Symptom management in premenopausal patients with breast cancer

Review

Symptom management in premenopausal patients with breast cancer Charles L Loprinzi, Sherry L Wolf, Debra L Barton, Nadia N I Laack

Women with breast cancer have many adverse symptoms, of which some are specific to premenopausal patients. Management of these common symptoms include non-hormonal drugs, such as antidepressants and antiseizure compounds to alleviate hot flushes. Non-oestrogenic vaginal lubricants seem to moderately decrease occurrence of vaginal dryness and dyspareunia. Transdermal testosterone alone has not been shown to improve libido in these women. Options for fertility preservation include cryopreservation of embryos or oocytes before chemotherapy. Exercise is the one evidenced-based intervention shown to positively affect cancer-related fatigue. However, effective prevention and treatments for peripheral neuropathy and paclitaxel acute pain syndrome remain elusive. Weightbearing exercise helps to maintain bone strength with adequate intake of calcium and vitamin D. Use of bisphosphonates in women taking aromatase inhibitors (combined with ovarian suppression in premenopausal women) to prevent bone fractures has not been substantiated, although it should be considered in women with osteoporosis. No specific drug has been shown to prevent radiation-induced dermatitis alone. Although some effective treatments can counteract symptoms related to cancer or treatments, research is needed to expand evidence-based care in premenopausal survivors of breast cancer.

Introduction An estimated 25% of patients in the USA are diagnosed with breast cancer while they are still premenopausal;1 these patients have many adverse symptoms as a result of cancer or treatment, in a manner similar to their postmenopausal counterparts. However, some symptoms are more prominent in premenopausal women, including: radiation-induced dermatitis, hot flushes, sexual health and infertility, fatigue, chemotherapyinduced peripheral neuropathy, chemotherapy-induced bone loss, and chemotherapy-induced cognitive dysfunction.

Radiation-induced dermatitis Dermatitis, a cause of clinically significant acute morbidity, is a major problem for patients receiving radiotherapy to the breast and, especially, the chest-wall (figure 1). Risk factors for severe skin reactions include post-mastectomy radiotherapy (which usually needs a bolus to intentionally increase skin dose), use of a radiotherapy boost, large breast size, and increased bodymass index.2,3 Previous chemotherapy4 and young age2 have also been associated with more severe skin reactions. Thus, premenopausal women who are younger and often receive chemotherapy could be at increased risk for acute skin toxic effects from radiotherapy. Although several prospective trials have assessed the efficacy of topical compounds in preventing acute skin reactions during radiotherapy,2–6 evidence is insufficient to recommend a specific drug at this time. Trials investigating the commonly used topical drugs, such as aloe vera gel and trolamine (biafine), have shown no benefit compared with best supportive care, usually an aqueous cream. The exception is a prospective study using Calendula cream,4 a derivative from a plant in the marigold family, which showed a reduction in severity of radiation dermatitis and pain compared with the control, trolamine. Because of the www.thelancet.com/oncology Vol 9 October 2008

Lancet Oncol 2008; 9: 993–1001 Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA (Prof C L Loprinzi MD, S L Wolf MS, D L Barton PhD); and Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA (N N I Laack MD) Correspondence to: Prof Charles Loprinzi, Mayo Clinic, Rochester, MN 55905, USA [email protected]

differences in consistency between the creams, patients were not masked to treatment, and since the Calendula cream was difficult to apply, some patients discontinued its use during the trial. Although topical steroids have been used to manage symptomatic itching and irritation during radiotherapy, data suggest that they could also prevent or reduce radiation dermatitis if used prophylactically. Preliminary information suggests that a steroidal preparation, mometasone cream, can help decrease radiation-induced dermatitis.7 A North Central Cancer Treatment Group (NCCTG) placebo-controlled trial (n=176) randomly assigned patients with breast cancer undergoing radiation to receive mometasone or placebo cream daily during radiation. Results from this trial are expected by early 2009.

Figure 1: Radiation dermatitis can be caused by radiation to the breast and chest wall

993

Review

Improved radiotherapy techniques have been associated with a reduction in acute radiation wounds and moist desquamation, especially in women with large breasts.8 Intensity-modulated radiotherapy (IMRT) has been used as a method to distribute the radiation dose homogeneously and reduce hot spots of radiation dose to the breast. In the only randomised study so far, IMRT use compared with traditional treatment resulted in a significant reduction in moist desquamation during the course of treatment (48% vs 31%, p=0⋅02).9 Although these studies need further validation, modern radiotherapy techniques are expected to reduce the maximum severity of radiation dermatitis, compared with traditional treatment. Since no methods have been established to prevent this toxic effect, treatment is still needed for dermatitis which becomes apparent during a course of radiotherapy. Current consensus recommendations for symptomatic care during radiotherapy include washing with water and gentle soap; the use of plain, non-scented, lanolin-free hydrophilic cream; and low-dose (typically 1%) steroid cream for symptomatic itching or irritation.10 Burn wounds that develop at the end of radiotherapy (moist desquamation) are treated similarly to thermal burns with occlusive creams (eg, Silvadene) or wound dressings that promote a moist wound environment (eg, xeroform dressing).10

Hot flushes Hot flushes are a common problem in women, generally starting in the late premenopausal period of their life. Hot flushes in survivors of breast cancer could be more distressing than in the general population,11 potentially because women having premature menopause due to chemotherapy or oestrogen deprivation treatment have hot flushes more abruptly and earlier in life than do those with a more natural menopausal transition. Medicinal treatments for amelioration of hot flushes can be divided into hormonal and non-hormonal medications. Although hormonal therapies are regarded as most effective, concerns regarding increased risk of tumour growth and promotion (especially in hormonereceptor positive tumours), currently limit their use in patients with breast cancer. Oestrogen treatment provides about an 80% reduction in hot flushes.12 Progesterone treatment alone seems to work as well as oestrogen at controlling hot flushes, with both megestrol acetate and medroxyprogesterone acetate also decreasing hot flushes by about 80%.13,14 Nevertheless, although lacking proof, progesterone treatment could be detrimental with regards to breast cancer risk, and the use of progesterone in patients with a history of breast cancer is currently limited. Because of these concerns, research efforts have focused on non-hormonal drugs to alleviate hot flushes, such as clonidine. Although clonidine decreases hot flushes by about 40%, this finding is only a 15% improvement over placebo.15 Although this additional 994

