in these clinical trials. This needs to be resolved for research to realistically continue along with some more impressive clinical data.

S-adenosylmethionine (SAM-e) is a nutritional supplement that has received a lot of attention recently in the USA beca use it is widely used in Europe for a variety of conditions especially osteoarthritis and depression (see depression section) [3]. SAM-e is a naturally occurring sulfur-containing compound produced from the amino acid l-methionine and adenosine triphosphate (ATP). Researchers are not sure how it can control pain but it does play a primary role in several pathways in the body including transmethylation, transsulfuration, and aminopropylation, which basically suggests it could impact multiple physiologic locations where it can help to ameliorate pain. SAM-e was actually brought into the USA in 1999 as a dietary supplement to improve joint health. In Europe it is a prescription drug in some countries and it is also given as an IV drug.

A recent review of numerous clinical trials of SAM-e compared to placebo or NSAIDs (most over the counter pain relievers and some prescription anti-inflammatory medications including Celebrex) concluded that the existing evidence points toward at least an equal efficacy of this supplement for osteoarthritis compared to NSAIDs and with a lower rate of side effects—in fact those taking SAM-e were almost 60 % less likely to experience a side effect compared to NSAIDs [51, 52]. SAM-e appears to have a slower onset of action for pain reduction but by the end of the first or second month of use the efficacy is again similar to over the counter and many popular pain medication.

SAM-e may help to build one component of cartilage based on some laboratory (not human) studies [3, 51]. More clinical studies are always needed especially again popular prescription medication and a placebo. The effective dosages have ranged from 600 mg to 1200 mg/day for at least 30–90 days usually on an empty stomach. Lower dosages of SAM-e did not use pills but were given IV (400 mg) in other countries. The amount of time SAM-e was tested in clinical trials was from 10 days to 3 months. The most common duration of treatment was 30 days, which means that overall SAM-e has not been tested in a long-term study (6–12 months). The average amount of time individuals were suffering from OA before receiving SAM-e was almost 6 years. SAM-e may reduce morning stiffness, swelling, pain at rest and in motion, and improving range of motion and walking ability and could even reduce the popping or cracking sounds associated with OA. More safety data are needed with these supplements and they are not low-cost. An older concern with SAM-e is that it may increase blood levels of homocysteine, which may be an indirect marker of cardiovascular risk and some doctors recommend taking B-vitamins (B6, B12, folate) with SAM-e but recent studies show this is not as much of an issue and maybe a non-issue [3].

Taking both NSAIDs and SAM-e is a possibility based on safety but has not really been studied. SAM-e has been studied primarily for knee osteoarthritis and some studies of hip and spine osteoarthritis but whether or not pain reduction in other locations can occur with SAM-e is not known. Finally, the biggest side effect of SAM-e in my experience is prohibitive cost because SAM-e can be more expensive than most over the counter pain medications. A review of lower cost retail sources (national pharmacies and shopping chains) could provide a more realistically priced SAM-e. Thus, the consistent preliminary efficacy of SAM-e in osteoarthritis would suggest this could have some efficacy in other areas such AIS, especially since there are anecdotal reports of NSAIDs providing benefits for some patients [30].

Obesity appears to increase bone mineral density (via greater aromatization and increased estrogen) which is a quant itative observation [53], but what about the qualitative aspects of bone health? Recent evidence suggests a challenging novel and now evidence-based theory that weight gain could be detrimental to bone health (not beneficial because of increased aromatase conversion to create more estrogen). For example, a review 8833 abdominal or thoracic CT scans in patients aged 18–65 years old from one major health system found adipose tissue appeared to infiltrate into muscle and bones [54]. Even when these results were adjusted for age, sex, and BMI there were significant correlation between visceral adipose tissue and lower bone and muscle quality. It is possible that weight gain at an early or older age is associated with poor bone quality and less bone formation. This also supports the notion that obesity may be associated with an increased risk of bone fracture. Muscle also surrounded by fat tissue appears to also lower muscle quality.

What are some other benefits of weight loss apart from the potential to increase the qualitative aspects of bone? It appears that despite weight gain being associated with lower blood levels of vitamin D, weight loss could “naturally” increase vitamin D levels. A total of 439 overweight and obese postmenopausal women (mean age 58 years) were assi gned to one of four groups: diet change, exercise, diet and exercise, or control. Diet change consisted of caloric reduction (total intake of 1200–2000 calories/day), and exercise consisted of 45 min of moderate to more high intense aerobic activity 5 days a week [55]. Vitamin D levels were measured at the beginning and after 12 months. Individuals that lost <5 %, 5–9.9 %, 10–14.9 %, or ≥15 % of their initial weight experienced significant increases in vitamin D blood levels of 2.1, 2.7, 3.3, and 7.7 ng/ml. Lower or higher baseline blood levels did not have an impact on the effectiveness of the interventions for weight loss. So, the researchers concluded that weight loss via caloric restriction or exercise could potentially increase vitamin D levels without ingesting more of this supplement.

A 1-year randomized trial of aerobic and resistance activity three times a week (45–60 min) in breast cancer survivors, including 40 % on aromatase inhibitors (AI), preserved bone mineral density (BMD) at the lum bar spine versus controls (0.47 versus −2.13 %; p = 0.001) [56]. Interestingly, the increases in lean mass were actually higher in women on AI versus controls not on AI (p = 0.01). One theory is higher free testosterone found in women on AI could improve muscle response. A previous smaller 6-month randomized trial found that 150 min per week of exercise that included brisk walking could also maintain BMD in postmenopausal breast cancer survivors [57]. Clinicians should emphasize some form of upper- and lower-body resistance activity to enhance bone and muscle effects. A series of exercises from a variety of past studies in breast and prostate cancer effective trials were culled and placed in 178 [1, 3]. Table 7.1 is not intended to have a patient following this specific program 2–3 days a week but rather review the diverse upper- and lower-body exercises used in past studies. Whether or not a patient and clinician choose 2 or 3 upper- and lower-body exercises from the list (as I recommend) is between the patient and clinician. Again, the list is not intended to be the exercises conducted at one time but rather to include a few of these in an individualized regimen.

The Women’s Health Initiative (WHI) was a double-blind, placebo-controlled clinical trial and the largest to addr ess the issue of calcium and vitamin D supplementation [58, 59]. This trial included 36,282 postmenopausal US women to 1000 mg elemental calc ium carbonate plus 400 IU of vitamin D3 (OsCal^®, GSK) or placebo for 7 years. The mean BMI was 29 and there were a greater number of obese vers us overweight women in the trial, which interestingly appears to reflect the current US population. The primary endpoint was the reduction in hip fractures, and secondarily total fracture and colorectal cancer. Calcium and vitamin D supplementation significantly increased hip and total bone mineral density (BMD) versus placebo (p < 0.01), but there was no overall evidence to suggest a reduction in hip or total fracture risk. However, among women compliant with the supplements (80 % or more utilization) there was a 29 % reduction in hip fracture risk, but this relationship cannot be accepted as solid evidence compared to an intention-to-treat analysis. In addition, further analysis found those not taking personal calcium or vitamin D supplements at baseline experienced a significant reduction in the risk of hip fracture (−38 %). There was an increased in kidney stone risk and there were no impacts on cardiovascular event or colorectal cancer risk but there was a suggestion of a reduction in breast cancer risk and total invasive cancer risk. This largest study of its kind continues to suggest that normalization or increased calcium and vitamin D supplementation could improve bone mineral density and reduce hip fracture risk [60].

A recent extensive analysis of the calcium and vitamin D supplementation data from the US Preventive Services Task Force found treatment of vitamin D deficiency in some asymptomatic person might prevent falls (not fractures) [61, 62]. And concluded their other findings the following way:

“Treatment with vitamin D, with or without calcium, may be associated with decreased risk for mortality and falls in older or institutionalized adults. Vitamin D treatment did not reduce fracture risk …” This is a critical initial finding from the research, which in my opinion also suggests breast cancer patients should normalize their calcium and vitamin D intakes to maximize the benefits of bone loss prevention and especially falls, which could lead to an increased risk of fractures. And there is enough evidence from these past reviews of the data that calcium and vitamin D are also integral for muscle health and coordination.

Additionally, most major trials of drug interventions to prevent bone loss and fractures in breast cancer patients, including denosumab and zoledronic acid, utilized some form of calcium (1000 mg/day) and vitamin D supplementation (400 or more IU per day) or normalization of intake to ensure adequate responses to these bone medications [63, 64]. Thus, when these drugs received FDA approval in breast cancer it was due to phase 3 trial evidence of the drug and calcium and vitamin D in combination (not by itself).

There are a vari ety of types of calcium supplements on the market if truly needed. It must first again be kept in mind that countless foods and beverages are now fortified with more calcium than milk (some almond milks have 455 mg per 8 ounces for example) [3]. Thus, it is easier than ever to reduce or eliminate calcium supplements. However, if a calcium supplement is needed it is important to understand the benefits and limitations of each when deciding on the right one. Table 7.2 is a summary of those benefits and limitations [1, 3].

Vitamin D2 (ergocalciferol) versus Vitamin D3 (cholecalciferol) also appears to be debated by experts on a regular basis. However, there are a few critical thoughts and observations in order to decide the appropriate personal choice and these are found in Table 7.3 [3, 65–72].

One large randomized trial can highlight the change in philosophy that should occur with integrative medicine and hormone suppressive bone loss. A large 3-year trial of denosumab given every 6 months (n = 734) compared to placebo (n = 734) in men receiving androgen deprivation therapy (ADT) for non-metastatic prostate cancer was published [73]. Participants were instructed to utilize 1000 mg or more of calcium and 400 IU of vitamin D. This represents one of the first long-term randomized studies to provide the placebo arm with re alistic and relevant dietary supplementation options. Median serum vitamin D levels at baseline were approximately 24–25 ng/ml, and increased to 31 ng/ml (normal range) after 36 months. Only 14–15 % of participants began the trial with osteoporosis (T score below −2.5) at any site, and the median time on ADT at baseline was 20–21 months. The primary endpoint was the percent change in BMD at the lumbar spine at 24 months, and secondary endpoints included percent change in BMD at the femoral neck and total hip at 24 months and at all three anatomic locations at 36 months, along with incidence of new fractures. After 24 months there was a significant loss in lumbar spine BMD at 24 months in the placebo group, but this loss was just 1 %, and minimally changed at 36 months. There were also significant reductions in femoral neck and total hip, but this loss was only 2–3 % at 36 months. The largest percentage of bone loss occurred in the distal radius. Fracture at any anatomic location was lower with denosumab compared to placebo, but the difference was not found to be statistically significant at 36 months. No significant differences were found in the time period to first fracture (non-vertebral or vertebral) between the groups. The authors reported that more than one fracture at any location occurred in significantly more patients on placebo compared to denosumab, and a significantly higher rate of vertebral fractures. Yet these were secondary endpoints, and more participants in the placebo group had a history of vertebral fracture (+2.6 %) and a history of osteoporotic fracture (+4.5 %) at baseline. The 36-month clinical difference of 2.4 % more new vertebral fractures (3.9 % versus 1.5 %) in the placebo group cannot be due to the intervention alone, but may also have been due to the slight inequality between groups as it related to vertebral and overall fractures at baseline in favor of denosumab. The difference between most clinical endpoints for the calcium and vitamin D group compared to pharmacologic treatment was minimal at 36 months. Furthermore, a less than 4 % total fracture percentage in the placebo arm (versus 1.9 %) over 3 years is low considering that no aggressive lifestyle and supplemental preventive therapy before ADT was initiated. How much difference would have existed if the placebo group were also assigned to regular resistance and aerobic exercises during this study period or before initiating ADT? Denosumab appears to be an option for accelerated spinal and hip bone loss despite aggressive supplemental intervention, and perhaps for those men that cannot adequately maintain distal radius density with aggressive lifestyle changes. Regardless, a clinical trial of non-metastatic patients on hormone suppression from breast and prostate cancer treatment with adequate calcium and vitamin D status with aerobic and resistance exercise may compare favorably to pharmacologic intervention over 1-year or more. Yet a long-term and more lifestyle and supplement balanced trial has not been conducted. In my clinical experience I have not observed significant differences between breast and prostate cancer patients adopting aggressive lifestyle and supplement measures versus prescription medications for osteoporosis unless the patients was also on steroid treatment. Again, this has not been tested in a clinical trial.

