Management of hot flashes in women with breast cancer receiving ovarian function suppression

Cancer Treatment Reviews 52 (2017) 82–90

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Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv

General and Supportive Care

Management of hot flashes in women with breast cancer receiving ovarian function suppression Roberto A. Leon-Ferre a, Neil Majithia b, Charles L. Loprinzi a,⇑ a b

Division of Medical Oncology, Mayo Clinic, Rochester, MN, United States Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States

a r t i c l e

i n f o

Article history: Received 27 July 2016 Received in revised form 25 November 2016 Accepted 26 November 2016

Keywords: Hot flashes Hot flushes Vasomotor symptoms Tamoxifen Breast cancer Estrogen

a b s t r a c t Most breast cancers express estrogen and/or progesterone receptors, allowing the opportunity to use anti-estrogen therapies, which have demonstrated substantial efficacy in both the metastatic and adjuvant settings. Young premenopausal women with early-stage high-risk or with metastatic hormonereceptor positive breast cancer may benefit from ovarian function suppression in addition to antiestrogen medications. While these endocrine manipulations have successfully improved breast cancer outcomes, they may lead to a significant proportion of women experiencing vasomotor symptoms. While not life-threatening, vasomotor symptoms adversely impact quality of life and can result in early treatment discontinuation. For these reasons, supportive management of this treatment-related toxicity is crucial, and clinicians caring for breast cancer patients and survivors should be familiar with the options available and the data behind them. This manuscript will review the pathophysiology, clinical manifestations, quality of life implications and non-estrogenic management options of vasomotor symptoms for women with breast cancer undergoing estrogen depletion. Ó 2016 Elsevier Ltd. All rights reserved.

Introduction Breast cancer remains the most frequently diagnosed cancer and the second leading cause of cancer death among American women. In 2016, an estimated 249,260 patients will be diagnosed with breast cancer, and 40,890 will die from the disease in the United States [1]. The vast majority of breast cancers are positive for the estrogen and/or progesterone receptors, allowing the opportunity to use antiestrogen therapies in their treatment, which have demonstrated substantial efficacy in both the metastatic and adjuvant settings [2]. In the adjuvant setting, endocrine therapy is typically administered for at least 5 years, with contemporary data suggesting that a subset of women may benefit from extension of endocrine therapy to up to 10 years [3,4]. Additionally, aggressive estrogen depletion with ovarian function suppression [OFS, via oophorectomy or gonadotropin-releasing hormone (GnRH) analogs] along with either tamoxifen or aromatase inhibitors in young premenopausal women with early-stage high risk breast cancer has recently proven to further improve outcomes [5,6]. In premenopausal women with metastatic disease, OFS is also commonly added to anti-estrogen medications and has been part of ⇑ Corresponding author at: Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, United States. Fax: +1 507 284 1803. E-mail address: [email protected] (C.L. Loprinzi). http://dx.doi.org/10.1016/j.ctrv.2016.11.012 0305-7372/Ó 2016 Elsevier Ltd. All rights reserved.

the strategy in modern endocrine therapy clinical trials [7]. While these endocrine manipulations have successfully decreased recurrence and mortality from breast cancer, tolerability remains an important challenge. Furthermore, administration of chemotherapy in patients with either hormone receptor positive or negative breast cancer can lead to cessation of ovarian function, causing symptomatology that can be similar to that experienced by women receiving anti-estrogen therapy. A significant proportion of women receiving endocrine therapy or with chemotherapy-induced ovarian failure experience vasomotor symptoms (VMS). While not life-threatening, VMS adversely impact quality of life and can result in early treatment discontinuation [8], which in turn might adversely affect cancer outcomes in women unable to tolerate aggressive estrogen depletion. In the SOFT and TEXT trials, while almost 80% of women treated with tamoxifen alone developed VMS, the addition of OFS increased the rate of hot flashes to 93% in the tamoxifen-OFS group and 92% in the exemestane-OFS group [9,10]. Other side effects of estrogen deprivation, like sweating, decreased libido, vaginal dryness, insomnia and depression, were also more frequent when OFS was added. The current manuscript will review the pathophysiology, clinical manifestations, quality of life implications and non-estrogenic management options of VMS for women with breast cancer undergoing estrogen depletion.