reduction of hot flushes is significant, it is only a moderate effect and comes with toxic effects, such as drowsiness, lightheadedness, and a dry mouth. In view of clonidine’s restricted benefit, its evident toxic effects, and the availability of other new drugs, clonidine is not often the first choice of treatment for hot flushes. New antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), represent the next class of non-hormonal drugs that have repeatedly been shown to reduce hot flushes. Initial anecdotal clinical findings (followed by pilot trials) have suggested that venlafaxine and paroxetine decreased hot flushes.16,17 Subsequently, one of the first double-blinded, placebocontrolled trials showed that controlled-release 75 mg venlafaxine reduced hot flushes by about 60% compared with 27% seen with placebo.18 Subsequently, two placebocontrolled clinical trials showed that 10–25 mg/day of paroxetine also decreased hot flushes by about 60%.19,20 Another double-blind, placebo-controlled trial21 showed that 20 mg/day of fluoxetine reduced hot flushes more than did placebo, but not as much as that seen with venlafaxine or paroxetine. Data from placebo-controlled clinical trials have shown that low doses of citalopram (10–20 mg/day) and desvenlafaxine (also a new drug) decrease hot flushes to a similar degree as do venlafaxine and paroxetine.22,23 Three additional placebo-controlled, double-blinded clinical trials investigated sertraline, another SSRI, for hot flushes.24–26 Although researchers saw some improvement in hot flushes in these trials, none of the results was significantly better than placebo, indicating that sertraline does not work as well as the other new antidepressants against hot flushes. Two clinical trials of new antidepressants have confused the picture regarding their use for hot flushes,27,28 suggesting that citalopram, fluoxetine, and venlafaxine are not effective. A major procedural issue with these two trials was they had not recorded a baseline period of hot flushes before the use of the antidepressants they studied. Thus, these trials were unable to determine whether the treatments reduced hot flushes from baseline.29 A meta-analysis of new antidepressants as treatment for hot flushes was lukewarm about the effectiveness of these drugs.30 This meta-analysis was not done on individual patient data but on reports from individual studies. The researchers of this meta-analysis attempted to report the effect of drugs to reduce hot flushes from baseline, using results of six studies looking at new antidepressants. Unfortunately, two of the studies included were those mentioned previously, which did not include baseline data.27,28 Thus, this meta-analysis has a major procedural problem that affects validity and interpretation of the results. A subsequent individual-case pooled analysis was done examining all the placebo-controlled studies of new antidepressants that were published before January, www.thelancet.com/oncology Vol 9 October 2008

Review

2008, which included a placebo group, and had a baseline period whereby hot flush information was obtained.31 These studies showed that, during a 4-week period, a reduction in hot flushes of about 25% was recorded in the placebo groups, whereas additional reductions in hot flushes (compared with placebo) were: 9–18% with sertraline, 13% with fluoxetine, 13–41% with paroxetine, and 33% with venlafaxine. The effect of these drugs on hot flushes was independent of patient age. Notably, some of these new antidepressants inhibit the cytochrome P450 enzyme CYP2D6,32 which is needed to metabolise tamoxifen to its most active metabolite in breast cancer, endoxifen. Paroxetine greatly inhibits CYP2D6, with reduced inhibition by fluoxetine and sertraline. Therefore, these compounds should be avoided if patients are given tamoxifen. However, venlafaxine does not seem to inhibit CYP2D6 substantially.32,33 Gabapentin, an anti-seizure medication, is another nonhormonal agent that has been shown to decrease hot flushes. On the basis of anecdotal findings,34 an initial pilot trial showed that gabapentin decreased hot flushes by 66%.35 Subsequently, three randomised, placebo-controlled trials were done, each of which included a baseline period of hot-flush monitoring before initiation of the study agent.36–38 These trials showed that gabapentin (300 mg three times daily) decreased hot flushes by about 50%, 4 weeks after it was initiated, and that higher doses (ie, 2700 mg/day) might work better. Two of these trials included data up to 12 weeks, showing maintenance of this decreased hot-flush activity for this period of time. There are other non-hormonal agents that have been prospectively studied in placebo-controlled trials. However, up to now, no convincing evidence for the efficacy of these drugs against hot flushes has been produced. These agents include vitamin E (only one trial which had a trend toward a slight decrease in hot flushes),39 black cohosh,40 and several soy products.41,42 Available data suggest that non-oestrogenic drugs for hot flushes work in patients taking tamoxifen as well as in those not taking tamoxifen43 An exception is that women given tamoxifen seem to have an abrupt increase of hot flushes for a few days after starting treatment with a progestational compound.44 However, after 4 weeks of treatment, hot-flush reductions are similar in patients who are given tamoxifen compared with those who are not. Non-pharmacological interventions for hot-flush reduction are also being investigated.45 Most studies so far have been pilot trials; results from randomised trials are pending. Hypnosis has been reported to substantially reduce hot flushes, with a pilot trial reporting a 60% reduction in hot-flush frequency and 70% reduction in hot-flush scores after five sessions of self-hypnosis training.45 Furthermore, preliminary data support that slow, abdominal breathing (paced respiration) once or twice per day could reduce hot flushes by about 40%.46 Case reports attesting to the efficacy of cognitive behavioural www.thelancet.com/oncology Vol 9 October 2008

Consider use of non-hormonal drug: new antidepressant (eg, venlafaxine or paroxetine) vs gabapentin vs clonidine If not effective Consider switch to alternative non-hormonal drug If not effective Consider non-oestrogenic hormonal treatment (ie, one intramuscular injection of medroxyprogesterone acetate or daily oral megestrol acetate) If not effective Consider oestrogen with or without progestogen

Figure 2: Hot flush pharmaceutical treatment options for premenopausal breast cancer survivors

therapy to reduce hot flushes use progressive muscle relaxation with slow, abdominal breathing to reduce physiological arousal and stress.47 Pilot studies have been small, with no more than 33 women, and only a few have included control groups. Large, randomised, wellcontrolled trials are in progress to try to define the precise role and efficacy of these paced breathing interventions. Pilot information has indicated that a stellate ganglion block can alleviate hot flushes.48,49 Finally, ambient temperatures have been thought to affect the frequency and severity of hot flushes.50 Data indicate that core body temperature rises as much as 20 min before a hot flush is experienced. Therefore, the core body temperature should be kept down. Cooling strategies include the use of air conditioning or a fan to control environmental temperatures, and the wearing of open-weave cottons to allow circulation around the skin. Affected women are recommended to avoid behaviours that can increase the body temperature, such as eating spicy foods, drinking warm or hot liquids, and drinking alcohol. Figure 2 shows a suggested schema for pharmacological treatment of hot flushes in young women.