Interesti ngly, an 18-month randomized trial of 180 healthy men aged 50–79 years allocated to exercise (resistance training 3 days a week) with and without fortified milk (1000 mg calcium and 800 IU of vitamin D) consumed daily was conducted [74]. Exercise increased femoral neck 2.1 % and improved lumbar spine (LS) trabecular BMD 2.2 % with no effect on mid-femur or mid-tibia BMD. No primary effects of fortified milk occurred at any skeletal site, which suggests exercise alone could have profound effects in excess of what supplementation provides. The results of this unique trial in men with baseline calcium intakes of 1000 mg/day and vitamin D blood levels of approximately 35 ng/ml suggests that individuals replete with this nutrients may allow for an optimal skeletal response to exercise as noted by the authors.

Of even greater interest for women was a similar multicomponent 19-month randomized trial in women 65 years and older (n = 246) observed significant 1–2 % benefit at the femoral neck and lumbar spine and a reduced risk of falls [75]! All participants were provided with 1500 mg of calcium and 500 IU of vitamin D3 supplements per day (Opfermann Arzneimittel, Wiehl, Germany). This trial was known as the Senior Fitness and Prevention (SEFIP) study.

A recent 2-year randomized trial of placebo, 800 IU of vitamin D3 (provided by Oy Verman Ab-Kerava, Finland), exercise, and vitamin D and exercise (4-arms trial) in Finland of 70–80 year old home-dwelling women (n = 409) found that the rate of “injurious falls and injured fallers” was reduced by 50 % with strength and balance train ing while 800 IU of vitamin D daily alone despite not impacting the rate of falls maintained femoral neck BMD and modestly increased tibial trabecular density [76]. The baseline intake of calcium and vitamin D was approximately 1100 mg/day and 400 IU and 25-OH vitamin D baseline was 27 ng/ml suggesting that women in this trial were already replete with calcium and replete or almost replete with vitamin D.

And a past 10-month trial in Chi nese postmenopausal women with low calcium intakes (less than 275 mg/day) when given 800 mg/day of calcium supplementation improved the impact of resistance bearing exercise on femoral neck BMD [77]! Again, suggesting the optimal benefits of exercise or synergy occur with normalization of calcium and vitamin D status (not excessive intakes).

The preliminary cumulative observation provides part of the reasoning of a “dream” trial in breast cancer with aggressive lifestyle changes and supplements versus prescription medications to prevent osteoporosis. Additionally, the cardiovascular, metabolic, psychological, and overall qualify of life benefits would arguably be far more impressive than the comparative pharmacologic intervention, and if needed would only serve to enhance the pharmacological product (3–4 arm trial ideally). Another unique trial utilizing a vibratory plate should only further increase the interest in exercise for bone health for patients.

Several few years ago I began to notice what looked like a large circular metal plate that you are suppose to stan d on and it vibrates at various speeds in order to improve your bones or BMD and reduce your risk of osteoporosis. And after a few more months I began to see these “whole-body vibration (WBV)” therapy machines in most very high-end (aka “expensive”) health clubs. The idea behind these machines seems logical, since the skeletal system similar to the rest of our bodies operate on a “use it or lose it” scale.

Whole bo dy vibration machines are costly (thousands of dollars), thus evidence was needed to justify cost. Some machines allow for more vibration compared to others, so that the intensity of WBV is expressed by vibration frequency (1 Hz = 1 oscillation/s). A research group from Toronto set up a 1-year randomized control trial of low-magnitude WBV at two frequencies (30 Hz and 90 Hz) compared to no WBV [78]. A total of 202 healthy postmenopausal women (average age of 60 years, 95 % of women did not smoke) with osteopenia and not receiving prescription bone drugs for osteoporosis were included in this study. Participants were placed in one of three groups that allowed them to stand on WBV platform for 20 min daily at one of two frequencies (first two groups), or not use the WBV device at all (group 3—control group). All of the groups were requested to utilize calcium and vitamin D supplements, so that their total daily intake from diet and supplements was approximately 1200 mg calcium and 1000 IU of vitamin D daily. This is important because many past studies of WBV did not have participants take calcium and vitamin D. However, after 12 months there was no difference in bone density changes between the WBV groups (high or low frequency) compared to the control group at any bone site measured in the body, which included the spine, hips, legs, and wrist. In fact, the group that just took calcium and vitamin D supplements had a similar outcome to the WBV groups! Interestingly, there were no differences in side effects reported among the groups, but three participants stopped WBV therapy within 60 days because of dizziness at night, shin pain, and foot pain. Other mild and temporary side effects reported included pain, numbness of feet, or weakness at different leg sites (five participants in WBV) group; nausea (two participants in WBV); worsening of headaches, bladder discomfort, inner ear sensitivity, or neck pain (one participant in WBV). The researchers also did an analysis on lower leg bone (tibial trabecular area) structure and found that some women seemed to achieve a slightly worse outcome with the WBV. However, in all fairness, overall the results were not different and the side effect rates were similar. It appears that the WBV groups in my opinion did not fare better compared to the control groups because these postmenopausal women were healthy in terms of overall lifestyle (mean BMI of 24, minimal alcohol intake, 380+ calories expended per day from exercise, nonsmokers primarily, 1350 mg calcium and 800 IU vitamin D baseline intake, …). Perhaps WBV will have more success in those with spinal cord injury and elderly frail individual or even specific children in need of this assistance [79]. Additionally, data in breast cancer is minimal [80], but it would be more optimal to test this therapy for lymphedema because patients have mentioned over time it appears to be of some benefit but this has not been studied. Regardless, when maximizing lifestyle changes it is not easy to provide results from a device or intervention that are far superior to these methods.

There are many dietary supplements that are touted to work better or as effectively as calcium and vitamin D [3]. However, since calcium and vitamin D are not needed in excessive dosages and can now be derived pri marily in realistic quantities from food/beverage and multivitamin sources what else is really needed apart from lifestyle options and pharmacologic interventions if really needed? Omega-3 supplements have a randomized trial being initiated in breast cancer patients to determine if they can improve lean body mass (LBM, for example MODEL study) and even preserve BMD, so there is not enough evidence to suggest a benefit or not at this point.

Strontium citrate supplements have been touted and it appears based on the results with the prescription oral drug strontium ranelate they could provide some benefit. However, the drug strontium ranelate is now being questioned because of an increased potential risk of cardiovascular events including a 60 % increased risk of myocardial infarction [81, 82]. Since strontium citrate and ranelate could theoretically have overlapping mechanisms of action [83], it would be prudent to not recommend strontium citrate or any strontium dietary supplements for bone loss or to breast cancer patients.

The only other dietary supplements that theoretically could provide some value currently and is being tested are vitamin K1 and K2 supplements. The overall data on bone markers and fracture risk is still embryonic and inconsistent [84]. And the long-term safety issues of ingesting high-dosages of vitamin K have not been established. For example, K2 is recommended in dosages as high as 45 μg and dosages as low as 10 μg could offset the effect of vitamin K antagonist prescription anticoagulation [85]. Increasing rates of cardiovascular disease (CVD) with age and those placed on prescription anticoagulants suggest a clear benefit over risk needs to be established with vitamin K1 or K2 in women and men before it could be considered as an adjunct to bone loss prevention. Thus, it would appear prudent to continue to follow the research before recommending large dosages of vitamin K for osteoporosis and fracture prevention.

Whey protein and other powders are the most concentrated protein sources available commercially with little to no su gar and aid with weight loss, and muscle development [3]. A protein powder with no sugar, no lactose, and over 20 g of protein for about 100–125 calories easily surpasses what could be found nutritionally in most protein bars. Compliance with protein intake is more important than time of day of ingestion and 14 randomized trials (n = 626) reviewed have found the ability of whey protein to enhance or act synergistically with muscle protein synthesis produced from resistance exercise and to act as a weight loss supplement [86]. Body weight in eligible studies was reduced by −4.20 kg and body fat by −3.74 kg when within group analysis was conducted and the increase in lean body mass was 2.24 kg (all significant). However, this meta-analysis does not appear to support this form of protein powder over others, and I agree [3]. Ongoing and recent trials continue to demonstrate benefits [87], although a large trial in breast cancer patients is needed.

The current maximum intake of protein per day is body weight in pounds divided in half to equal maximum intake (150 pound person should get a maximum intake of 75 g of protein per day), which is not an easy task and protein powder can assist with this goal [3]. It appears that all types of animal-based (whey, casein, egg white, …) and plant-based (soy, pea, brown rice, hemp, …) could all be effective but apart from soy protein powder the plant based protein powder have suboptimal taste when mixed with water unlike animal based protein powders and this could cause a compliance issue.

Chocolate milk can contain 200 calories or more while whey or soy is about 100 calories. And chocolate milk has less than 10 g of protein while whey/soy contains around 20–25 g of protein! Chocolate milk has about 30 g of carbohydrate and simple sugars (27 g in one serving—in many cases as much as a full calorie soda) and whey and soy isolate have little to no carbohydrates and fat and a low sodium content and can function as an appetite suppressant. Thus, for the average exerciser trying to combat weight loss it does not appear to be the best option. However, the 4:1 carbohydrate to protein ratio (identical to commercial athletic beverages) is a good option for endurance workouts or high-intensity regimens where muscle glycogen concentrations are compromised and adequate muscle recovery from fatigue is required on a regular basis [88]. Arguably, another common compound, caffeine, utilized in moderate dosages (coffee, tea, other beverages) has increasing evidence as a compound that improves glycogen storage potential, reduces muscle fatigue and enhances exercise regimens so I often mention this in a consult (“few sips of a beverage before, during and after a workout”) [3].

Creatine monohydrate has minimal long-term data in elderly individuals but it appears to be synergistic with resistance exercise from dosages as high as 20 g/day by improving lean muscle mass and function [89]. A small meta-analysis of older adults (n = 357, mean age 56–70 years, dosages generally from 3 to 5 g/day) from ten studies found that it could significantly increase fat-free mass and increase the performance of some resistance exercises [90].

Note: Please see Chaps. 3, 4, 5, and 6 (statins, aspirin, and metformin) for detailed information on the preferred options.

Note: Please see Chap. 3 on lifestyle changes and the different forms of fiber and please see the hot flash section of this chapter and the results with magnesium dietary supplements. In addition, diarrhea was not treated as a separate topic since the conventional options with this side effect from cancer treatment should be the primary option. In the future, the data with antibiotic associated diarrhea (AAD) and probiotics (Lactobacillus, Saccharomyces, …) could be an option in cancer patients but the majority of the data now has been for Helicobacter pylori eradication [3]. There have been some rare causes of sepsis from probiotics (bacteremia/fungus/positive blood cultures …) that must be addressed and benefit needs to greatly exceed risk for this medical condition.

Unfortunately, exercis e is often advocated as having mild or moderate changes in those with depression from the clinical research, or there appears to be a tone of indifference when reviewing the entire research. For example, in an extensive review of 39 clinical trials involving 2326 participants exercise was found to be “moderately more effective than a control intervention” and in more robust trials only “a smaller effect in favor of exercise” [91]. Still, in this same publication the authors point out that “exercise appears to be no more effective” compared to pharmacologic or psychological therapies! The consistent findings with exercise even as a potential treatment option is what is most striking and it is an intervention that combats overall disease morbidity and mortality.

Recently, it was more lucidly explained that the majority of clinical studies (13 out of 16) with exercise demonstrated a 5-point improvement on average compared to prescription medication for depression with an average of a 2–3 point improvement over placebo [92]. Thus, this is not an indication to abandon conventional medicine in favor of exercise but rather the potential synergism of these two agents. In fact, there are notable past clinical trials where exercise not only enhanced the response of notable FDA approved prescription antidepressants agents and increased the likelihood of remission [93].

