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,**,2
* Division of Hematology Oncology, University of Pennsylvania School of Medicine, Rena Rowan Breast Center, and ** Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA 19104
2 To whom correspondence should be addressed. E-mail: dma{at}mail.med.upenn.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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-lipoic acid, and capsaicin may all play a role in the empiric options available to patients with chemotherapy-induced neuropathy. Plant-derived preparations including black cohosh (Actaea racemosa), dong quai (Angelica sinensis), evening primrose (Oenothera biennis), and red clover (Trifolium pretense) are used by patients experiencing hot flashes due to premature menopause despite a paucity of clinical trial data demonstrating either safety or efficacy. Calcium and vitamin D are widely accepted as an effective means to retard bone loss leading to osteoporosis. Nutritional approaches to late effects of breast cancer chemotherapy offer the prospect of preventing or ameliorating these sequelae of treatment. However, except for vitamin D and calcium for prevention of bone loss, current clinical evidence supporting use of nutritional agents remains sparse.
KEY WORDS: • nutrition • breast cancer • chemotherapy • survivorship
An estimated 212,600 new breast cancers will be diagnosed during 2003 in the United States. Of these patients, 86% are expected to survive for at least 5 y, 71% for at least 10 y, and 53% for at least 20 y. Consistent with this generally positive outcome, two million breast cancer survivors now reside in this country. With more than three-quarters of women in all age groups surviving for at least 5 y after diagnosis, survivorship issues among breast cancer patients have risen in importance and warrant attention to education and research.
A majority of women with stage II and III breast cancer as well as a growing percentage of stage I cases now receive adjuvant chemotherapy after surgical excision of their primary tumor. Adjuvant chemotherapy typically lasts for 3–6 mo and includes multiple agents having distinct mechanisms of action and nonoverlapping toxicities. Table 1 summarizes commonly used regimens for adjuvant treatment of breast cancer. Important late effects of chemotherapy vary with cytotoxic agent used (Table 2) but include most prominently cardiac dysfunction, chemotherapy-induced neuropathy, ovarian dysfunction and failure, and skeletal problems following from bone loss (Table 3). In this article, we present an overview of these chronic morbidities including mechanisms by which they occur, medical management, nutritional approaches to prevention and treatment, and unresolved areas for future research.
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Cardiotoxicity was observed coincident with the introduction in the late 1960s of anthracyclines (e.g., doxorubicin) and can also occur more rarely after the use of other agents such as cyclophosphamide and fluorouracil. In an autopsy series of 64 patients who had received doxorubicin, 36 (56%) had histological signs of anthracycline-induced cardiotoxicity, although only 20 (31%) had prior documented impairment in left ventricular systolic function (1). Increased histological and clinical toxicity have been associated with doses >450 mg/m2, mediastinal radiation, and age >70 y. Additional identified risk factors include preexisting cardiac disease, nutritional status, schedule of doxorubicin administration, and other cytotoxic agents used, particularly paclitaxel and trastuzumab (2–5). In a study of 534 patients receiving cyclophosphamide, doxorubicin, and fluorouracil chemotherapy for breast cancer, incidence of clinical congestive heart failure was 1% in patients receiving up to 300 mg/m2 of doxorubicin and 4% in those receiving 450 mg/m2 (6). As many as 26–30% of patients receiving 
550 mg/m2 of doxorubicin may develop clinically significant congestive heart failure (7,8).
Histopathology of anthracycline-induced cardiac toxicity includes myofibril loss and disruption, mitochondrial swelling, and disruption of the sarcoplasmic reticulum (9). Clinical progression to severe heart failure coincides with myocyte necrosis. The most widely accepted mechanisms to account for anthracycline-induced cardiotoxicity involve reactive oxygen species generation and ATP depletion in cardiac myocytes. Anthracyclines bind cardiolipin, a phospholipid of the inner mitochondrial membrane required for full activity of respiratory chain enzymes (10). As a result of this binding, NADH donates electrons to the anthracycline rather than to cytochrome c, leading to two effects. First, ATP generation is inhibited. Second, the anthracycline transfers electrons to molecular oxygen, forming free radicals that produce direct myocardial injury (11). Mitochondria in noncardiac tissues do not rely on NADH-driven reduction from cytosol to respiratory chain and thus fail to activate anthracycline in this way (12). Doxorubicin also generates free radicals through a nonenzymatic pathway involving iron. Finally, in the face of such free radical induced oxidant stress, antioxidant enzymes are less abundant in the heart than in other metabolically active tissues such as the kidney and liver (13).