Sexual health Sexual-health problems can adversely affect up to 90% of women diagnosed and treated with cancer. The highest rates have been reported in women with gynaecological cancers but women with breast cancer are also affected to a large degree. Areas that are vulnerable, with respect to sexual-health problems, include self-image changes, partner issues, and sexual functioning. The latter includes vaginal dryness and dyspareunia as well as decreased desire and arousal.

Self-image and relationship changes Surgery and medical treatment for cancer can alter body image because of changes in form, loss of body hair, and differences in organ sensations. These changes can affect how a woman thinks about herself and how a couple intimately relates to each other. Preparatory information about possible changes and resources for coping, provided early in the cancer experience, could be helpful.51 995

Review

Vaginal dryness and dyspareunia Vaginal changes, as a result of oestrogen depletion, can cause a sensation of dryness and pruritus, with an increased risk of urinary-tract infection (due to decreased pH) and dyspareunia. By contrast with hot flushes, which generally last for a few years in most women and then dissipate, vaginal dryness often becomes a prominent problem in women the longer they are oestrogendepleted. Non-oestrogenic vaginal lubricants seem to moderately decrease symptoms of both vaginal dryness and dyspareunia. These lubricants include water-based lubricants and polycarbophil moisturisers. Polycarbophil moisturisers bind to the tissues, providing more than simple surface lubrication.52 In general, studies that have compared these two types of lubricants, however, have shown similar efficacy with respect to symptoms of vaginal dryness. But the polycarbophil moisturiser could provide more help against dyspareunia.53 Subjectively, some women do not like using vaginal lubricants in cream or gel form, because they can be messy.54 Nonhormonal vaginal lubricants have been compared with local oestrogen preparations,55 with results revealing that local oestrogen preparations seem to improve a broader range of symptoms, probably due to benefits in vaginaltissue health. Oestrogen, given systemically or locally, can alleviate vaginal dryness in most women to whom it is given. Nevertheless, in patients with hormone-receptor-positive breast cancer, the use of systemic oestrogen or vaginal oestrogen preparations clearly raise concerns. Virtually all local oestrogen preparations are probably absorbed systemically, at least to some degree. Sensitive methods that are used to measure serum oestrogen56 and changes in serum lipid concentrations support this contention.57 Also, data from the Anastrazole, Tamoxifen, Alone, or in Combination (ATAC) trial58 suggest that the addition of tamoxifen to aromatase inhibitors could decrease the benefit of aromatase inhibitors (potentially from the small amount of oestrogenic activity from tamoxifen). Thus, vaginal oestrogen use for patients receiving aromatase inhibitors leads to increased concerns. In view of these concerns, efforts have been underway to look for other means of alleviating vaginal dryness. Preliminary data from a study in patients with Sjögren’s syndrome suggest that pilocarpine can be helpful.59 The main outcome of this trial was related to oral and ocular dryness. Nevertheless, a significant decrease in vaginal dryness was reported (p=0⋅02, 25% vs 14% reduction). Furthermore, anecdotal information suggests that pilocarpine can alleviate vaginal dryness in patients with breast cancer.60 Currently, an NCCTG clinical trial is investigating pilocarpine for treatment of vaginal dryness in a randomised, double-blind manner.61 Thus, to err on the side of safety, non-oestrogenic vaginal preparations to treat vaginal dryness in survivors of hormone-receptor-positive breast cancer are 996

recommended. The choice to use oestrogen treatment needs careful contemplation. Patients with severe vaginal dryness may wish to try vaginal oestrogen despite the risks. A dose effect exists with respect to systemic absorption, with high doses yielding the highest systemic absorption and effects.54 Therefore, the lowest dose possible should be used to obtain improvement.

Desire Sexual desire, or libido, can also decrease as a result of the cancer experience. Reduced hormone concentrations that lead to depressed mood, poor sleep, and vaginal atrophy can contribute to these problems. Furthermore, changes in sensation in various erogenous areas of the body can decrease motivation to engage in sexual activity. Testosterone is often regarded as the hormone of desire, and several clinical trials have investigated the addition of testosterone to oestrogen to enhance libido in women.62 Many of these trials have revealed positive effects on libido in women with healthy oestradiol concentrations. In a study, 150 women with a history of cancer were given transdermal testosterone only (ie, not with concurrent oestrogen) to see if low libido improved.62 Women in both treatment groups, on average, reported a moderate improvement in libido over the course of the study. However, testosterone did not significantly increase libido compared with placebo, despite substantially improved free testosterone concentrations in the active treatment group. A focus on the many comorbid causes that contribute to libido—such as hot flushes, vaginal dryness, stress, and fatigue—can be useful. Cognitive behavioural interventions to change cognitions and manage stress could also be helpful for these issues.63

Fertility issues The increasing number of premenopausal women diagnosed with breast cancer, coupled with improved survival, emphasises the issue of ovarian dysfunction and fertility. The risk of chemotherapy-related amenorrhoea, menopause, and infertility is related to patient age and treatment received, with alkylating drugs being the most likely to induce premature ovarian failure.64 In women receiving doxorubicin and cyclophosphamide, 37–55% develop chemotherapy-induced amenorrhoea,65 with younger women (aged 40 years or younger) less likely to become amenorrhoeic and more likely to resume menstruation if they do become amenorrhoeic. Duffy and colleagues surveyed 166 patients with breast cancer diagnosed at age 50 years or younger and found that only 34% recalled a discussion with a physician about fertility, although 68% recalled a discussion about menopause.66 In a survey of young survivors of breast cancer aged 40 years or younger, 73% expressed some concern regarding infertility and 27% indicated that such concern affected their treatment decisions.67 www.thelancet.com/oncology Vol 9 October 2008