Exercise also appears to be as effective as conventional treatment in patients being monitored for different disease conditions that experience a higher rate of depression [94]. And the beneficial effects occur with only three times a week of activity and within the first 4 months. For example this is what was found in the UPBEAT (Understanding the Prognostic Benefits of Exercise and Antidepressant Therapy) study, which included patients with heart disease and depression.

Yet one question that is more pertinent to answer in terms of exercise is the impact of the socialization of exercise versus the isolation of exercise. In other words, in many clinical trials there have been trainers or exercise leaders (supervised) working with patients with major depressive disorder (MDD), thus it could also be argued that this socialization or instruction type exercise has a higher probability of being successful versus isolated work outs. This question and the potential contribution of each form of exercise need to be further researched. Some preliminary clinical trials suggest profound effects even with home-based exercise but placebo responses are also high which suggests multiple factors, including more attention given to patients, could have profound impacts [95].

The data with aerobic or resistance exercise in breast cancer patients appears to be more consistent with an overall improvement in energy levels or a reduction in fatigue than with most other subjective parameters [96, 97].

Regardless, one of the most extensive reviews of this research over 25 years in breast cancer utilizing 51 studies found consistent suggestions of objective benefit for body composition, strength, and cardiorespiratory function and subjective benefits including improvements in fatigue, depression, and overall quality of life [98].

C. S-adenosyl- l -methionine (SAM-e—why not if in need of more options?)

The most common dosage utilized in clinical trials of major depressive disorder (MDD) was 800–1600 mg a day, or 400–800 mg twice a day. However, there is a lack of good data in breast cancer patients [3]. Reg ardless, this supplement (actually drug in some countries and also has an IV form) should be reviewed since it has preliminarily impressive data [99, 100]. SAMe is an option with and without conventional antidepressant treatments. SAM-e is a compound that is involved in methylation and improving the creation and utilization of several brain neurotransmitters including dopamine, epinephrine, and serotonin as well as donating methyl groups to membrane phospholipids, myelin, choline, and other compounds commonly found I brain tissue. It has some features similar and different to prescription medications for depression. The overall impact of SAM-e appears similar to other antidepressants. Past systematic reviews have been positive with seven of seven trials using IV SAM-e and four of five studies using oral doses of 1600 mg/day [99, 100]. It was shown more efficacious than placebo and as efficacious to tricyclic antidepressants in three trials. Overall, there was reduction in Ham-D (Hamilton Rating Scale for Depression) scores in four of the five randomized controlled trials of the oral supplement. Still, more data was needed to determine if it could provide a modern day clinical benefit.

A preliminary Harvard study suggested a benefit of SAM-e at 800 mg twice a day when added to conventional drug treatment (SSRI drugs) in individuals that were not responding to SSRI medications [101]. This 6-week study was funded by the National Institutes of Health and included 73 nonresponders and compared to placebo the HAM-D response (36 % versus 18 %) and remission (18 % versus 12 %) rates, low number needed to treat (1 out of 6–7) and discontinuation rate similar to placebo was interesting. Further trials with this group have also found efficacy similar to some standard antidepressants (escitalopram or Lexapro), and in fact nonsignificantly higher response and equal remission rates. However, the SAM-e dosage utilized was higher (1600–3200 mg/day) and side effects occurred in 20 % of the SAM-e group (stomach upset and diarrhea) and interestingly the FDA approved drug and supplement did not statistically beat placebo in this major trial [102–104]. It also appears that men could have experienced a greater response rate versus women but more research is needed in this area.

There has been a concern that SAM-e raises blood levels of homocysteine (a controversial marker of heart disease) but this has really not occurred in more recent studies but patients should still be followed periodically with this blood test [105].

Side effects like gastrointestinal upset and diarrhea can occur but they are rare when using the standard dosages (up to 1600 mg/day) [99, 100]. Other rare side effects that have been reported are: nausea, dry mouth, headache, mild insomnia, anorexia, sweating, dizziness, nervousness especially at high dosages, and it can make some people with depression feel anxious. SAM-e might lead to toxic reaction when used with cough suppressant dextromethorphan, certain antidepressants, or narcotic pain relievers; could worsen symptoms when taken with Parkinson’s drug levodopa.

Regardless, the biggest side effect with SAM-e is the cost (one of the most expensive supplements I have observed in my career for treating a condition), so comparisons on the internet and stores can save a very large amount of money (FYI—in Europe it is a prescription drug that can get covered) [3]. SAM-e also oxidizes quickly in a bottle the expiration date should be reviewed carefully because this is one the only supplements I have observed that really expires at the date is says it expires (pills can change color …), compared to most other pills which you can use up to a year or two after expiration.

Arguably there are two notable preliminary potentially side benefits observed with SAM-e, which is the lack of sexual side effects that commonly occur with many of the conventional prescription antidepressants that did not occur in a recent trial with SAM-e. It appeared to have a positive benefit on male arousal and erectile dysfunction, and further research with women and sexual health should also be investigated from SAM-e depression trials [106]. And again it may be one of the best supplements for pain reduction (600 mg/day) from osteoarthritis (work as well as over the counter pain relievers with less side effects from preliminary studies—see AIA section in this chapter) [3].

SJW or St. John’s Wort at 500–1200 mg/day is commonly recommended in authoritative dietary supplement texts and medical reviews [3, 100]. SJW at a dose of 500–1200 mg/d over 4–12 weeks has been moder ately effective when used as 2–3 divided doses and extracts standardized to contain 0.3 % hypericin—the active ingredient (the most common dosage in clinical trials was 900 mg/day). SJW is an extract of the plant Hypericum perforatum, which is a yellow-flowering perennial herb fou nd in temperate areas worldwide. It was actually a recorded medicinal compound in ancient Greece and has been used in Europe for depression as an IV and oral medication since the 1980s. The exact mechanism of action has not been elucidated but it appears to block serotonin uptake and alters levels of multiple brain neurotransmitters including dopamine, norepinephrine, and gamma-aminobutyric acid (GABA). Side effects have been low or rare in clinical trials, but critics have mentioned that SJW has the potential to interact or reduce the effectiveness of almost half of the available prescription drugs including the birth control pill and this is true. And SJW should not be combined with prescription antidepressants including SSRIs, Tricyclic antidepressants (TCA), or monoamine oxidase (MAO) inhibitors. It should also be avoided in those individuals on specific drugs such as immunosuppressants, antiretrovirals (anti-HIV drugs), blood thinners like warfarin, oral contraceptives, chemotherapy drugs. Still, SJW is often inappropriately tagged as being the supplement that should rarely be utilized in patients because of its potential drug interactions, especially its ability to induce CYPs and P-glycoprotein, thus reducing the concentration of another drug’s active ingredient as mentioned above. Yet it still has a role in clinical medicine [107].

Many individuals and doctors still utilize it as a single agent or monotherapy. A notable past Cochrane review of 29 past trials with approximately 5500 patients found it may work as well as conventional antidepressants and participants were 50–75 % less likely to drop out of a clinical trial compared to a prescription antidepressant and concluded with the following statements that St. John’s wort for major depression is [108]:

Currently, most objective reviews of St. John’s wort for depression continue to suggest it is arguably an integrative medicine with perhaps the strongest evidence for depression [109]. Some alternative “experts” comment that SJW works as well as most conventional drug options for depression and that is not accurate because many of the positive head-to-head clinical trials were with older prescription drugs that are not commonly used today.

Side Effects of SJW include: Insomnia, vivid dreams, anxiety, dizziness and can cause skin to become sensitive to the sun [3].

Several preliminary clinical trials have demonstrated a potential for benefit in breast cancer survivors even when also utilizing tamoxifen [110]. An ethanolic extract of St. John’s wort extract (900 mg three times a day, extract standardized to 0.3 % hypericin extracted in 50 % ethanol and tablets taken at mealtime) versus placebo showed a nonsignificant benefit in a reduction of hot flash frequency and hot flash scores. There were significant benefits observed with menopause-specific quality of life (p = 0.01) and reduced sleep problems (p = 0.05) and 26 of the 42 patients were breast cancer survivors. More primary endpoint depression trials with this herb in cancer patients of course are needed. Some cancer drugs are reduced more than others in efficacy such as imatinib and irinotecan, and regardless caution does not be followed when combining this product with any cancer medication [111].

E. Miscellaneous—Omega-3 Supplements have bias, folate or perhaps l-methylfolate at 15 mg/d for SSRI-partial/nonresponders? Chromium? Inositol? Rhodiola? 5-HTP?

Omega-3 supplements have a mixed and modest history at best for preventing or treating major depressive disorder (MDD). A meta-analysis of 13 randomized, placebo-controlled trials of 731 participants and found no significant ben efit over placebo [112]. In addition there was significant heterogeneity and publication bias. There was an increasing pattern of omega-3 fatty acid effectiveness in trials of lower methodology, shorter duration trials, greater baseline depression severity trials and trials that did not use intention-to-treat analysis but completers only for data. More recent clinical trials of either 1000 mg EPA or 1000 mg DHA per day for 8 weeks versus placebo in MDD patients (n = 196, 53 % female) found no benefit over placebo [113]. If omega-3 were to assume some role for depression there appears to be some preliminary recent data to suggest they may augment the response to an SSRI medications [114, 115]. Future better studies to access the impact of these supplements alone or compared to prescription antidepressants are being conducted (for example “The Beyond Ageing Project Phase 2”) [116]. In the meantime, the reader should see the section on hot flashes or follow the data on omega-3 in breast cancer for other side effects for treatment because these can provide an additional insight into the cognitive or antidepression effects (or not) of omega-3 supplements. Overall, these effects thus far have been modest at best.

Folate has had minimal eff ects in past randomized controlled trials (small reduction in HAM-D scores) [100], but the more bioavailable or the active form known as “l-methylfolate” at a dosage of 15 mg/day has shown some preliminary clinical promise (32 % response rate versus 15 % with placebo and similar side effects) in SSRI partial or nonresponders that should receive more investigation [117]. A dosage of 7.5 mg/day of l-methylfolate in this same trial was not effective. l-methylfolate is also the only form of folate that crosses the blood–brain barrier and it also has a regulatory role for a major cofactor for neurotransmitter production known as “tetrahydrobiopterin” or BH4. And BH4 is also need for several enzyme systems required for the production of the neurotransmitters serotonin, dopamine, and norepinephrine. Thus, low levels of l-methylfolate could theoretically lead to low concentrations of brain neurotransmitters.

Other dietary supplements being investigated for more specific types of depression include chromium for atypical depression and seasonal affective disorder, inositol in combination with mood stabilizers for the treatment of bipolar depression, Rhodiola rosea for lethargic or asthenic depression and in combination with conventional medications could reduce some of their adverse effects, and 5-hydroxytryptophan (5-HTP) to improve the concentration of serotonin in some patients should also receive more attention [118]. Other alternative agents/methods such as acupuncture have not demonstrated consistent efficacy [100].

All of the above me dical conditions have minimal to moderate effective sufficient evidence-based options especially in the area of dietary supplements and integrative medicines.

There are arguably some lifestyle options that have some moderate data that should be mentioned [3]. Diets higher in omega-3 fatty acids from fish and plants have shown a potential to reduce the risk of dry eye. Interestingly, consuming fish such as tuna several times weekly has been associated with a lower risk of dry eye. Keep in mind that these were diet studies of preventing dry eye and not treatment. Again, for the most part they support was is supported in the area of dietary supplements. Blinking produces Meibum (secretions) because the ever so tiny muscles squeeze the glands around the eyes. Try full blinks when at the computer for a long time and squeeze eyelids together for several seconds every 15–20 min. Eye movements from side to side and up and down (eye yoga) also helps. Sunglasses protect the eyes especially from wind that can cause tears to evaporate quickly and cause inflammation. Eyeglasses used regularly help to discourage the evaporation of tears and just improve vision. If dry air is a problem so purchase and use a humidifier (40–50 % in your living environment) or do more blinking exercises on airplanes. Avoid smoke, pollutants or anything that can irritate the eyes. Better contact lens care is helpful especially taking a break and wearing glasses every few days, and take your lenses out at night and use a gentler contact solution. Massaging upper and lower eyelids with a cotton swab (small circles around each eyelid). Hot compress helps to loosen and release hardened oil in clogged meibomian glands. So, twice a day wash your face with a cloth then rinse the cloth with warm water and use it as a compress over your closed eyelids for 30 s. Next, clean the lower lids with a dry, tightly wrapped cotton swab. This process removes lid debris that could be disrupting with the tear film, stimulates your own reflex tears, and the meibomian glands release oily secretions into the tear film.