Anthracycline-induced cardiomyopathy presents clinically as congestive heart failure as well as possibly acceleration of coronary artery disease. Presentation of heart failure may occur at any time after the last dose of doxorubicin. The diagnostic gold standard remains endomyocardial biopsy, an invasive procedure requiring cardiac catheterization. Once systolic or diastolic dysfunction has been detected, outcome is variable, with some patients improving markedly on medical therapy and others progressing either to death or cardiac transplantation (14,15). Prediction of susceptibility remains a significant pharmacogenetic challenge. Dexrazoxane, an iron chelator, is recommended to decrease the incidence of doxorubicin-induced cardiotoxicity in patients receiving high cumulative doses of anthracyclines (16). Probucol, an antioxidant and lipid-lowering agent, can protect rats from anthracycline-induced cardiotoxicity and inhibits anthracycline-induced apoptosis of cardiac myocytes (17,18).
Nutritional approaches to prevention of anthracycline-induced cardiac toxicity have focused on free radical scavengers including vitamins, endogenous antioxidants, and plant-derived flavonoids (Table 4). Early efforts focused on prevention of cardiotoxicity by use of endogenous or diet-derived antioxidants. Encouraging results were observed in animals treated with vitamins C, A, and E (19–23). Early optimism faded, however, as the limitations in this approach became better appreciated. In general, dosages of these agents used in preclinical studies (e.g., 2 g/kg of ascorbic acid to prolong lives of mice receiving doxorubicin [19]) are not practical in humans. In addition, whereas zinc and selenium levels are decreased in patients with cancer, vitamins A, E, and ß-carotene typically are not (24). Ironically selenium was observed to protect against doxorubicin-induced cardiotoxicity in rats and rabbits (25,26), but deficiency of this mineral in rats led to no exacerbation of doxorubicin-induced heart damage (27). A single human study with -tocopherol showed no protective effect (28).
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Flavonoids are polyphenolic benzo-
-pyrone derivatives that are ubiquitous in plants, possess radical scavenging properties, and chelate iron. Grape seed proanthocyanidin extract has free radical scavenging activity superior to that of antioxidant vitamins and showed activity in multiple rodent models of doxorubicin-induced cardiac toxicity (39–41). Spinach flavonoids showed activity in preventing doxorubicin-induced heart damage in mice (42,43). No data are available on the use of any flavonoid-based preparation to prevent anthracycline-induced cardiotoxicity in humans. As has been true with other antioxidants mentioned above, naturally occurring flavonoids may be limited in utility because of the high doses (e.g., 500 mg/kg) required to protect against doxorubicin-induced cardiotoxicity in mice (44). Ultimately, synthetic flavonoids may prove more effective (45).
Thus far there has been no convincing demonstration that nutritional agents can prevent or forestall the progression of chemotherapy-induced cardiomyopathy. An enduring obstacle to the identification of such agents will be the difficulty of performing placebo-controlled trials with sufficient power to detect a modest effect in a low prevalence disorder (e.g., 1% of patients receiving adjuvant chemotherapy with anthracyclines who develop life-threatening heart failure). Even dexrazoxane, the single agent to prevent anthracycline-mediated cardiac toxicity that has been approved by the Food and Drug Administration, was only shown to be effective at cumulative doxorubicin doses well in excess of those known to be effective in adjuvant treatment of breast cancer. Pharmacogenetic approaches may yield a gene profile that predisposes to anthracycline-mediated cardiac toxicity. Further study of nutritional means to prevent or stabilize a decline in cardiac function might be more fruitful in such a subpopulation.