Review

Historically, women were recommended not to become pregnant after a diagnosis of breast cancer, because of concerns that a pregnancy might increase the risk of breast-cancer recurrence. However, epidemiological studies have failed to support this recommendation and suggest that women who become pregnant after breast cancer actually live longer than those who do not.68 Pregnancy is unlikely to protect against breast-cancer recurrence. Instead, it is likely that women who have an early breast-cancer recurrence do not get pregnant often, compared with those who do well for years and survive long enough to get pregnant. This event has been called the healthy mother effect.69 Despite the absence of long-term efficacy data, options for fertility preservation include cryopreservation of embryos or oocytes. Studies have examined the use of tamoxifen and aromatase inhibitors as part of a regimen to reduce oestradiol amounts during ovarian stimulation. Results have led to successful cryopreservation of embryos with reduced oestrogen concentrations.70 A report has suggested that egg retrieval does not have to delay the time to breast-cancer treatment.71 Laparoscopic surgery to remove ovarian tissue for cryopreservation is another option, although concerns about the reintroduction of malignant cells by implantation and also the low success rates have limited use of the procedure. Despite concerns, a detectable increased risk of disease recurrence associated with most fertility preservation options and pregnancy has not yet been shown, even in hormone-sensitive tumours.68 To meet the needs of young women who use fertility preservation before initiating adjuvant chemotherapy, integration of reproductive endocrine expertise is needed. Unfortunately, not all patients are in close proximity to reproductive medicine clinics offering such services. An expert panel from the American Society of Clinical Oncology recently summarised recommendations for fertility preservation to provide guidance to oncologists about this subject.72 Many providers recommend that women wanting to conceive should wait at least 2 years after diagnosis before becoming pregnant. This recommendation is not based on concerns about pregnancy increasing breast-cancer recurrence, but rather on the concern that a breastcancer recurrence occurring soon after diagnosis carries a poor prognosis and could have adverse social effects on the family. In women who do deliver, no long-term effect of their previous chemotherapy on their offspring has been noted.73 Women with anatomical changes after breast cancer can breastfeed on the affected side if the nerves remain intact and the milk ducts are connected to the nipple. In women who receive radiotherapy as a part of breast-conservation treatment, lactation is possible in the untreated, contralateral breast. In the treated breast, up to 60% of women can have successful lactation, although milk volume is reduced in 80% of treated breasts.74 www.thelancet.com/oncology Vol 9 October 2008

Panel: Standard recommendations for premenopausal women at risk for chemotherapy-induced bone loss Regular weight-bearing exercise Control bodyweight Adequate calcium and vitamin D intake Monitor bone density in women at risk for osteopenia Consider bisphosphonates in women with pronounced osteopenia or with osteoporosis

Lactation consultants should be incorporated into the care of these patients early in the prenatal and postnatal periods for support and guidance.75

Fatigue Fatigue is one of the most prevalent side-effects of cancer diagnosis and treatment and can persist long after treatment is completed. Women who are premenopausal at diagnosis are probably working, could be at important stages of their careers, and could have young children and ageing parents for whom they are primary caregivers. The experience of fatigue can make these already exhausting roles even more difficult, and can also affect many other areas of life, including sexual and cognitive energy. The physiology of fatigue, with respect to breast-cancer survivors, is not clearly understood. Some hypotheses based on scarce data have pointed to the cause of fatigue. One such hypothesis states that the hypothalamicpituitary-adrenal axis is not as efficient after chemotherapy. This effect results in the inability to combat physiological stress with an increase in proinflammatory cytokines and a flattened cortisol response.76 Exercise is the one evidenced-based intervention so far that has shown to positively affect cancer-related fatigue.77 Exercise can improve the body’s immune regulation.78 Current recommendations for exercise include moderate walking, building up to 30 min/day, three or more times per week. Pharmacological and herbal preparations, such as modafinil, long-acting methylphenidate, and Wisconsin ginseng, are currently being studied in clinical trials61,79,80 but are not currently recommended for routine use in clinical practice.

Chemotherapy-induced peripheral neuropathy (CIPN) Peripheral neuropathy is a common problem related to some chemotherapy drugs, including taxanes, platinum compounds, and epothilones. Peripheral neuropathy usually develops over several courses of chemotherapy and can be a dose-limiting toxic effect. Symptoms, such as numbness, tingling, dysaesthesias, and pain, are usually most prominent in the fingers and toes, spreading proximally as they become more established. Pilot data suggest that vitamin E could prevent CIPN.81 An interim analysis of 50 patients who received a total 997

Review

cumulative cisplatin dose of 300 mg/m² with vitamin E, versus a placebo, revealed that patients receiving vitamin E had significantly decreased CIPN.82 A separate NCCTG trial has assigned 200 patients who, while receiving neurotoxic chemotherapy, also received vitamin E versus placebo. These results should be available by 2009. If vitamin E is confirmed to help reduce CIPN, then further safety information should be obtained before it can be established as a treatment for patients with curable cancers. This information is important because vitamin E has been suggested to interfere with antitumor activity, especially in patients receiving radiotherapy.83 In addition to the prophylactic treatments discussed above, some drugs have been identified to use for the treatment of established CIPN. Gabapentin,84 lamotrigine,85 and nortriptyline86 have all been tested in randomised, placebo-controlled, double-blinded manners. Unfortunately, none has provided any suggestion of benefit. Patients receiving paclitaxel, especially at large doses given every 2–3 weeks, often develop aches and pains, generally starting 1–2 days after chemotherapy initiation and commonly lasting a few days to about a week. This syndrome has been labelled as paclitaxel-induced arthralgias or myalgias. However, new information suggests that these pains are not from joints or muscle, and thus arthralgias and myalgias do not seem to be appropriate terms to describe them.87 Instead, characteristics from this pain are most consistent with pain from nerve injury. Data from a rat model system substantiate that paclitaxel can acutely cause nerve injury because of histological evidence of dorsal root ganglia injury seen within 24 h of paclitaxel use.88,89 Although pilot reports90,91 have suggested that gabapentin might help decrease the acute pain syndrome from paclitaxel, this treatment has yet to be studied in a placebo-controlled trial. The only placebo-controlled trial to investigate treatment of this acute pain syndrome after paclitaxel randomly assigned patients to glutamine versus placebo, and then vice-versa for another cycle of paclitaxel, but no benefit from glutamine was recorded.92