Regardless, the most promising and recent research with omega-3 and/or omega-6 supplementation for dry eye is interesting and several large-scale clinical trials are currently addressing this issue. Interestingly, dry eye is the number one reason people visit the eye doctor [3]. Specific dosages are mentioned below of omega-3 and/or omega-6 supplementation but the clinician and patients should not get caught in the minutiae but instead realize there is good preliminary evidence to support the use of these dietary supplements for dry eye of various etiologies because they may simply just increase tear production and tear volume. And please keep in mind that in many cases omega-3 and omega-6 pills are no longer needed because liquid flavored options that are low in calories offer wonderful non-pills options utilizing several teaspoons or 1–2 tablespoons per day that equate with all the effective pill dosages (for example see Barlean’s Omega Swirl^® and other non-pill options).

A meta-analysis of seven independent studies (n = 790) demonstrates the positive data with omega-3 fatty acid supplements [119]. For example with flaxseed oil at 1000 mg/day divided into three daily doses (total of 3300 mg of plant omega-3 alpha-linolenic acid), or just ingesting 800–1500 mg of the active ingredients in marine or fish oil (EPA and DHA omega-3 fatty acids) has been beneficial (1–2 fish oil pills on average) in preliminary clinical trials [3].

Omega-6 supplementation is controversial because some “experts” have been falsely touting that omega-6 fatty acids create inflammation and are bad for you and this is not accurate and it is a gross generalization. Some omega-6 compounds have anti-inflammatory effects, which is why they are potentially effective for dry eye symptoms and are low cost [120]. For example, an omega-6 compound known as LA (linoleic acid) can be converted in humans to gamma-linolenic acid (GLA) and further converted to another omega-6 known as DGLA (dihomo-gamma-linolenic acid), which can result in an anti-inflammatory effect and may stimulate tear production [3].

LA at 57–224 mg and/or 30–300 mg GLA in studies has been beneficial in reducing symptoms of dry eye. The human study that also relates to my experience with individuals with dry eye from diverse causes including contact lenses (as was the participants of this study) involved using 300 mg of gamma-linolenic acid (GLA) from evening primrose oil (or black current oil can also be used—whatever is cheaper). Evening primrose has the better research taken as capsules but this is cumbersome and could require up to six capsules a day.

Additionally, the combination of omega-3 and omega-6 supplementation could also be effective against dry eye [3, 119–122]. Using at least 750–1000 mg of the active omega-3 ingredients in fish oil (EPA and DHA), and 1000 mg of flaxseed oil daily for 90 days, or using the same dosage of fish oil with 15–82 mg GLA and 126 mg LA showed benefits in multiple small but noteworthy clinical trials. It should also be kept in mind that topical omega-3 and/or omega-6 preparations also have preliminary positive data [121].

Interestingly, other supplements which harbor omega-3 and omega-3 compounds also have preliminary data such as oral sea buckthorn (Hippophae rhamnoides) oil [123, 124]. A study of 2000 mg a day (two capsules twice a day with meals) in 20–75-year-old men and women appeared to improve the tear film and potentially reduce redness and burning in the fall and winter (consumed for 3 months). Again, this study was not provided to promote this oil but to show that omega-3 and/or supplements are promising for dry eye. This oil has a high content of the omega-6 LA, and plant omega-3 and some monounsaturated fat.

A large (n = 150) study from Korea that used vitamin A (retinyl palmitate, 0.05 % and polysorbate 80 1 % and preservative free from Vision Pharmaceuticals Inc., Mitchell, South Dakota known as “Viva Drops^®”) drops four times daily for dry eye and it was found that the vitamin A improved blurred vision, tear film and produced results that appear to be similar to the FDA approved drug cyclosporine A (0.05 %, also known as “Restasis”) [125]. The participants of this study were on average 30–40 years old and their dry eye did not respond to conventional suggestions. Both options significantly improved the symptoms of dry eye within 2–3 months. It appears that either of these options worked fine in this study with an artificial tears product. You can find Viva Drops online (www.​vivadrops.​com).

Check medications (beta-blockers, antidepressants, anticonvulsants, anti-parkinsonian, antihistamines, decongestants, antipsychotics, and even some pain medications, antithyroid, cancer drugs, antiemetic, acid reflux medications, blood pressure meds, urinary incontinence, antiviral, antimalarial, respiratory medications, … the list is long) and supplements including your topical ones because they could be a problem. For example, niacin supplements have a history of causing eye issues in some individuals including dry eye and blurred vision [126]. One popular line of prescription antiaging skin creams known as “retinoids” (high potency vitamin A derivatives) can cause dryness of the skin as a side effect. These medications reduce sebaceous gland size, which is why they were also tried on acne in the past but can cause dry eye because the meibomian glands are sebaceous glands, and accidentally getting some in the eyes can cause burning sensation and inflammation and potential dry eye.

Although studies of dry eye in breast cancer have received minimal attention, the subject itself from cancer treatment is an issue. For example, preliminary retrospective chart reviews of patients on aromatase inhibitors suggest that dry eye could be more prevalent in this breast cancer population [127]. Estrogen receptors exist in the eye and eye glands and the risk of dry eye does increase with age and lower estrogen levels [128].

Often dry eye and dry mouth can occur together, so integrative medicines that work for one should be tested for the im pact on the other. Still, dry mouth has few integrative medical options at this time, especially from cancer treatment. Interventions that appear to reduce this medical condition especially from Sjogrens syndrome and radiotherapy to the head and neck should also provide some clues on how to treat dry mouth from other causes [129]. Few adequate studies have been conducted in this area. However a review of six studies (three randomized and three prospective) that met more rigorous methodology criteria the following options could be tried [130]:

Yohimbine (4 or 6 mg to a maximum of three times a day) could be another option for dry mouth based on preliminary data outside of cancer treatment [131, 132]. Yohimbine comes from the West African Yohimbe tree and can be found as a supplement and a prescription drug (Yocon^® etc.) [3]. Whether or not it is consistently effective is controversial, but what is not controversial is that it is a “alpha-2-adrenoreceptor antagonist” (alpha-2-adrenergic agonist), which has increased salivary secretion in animals, healthy volunteers and in some medication-induced and other etiologies of dry mouth. Arguably an intact salivary gland with some functional parasympathetic stimulation is needed for efficacy. Additionally, because of its mechanism of action some of the side effects include: headache, sweating, nausea, dizziness, nervousness/agitation, tremors, sleeplessness, antidiuresis, and elevated blood pressure and heart rate. It cannot be used by individuals with kidney diseases, those on antidepressants, or other mood-altering drugs, and in some individuals with specific cardiovascular, neurological, and psychological issues. Since yohimbine can increase brain norepinephrine, and increased norepinephrine can trigger some hot flashes then caution should also be exercise when dealing with severe hot flashes and dry mouth. Interestingly, clonidine has provided a mild benefit for some women with hot flashes and this drug is an alpha-adrenergic agonist, which can reduce brain norepinephrine.

Many media and other credible sources appear to suggest yohimbine is as an alternative medicine or over the counter dietary sup plement, but this is really not the case based on its clinical trial efficacy [3]. And this is the real problem here, which is yohimbine HCL is a prescription drug, but many dietary supplements that mimic this drug have quality control problems and are dangerous (like the drug). Again, yohimbine HCL is the active ingredient found in the bark of a West African tree, but many dietary supplements really sell “yohimbe” which in may cases has little to no or variable quantities of the active ingredient “yohimbine HCL” in it. Again, if there is an interest in yohimbine HCL in the area of dry mouth I believe the prescription drug should be utilized because of quality control issues and because the successful clinical trials throughout medicine primarily utilized this version.

Note: Most moistu rizer conventional options or lotions that also contain a broad-spectrum sunscreen (UVA and UVB such as Lubriderm and others) are adequate. Replacing the conventional options or acting as an adjunct with integrative medicines without adequate minimal evidence is not advised.

A Cochrane rev iew of 56 studies (n = 4068) found aerobic exercise to be especially helpful in significantly reducing CRF during and after cancer treatment especially in the area of breast and prostate cancer patients [133]. Resistance activity appeared to be benefit in numerous studies but aerobic exercise had more significant data. The type, intensity and timing of exercise to achieve a benefit were not consistent or clear, but suggest a variety of types of exercise could have profound benefits for patients. Another extensive review of this research over 25 years, but only in breast cancer utilizing 51 studies found consistent suggestions of objective benefit for body composition, strength, and cardiorespiratory function and subjective benefits including improvements in fatigue, depression and overall quality of life [98].

“Nevertheless, for p atients who want to try a ph armacologic product and physicians who are early adapters of new promising agents, the pure ground root American ginseng product, as used in the above studies, might be an option to consider” [134].

This wa s an editorial from some of the top experts in the field of conventional treatments for CRF, which is arguably one of the strongest potential partial endorse ments of a dietary supplement to prevent or treat a common cancer treatment side effect.

The reason for such an initial positive reaction for American ginseng (Panax quinquefolius) was based on two strong in methodology clinical trials—somewhat similar to a phase 3 trial and also reviewed in Chap. 2 of this text [135, 136]. A total of 364 participants were enrolled from 40 medical centers (clinical trial sites or primarily community cancer centers) and approximately 60 % of the participants were being treated for breast cancer (the others consisted of colon at 12 %, hematologic 5 %, and prostate 4 %, and then gynecologic and others) and the average age was 55 years [135]. After approximately 2 months a significant difference (twice the effect at reducing fatigue compared to placebo) was observed and side effects were similar to placebo. Regardless, in the first month there was a nonsignificant benefit, but again it did not become statistically significant until after 2 months. Participants received 2000 mg of Wisconsin ginseng, which is just a common type of American ginseng or placebo. Ginseng consisted of pure ground root from one production lot and it contained 3 % ginsenosides (theorized active ingredients). Keep in mind that most ginseng products on the market have at least 3 % and some as high as 50 %, but you would need to try ginseng at lower dosages as the potency or concentration of ginsenosides increases. Ideally one should mimic what worked in the clinical trial but this same research group from Mayo Clinic also observed efficacy at 1000 mg/day with a 5 % ginsenoside (Rb1 ginsenoside being the most prevalent) product in a previous clinical trial (n = 290) that included 109 breast cancer patients (39 % respectively) [136]. The pure ground root ginseng in these studies was donated by the Ginseng Board of Wisconsin (Wausau, WI, go to www.ginsengboard.com to find information on the product used in the clinical trial) and was manufactured by Beehive Botanicals (Hayward, WI). It is also of interest that in these large clinical trials patients appeared to receive greater antifatigue benefits the earlier in the course of treatment the ginseng was utilized as opposed to later or after treatment. In other words, the preventive aspects of this treatment may be greater than simply trying to treat more significant fatigue after it has already occurred.

Another small single arm trial of 800 mg/day of Panax/Asian Ginseng (Indena S.p.A. Milan, Italy) at MD Anderson Cancer Center found a significant reduction in CRF within one month utilizing a 7 % ginsenoside product that needs confirmation in a randomized trial [137]. This supplement also appeared to significantly improve quality of life and this also appeared to improve sleep, appetite, pain, and other issues related to CRF in 30 days.

Thus, the cumulative evidence from the Mayo Clinic directed and MD Anderson Cancer Center studies are arguably sufficient evidence currently to offer ginseng as a primary antifatigue option especially since patients have few options in this area, and some of the more expensive pharmaceutical based products (psychostimulants …) have been disappointing when further studied [134].