Peripheral neuropathy
Peripheral neuropathy after use of taxanes (paclitaxel and docetaxel) is dose limiting; high doses are associated with severe acute neurotoxicity in virtually all patients (46–48). Of the taxanes, paclitaxel is more likely to produce dose-limiting neurotoxicity whereas docetaxel is more likely to be associated with cumulative fluid retention (49). At doses used in patients receiving adjuvant treatment for breast cancer, up to 88% of patients receiving paclitaxel experience mild-to-moderate neurotoxicity, 21% of whom may require chemotherapeutic dose reduction. Severe toxic effects occur in 0–3% of such patients (46,50).
Taxanes act by stabilizing microtubules and lead to cell cycle arrest following from dysfunction of the microtubular mitotic spindle during mitosis (51). Microtubules are also required for axonal transport in nerve fibers, which may account for taxane-induced neurotoxicity that occurs in both large myelinated (proprioception, vibration) and small unmyelinated (temperature, pinprick) nerve fibers. As a general rule, muscle stretch reflexes are diminished in virtually all patients. Sensory symptoms typically include numbness and dysesthesias that begin in distal lower extremities and commonly occur in a stocking and glove distribution. Autonomic involvement and weakness with myalgias may occur in more severe cases. Most cases resolve after the completion or discontinuation of chemotherapy. Symptoms may worsen for weeks after cessation of taxanes and then generally improve over months. Recovery may be slow or incomplete. Diabetes, alcohol abuse, and inherited neuropathic syndromes can exacerbate the condition.
Prevention of severe chemotherapy-induced peripheral neuropathy can be accomplished by dose reduction or discontinuation of taxane containing regimens when symptoms become severe. No change in severity of neuropathy was observed when the same dose was given over 3 vs. 24 h (52). Development of agents for prevention and treatment of neuropathy in general has been hampered by three obstacles. First, interpreting results across studies is complicated by both the use of different scales for neurotoxicity grading and interobserver variability across grades of severity within a particular scale (53). Second, results in any given study may be statistically significant yet clinically insignificant in providing effective pain relief to a substantial number of subjects (54). Finally, the pathogenesis of peripheral neuropathy is multifactorial, and results obtained in one setting are not necessarily transferable to another. For example, a number of trials were performed to assess agents that might limit neuropathy induced by high dose cisplatin (55–57). However, cisplatin-induced neuropathogenesis is distinct from that caused by paclitaxel, so results are not necessarily applicable across chemotherapeutic agents. With respect to taxane-induced peripheral neuropathy, a single trial was reported that showed that pretreatment with corticosteroids has no effect on the development of docetaxel-related neuropathy (58).
Because of the large number of breast cancer survivors, neuropathy remains a significant clinical concern. Thus, an empiric approach to treatment of this problem can be applied based on results observed in other types of neuropathy, particularly diabetic neuropathy. Tricyclic antidepressants (TCA)3 are the best-studied agents in diabetic neuropathy; they reduce neuropathic pain by 
50% in one-third of all patients but are poorly tolerated (59). Gabapentin at 1600 mg/d appears to have activity similar to that of TCA and is much better tolerated (60). Anticonvulsants appear to have activity equivalent to TCA in diabetic neuropathy but are very poorly tolerated (61). Selective serotonin reuptake inhibitors including paroxetine and citalopram are reasonably well tolerated and reduce neuropathic pain in diabetic neuropathy better than placebo though somewhat less than TCA (62,63). Venlafaxine and bupropion have also shown activity in diabetic neuropathy (64,65).