Chemotherapy-induced bone loss Bone density increases and it peaks in women when they are in their mid-30s. At the time of menopause, pronounced bone loss occurs, which is related to oestrogen depletion. Premenopausal patients with breast cancer are at risk for bone loss because cancer treatments can decrease oestrogen. These treatments include chemotherapy-induced suppression of oestrogen and directly planned suppression of ovarian function (by surgical or medical means). Furthermore, premenopausal patients receiving ovarian function suppression are sometimes additionally treated with aromatase inhibitors, which further deplete oestrogen concentrations. Last, tamoxifen can induce bone loss in premenopausal 998

women who have ovarian function, by contrast with postmenopausal women in whom tamoxifen seems to maintain bone. The best explanation for this paradox is that tamoxifen has oestrogenic activity in the bone of postmenopausal women, who have little circulating native oestrogen. However, in premenopausal women, data support that oestrogen is a stronger stimulus of bone density; thus, tamoxifen prevents the stronger oestrogenic activity on bone, leading to bone loss. General recommendations for premenopausal patients at risk for bone loss are similar to those in the general population. Weight-bearing exercise helps to maintain bone strength.93 Adequate intake of calcium (1000–1500 mg/ day) to include both dietary intake and supplemental use and vitamin D (oral dose of 1000 IU/day being a reasonable dose) is suggested to provide building-blocks for bone deposition. Furthermore, maintenance of ideal bodyweight is important, as is avoidance of smoking and excessive alcohol use.93 In addition to these interventions, patients at risk for bone loss should be monitored with bonemineral-density testing. In patients who develop evidence of osteoporosis or pronounced osteopenia, the use of bisphosphonates is recommended.93 Because of concerns regarding the risks of early osteoporosis in survivors of breast cancer, prophylactic use of bisphosphonates to prevent sequelae of oestrogendepletion on bone has been investigated. Clinical trials have shown that bisphosphonates can decrease bone loss in postmenopausal women receiving aromatase inhibitors.94 This effect is also seen in premenopausal women who are rendered postmenopausal and then are given aromatase inhibitors.95 Nevertheless, these trials have so far failed to show that bisphosphonates actually prevent bone fractures. Furthermore, information suggests that bone loss related to aromatase inhibitors is reversible if aromatase-inhibitor treatment is stopped.96 Thus, at this time, bisphosphonates are not recommended to be given to women prophylactically, but should be reserved for the treatment of osteoporosis or pronounced osteopenia.93 Two trials have been investigated the use of bisphosphonates in premenopausal women receiving adjuvant chemotherapy for breast cancer. In one trial,97 bone mineral density was measured at the start of the study, after which half the patients received risedronate (35 mg/day) and the other half received placebo. At the end of 1 year, no substantial change in bone density was seen between the two groups. The second trial98 investigated oral clodronate (versus an unmasked control group) in 148 premenopausal women who were to receive six cycles of chemotherapy with cyclophosphamide, methotrexate, and fluorouracil. Data indicated that clodronate did significantly decrease loss of bone mineral density. The effect of zoledronic acid in premenopausal women with breast cancer was studied in another trial,95 for the www.thelancet.com/oncology Vol 9 October 2008

Review

prevention of bone loss in women receiving adjuvant endocrine treatment. This trial, again with an unmasked, non-treatment, control group, did note that this bisphosphonate did significantly reduce bone density loss at 3 years.95 To substantiate and refine these results, further well-conducted studies are needed to assess the efficacy of bisphosphonates in premenopausal women. In the meantime, the panel lists reasonable recommendations for the management of bone function in premenopausal women receiving adjuvant chemotherapy.

Chemotherapy-induced cognitive dysfunction Although women with breast cancer have been describing problems with cognitive function for many years, the exact nature and cause of changes are still not clearly understood. The latest information from descriptive studies87 is that chemotherapy, endocrine treatments, and a breast-cancer diagnosis itself can all cause cognitive dysfunction. Longitudinal differences in objective neuropsychological tests have not yielded definitive insight, often due to little differentiation between survivors of cancer and controls. Functional imaging studies have revealed more brain effects while doing tasks in women who have had chemotherapy than those who have not had such treatment. Therefore, the mental effort to do tasks could be increased in cancer survivors, compared with matched controls, thus resulting in subjective reports of cognitive dysfunction when objective tests show few differences.99 Although further studies are needed to help guide treatment in these patients, reassurance and instruction in the use of compensatory strategies and mental exercises could be helpful. First, patients should be reassured that cancer diagnosis and treatment is expected to be a time of increased stress, and patients and their families should be reminded that even people without cancer diagnoses can be forgetful or absent-minded during stressful times. The use of compensatory strategies—eg, lists, reminders, wristwatch alarms, and careful scheduling—should also be implemented. Second, stress management techniques, such as relaxation and deep breathing, could help. Third, mental exercises that keep the brain engaged but not overstressed, have shown preliminary promise.100 Finally, physical exercise could improve circulation and decrease cytokine concentrations that have been increased due to stress, having a positive effect on cognition. So far, no pharmacological interventions have definitively been shown to be effective.

Conclusions Premenopausal women with breast cancer suffer from many untoward symptoms, of which some also afflict postmenopausal patients and some are more specific to this younger cohort. Although effective treatments are available to counteract these symptoms, more research is needed to expand evidence-based care for this population. www.thelancet.com/oncology Vol 9 October 2008

Search strategy and selection criteria Data for this Review were identified by searches of Medline, Current Contents, PubMed, and references from relevant articles with the search terms “breast cancer”, “premenopause”, “chemotherapy”, and “side effects”. Searches were also done for known side-effects of cancer and cancer treatment, including: “hot flushes”, “peripheral neuropathy”, and “radiation dermatitis”. Abstracts and reports from meetings were included. Only papers published in English between 1980 and 2006 were included.