Ginseng may be reducing the inflammatory process associated with cancer or chronic fatigue due to inflammation in general [3, 134–137]. Ginseng could reduce cortisol and reduces stress overall and then improve energy levels. Whether or not the primary antifatigue effects are being derived from the ginsenoside and/or polysaccharides or another compound is a matter of debate and more research. Again, the fact that there were no side effects beyond placebo and American ginseng has been found to have no real strong drug interactions or interfere overtly with drug metabolism is noteworthy. Ginseng from water extraction or from pure ground root has been associated with the best results and safety, and ginseng extraction methods due to alcohol or methanol based procedures could be less effective and some researchers believe toxic or even estrogenic with long-term use [135]. Additionally, ginseng (Panax or American ginseng) has a long history of having an ability to improve energy levels in healthy individuals, but again because it worked for more extreme fatigue from cancer treatment it can help with many types of fatigue from my experience. Ginseng can be ingested with or without food, but with a meal could reduce gastrointestinal side effects caused by pill consumption in general.

Caffeine is found in m any products and plants and so reco mmending a caffeine product is easy based on the proven track record of imp roving energy and attention levels [3]. Guarana is a plant from the Amazon basin that has been utilized for fatigue because it has caffeine in it, which comprises on average 2.5–5 % of the dry weight (some can be slightly higher), but it also has a high content of saponins and tannins, which suggests it could provide other nutritional properties.

The Bayer company (Consumer Care Division, Basel, Switzerland) sponsored a study of over 222 mg of guarana in a dissolvable tablet in liquid that contained 40 mg of caffeine and found it worked better than placebo in reducing mental fatigue and improving focus and attention to different tasks (n = 129 healthy adults ages 18–24 years) [138]. Other clinical studies of 75 mg of Guarana appeared to improve memory in multiple studies. In other words, there is enough preliminary research on caffeine itself along with the fact that guarana contains low doses of other compounds to recommend guarana supplementation to improve energy levels.

Past data was of only a passing interest until preliminary studies have found a potential antifatigue effect from cancer treatment [139]. The guarana standardized extract used in an adequate 21-day study (n = 75) was from Cathedral Pharmaceutical Industry (Nova Pampulha, Vespasiano, Minas Gerias, Brazil), and it had a 6.46 % caffeine content and 1.7 % tannin content. This suggests that patients in this study only received approximately 5 mg of caffeine a day from guarana compared to a standard cup of coffee, which is 50–100 mg or more. There was a large reduction in fatigue that approached 50 % in patients in the guarana supplement (50 mg supplement twice a day) compared to placebo group in breast cancer patients experiencing progressive fatigue after their first cycle of chemotherapy. The guarana caffeine content again is fairly low, which is understandable why anxiety and insomnia have not been observed to increase in these clinical trials unlike what one would witness with pure caffeine. Interestingly, a guarana extract (75 mg once a day—similar research group as in the previous study) used in breast cancer patients experiencing post-radiation fatigue did not appear to work as well as a placebo [140], which could suggest that the study was either too small (n = 36 total), caffeine content was not high enough or there is no impact in this setting.

Still, the reader should keep one important issue in terms of caffeine and studies, which is when precisely participants stopped drinking coffee or ingesting caffeine. For example, if a washout occurs several weeks before a study the benefits of caffeine look better when reinitiated [3]. This is not what appeared to be the case in these and other studies of guarana, which makes these results even more believable. Keep in mind the half-life of caffeine can vary from a few hours to up to 6–8 h which is why anything with caffeine in it should not be used in the later afternoon or early evening because of its ability to cause insomnia. Yerba mate is another plant with caffeine in it, which is also beginning to show some benefits for improved energy when placed in beverages and arguably may soon be found to work as well as guarana supplements but needs more research right now in terms of safety. Pregnant women should not use guarana because although it is a mild stimulant it is still cannot be considered safe in pregnancy unless it receives more safety research in this area.

Caffeine pills appear tantamount to concentrated energy [3]. I do not mind a single 5-h energy or other similar drinks, but taking more than 2 a day is an excessive amount of concentrated (not diluted like soda, coffee, tea..) caffeine or energy. For example, shots of hard liquor allow a shorter interval to feel inebriated, but more diluted sources of alcohol like light beer require large volumes of the beverage to feel the same effects. I often explain to patients that caffeine is somewhat similar that when you concentrate the amount in a very small volume of liquid it is easy to overdose and produce anxiety, anxiousness, and palpitations (cardiovascular effects). It is for this reason that I am not a caffeine pill advocate for most individuals except for some rare situations where nothing else is working. Another problem with becoming addicted to higher doses of caffeine is tolerance or tachyphylaxis, whereby much larger doses are needed over time to have any effect. Finally, withdrawal from these very high doses of caffeine provided by pills and energy drinks is difficult and often can cause moderate to severe headaches.

E. B-vitamin injections versus supplements = similar = nothing

A total of 236 women (Wake Forest Associated Study) with newly diagnosed breast cancer and planed adjuvant chemotherapy were randomized to 300 mg CoQ10 or placebo and each combined with 300 IU of vitamin E divided into three daily dosages and the treatment was continued for 24 weeks [145]. Supplementation caused improvement in plasma CoQ10 but no improvement in fatigue, depression or quality of life. This is arguably equi valent to a phase-3 like clinical trial for CRF and 300 mg of CoQ10 is not a small dose and can be costly. It is also of interest that CoQ10 had promising preliminary data in early Parkinson disease to improve daily function and was elevated to a phase-3 trial called “QE3 Study” and at a dosage of 1200 mg or 2400 mg/day or placebo (all participants received 1200 IU a day of vitamin E) and conducted in 67 medical centers in North America (n = 600) and the trail was stopped after 16 months because of futility [146]. This trial is a reminder of how preliminary extensive data in one area of medicine that does not show any activity in a phase 3 could provide some clue in another seemingly unrelated area of medicine.

G. d -ribose

d-ribose is a natural pentose sugar that can be purchased as a powder to place into beverages and can be purchased at health food stores or online. Ribose (also known as “d-ribose”) can also be purchased as a pill. There have been a few preliminary studies that suggest that when utilizing 5 g a day with a beverage at breakfast, lu nch and dinner (15 g total) that it can help to reduce fatigue from fibromyalgia and chronic fatigue syndrome [147]. The problem is not only preliminary indirect studies demonstrating no impact [148], but the lack of a well-done large study in those with any type of chronic fatigue that proves it can beat a placebo and the lack of any adequate trial of methodology over the last decade.

H. l -carnitine (mechanism of action without impressive data in a Phase-3 trial)

l-carnitine is a dietary supplement that had a lot of researchers excited because it just makes sense as to why it m ight work to reduce fatigue [3]. l -carnitine is a compound that exists in every cell of the human body to aid in the transport of long-chain fatty acids into the mitochondrion to increase energy (ATP) production. However, the more sound clinical trials have not followed all the hype and a recent phase-3 trial was a disappointment in multiple ways [149]. There have been a few small studies to suggest that getting 1–2 g (1000–2000 mg)/day of l-carnitine supplements or pills may reduce fatigue in some individuals, but this recent large phase-3 study of 2000 mg/day of l-carnitine over 4 weeks in cancer patients did not show a benefit compared to placebo [149]. Some might argue that the study was not long enough, but no trend in improvement was observed, even in the subgroups. The real limitation of this study was the 25–30 % failure to complete the assessments by the participants, which “weakens the conclusions of the study.” A total of 367 patients were included in this trial (conducted by the reputable Eastern Cooperative Oncology Group or ECOG—funded by the National Cancer Institute or NCI) and supplementation caused a significant rise in carnitine plasma level by week 4 in the supplement versus the placebo arm. None of the primary or secondary endpoints using validated instruments for fatigue found a difference between the placebo and no impact on depression and pain. More importantly, when examining a subset of patients who were actually carnitine-deficient at baseline there was also no significant improvement in fatigue or other outcomes with this supplement.

Interestingly, a recent preliminary 3000 mg l-carnitine versus placebo per day trial for 2 weeks, followed by a 2-week, open-label phase with the exact same dosage of l-carnitine for all patients was conducted by similar researchers that performed the past phase-3 cancer trial [150]. In this case, patients with terminal HIV/AIDS were included and 18 patients in the treatment arm and 17 in the placebo completed the trial. Significant increases in the total (28–48 nM/L, p < 0.001), and free carnitine (24–40 nM/L, p < 0.001) occurred with the supplement and there were no changes in these levels in the placebo arm. And the primary outcome, fatigue at the end of the blinded phase, did not improve. Secondary outcomes of function, quality of life, and mood also demonstrated no changes versus placebo. A secondary outcome–serum lactate–was reduced significantly (p < 0.005) with l-carnitine (1.45–1.28 nmol/L) and increased (1.38–1.84) in the placebo arm. And although this is interesting and again statistically significant, it did not translate into any documented clinical significance.

Some advocates of l-carnitine refer to two studies of combinations of drugs and supplements to suggest l-carnitine has some activity against fatigue, but a closer examination of these investigations does not actually suggest directly that l-carnitine by itself has a positive impact [151, 152], so it seems like an exhaustive attempt to find some level of evidence where currently none to minimal exists. Another thought that is often lost in the cacophony or desire of a supplement to work is the observation that l-carnitine is not a low cost product, and it is generally supplied to patients in 500 mg capsules (even though in the phase-3 and HIV/AIDS trial a liquid suspension was utilized—another credit to the sensitivity of the ECOG group). Even if l-carnitine did demonstrate some efficacy patients would be consuming at least 4–6 capsules a day in the best-case scenario and ten or more capsules for those that cannot tolerate the larger sized pills! The accessible and affordable delivery system for any supplement or medication needs to be practical and realistic for compliance regardless of the overall efficacy against the specific medical condition. Therefore, cumulatively the overall evidence currently suggests l-carnitine should not be utilized to improve fatigue.

There are co untless dietary supplement options espoused on the internet and even from integrative medicine “experts” in the medical literature. However, as was the case with l-carnitine there is nothing more than a wonderful theory defiled by good clinical trial results. In other words, just because a mechanism of action exists to explain why something will be effective does not always and in many cases translate to real world effectiveness. If a placebo response can occur in one-third to one-half of patients with subjective outcomes then these generally costly supplements and prescription medications need to be rigorously and objectively tested.

For example, Ganoderma lucidum (“Reishi” mushroom) spore powder (1000 mg three times a day for 4 weeks) in breast cancer patients (n = 48) did appe ar to reduce fatigue versus a control group, but there were no specific details provided on the placebo arm (no focus or section of description) nor were statistics completed on side effects (even on the placebo) which appeared to be statistically significant for the intervention but dismissed [153]. In other words, in order to elevate the status of some dietary supplements the description or methodology and the peer review of the journal that accepts the article needs to be rigorous enough to convince the reader that the compound really functions greater than a placebo. This and so many well-done studies would receive more objective appreciation if greater transparency or descriptive details were provided. And this is a limitation I find in some dietary supplement and pharmacologic clinical studies. The intervention and study appear sound but the ability to objectively review the evidence is compromised by the written article itself.

CRF and fatigue treatment in general is desperate for more and better studies, and integrative medicine has the potential to provide and is currently first-line evidence-based treatment for this condition, as was recently demonstrated from American ginseng phase-3 trial and past exercise interventions [133–136]. This is a profound moment for integrative medicine and breast cancer especially at a time that pharmacologic treatments have struggled overall to find success in this category as a recent Cochrane Review of 18 drugs, 4696 participants and 1645 publications concluded with the following statement: “Based on limited evidence, we cannot recommend a specific drug for the treatment of fatigue in palliative care patients” [154].

Vasomotor symptoms were the number one reason women stopped tamoxifen in the landmark P-1 study and it was more common in the tamoxifen arm. Researchers looked back on this data and found something remarkable when comparing the women of normal BMI to those obese women in the trial [155]. They analyzed data from 11,064 women enrolled at least 3 years before the trial unblinding in May, 1998. It appears that hot flashes, night sweats and cold sweats were significantly worse in obese women and all three symptoms (hot flashes 57 % greater, night sweats 50 % greater, and cold sweats 64 % greater) were more likely to lead to non-adhering to the study medications. Contrary to past belief that obese women have more aromatase activity, arguably from gre ater estrone concentrations (also conversion of androstenedione to estrone) that should reduce frequency and severity of hot flashes, it appears in menopausal and women with breast cancer hot flashes become more severe with weight gain [156, 157]. A preliminary and interesting observation from a randomized trial of weight loss (n = 154) found decreases in weight, BMI, and waist circumference were each correlated with improvements in flushing after 6 months [158]. Potential mechanisms of action proffered include increased adipose insulation against heat dissipation, increased sympathetic neural activity correlated with increased visceral fat, and changes in cytokines such as leptin from adipose tissue that impact thermoregulatory centers. Obesity with more severe or frequent hot flashes could also be a marker for a higher risk of metabolic syndrome and overall cardiovascular risk [159], as well as other comorbidities such as depression that could impact vasomotor symptoms [160], and even breast cancer patients with greater weight/waist size could be responsible for a plethora of negative effects on quality of life [161].