Nutritional approaches to treatment of chemotherapy-induced neuropathy draw on randomized controlled clinical trials in diabetic neuropathy of evening primrose oil, -lipoic acid, and capsaicin (Table 5) (66). Evening primrose oil (EPO) is rich in (n-6) essential fatty acids that are essential components of nerve cell membranes. Commercial EPO typically contains 8% -linolenic and 72% linoleic acids. EPO has produced equivocal results in three trials of diabetic neuropathy, with two of these trials showing an improvement in nerve function measurements and symptoms and the third showing no improvement in vibratory perception threshold over placebo after the use of EPO (67–69). -Lipoic acid is an 8-carbon open or cyclic disulfide that both scavenges a wide array of reactive oxygen species and restores other antioxidants, such as vitamins C and E, in vivo (70). Three trials support the use of -lipoic acid in diabetic neuropathy, and it is approved for this use in Germany (71–73). In addition, a small case series suggests that -lipoic acid may ameliorate chemotherapy-induced neuropathy caused by a combination of docetaxel and cisplatin (74). Capsaicin is an ingredient of chili pepper that depletes substance P from unmyelinated sensory C fibers that transmit shooting, burning, and sharp pain. After several weeks of topical applications (typically associated with a burning sensation), endogenous neurotransmitter stores decline. Afferent sensations of touch, temperature, and vibration are unaffected (75). Two studies show moderate efficacy of capsaicin in relieving diabetic neuropathy (76,77), whereas another shows no effect or an effect that loses significance on application of intention-to-treat analysis (78).
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Ovarian dysfunction or failure is common in premenopausal women receiving chemotherapy. Patient age and drug dosage predict risk most strongly. Approximately 30% of women under age 35, 50% of women aged 35–40, and 75–90% of women in their 40s may experience permanent cessation of menstrual function after chemotherapy, leading to premature menopause (79,80). It is estimated that as many as 150,000 women were rendered prematurely postmenopausal by breast cancer treatment (81). In vitro studies reveal that chemotherapy induces apoptosis in pregranulosa cells of primordial follicles, reducing their likelihood of successful subsequent ovulation (82).
Consequences of menopause include hot flashes, sleep disturbance, sexual dysfunction, and cognitive impairment. Although estrogen replacement therapy (ERT) has long been used for these symptoms, recent results from the Women's Health Initiative concerning the increased risk of breast and other cancers as well as the lack of efficacy of ERT to remedy these conditions has called this strategy into question (83–87). Furthermore, ERT is contraindicated in most women with a history of breast cancer because of the possibility of estrogen stimulating dormant metastatic cancer cells, particularly if the original tumor was estrogen receptor positive. This issue remains controversial (88,89). Thus alternative methods have been pursued for managing menopausal symptoms in breast cancer survivors.
Vasomotor symptoms, including hot flashes, night sweats, insomnia, headaches dizziness, and palpitations are common in breast cancer survivors experiencing premature menopause. Several nutritional approaches to management of menopausal symptoms in breast cancer survivors have been embraced despite a paucity of data from randomized trials showing safety, efficacy, or optimal dosing. Hot flashes are the most common and bothersome of perimenopausal symptoms, and several natural substances have been purported to provide relief. These include black cohosh (Actaea racemosa), dong quai (Angelica sinensis), evening primrose (Oenothera biennis), and red clover (Trifolium pretense) (Table 6).
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Dong quai is a common Chinese herb extracted from the root of A. sinensis. Although typically used in combination with other Chinese herbs as part of traditional Chinese medicine, this herb can be purchased as a single agent in the United States. A single randomized, double-blind, placebo-controlled trial was reported by Hirata et al. (96); 71 postmenopausal women with >14 hot flashes weekly (of any severity) or >5 moderate or severe hot flashes weekly were given either placebo or dong quai, three capsules, 3 times/d, the equivalent of 4.5 g/d of dong quai root over 6 mo (96). No significant benefit was seen in the dong quai group. Dong quai does not contain phytoestrogens, and data on stimulation of estrogen receptor–positive breast cancer cells or binding to estrogen receptors are conflicting (97). Thus the safety of dong quai in breast cancer survivors is unknown. Dong quai contains coumarins and can cause bleeding when administered concurrently with warfarin. Photosensitivity has also been reported due to the presence of furocoumarins (98).
Evening primrose flowers and seeds are pressed to make oil that contains a high amount of the (n-6) fatty acid -linolenic acid, a precursor of prostaglandin E1. Chenoy et al (99) reported results of a randomized, double-blind, placebo-controlled trial in postmenopausal women who had hot flashes at least three times daily and either elevated gonadotropin levels or amenorrhea for at least 6 mo. Subjects were administered either placebo (n = 28) or twice daily doses of a preparation containing 2 g evening primrose oil and 40 mg vitamin E (n = 28) over 6 mo. Only 18 women in the treatment group and 17 women in the placebo group completed the trial. There were no differences observed between the groups with respect to the frequency of either daytime or evening flashes. Common adverse effects include upset stomach, nausea, headache, and soft stool (90). Evening primrose can lower seizure threshold. There are no data on safety or efficacy of this preparation in breast cancer survivors.