Conflicts of interest The authors declared no conflicts of interest. References 1 American Cancer Society. Breast cancer facts & figures. Altanta, GA: American Cancer Society, 2007–2008. 2 Heggie S, Bryant GP, Tripcony L, et al. A phase III study on the efficacy of topical aloe vera gel on irradiated breast tissue. Cancer Nurs 2002; 25: 442–51. 3 Wells M, Macmillan M, Raab G, et al. Does aqueous or sucralfate cream affect the severity of erythematous radiation skin reactions? A randomised controlled trial. Radiother Oncol 2004; 73: 153–62. 4 Pommier P, Gomez F, Sunyach MP, D’Hombres A, Carrie C, Montbarbon X. Phase III randomized trial of Calendula officinalis compared with trolamine for the prevention of acute dermatitis during irradiation for breast cancer. J Clin Oncol 2004; 22: 1447–53. 5 Fisher J, Scott C, Stevens R, et al. Randomized phase III study comparing best supportive care to biafine as a prophylactic agent for radiation-induced skin toxicity for women undergoing breast irradiation: Radiation Therapy Oncology Group (RTOG) 97-13. Int J Radiat Oncol Biol Phys 2000; 48: 1307–10. 6 Williams JR. Scatter dose estimation based on dose-area product and the specification of radiation barriers. Br J Radiol 1996; 69: 1032–37. 7 Bostrom A, Lindman H, Swartling C, Berne B, Bergh J. Potent corticosteroid cream (mometasone furoate) significantly reduces acute radiation dermatitis: results from a double-blind, randomized study. Radiother Oncol 2001; 59: 257–65. 8 Pignol JP, Olivotto I, Rakovitch E, et al. A multicenter randomized trial of breast intensity-modulated radiation therapy to reduce acute radiation dermatitis. J Clin Oncol 2008; 26: 2085–92. 9 Harsolia A, Kestin L, Grills I, et al. Intensity-modulated radiotherapy results in significant decrease in clinical toxicities compared with conventional wedge-based breast radiotherapy. Int J Radiat Oncol Biol Phys 2007; 68: 1375–80. 10 Bolderston A, Lloyd NS, Wong RK, Holden L, Robb-Blenderman L, Supportive Care Guidelines Group of Cancer Care Ontario Program in Evidence-Based Care. The prevention and management of acute skin reactions related to radiation therapy: a systematic review and practice guideline. Supportive Care Cancer 2006; 14: 802–17. 11 Carpenter JS, Andrykowski MA, Cordova M, et al. Hot flashes in postmenopausal women treated for breast carcinoma: prevalence, severity, correlates, management, and relation to quality of life. Cancer 1998; 82: 1682–91. 12 Notelovitz M, Lenihan JP, McDermott M, Kerber IJ, Nanavati N, Arce J. Initial 17beta-estradiol dose for treating vasomotor symptoms. Obstet Gynecol 2000; 95: 726–31. 13 Goodwin JW, Green SJ, Moinpour CM, et al. Phase III randomized placebo-controlled trial of two doses of megestrol acetate as treatment for menopausal symptoms in women with breast cancer: Southwest Oncology Group Study 9626. J Clin Oncol 2008; 26: 1650–56. 14 Loprinzi CL, Levitt R, Barton D, et al. Phase III comparison of depomedroxyprogesterone acetate to venlafaxine for managing hot flashes: North Central Cancer Treatment Group Trial N99C7. J Clin Oncol 2006; 24: 1409–14. 15 Goldberg RM, Loprinzi CL, O’Fallon JR, et al. Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol 1994; 12: 155–58.

999

Review

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34 35 36

37

38

39

1000

Loprinzi CL, Pisansky TM, Fonseca R, et al. Pilot evaluation of venlafaxine hydrochloride for the therapy of hot flashes in cancer survivors. J Clin Oncol 1998; 16: 2377–81. Stearns V, Isaacs C, Rowland J, et al. A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil) in controlling hot flashes in breast cancer survivors. Ann Oncol 2000; 11: 17–22. Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 2000; 356: 2059–63. Stearns V, Slack R, Greep N, et al. Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial. J Clin Oncol 2005; 23: 6919–30. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA 2003; 289: 2827–34. Loprinzi CL, Sloan JA, Perez EA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 2002; 20: 1578–83. Barton DL, LaVasseur B, Sloan J, et al. A phase III trial evaluating three doses of citalopram for hot flashes: NCCTG Trial N05C9. Proc Am Soc Clin Oncol 2008; 26 (suppl): abstr 9538. Speroff L, Gass M, Constantine G, Olivier S, Study I. Efficacy and tolerability of desvenlafaxine succinate treatment for menopausal vasomotor symptoms: a randomized controlled trial. Obstet Gynecol 2008; 111: 77–87. Gordon PR, Kerwin JP, Boesen KG, Senf J. Sertraline to treat hot flashes: a randomized controlled, double-blind, crossover trial in a general population. Menopause 2006; 13: 568–75. Grady D, Cohen B, Tice J, Kristof M, Olyaie A, Sawaya GF. Ineffectiveness of sertraline for treatment of menopausal hot flushes: a randomized controlled trial. Obstet Gynecol 2007; 109: 823–30. Kimmick GG, Lovato J, McQuellon R, Robinson E, Muss HB. Randomized, double-blind, placebo-controlled, crossover study of sertraline (Zoloft) for the treatment of hot flashes in women with early stage breast cancer taking tamoxifen. Breast J 2006; 12: 114–22. Evans ML, Pritts E, Vittinghoff E, McClish K, Morgan KS, Jaffe RB. Management of postmenopausal hot flushes with venlafaxine hydrochloride: a randomized, controlled trial. Obstet Gynecol 2005; 105: 161–66. Suvanto-Luukkonen E, Koivunen R, Sundstrom H, et al. Citalopram and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized, 9-month, placebo-controlled, double-blind study. Menopause 2005; 12: 18–26. Loprinzi CL, Barton DL, Sloan JA, Novotny PJ, Wolf S. Newer antidepressants for hot flashes-should their efficacy still be up for debate? Menopause (in press). Nelson HD, Vesco KK, Haney E, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA 2006; 295: 2057–71. Loprinzi C, Sloan J, Stearns V, et al. Newer antidepressants and gabapentin for hot flashes: an individual subject pooled analysis. Proc Am Soc Clin Oncol 2008; 26 (suppl): abstr 9537. Goetz MP, Rae JM, Suman VJ, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005; 23: 9312–18. Jin Y, Desta Z, Stearns V, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 2005; 97: 30–39. Guttuso TJ Jr. Gabapentin’s effects on hot flashes and hypothermia. Neurology 2000; 54: 2161–63. Loprinzi L, Barton D, Sloan J, et al. Pilot evaluation of gabapentin for treating hot flashes. Mayo Clin Proc 2002; 77: 1159–63. Guttuso T, Kurlan R, McDermott MP, Kieburtz K. Gabapentin’s effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol 2003; 101: 337–45. Pandya KJ, Morrow GR, Roscoe JA, et al. Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial. Lancet 2005; 366: 818–24. Reddy SY, Warner H, Guttuso T Jr, et al. Gabapentin, estrogen, and placebo for treating hot flushes: a randomized controlled trial. Obstet Gynecol 2006; 108: 41–48. Barton DL, Loprinzi CL, Quella SK, et al. Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. J Clin Oncol 1998; 16: 495–500.