It appears from this past trial and a Cochrane review of five studies (n = 733) that exercise has an inconsis tent effect on hot flushes [162]. It has been my clinical experience with hot flashes in cancer patients for decades that some were convinced their exercise regimen cured them and others will find that they exacerbated them. Still, the overall profound impact of exercise on symptoms from sleep quality, reduced insomnia and depression [163–165], should always be discussed with breast cancer survivors. Another option that appears to be espoused by some alternative medicine educational sources is “Paced Respiration” or abdominal breathing exercises at a slower pace to control hot flash frequency and/or severity and although in theory it appears to make some sense the clinical research to support this activity thus far in menopausal and breast cancer patients is weak [166, 167].

Before a discussion of lifestyle interventions and/or other integrative medicines can commence it must be keep in mind that a p ersonal hot flash diary is critical to utilize for maximum benefit and control of hot flashes. Patients can utilize these diaries (or simply create their own) for 1–2 weeks to determine the average frequency and severity of their hot flashes [1]. A hot flash diary allows the health care practitioner and patient a better method of determining whether or not vasomotor symptoms could also be controlled by lifestyle, and/or supplements, and/or prescription medication. For example the mild to moderate hot flashes are usually controlled through lifestyle/supplements and more severe and very severe or frequent hot flashes that clearly interfere with day-to-day activities and sleep patterns are better controlled through prescription medications. An example of how to score hot flashes themselves is found in Table 7.4 [1].

Overall, lifestyle changes and breast cancer and vasomotor symptoms have minimal data, but there are common sense changes that should be applied where benefit always seemed to outweigh risk and these are found in Table 7.5 [1].

Hot flashes and inte grative medicine have a research background unlike arguably anything else tested in the field of supplements for breast cancer. Multiple phase III clinical trials of popular dietary supplements in breast cancer patients demonstrated that it is difficult to beat a placebo. Thus, although hormonal (estrogen and/or progesterone based) treatment can reduce hot flashes by 80–90 % and antidepressants and anticonvulsants by 50 %, the dietary supplements appear to reduce them by 20–33 % (similar to placebo). And there is always the possibility that some supplements could make hot flashes worse either because they discourage lifestyle changes or lengthen the time a patient requests more effective pharmacologic treatments from her/his doctor, or they simply may be associated with worsening vasomotor symptoms [168].

A recent meta-analysis of breast cancer patients experiencing menopause symptoms utilized seven studies of 342 patients and fo und a small benefit to acupuncture except when compared to sham acupuncture the benefit was not statistically significant [169]. A similar finding with arguably one of the largest reviews of acupuncture for cancer patients found minimal to no benefit for hot flashes from a review of 41 randomized clinical trials (2151 publications) but did find some potential benefit for chemotherapy-induced nausea and vomiting [170]. And a similar finding for women dealing with menopausal symptoms was reported for 16 studies that included 1155 women, but eight of these studies compared acupuncture to sham acupuncture and when this occurred found a minimal to no benefit for hot flashes [171].

Black cohosh (Cimicifuga racemosa, or Remifemin^® from GSK was unable to be obtained so another pro duct was chosen—Hi-Health Corporation, Scottsdale, Arizona—standardized to contain 1 mg of triterpene glycosides) was utilized in a phase-3 double-blind crossover trial with two 4-week periods, and one 20 mg capsule of this supplement twice a day versus placebo (n = 132 women with a history of breast cancer from over 10 medical centers) were the interventions [172]. Patients were included if they had “bothersome” hot flashes, which was defined as 14 or more per week for at least 1 month and desired some intervention. Patients receiving black cohosh reported a reduction of 20 % in the hot flash score versus 27 % reduction with placebo, and mean hot flash frequency was reduced 17 % on black cohosh and 26 % on placebo. Thus, there were no statistically significant differences throughout the trial and on the primary outcomes.

Postmeno pausal women with breast cancer (50 % of the participants) and without breast cancer were randomly allocated to consume a flaxseed bar (7.5 g of flaxseed—5 % lignans or 410 mg of lignans, 6 g of protein, 20 % fiber, and 190 calories from Glanbia Nutritionals) for 6-weeks versus a placebo bar (no flaxseed, lignans or soy) [173]. A total of 188 women from 22 medical centers were included in the trial and mean hot flash score was reduced by 4.9 in the flaxseed group and 3.5 in the placebo arm (p = 0.29). Approximately one-third of women in both groups experienced a 50 % reduction in hot flash scores (mean 30 % change overall in frequency and score). Grade 1 pruritus was the only side effect more common between groups with 8 % experiencing this event with placebo versus 1 % with flaxseed. Both groups reported gastrointestinal upset arguably related to the fiber content of the bars.

Arguably, this intervention/flaxseed powder continues to be my favorite dietary intervention for women and men dealing with hot flashes from cancer treatment because it appears to work the same or slightly better than placebo, it is low cost, provides a good source of fiber, it is low in calories, and it has been shown to be heart healthy and contains one of the largest sources of plant omega-3 fatty acids [3]. A total of 2–3 tablespoons of fl axseed powder can be applied to diverse sources (cereal, oatmeal, beverages, salad, …) and it discourages expensive dietary supplement pill utilization that can occur with this medical condition. I have found no greater benefit versus risk for any other product currently (except perhaps for soy protein powder [174]) especially when dealing with aging issues (from constipation, hemorrhoids, to glucose and lipid control). Please see Chap. 3 for more information on the heart healthy effects of flaxseed powder in women with breast cancer. And there are numerous high-quality objective reviews of past clinical data on flaxseed for heart health found in the literature, for example a review of 28 studies that found modest LDL lowering benefits for flaxseed (not the oil) especially in postmenopausal women [175].

An outstan ding double-blind, placebo-controlled, randomized arguably phase-3 trial was recently completed that included 289 postmenopausal women from over 20 medical centers with a history of breast cancer and “bothersome hot flashes” (greater than 28 times per week and of a severity to request intervention) were randomized to [176]:

No differences were fo und for magnesium or placebo for all endpoints including mean hot flash score (number multiplied by the mean severity) and frequency using a validated hot flash diary, but an increased incidence of diarrhea at a lower incidence of constipation was found with magnesium [176]. No other significant differences in side effects or quality of life were found. Approximately a steady reduction over 8-weeks in hot flash score and frequency occurred eventually leading to a 30–35 % reduction in these values over time for all the groups. Thus, despite preliminary non-randomized trials of magnesium observing large reductions in hot flashes [177, 178], it appears the placebo provided a reality check. It is of interest that magnesium is touted for a plethora of health conditions on the internet but many of these conditions have not received high-powered clinical trials such as the one mentioned previously [176], but at least it is well-known now that if a patient suffers from regular constipation and some vasomotor symptoms then magnesium supplements could be an appropriate choice in this specific setting.

A large 12-week phase-3 like trial of omega-3 supplements (n = 177, 1800 mg/day) versus placebo (n = 178) in perimenopausal and postmenopausal women for 12 weeks found no improvement in vasomotor symptoms freq uency, bother, sleep, or mood versus placebo [179]. One could argue that the dosage was not high enough to observe a response but there was no trend in benefit and ingesting large numbers of capsules for the potential of a modest benefit is not practical. In the future, perhaps a trial of a higher dose liquid product could be conducted to resolve this issue.

Overall, these supplements touted as high in plant estrogens have failed overall to provide a consistent reduction over placebo in vasomotor symptoms [180, 181]. Some of the more costly and best selling bra nds were tested in some of these studies. And some past studies that failed to demonstrate a benefit over placebo were 1 year in length [182]. Another 1-year trial (n = 89) of 120 mg of red clover demonstrated an impressive 57 % reduction in vasomotor symptoms (black cohosh = −34 %), but the placebo demonstrated a 63 % reduction and 0.625 mg conjugated equine estrogen/2.5 mg medroxyprogesterone acetate group had a 94 % reduction [183]!

Sage, a plant native to Mediterranean Europe has been used in food and folk medicine to treat menopausal symptoms for many years but has no strong methodology clinical studies [1]. There was one open, multicenter clinical trial completed in eight practices in Switzerland [184]. A total of 71 patients with an average age of 56 years, menopausal for at least 12 months, and with a minimum of five hot flushes daily were recruited. There w as no placebo arm. Participants were given a hot flash diary and a once-daily tablet of fresh sage leaves for 8 weeks. The average number of hot flushes was significantly reduced within 4 weeks, and they continued to be reduced even further after 8 weeks. Severe and very severe hot flushes were reduced by 79 % and approximately 100 % over 8 weeks. A total of two participants experienced gastrointestinal issues during the study attributed to the sage preparation. Sage is a safe herbal spice that can be added to food. So, perhaps it should be used as a seasoning for tomato sauce, add to morning eggs or omelets, or on a piece of pizza, in salads, and to chicken or fish when cooking so the food will absorb the herbs nice flavor. Sage dietary supplements are generally low cost, but how can one recommend a dose when a trial that can be replicated in the real world has not been published? Currently there is also minimal information on potential drug–supplement interactions in the medical literature. The sheer dearth of overall clinical trials with this supplement is noteworthy and does not allow for a benefit-versus-risk analysis (except more of the spice in food is always an option).

A total of 177 women in a phase-3 like trial with a history of breast cancer from over ten medical centers were randomized and 149 had complete data over the 9-week study period [185]. Patients utilized soy tablets (600 mg tablets containing 50 mg of soy isoflavones in each tablet—40–45 % genistein, 40–45 % daidzein, and 10–20 % glycitein; one tablet three times a day for 150 mg isoflavones per day, amount similar to three gl asses of soy milk, product provided by Pharmavite, Mission Hills, CA) or placebo for 4-weeks and then crossed-over to other regimen. The percentage of patients reporting a greater than 50 % reduction in hot flash score was 38 % with placebo and 35 % with soy, and 36 % of patients on placebo reported their hot flash frequency reduced to half and 24 % with soy (p = 0.01). There was no difference found versus placebo and patients preferred the soy supplement 33 % of the time, placebo 37 % of the time, and neither pill 31 % of the time. There were no differences in side effects between the pills. This is does not quell my enthusiasm for recommending soy protein or traditional soy sources (edamame, tofu, …) for heart health and based on the potential benefit in breast cancer for some patients that are comfortable utilizing it as part of a cholesterol and weight loss reducing regimen [181].

A total of 120 patients from over ten medical centers with a history of breast cancer were recruited for a 4-week crosso ver trial of 800 IU of vitamin E succinate daily versus placebo or vice versa [186]. There was a similar reduction in hot flash frequency during the first crossover period (25 % with vitamin E and 22 % with placebo), but a minimal significant decrease in hot flashes (one less per day with vitamin E versus placebo, p = 0.05), but at the end of the study patients did not prefer vitamin E over the placebo (32 % versus 29 %).

DHEA has had inconsistent data an d could have androgenic side effects and has unpredictable conversion (patient-to-patient variability) to testosterone and estrogen, but potentially has a role for some women with sexual dysfunction due to adrenal insufficiency [3, 187]. DHEA also has inconsistent effects on lipid parameters and can lower HDL in some patients. 5-HTP has had minimal research against placebo for hot flashes and even at 150 mg/day has not dem onstrated preliminary benefit. And SJW has had mixed results, bu t it is the dietary supplement antidepressant mimics such as these that should receive more research since venlafaxine and other prescription antidepressants with similar mechanisms of action have displayed some success for treating vasomotor symptoms in breast can cer patients. Sesame seed (Sesamum indicum) powder has an adequate content of protein and fiber and had some preliminary heart healthy data that would need to be replicated [188–190]. It is also a good sources of lignans (like flaxseed) that could be tested in a hot flash study but based on past hot flash trial with similar products there is little confidence it could provide a significant benefit over placebo.