Red clover contains phytoestrogens formononetin, biochanin A, daidzein, and genistein. Two small, 3-mo Australian clinical trials showed no benefit of red clover extract for hot flashes (100,101). More recently, U.S. investigators reported the results of a larger, randomized, placebo-controlled, double-blind trial of menopausal women aged 45–60 y who were experiencing at least 35 hot flashes per wk (102). After a 2-wk placebo run-in, 252 subjects were randomly assigned to receive Promensil (82 mg of total isoflavones per d), Rimostil (57 mg total isoflavones per d), or placebo, administered for 12 wk. Ninety-eight percent of the patients completed the 12-wk protocol. Although Promensil and Rimostil reduced hot flashes by 41 and 34%, respectively, compared with placebo, the authors concluded that neither supplement had clinically important effects on hot flashes or other symptoms of menopause. There are no data on these supplements specifically in breast cancer patients. Although the profile of isoflavones differs between soy and clover extracts, the latter retain the potential to stimulate breast cancer cells, and data on safety in breast cancer patients is lacking.
Vitamin E has a long history of use for hot flashes, both in the general population and in breast cancer survivors, but reports of efficacy have been anecdotal. In 1998, Barton et al. (103) reported the first (and to date only) randomized, placebo-controlled trial of vitamin E for hot flashes in breast cancer survivors. In this trial, patients received vitamin E at 800 IU/d for 4 wk followed by an identical-appearing placebo for 4 wk or vice versa. Diaries were used to measure toxicities and hot flash frequencies. Of the 120 patients who enrolled, 105 completed the treatment. Overall, the use of vitamin E was found to result in one less hot flash per day compared with placebo. Although toxicities were nonexistent, patient preference did not favor the vitamin E arm. Thus, although vitamin E appears to be safe for hot flashes in breast cancer survivors, no established data support its efficacy for this indication.
Bone loss
Bone loss is an established complication of aging and is intimately linked to the development of natural menopause (104). In addition to the induction of premature menopause, breast cancer survivors may have other risk factors for bone loss, and osteoporosis is one of the long-term complications of successful tumor treatment (105). Osteoporosis is a condition in which bone mass is decreased, leading to increased fracture, hospitalization, and subsequent decrease in function and independence. It is defined in terms of bone mineral density (BMD), and measurement is becoming essential for early diagnosis. Few studies have examined BMD to determine the incidence of clinically significant bone loss among women with nonmetastatic breast cancer. Shapiro et al. (106) performed a small but well-designed study of 49 premenopausal women with stage I or II breast cancer receiving adjuvant chemotherapy. BMD, osteocalcin, and alkaline phosphatase were measured at baseline and at 6- and 12-mo posttherapy. As a result of chemotherapy, 35 of 49 women became postmenopausal. Women who developed ovarian failure had statistically significant bone loss from baseline (in the spine, femoral neck, and trochanter at 6 mo: -4, -2.6, -3%, respectively; at 12 mo: -3.7, -2, and -1.1%, respectively) in contrast to the 14 women who retained ovarian function. However, this study did not include a multivariate analysis adjusting for other factors that might have affected these findings. An earlier pilot study by Headley et al. (107) examined the BMD of women undergoing adjuvant chemotherapy for breast cancer. Of the 27 patients who had BMD measurements before and immediately after the administration of chemotherapy, 16 developed amenorrhea. In this small pilot study, mean BMD measurements immediately posttreatment were found to be 14% lower in women with ovarian failure than in those who continued menstruating. Chemotherapy has been hypothesized to increase the risk of osteopenia and osteoporosis either through direct effects on the bone matrix or indirectly as a consequence of premature ovarian failure. Three additional studies have yielded information on the effects of chemotherapy on bone loss (108–110). All three were randomized clinical trials of bisphosphonate treatment (clodronate or risedronate) given during chemotherapy and were thus not designed to address the questions of extent, time course, or reversibility of bone loss during treatment. Table 7 shows the changes in BMD measured for patients in the placebo group of each of these trials. Declines in lumbosacral spine density ranged from 2.7 to 9.5% whereas changes in femoral neck density ranged from 3.3 to 4.6% without the use of bisphosphonates. In all three studies, the bisphosphonate agent was able to prevent bone loss. However, none of the studies followed patients beyond 24 mo after completion of treatment, compared these patients with age-matched controls, or examined the role of other risk factors in modulating the effect of chemotherapy.