40

41

42

43

44 45

46 47

48

49 50

51

52

53

54

55

56

57

58

59

60

61 62

Pockaj BA, Gallagher JG, Loprinzi CL, et al. Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes: NCCTG Trial N01CC1. J Clin Oncol 2006; 24: 2836–41. Quella SK, Loprinzi CL, Barton DL, et al. Evaluation of soy phytoestrogens for the treatment of hot flashes in breast cancer survivors: a North Central Cancer Treatment Group Trial. J Clin Oncol 2000; 18: 1068–74. Van Patten CL, Olivotto IA, Chambers GK, et al. Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: a randomized, controlled clinical trial. J Clin Oncol 2002; 20: 1449–55. Bardia A, Novotny PJ, Sloan J, et al. Does efficacy of non-estrogenic therapies for hot flash among women vary by breast cancer history and tamoxifen use? Proc Am Soc Clin Oncol 2008; 26 (suppl): abstr 9595. Loprinzi CL, Michalak JC, Quella SK, et al. Megestrol acetate for the prevention of hot flashes. N Engl J Med 1994; 331: 347–52. Elkins G, Marcus J, Stearns V, Hasan Rajab M. Pilot evaluation of hypnosis for the treatment of hot flashes in breast cancer survivors. Psychooncology 2007; 16: 487–92. Freedman RR. Hot flashes: behavioral treatments, mechanisms, and relation to sleep. Am J Med 2005; 118 (suppl 12B): 124–30. Wijma K, Melin A, Nedstrand E, Hammar M. Treatment of menopausal symptoms with applied relaxation: a pilot study. J Behav Ther Exp Psychiatry 1997; 28: 251–61. Lipov EG, Joshi JR, Sanders S, et al. Effects of stellate-ganglion block on hot flushes and night awakenings in survivors of breast cancer: a pilot study. Lancet Oncol 2008; 9: 523–32. Loprinzi CL, Barton DL, Carns PE. Stellate-ganglion block: a new treatment for hot flushes? Lancet Oncol 2008; 9: 506–07. Freedman RR, Krell W. Reduced thermoregulatory null zone in postmenopausal women with hot flashes. Am J Obstet Gynecol 1999; 181: 66–70. Shell JA. Evidence-based practice for symptom management in adults with cancer: sexual dysfunction. Oncol Nurs Forum 2002; 29: 53–66. Gelfand M, Wendman E. Treating vaginal dryness in breast cancer patients: results of applying a polycarbophil moisturizing gel. J Womens Health 1994; 3: 427–34. Loprinzi CL, Abu-Ghazaleh S, Sloan JA, et al. Phase III randomized double-blind study to evaluate the efficacy of a polycarbophil-based vaginal moisturizer in women with breast cancer. J Clin Oncol 1997; 15: 969–73. North American Menopause Society. The role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women: 2007 position statement of The North American Menopause Society. Menopause 2007; 14: 355–69. Bygdeman M, Swahn ML. Replens versus dienoestrol cream in the symptomatic treatment of vaginal atrophy in postmenopausal women. Maturitas 1996; 23: 259–63. Santen RJ, Pinkerton JV, Conaway M, et al. Treatment of urogenital atrophy with low-dose estradiol: preliminary results. Menopause 2002; 9: 179–87. Naessen T, Rodriguez-Macias K, Lithell H. Serum lipid profile improved by ultra-low doses of 17 beta-estradiol in elderly women. J Clin Endocrinol Metab 2001; 86: 2757–62. ATAC Trialists’ Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 2005; 365: 60–62. Vivino FB, Al-Hashimi I, Khan Z, et al. Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sjogren syndrome: a randomized, placebo-controlled, fixed-dose, multicenter trial. P92-01 Study Group. Arch Intern Med 1999; 159: 174–81. LeVeque G, Hendrix S. Oral pilocarpine to treat vaginal xerosis associated with chemotherapy-induced amenorrhea in premenopausal women. J Clin Oncol 2004; 22: 749. Loprinzi CL, Barton DL, Jatoi A, et al. Symptom control trials: a 20-year experience. J Support Oncol 2007; 5: 119–25. Barton DL, Wender DB, Sloan JA, et al. Randomized controlled trial to evaluate transdermal testosterone in female cancer survivors with decreased libido; North Central Cancer Treatment Group protocol N02C3. J Natl Cancer Inst 2007; 99: 672–79.