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R.A. Leon-Ferre et al. / Cancer Treatment Reviews 52 (2017) 82–90 Table 1 Summary of drugs with good evidence of efficacy against hot flashes. Agent

Recommended dose

Major side effects/cautions/comments

Major trials

37.5 mg daily  1 week, then increase to 75 mg daily

Dry mouth, insomnia, decreased appetite, constipation

Nausea, insomnia, dry mouth

Citalopram

50 mg daily  3 days, then increase to target dose of 100 mg daily 10 mg daily

Loprinzi et al. [33] Evans et al. [37] Boekhout et al. [36]Bordeleau et al. [51] Speroff et al. [38] Archer et al. [39]

Escitalopram

10–20 mg daily

Paroxetine

Nausea, headache, insomnia.Potent CYP2D6 inhibitor (Caution with concomitant tamoxifen use)

Sertraline

10 mg daily, if ineffective consider increasing to 20 mg daily 50 mg daily

Fluoxetine

20 mg daily

Nausea, fatigue insomnia, nervousness, constipation; Does not appear to work as well as most other noted antidepressants; Potent CYP2D6 inhibitor (Caution with concomitant tamoxifen use)

Gabapentinoids Gabapentin

900 mg daily

Somnolence, dizziness, rash, peripheral edema.

Pregabalin

75 mg twice daily (target)

Insomnia, dizziness, weight gain. Cognitive dysfunction with higher doses (150 mg daily)

Progesterone analogs Megestrol acetate

40 mg daily

Some theoretical concerns about potential increased risk of breast cancer

500 mg IM ever 2 weeks  3 doses

Some theoretical concerns about potential increased risk of breast cancer

15 mg/daily

Antidepressant drugs Venlafaxine

Desvenlafaxine

Medroxyprogesterone

Miscellaneous Oxybutynin

No difference compared to placebo; Potential preferred antidepressant to use first, based on good tolerance and cost No difference compared to placebo

Nausea, fatigue, dry mouth, dizziness, diarrhea, anxiety/nervousness; Does not appear to work as well as most other noted antidepressants; Potent CYP2D6 inhibitor (Caution with concomitant tamoxifen use)

Clonidine

0.1 mg daily (or equivalent transdermal dose)

Dry mouth, dyspepsia, diarrhea; Lower doses being evaluated in a clinical trial Dry mouth, constipation, pruritus, drowsiness, insomnia, dizziness; not commonly used due to toxicity and other better options availability

Zolpidem (as an adjunct to an antidepressant to decrease nighttime awakenings)

10 mg daily

Nausea, headache, fatigue, dry mouth

Pathophysiology Hot flashes represent thermoregulatory dysfunction at the level of the hypothalamus and are precipitated by a drop in estrogen levels [11]. In the postmenopausal state, there is recalibration in the core body temperature set-point, such that standard physiologic mechanisms to dissipate heat are initiated at lower body temperatures than is the case for premenopausal women [12]. This results in the characteristic features of hot flashes, such as sensation of warmth, flushing, and perspiration. As heat is lost and body temperature drops, corrective physiologic responses, such as shivering, are experienced. The specific mechanism of how decreased estrogen levels contribute to hot flashes is not known, but the phenomenon of estrogen withdrawal appears to be instrumental to this process [13]. This is supported by the observation that oophorectomy precipitates rapid onset of hot flashes in premenopausal women, whereas gonadal dysgenesis (which represents a chronic state of low estrogen levels) does not [14]. Similarly, when women with gonadal

Barton et al. [43] Freeman et al. [44] Stearns et al. [40] Stearns et al. [61] Gordon et al. [42] Kimmick et al. [45] Grady et al. [46] Loprinzi [34] Suvanto-Luukkonen et al. [41] Guttuso et al. [47] Pandya et al. [48] Reddy et al. [49] Bordeleau et al. [51] Loprinzi et al. [52] Loprinzi et al. [67] Bertelli et al. [69] Loprinzi et al. [68] Bertelli et al. [69] Simon et al. [71] Goldberg et al. [63] Pandya [64] Joffe et al. [62]

dysgenesis abruptly discontinue exogenous estrogen therapy, they experience hot flashes [13]. The neuro-regulatory source of hot flashes appears to be centered in the hypothalamus [15]. Perspiration and vasodilation are initiated in the preoptic area of the hypothalamus and serve as heat loss mechanisms to regulate core body temperature [13]. It has been shown that changes in core body temperature tend to occur about 15 min before the majority of hot flashes [16], and that postmenopausal women seem to have a particularly sensitive homeostatic physiology that results in triggering of compensatory heat loss mechanisms even with subtle core temperature changes [17]. At the molecular level, multiple neurotransmitters have been implicated along complex neuro-hormonal pathways in the development of hot flashes, but norepinephrine is thought to be the most important neurotransmitter in lowering the thermoregulatory set point [17,18]. Norepinephrine release in the thermoregulatory nucleus is inhibited by endorphins and catecholestrogen, which is a by-product of estrogen metabolism [13,18]. Serotonin