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Taken together, these findings suggest that breast cancer survivors, particularly those receiving adjuvant chemotherapy, are at risk of developing defects in bone mineralization and that these effects may be modulated by the development of treatment-induced menopause. Definitive conclusions cannot currently be drawn regarding the independent contribution of chemotherapy or menopausal status on the subsequent risk for osteoporosis or osteopenia. The identification of differences in bone loss by chemotherapy type is unknown, as is the effect of tamoxifen on bone mineralization in premenopausal women. Without routine screening or an understanding of risk factors for bone loss, endocrinologists often see patients with therapy-induced osteoporosis at an advanced stage of disease, when fractures are already present. Because fractures can cause significant morbidity, mortality, and financial cost, and the best treatment results are achieved with early-stage osteoporosis, it is key to identify cancer survivors at increased risk for osteoporosis and screen them at appropriate intervals.
Nutritional approaches to managing bone health in breast cancer survivors focus primarily on maintaining adequate intake of calcium and vitamin D. Calcium intake is critical to bone maintenance. However, recommendations for optimal intake vary, and several methods have been devised to assess dietary requirements (113). Total daily requirement depends upon both the rate of bone accretion and the rate of gastrointestinal calcium absorption. The National Institutes of Health (NIH) Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy recommends 1000–1500 mg/d for adults aged 17 y and over (b). Specific recommendations for breast cancer survivors or those who have received chemotherapy in general are lacking. Risk factors for inadequate dietary intake include restricted intake of dairy products, low intake of fruits and vegetables, and high consumption of low calcium beverages such as carbonated soft drinks (113).
Vitamin D is required for optimal calcium absorption, and thus adequate intake is critically important to maintaining bone health. The current recommendation is 400–1000 IU/d for adults (113). Endogenous synthesis is the main source of vitamin D in individuals with adequate sun intake (112); however, vulnerable groups may need supplementation. For those with borderline endogenous synthesis, other factors such as high protein diet, caffeine, phosphorus, and low sodium intake can drive levels down further into the danger zone (112).
Exercise and physical activity early in life contribute to peak bone mass, and both resistance and high impact exercise types appear to be the most beneficial (114). Few studies have documented the benefits of exercise on bone density in middle and late life. Several prospective studies designed to examine the long-term health benefits of exercise in breast cancer survivors are currently underway.
Nutritional approaches to chronic toxicities of adjuvant chemotherapy for breast cancer stem from diverse origins including pathogenesis of toxicity, application of agents used for closely related problems, and traditional medicine. Evidence is strongest for use of calcium and vitamin D to retard bone loss. For other toxicities, evidence is weak and in most cases will remain so because of either the large sample numbers needed to show an effect in a disorder of low prevalence (anthracycline-induced cardiotoxicity) or the lack of a proprietary commercial interest driving performance of trials (natural products for neuropathy or menopausal symptoms). Flavonoids may ultimately be useful in prevention of anthracycline-induced cardiotoxicity. EPO and -lipoic acid are a reasonable complement to other empiric therapies for treatment of chemotherapy-induced neuropathy. Black cohosh, dong quai, evening primrose, and red clover will likely continue to be used for treatment of hot flashes despite marginal evidence of efficacy. Safety remains a concern.
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FOOTNOTES |
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3 Abbreviations used: BMD, bone mineral density; EPO, evening primrose oil; ERT, estrogen replacement therapy; TCA, tricyclic antidepressant.
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