www.thelancet.com/oncology Vol 9 October 2008

Review

63

64

65

66

67

68 69

70

71

72

73

74

75 76

77

78

79

80

81

82

83

Schover LR. Premature ovarian failure and its consequences: vasomotor symptoms, sexuality, and fertility. J Clin Oncol 2008; 26: 753–58. Tham YL, Sexton K, Weiss H, Elledge R, Friedman LC, Kramer R. The rates of chemotherapy-induced amenorrhea in patients treated with adjuvant doxorubicin and cyclophosphamide followed by a taxane. Am J Clin Oncol 2007; 30: 126–32. Kil WJ, Ahn SD, Shin SS, et al. Treatment-induced menstrual changes in very young (<35 years old) breast cancer patients. Breast Cancer Res Treat 2006; 96: 245–50. Duffy CM, Allen SM, Clark MA. Discussions regarding reproductive health for young women with breast cancer undergoing chemotherapy. J Clin Oncol 2005; 23: 766–73. Partridge AH, Gelber S, Peppercorn J, et al. Web-based survey of fertility issues in young women with breast cancer. J Clin Oncol 2004; 22: 4174–83. Ives A, Saunders C, Bulsara M, Semmens J. Pregnancy after breast cancer: population based study. BMJ 2007; 334: 194. Sankila R, Heinavaara S, Hakulinen T. Survival of breast cancer patients after subsequent term pregnancy: “healthy mother effect”. Am J Obstet Gynecol 1994; 170: 818–23. Azim A, Oktay K. Letrozole for ovulation induction and fertility preservation by embryo cryopreservation in young women with endometrial carcinoma. Fertil Steril 2007; 88: 657–64. Madrigrano A, Westphal L, Wapnir I. Egg retrieval with cryopreservation does not delay breast cancer treatment. Am J Surg 2007; 194: 477–81. Lee SJ, Schover LR, Partridge AH, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 2006; 24: 2917–31. Fossa SD, Magelssen H, Melve K, Jacobsen AB, Langmark F, Skjaerven R. Parenthood in survivors after adulthood cancer and perinatal health in their offspring: a preliminary report. J Natl Cancer Inst Monogr 2005; 34: 77–82. Moran MS, Colasanto JM, Haffty BG, Wilson LD, Lund MW, Higgins SA. Effects of breast-conserving therapy on lactation after pregnancy. Cancer J 2005; 11: 399–403. Camune B, Gabzdyl E. Breast-feeding after breast cancer in childbearing women. J Perinat Neonatal Nurs 2007; 21: 225–33. Collado-Hidalgo A, Bower JE, Ganz PA, Cole SW, Irwin MR. Inflammatory biomarkers for persistent fatigue in breast cancer survivors. Clin Cancer Res 2006; 12: 2759–66. Mitchell SA, Beck SL, Hood LE, Moore K, Tanner ER. Putting evidence into practice: evidence-based interventions for fatigue during and following cancer and its treatment. Clin J Oncol Nurs 2007; 11: 99–113. Miller AH, Ancoli-Israel S, Bower JE, Capuron L, Irwin MR. Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer. J Clin Oncol 2008; 26: 971–82. Barton DL, Soori GS, Bauer B, et al. A pilot, multi-dose, placebocontrolled evaluation of american ginseng (panax quinquefolius) to improve cancer-related fatigue: NCCTG trial N03CA. Proc Am Soc Clin Oncol 2007; 25: abstr 9001. Kohli S, Fisher S, Tra Y, Wesnes K, Morrow G. The cognitive effects of modafinil in breast cancer survivors: a randomized clinical trial. Proc Am Soc Clin Oncol 2007; 25: abstr 9004. Argyriou AA, Chroni E, Koutras A, et al. Vitamin E for prophylaxis against chemotherapy-induced neuropathy: a randomized controlled trial. Neurology 2005; 64: 26–31. Pace A, Carpano S, Galiè E, et al. Vitamin E in the neuroprotection of cisplatin induced peripheral neurotoxicity and ototoxicity. J Clin Oncol 2007; 25 (suppl): 18S. Bairati I, Meyer F, Gelinas M, et al. Randomized trial of antioxidant vitamins to prevent acute adverse effects of radiation therapy in head and neck cancer patients. J Clin Oncol 2005; 23: 5808–13.

www.thelancet.com/oncology Vol 9 October 2008

84

Rao RD, Michalak JC, Sloan JA, et al. Efficacy of gabapentin in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled, crossover trial (N00C3). Cancer 2007; 110: 2110–18. 85 Renno SI, Roa R, Sloan JA, et al. The efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy: a phase III randomized, double-blind, placebo-controlled NCCTG trial, N01C3. J Clin Oncol 2006; 24 (suppl): 18S. 86 Hammack JE, Michalak JC, Loprinzi CL, et al. Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy. Pain 2002; 98: 195–203. 87 Loprinzi CL, Maddocks-Christianson K, Wolf S, et al. The paclitaxel acute pain syndrome: sensitization of nociceptors as the putative mechanism. Cancer J 2007; 13: 399–403. 88 Jimenez-Andrade J, Peters C, Mejia N, Ghilardi J, Kuskowski M, Mantyh P. Sensory neurons and their supporting cells located in the trigeminal, thoracic and lumbar ganglia differentially express markers of injury following intravenous administration of paclitaxel in the rat. Neurosci Lett 2006; 405: 62–67. 89 Peters CM, Jimenez-Andrade JM, Jonas BM, et al. Intravenous paclitaxel administration in the rat induces a peripheral sensory neuropathy characterized by macrophage infiltration and injury to sensory neurons and their supporting cells. Exp Neurol 2007; 203: 42–54. 90 Nguyen VH, Lawrence HJ. Use of gabapentin in the prevention of taxane-induced arthralgias and myalgias. J Clin Oncol 2004; 22: 1767–69. 91 van Deventer H, Bernard S. Use of gabapentin to treat taxaneinduced myalgias. J Clin Oncol 1999; 17: 434–35. 92 Jacobson SD, Loprinzi CL, Sloan JA, et al. Glutamine does not prevent paclitaxel-associated myalgias and arthralgias. J Support Oncol 2003; 1: 274–78. 93 Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003; 21: 4042–57. 94 Mincey B, Dentchev T, Sloan J, et al. N03CC A randomized, controlled, open label trial of upfront vs delayed zoledronic acid for prevention of bone loss in postmenopausal (PM) women with primary breast cancer (PBC) starting letrozole after tamoxifen. Proc Am Soc Clin Oncol 2008; 26 (suppl): abstr 564. 95 Gnant MF, Mlineritsch B, Luschin-Ebengreuth G, et al. Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormoneresponsive breast cancer: a report from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol 2007; 25: 820–28. 96 Coleman RE. Long-term effects of anastrozole on bone mineral density: seven-year results from the ATAC trial. Proc Am Soc Clin Oncol 2008; 26 (suppl): abstr 587. 97 Hines S, Mincey B, Sloan J, et al. N02C1 A phase III randomized, placebo controlled, double blind trial of risedronate for prevention of bone loss in premenopausal women undergoing adjuvant chemotherapy for breast cancer (BC). Proc Am Soc Clin Oncol 2008; 26 (suppl): abstr 525. 98 Saarto T, Blomqvist C, Valimaki M, Makela P, Sarna S, Elomaa I. Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: a randomized study in premenopausal breast cancer patients. J Clin Oncol 1997; 15: 1341–47. 99 Ferguson RJ, McDonald BC, Saykin AJ, Ahles TA. Brain structure and function differences in monozygotic twins: possible effects of breast cancer chemotherapy. J Clin Oncol 2007; 25: 3866–70. 100 Ferguson RJ, Ahles TA, Saykin AJ, et al. Cognitive-behavioral management of chemotherapy-related cognitive change. Psychooncology 2007; 16: 772–77.

1001