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is another important mediator of heat loss, and estrogen withdrawal is associated with upregulation in serotonin receptors, suggesting that this neurotransmitter may contribute to hot flashes [19]. Of note, the complexity of this pathway is highlighted by the relevance of various serotonin receptors in temperature control [20]. Clinical manifestations and quality of life implications Hot flashes are characterized by a sudden feeling of warmth that typically starts at the upper chest and face, with subsequent involvement of the rest of the body. The sensation persists for several minutes and can be associated with sweating, palpitations, and anxiety. As heat is lost and body temperature drops, chills and shivering may develop. The timing and frequency of these episodes are variable, with some women having a tendency to predominantly experience symptoms at nighttime. In many women, hot flashes can result in nighttime awakenings [21], anxiety, and a significant deterioration of sleep quality [22]. The effect of hot flashes on quality of life is variable on an individual basis. Heterogeneity in the assessment and measurement of VMS complicates the interpretation of results of clinical trials evaluating the efficacy of different pharmacologic agents. Use of daily diaries to quantitate hot flash frequency and hot flash score (frequency multiplied by average severity) has shown to produce the most consistent results [23]. Clinicians must consider the frequency and severity of symptoms and their impact in the patient’s quality of life as they approach management decisions. Management General principles Hormone replacement therapy (HRT), the most effective antiVMS treatment [24], is not an ideal option for women with, or at high risk for breast cancer, especially for those with hormonereceptor positive tumors. There are reports linking estrogen and progesterone supplementation with higher incidence of breast cancer among healthy women [25,26]. The data on the use of HRT after a breast cancer diagnosis is conflicting, with two randomized trials reporting a significant excess risk of recurrence among women receiving HRT [27,28], and one trial reporting no difference [29]. Given the mixed data, significant hesitation exists about the use of HRT among women with a diagnosis of breast cancer, particularly if undergoing active adjuvant endocrine therapy, as HRT would directly antagonize the therapeutic effects of OFS and/or tamoxifen or aromatase inhibitors and defeat their purpose. As such, considerable efforts have been invested in evaluating different non-estrogenic anti-VMS treatment options for this patient population.

nent of the conventional wisdom surrounding conservative treatment of hot flashes. Lifestyle interventions such as weight loss have been proposed as management for hot flashes, given the association between obesity and the development of VMS. In one study, involving 338 patients, patients were randomized to a weight loss program versus structured health education, with the finding that an intensive behavioral weight loss intervention yielded significant improvement in hot flashes, relative to control [31]. Independent from weight loss, exercise has not been shown to have a beneficial effect on VMS [32]. Non-estrogenic pharmacologic therapy Several non-estrogenic agents have been found to be effective in improving VMS in a number of placebo-controlled, doubleblinded, randomized clinical trials (Table 1). These include serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine inhibitors (SNRIs) [33–46] and anticonvulsants (i.e., gabapentin, pregabalin) [35,47–52]. Other agents, such as long-acting nitroglycerin [53] and oxybutynin [36,54–56] appear promising. While many of the clinical trials evaluating non-estrogenic treatments have not exclusively enrolled patients with breast cancer, a pooled analysis of 1396 women and 20 hot flash studies found that patients with a history of breast cancer and/or a history of tamoxifen use benefited similarly from anti-VMS interventions as did patients without breast cancer and/or a history of tamoxifen use [57]. Women with breast cancer had similar hot flash scores at baseline. Even though tamoxifen users had higher hot flash scores, the percent reduction of hot flashes in the active treatment arms of the placebo-controlled trialas was similar among tamoxifen users and non-users. Given these data, it is reasonable to consider the data on non-estrogenic compounds involving non-breast cancer patients to be applicable to breast cancer patients. When evaluating the potential efficacy of an anti-VMS agent, a few challenges must be considered. First, there is a nontrivial placebo effect that has been consistently demonstrated in randomized clinical trials and needs to be accounted for. This becomes especially relevant when assessing results of single arm studies or non-placebo controlled trials. Second, clinical trials may use different instruments and definitions to assess and grade hot flash frequency and severity, which may limit cross-trial comparisons. Third, duration of follow-up after an intervention has been instated may differ between trials. Lastly, some of the pharmacologic agents discussed in this section, particularly SSRIs, are metabolized by the CYP2D6 enzyme system [58], which also has a critical role in the metabolic activation of tamoxifen. While studies have shown that some SSRIs can lower levels of endoxifen (a very active metabolite of tamoxifen) [59], the clinical importance of this interaction is still a matter of extensive controversy [60]. Antidepressants

Non-pharmacologic measures Patients with mild symptoms may benefit from behavioral modifications designed to adjust to the symptoms of excess warmth that characterize hot flashes. However, recommendation of these methods is based on limited data. An incidental finding from a study designed to evaluate the use of propranolol in the management of hot flashes found that environmental temperature correlated with the number of hot flashes [30]. Further simple interventions include circulating air, dressing in layers that can be removed during onset of symptoms, and limiting exposure to inciting factors such as spicy foods. These latter strategies have not been evaluated in clinical trials, and such studies would be difficult to perform; however, their use remains a reasonable compo-