Hot flash frequency and severity in breast cancer and other scenarios is simply daunting and not simple to resolve. If the hot flashes are mild to moderate the placebo response is extremely high and difficult to exceed with any supplement. If the hot flashes are more severe or very severe then pharmacologic interventions or something with a more overt benefit-to-risk ratio ne eds to be discussed. The idea that a dietary supplement with side effects seemingly similar to placebo could consistently surpass a placebo in a clinical trial or be as effective or more effective than some pharmacologic agents is optimistic. However, I am always hopeful of an exception to the rule (as is the case with American ginseng and cancer-related fatigue or CRF).

Most patients experience problems falling asleep or maintaining sleep, but a smaller percentage meet the clinical criteria for insomnia (20 %) [191, 192]. Insomnia is associated with reduced quality of life and increased rates of depression. Sleep problems in cancer patients are a real problem with some studies reporting as high as six out of every ten individuals having issues with sleep. Pharmacologic options are not of low cost and have been estimated to cost 50–100 dollars per month but dietary supplements from this chapter run 10 dollars a month maximum in many cases if used daily.

Multiple clinical trials co ntinue to demonstrate the impact of light to heavy exercise on sleep quality in breast cancer patients. A Canadian multicenter trial of over 300 breast cancer patients on chemotherapy found that light to moderate aerobic exercise improves sleep but a combination of aerobic and resistance activity 50–60 min three times a week may provide the best results [193]. Some studies suggest the improvement in sleep with exercise is not significant enough, which opens the door to other potential interventions in these patients [194]. Still, multiple exercise options appear promising, for example, yoga in 75 min sessions twice a week over 4 weeks demonstrated significant improvement in multiple aspects of sleep quality including reducing sleep medication among cancer survivors compared to those that did not participate (n = 410) [195].

Dietary supplements could play a significant role for insomnia breast cancer patients. It should be kept in mind that the potential out of pocket costs and toxicity of prescription medications again are not insignificant. For example, recently the FDA reduced the daily dosage of prescription eszopiclone because of serious reports of fugue or abnormal changes in behavior a nd even driving while the patient was not even aware of these actions the next day [196]. And the leading causes of unintentional overdose leading to morbidity and mortality from medications in the USA are opioids, and then antianxiety drug, but in third or fourth position are the insomnia-based prescription medications [197]. Still, first-line of treatment should be lifestyle changes and sleep hygiene options (including behavioral therapy—bedroom is for sleep, no TV, computer, bright lights, …) that receive enormous attention today and are best handled by other reviews on the subject and/or insomnia professional.

Melatonin is produced fr om the amino acid tryptophan in the pineal gland of the brain and is released in a circadian pattern [3, 198]. It binds to melatonin receptors and reduces the firing of neurons in the suprachiasmatic nucleus in the hypothalamus (where a high receptor concentration exists), promoting sleep induction or the ability to fall asleep.

Melatonin is ac tually available over the counter in several forms but the immediate and prolonged release (PR) forms enjoy most of the positive clinical data. Controlled release (CR) melatonin or slow release is basically identical to PR melatonin. Whether or not sustained release (SR) or extended release (ER) works similarly than PR melatonin is not known and when immediate release is not effective then PR is an option because it has multiple clinical trials and is an improved medication in Europe for the treatment of primary insomnia with poor sleep quality in patients aged 55 years and older. This is important because age can reduce melatonin production as measured by the primary urinary metabolite 6-sulfatoxymelatonin (6SMT), which is also a test to show the circadian release of this hormone.

Interestingly, the use of PR mela tonin has not been associated with a reduction in endogenous melatonin production [198]. It has not been associated with psychomotor effects or memory and driving issues at the most common dosage (2 mg) and had significantly less impairment with prescription medications such as zolpidem. And it has not been associated with dependence, hangover, tolerance, rebound insomnia or withdrawal symptoms and has even shown excellent efficacy and safety in a variety of patient populations, for example Alzheimer’s disease. PR melatonin is usually given 1–2 h before bedtime. Alcohol can reduce the efficacy of melatonin. The bioavailability of oral melatonin is only approximately 15 %, and there is significant first pass metabolism and food can also lower the absorption. The half-life of immediate release melatonin is less than 30 min, which is why there is increasing interest in PR melatonin. A 2-mg preparation of PR melatonin known as “Circadin^®” was developed by Neurim, Tel Aviv, Israel, and again has been approved by European Medicines Agency (EMEA) since 2007. It has a terminal half-life of 3.5–4 h. Keep in mind the FDA even approved a drug that acts as a melatonin receptor agonist (ramelteon) back in 2005. Numerous reviews, meta-analysis, and recent clinical trials continue to demonstrate the efficacy of melatonin and overall safety profile in a variety of patients from those with cancer to Autism and Alzheimer disease, but at the lowest potential dosage in order to mimic physiologic levels [199–203].

A Dana-Farber Cancer Institute (DFCI, Boston, MA) randomized, double-blind trial of 95 postmenopausal women with a prev ious history of stage 0–III breast cancers with a mean age of 59 years and BMI of 25 who completed conventional treatment were assigned to 3 mg of oral melatonin or placebo for 4 months [204, 205]. Melatonin was purchased from a single supplier who also guaranteed the composition and purity of these supplements (Rugby Laboratories, a subsidiary of Watson Laboratories—Duluth, GA, USA). Melatonin was ingested at 9 PM each evening because of the potential sedating effects of this supplement. The primary endpoint of the trial was estradiol, IGF-1, or IGF-binding protein-3 and there was no change in these measurements with melatonin. Other endpoints included sleep quality, depression scores, and hot flashes. At baseline, 52 % of participants reported poor sleep in the month before trial enrollment. Subjects utilizing melatonin had significantly greater improvements in sleep quality (PSQI, Pittsburgh Sleep Quality Index) including domains on sleep quality, daytime dysfunction, and total score. Melatonin has no impact on depression or hot flashes.

This was arg uably the fist randomized placebo-controlled trial of breast cancer survivors to demonstrate melatonin improves subjective sleep quality with no significant adverse effects compared to placebo. Still, headache, fatigue and bad dreams were the most common side effects reported with melatonin. The dosage of 3 mg is still s supra-physiologic level, but returns to normal with minimal hangover effect in morning as shown in insomnia and jet lag. It would be informative to test the 2 mg PR-melatonin (for example the approved product Circadin^® in Europe) in breast cancer patients to determine if overall sleep outcomes would improve compared to immediate-release.

Again, mela tonin has been well studied in cancer patients as a standalone agent and even with chemotherapy without significant adverse events [3]. Dosages of 0.1–5 mg have been the most commonly tested and exceeded this dosage could favor risk over benefit. In fact, from experience some breast cancer patients have been told to utilize high dosages of melatonin (for example 10–20 mg/day) because of preliminary evidence that it may have anti-breast cancer effects and because of ongoing clinical trial addressing this issue. Not only is this unproven but this is unsafe because of the daytime drowsiness and fatigue can impair quality of life and could be dangerous when driving or operating machinery. This is no different than the recent FDA concern of sleep medication dosages and their ability to create fugue or dysfunction in my opinion. There are some reviews of past clinical studies that suggest melatonin has anticancer effects at higher dosages [206], but until more definitive proof is provided and better methodology in a clinical trial this should not be recommend.

Apart for the encouragement by some in the integrative medicine world for cancer patients to take excessive dosages, the other concerns from this author are more minor at this time. Melatonin for insomnia and jet lag and has an excellent safety record over a ra nge of dosages and duration of use [3]. Arguably more daytime fatigue and a potential reduction in nocturnal blood pressure are some concerns but these events occur more often with excessive dosages that again should not be recommended. Side effects have been rare—similar to placebo overall at the 3 mg and below dosages.

The impact on melatonin and blood pressure should be reviewed with patients. Melatonin could reduce nocturnal blood pressure in normotensive and even in hypertensive patients, but its impact on heart rate is inconsistent and co uld be an issue of dosage [207, 208]. An older study of 47 patients found 5 mg melatonin over 4 weeks blunted the effects of the calcium channel blocker nifedipine, which caused significant increases during the daytime in blood pressure and heart rate [209]. A meta-analysis of seven studies (n = 221) found no impact of melatonin on blood pressure but subgroup analysis found a significant reduction in nocturnal systolic (−6.0 mmHg) and diastolic (−3.5 mmHg) blood pressure with controlled release melatonin and no impact with immediate- or fast-release melatonin [210]. Safety issues were similar to placebo overall and authors argued that “the safety of melatonin in hypertensive patients is good, and implies that add-on melatonin therapy does not present significant risks of detrimental drug interactions with the main major drugs used to treat hypertension.” And even recent randomized trials utilizing sublingual melatonin at 3 mg to reduce anxiety demonstrate no blood pressure effects. It has the potential to be a preoperative anxiolytic that could replace the concerns with Benzodiazepines [211, 212]. Melatonin (1–3 mg immediate-release or 2 mg prolonged release) helps with sleep induction or falling asleep but not necessarily for sleep maintenance in my experience, which also allows some patients to only utilize the immediate release form of melatonin if they awake in the night and can’t get to sleep. Otherwise, headache, drowsiness, dizziness, nightmares, and fatigue are more common in my experience but this again appears to be primarily dose-related.

Valerian (also known as Valeriana officinalis that comes from aqueous or ethanol extracts usually) is actually the dietary supplement that has been moderately effective in some studies for helping someone fall asleep and stay in de eper and more refreshing states of sleep from preliminary studies [3]. Some would argue that this supplement has yet to prove itself or has not worked in some studies, and there is some merit to this argument in regards to objective parameters, but in terms of subjective sleep parameters it has multiple randomized trials demonstrating success and safety (minimally demonstrated drug interactions thus far) [213, 214] . Regardless, this supplement should never be combined with any other type of sleeping pills, or other what is known as “central nervous system depressants” such as strong pain medications, and a review of the latest specific drug interactions with this supplement is always prudent. Some clinical trials have reported diarrhea as a potential side effect in a small percentage of individuals. Valerian should be purchased as a root extract with at least 0.8 % valerenic acids in it (active ingredient), and it could several weeks to become effective (2–4 weeks in the studies). The most well studied dosage has not been determined, but studies that have used 200–600 mg (most common is arguably 600 mg) of Valerian daily have been proven to be safer and more effective in my opinion. The supplement is usually taken 30–60 min before bedtime. Additionally, valerian should be purchased itself and not mixed in with other herbs because most of the well-done studies utilized valerian as a stand along, and the more ingredients added to the effective ingredient only potentially dilutes the effectiveness of a drug or supplement (see Chap. 2). Side effects in clinical studies have been rare with some cases of morning grogginess, headache, and vivid dreams that in some cases were not pleasant.

There was one notable randomized phase 3-like trial that applies to breast cancer patients utilizing valerian conducted at approximately 20+ medical centers [215]. This Mayo clinic led trial consisted of patients undergoing cancer treatment (64 % breast cancer, 25 % other cancers, less than 5 % colon or prostate cancer, mean age 59 years) randomized to 450 mg of valerian or placebo daily for 8 weeks taken 1 h before bedtime. The valerian utilized in this trial was “pure ground, raw root, from one lot and standardized to contain 0.8 % valerenic acid,” which were supplied by Hi-Health (Scottsdale, Arizona). The primary endpoint was the Pittsburgh Sleep Quality Index (PSQI), and secondary endpoints several other measures of sleep, fatigue and mood. A total of 227 patients were randomized and 119 evaluated for the primary endpoint (patients were currently being treated for cancer and more dropouts occurred with placebo), which was found to be no different from placebo by the end of the trial. However, several other secondary measures showed significant difference in favor of valerian including several fatigue endpoints as measured from Brief Fatigue Inventory (BFI), and Profile of Mood States (POMS) Fatigue-Inertia subscale. Secondary endpoints should be interpreted with some hesitation but in this case the differences were large or usually over 10 points on a 100-point scale suggesting a real effect. Participants reported less trouble with sleep and less drowsiness on valerian. Additionally, other secondary endpoints including the change from baseline related to sleep latency, amount of sleep per night, improvement in sleep problems, and less drowsiness all supported the valerian group performing better than the placebo and similar side effects with valerian compared to placebo. The researchers concluded by stating “Further research with valerian exploring physiologic effects in oncology symptom management may be warranted.” It was noted in the publication that the main impact of valerian in past trials was on sleep latency or the time needed to fall asleep and regardless the 10 dollars a month cost compares favorably with some 50–100 dollar a month pharmacologic sleep aids. This trial was supported in part by Public Health Services grants.

Another randomized trial of 100 postmenopausal women (not breast cancer) aged 50–60 years experiencing insomnia were randomized to 530 mg of concentrated valerian root extract or placebo twice daily (1060 mg/day total) for 4 weeks [216]. Quality of sleep was significantly improved (p < 0.001) with valerian over placebo (30 % demonstrated improvement versus 4 %).

Massage therapy could also improve sleep quality and should also be discussed based on positive preliminary evidence [217]. Ideally, again finding a non-pill based option (mediation, yoga, other exercises) should always be the first line treatment including any improvements in sleep hygiene [3]. Other diet ary supplement sleep aids do not have the evidence to feel confident that the benefit truly outweighs the risk in breast cancer patients. For example, 5-HTP, tryptophan, passionflower, and nume rous other herbals that are also utilized for stress and anxiety in some cases have minimal clinical evidence and promoting them for sleep appears no different in my opinion than promoting antistress or antianxiety medication for sleep where toxicity and dependence are major issues. For example, 5-HTP and tryptophan could alter brain neurotransmission significantly at higher dosages and there are not enough long-term safety trials to feel confident utilizing them in cancer patients. It has been known that they also function as sedatives increasing REM (Rapid Eye Movement) sleep in some patients but also reducing NREM (non-REM) or deep sleep [218, 219]. These supplements have a good observational safety record overall (except of course for the l-tryptophan dietary supplement contaminant that cause Eosinophilia Myalgia Syndrome due to a contaminant and removal of the product in 1989) [220, 221], but in my experience the sedative nature and dependency it could create is a reminder of how individuals chronically depend on pharmacologic agents for assistance. Since there are virtually no reliable studies in breast cancer patients with these supplements nor consistent benefit versus risk dosage ranges for sleep promotion it is difficult to recommend these dietary supplements for insomnia unless all else has failed.

There is no optimal program to treat lymphedema that can occur in up to 40 % of women treated for breast cancer [222–224]. One standard of care is to utilize complete decongestive therapy (CDT) , which includes exercise, manual lymphatic drainage, daily bandaging, skin care and compression over 3-phases. CDT can reduce limb volu me and improve overall quality of life, but again provides no clear consistent advantage in other studies and there has been plenty of heterogeneous comparisons which create further comparative issues. CDT is also costly, time consuming, and could involve lifelong attention or maintenance. Yet there is sufficient evidence to also recommend exercise rehabilitation to improve lymphedema (and shoulder mobility) in breast cancer patients. Strength training is also encouraged and does not appear to improve or exacerbate lymphedema but improves whole body fitness and provides countless benefits for breast cancer patients as observed in this chapter. Resistance training in the impacted lymphedema limb appears to be safest and not exacerbate lymphedema if the condition is stable and has not needed therapy over the past 3 months. Overall, reviews of approximately 20 studies and well as the consistent recent medical literature message suggests that exercise with proper supervision could be safe and generally does not increase the risk of lymphedema or exacerbate symptoms. And since obesity and weight gain in general increases the risk of lymphedema exercise is critical as a preventive method. Each BMI single point increase appears to increase risk 1.11 times versus someone of a single point lower in BMI (30 versus 29 for example). Most of the recommendations for exercise in breast cancer survivors at-risk for lymphedema are similar for the breast cancer survivors with lymphedema. In other words, initiating exercise at lower intensity gradually, low impact aerobic exercises and increased flexibility exercise, adequate warming up and cooling down and compression garments should be worn during exercise especially in those with lymphedema.

Any supplement that appears to red uce the impact of Chronic Venous Insufficiency (CVI) and varicose veins also has the potential to help in the treatment of hemorrhoids [3]. Supplements that can reduce swelling and inflammation of the veins and improve the integrity of the veins can serve other potential purposes and need research, for example especially lymphedema prevention or perhaps even reduction from breast and other cancer treatments. It is for this reason a quick review of supplements in the area of CVI and hemorrhoids will be reviewed.

C. Daflon (also known as MPFF—micronized purified flavonoid fraction—a drug) or 450 mg of Diosmin dietary supplement and 50 mg of other flavonoids, or 500 mg 2–3 times a day for at least 12 weeks. Good for CVI but lymphedema prevention or treatment in breast cancer?

Daflon^® (Servier, France) is a well-known semisynthetic prescription drug in France and Europe that is actually 450 mg of Dios min (a compound found in plant like in citrus fruits) and 50 mg of other flavonoids found from plants primarily hesperidin (and possibly linarin, and isorhoifolin from other similar products) [3, 225, 226]. Daflon can also be known as an MPFF (micronized purified flavonoid fraction), and individuals usually take at least 500 mg tw ice a day of this product minimally to notice a benefit and some studies used 500 mg three times a day (divided in three doses every 8 h). “Micronized” means that particles were reduced in size to less than 2 μm (real tiny) so that improved its solubility and absorption. It is a drug in other countries but a similar plant product (Diosmin) ca n be purchased in the USA as a dietary supplement. Most of the studies of Daflon have been from 2 to 6 months. Keep in mind that it is also possible to purchase MPFF from numerous other companies. MPFF refers to a 90 % diosmin and 10 % hesperidin product, and the product with the most research is Daflon, but again it is a drug in Europe and many supplements can be found that can come close to what is in this drug. In other words, “Diosmin” is the supplement and it is usually combined with Hesperidin in US vein health supplements.

There is evidence that Daflon helps in many ways including prevents endothelial damage, reduces the inflammatory response seen in the microcirculation, improves venous tone and lymph drainage, protects veins from damage, and reduces the calf and ankle swelling and other symptoms of CVI [3, 225–228]. Most of the impressive data from Daflon comes from individuals with more serious CVI such as leg ulcers because of poor circulation so it is believed it can also help with varicose veins or at least preventing more varicose veins. It has also reduced symptoms of pain, heaviness and edema. There is also some preliminary evidence to suggest it can be used with conventional treatments for CVI. Daflon has also been used for the treatment of hemorrhoids, which makes some sense because this is also a problem of increased pressure to an area of the body that contains a concentration of veins. Daflon has not received any good research in the area of potential drug interactions so be careful and do not use in pregnancy or when breast feeding, and it theoretically can affect the metabolism of other drugs but there just have not been enough of these studies. There is also not enough description beyond placebo of potential side effects of diosmin but some clinical trials have reported a higher rate of gastrointestinal side effects. Another concern I have is that I would be careful about combining Diosmin with aspirin or other blood thinning medications only because diosmin can cause a reduction in red blood cells clumping and blood viscosity which means it may increase blood thinning.

Although no supplement is of course endorsed for lymphedema from objective reviews of the literature [229], there was one trial with Daflon (MPFF) 500 mg twice a day and breast cancer lymphedema reported in these reviews and published elsewhere [230, 231]. This was a randomized study of 104 women with upper limb edema following treatment and lymphoscintigraphy was used to evaluate lymph flow at baseline and end of 6-months. And changes in limb volume, measured every 2-months was the other endpoint. Interestingly, a 24-patient subset with severe edema was analyzed separately and demonstrated a significant improvement in the lymphoscintigraphic measurements in the MPFF group. However, overall there were no significant differences found between the lymphoscintigraphy parameters or limb volume of the MPFF and placebo groups at any measured interval of the trial (difference was only in the subset of patients with severe edema). The only parameters where significant differences occurred in the entire group that completed the trial was for symptom analysis. A significant reduction in heaviness symptoms was found for the MPFF (n = 45) product versus placebo (n = 48), and a significant decrease in discomfort for both the MPFF (n = 45) and placebo (n = 48) groups. It was pointed out that the authors failed to discuss the randomization method, blinding protocol, and no confidence intervals or standard deviations were published. And the study failed to provide information on withdrawals (94 patients completed the study) or side effects, which were reported in eight patients in the MPFF group and six patients in the placebo group.

A previously published pilot study of ten female patients treated for breast cancer utilizing 500 mg of Daflon twice a day for 6 months was also published by the same group of researchers before the larger clinical trial described previously [232]. All patients appeared to have improvement of symptoms and limb volume, and mean reduction in limb volume was 6.80 %, and functional parameters were determined by scintigraphy were significantly improved. Thus, it is understandable why a larger study was then conducted. And it raises the question of the potential for further study and the benefit versus risk scenario for utilizing this in breast cancer patients? How could 20-years have passed with no additional published reports on this compound or the supplement and breast cancer patients with lymphedema? This could be due to unpublished negative data or simply a lack of funding, but it is perplexing that not even a case study or case series has since been published (hint hint).

Horse Chestnut Seed Extract (HCSE or Aesculus hippocastanum) has been shown to reduce leg pain, swelling, itching, ankle and calf swelling to a similar extent as compression stockings [3, 233]. The active compound in HCSE is “escin” (complex active triterpenoid saponins, sometimes also referred to as “aescin”), which has been shown to block the activity of the enzyme hyaluronidase, which can degrade proteoglycans or st ructural support for veins especially when released in higher am ounts of legs during CVI because a large number of white bl ood cells are attracted to these areas. In other words, it blocks the destruction of components in the wall of the smallest blood vessels. However, gastrointestinal upset and dizziness were reported in up to one-third of the individuals in about half of the studies conducted, but other studies reported mild to minimal side effects. Studies are of short duration (4-weeks) so HCSE could be an option for the short-term relief of symptoms or swelling (edema) in individuals that do not receive a benefit or do not like to use compression stockings.

Dosage has been in the range of one capsule twice a day and each capsule was standardized to 50–75 mg of escin (again taken twice a day) and the initial treatment period was at least 12 weeks. Again, this supplement can strengthen the veins, reduce swelling and other issues over a short period of time. Studies of taking over long periods of time have not been done. Still, over seven placebo-controlled trials makes this one of the best dietary supplement options for CVI, which can be used with conventional treatment in many situations. HCSE has not received adequate research in the area of potential drug interactions so be careful and do not use in pregnancy or when breastfeeding and if a patient is on an anticoagulant.

Unfortunately no major published trials of this supplement have occurred to date (only an abstract of interim results). There was one phase-2 trial for lymphedema treatment in breast cancer survivors listed on clinicaltrials.gov and conducted at the University of Wisconsin (NCT00213928) and the study was apparently completed and funded by the Susan G. Komen Breast Cancer Research Foundation [234, 235]. It was a double-blind, randomized, and placebo-controlled study of breast cancer patients with arm lymphedema receiving HCSE (50 mg escins) twice a day for 3 months followed by a 1 month washout or placebo. A total of 25 patients were evaluable at 3 months and 24 patients were at intermediate assessment and although it appeared safe there were no statistically significant differences in lymphedema at 3 months by any of the measured techniques (no objective or subjective improvement).

The active ingredient is the “rutosides” [3, 229, 236]. It also comes in a topical 2 % gel that can be applied up to three times a day along with taking the supplement. One of the most commonly tested products is “Venoruton” (from Novartis, Basel, Switzerland) is actually a prescription drug in Europe (known as “oxerutins” or “hydroxyethylrutosides”—mixture of semisynthetic flavonoids), but a potential equivalent can be found over the coun ter in other countries if it cannot be purchased from Europe. “Oxerutins” in head-to-head testing against Daflon for example 2000 mg/day was the most common dose tested. It actually performed better in treating CVI and reducing ankle swelling compared to Daflon in one older head-to-head study. Rutosides appear to protect blood vessel walls from damage, and discouraging cells from adhering to the walls so that they can continue to function normally. Cramps, pain, heavy leg feeling, and swelling have been reduced with this product.