Venlafaxine Venlafaxine has been shown to be effective in decreasing hot flashes compared to placebo in several clinical trials. The first published trial of any antidepressant, as a potential treatment for hot flashes, evaluated three doses of venlafaxine (37.5, 75 or 150 mg daily) against placebo, and found that a dose of 75 mg daily appeared to be optimal [33]. After 4 weeks, venlafaxine 37.5 mg daily reduced hot flashes by 37%, while venlafaxine 75 mg daily and 150 mg daily both reduced hot flashes by 61%. Patients on the placebo arm still experienced a decrease in hot flashes, but only by 27%. A subsequent trial also evaluated an extended-release formulation of venlafaxine 75 mg daily versus placebo for 12 weeks. Venlafaxine was again found to be superior, decreasing hot flashes

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by 51% compared to 15% with placebo [37]. A third and more recent clinical trial randomized patients to either venlafaxine 75 mg, clonidine 0.1 mg, or placebo daily for 12 weeks [36]. This trial, which had fewer patients per study arm and started with too high a dose of venlafaxine (75 mg daily, as opposed to starting at 37.5 mg daily for the first week) also supported its utility for managing hot flashes. Venlafaxine also resulted in a more immediate reduction of hot flashes than the other two arms. In all three trials, venlafaxine was generally well-tolerated, with the most common side effects being dry mouth, insomnia, decreased appetite, and constipation. Side effects were significantly more common with 150 mg daily. Desvenlafaxine Desvenlafaxine, the succinate salt form of the major active metabolite of venlafaxine, has also demonstrated activity against hot flashes in two randomized trials. The first trial evaluated increasing doses of desvenlafaxine (50, 100, 150, or 200 mg daily) versus placebo. In this study, desvenlafaxine achieved a significantly greater reduction in the baseline number and severity of hot flashes and the number of nighttime awakenings at 12 weeks after treatment initiation [38]. The average daily number of moderate-to-severe hot flashes was decreased by up to 64%, with the highest reduction seen with the 100 mg daily dose. A subsequent trial evaluated the two intermediate desvenlafaxine doses (100 and 150 mg daily) versus placebo, and found similar results, with both doses reducing the number of hot flashes by up to 67% compared to placebo [39]. The toxicity profile was similar in both of these studies, with desvenlafaxine being well-tolerated and most side effects being mild or moderate in severity and not leading to treatment discontinuation. The most common side effects were nausea, insomnia and dry mouth. While patients on desvenlafaxine had a higher frequency of side effects than patients on placebo, this was noted only during the first week of treatment. Paroxetine Paroxetine was evaluated against placebo in two randomized clinical trials. The first trial randomized patients to paroxetine controlled-release 12.5 mg daily, 25 mg daily, or placebo for 6 weeks [40]. While placebo reduced hot flashes by 38%, both doses of paroxetine achieved reductions of 62% and 65%, respectively. A subsequent trial randomized women to paroxetine 10 mg daily, 20 mg daily or placebo [61]. At 4 weeks, paroxetine 10 mg decreased hot flashes by 41%, 20 mg by 52%, and placebo by 14%. While paroxetine was clearly superior to placebo, the difference observed between the two paroxetine doses was not statistically significant. The more common side effects were headache, nausea, and insomnia. The main caveat with paroxetine is that it is a potent CYP2D6 inhibitor, which interferes with the metabolic activation of tamoxifen and, thus, it should be used with caution in women taking this medication. Fluoxetine In two randomized placebo-controlled studies, fluoxetine was evaluated as an agent to decrease hot flashes. The first trial randomized patients to fluoxetine 20 mg daily or to placebo for 4 weeks [34]. Fluoxetine decreased hot flashes by 50%, while placebo decreased them only by 36%. A second trial randomized patients to fluoxetine 20 mg daily, citalopram 20 mg daily or placebo [41]. While this trial did not find a difference between the three arms, the investigators measured baseline hot flashes on the first day of treatment rather than before initiation of treatment, which may have artificially reduced the baseline hot flashes and underestimated the benefit by both citalopram and fluoxetine. This is particularly noteworthy as other data have supported that there was a significant reduction of hot flashes with a single day of ven-

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lafaxine, compared to a placebo. Fluoxetine was well-tolerated. The more common side effects included nausea, fatigue, insomnia, nervousness and constipation. Fluoxetine is also a potent CYP2D6 inhibitor and should be used with caution in women taking tamoxifen. Given these data, fluoxetine is less favored in clinical practice. Citalopram In a trial of 254 postmenopausal women, citalopram decreased hot flashes by 49–55% within 6 weeks of therapy initiation, compared to 23% with placebo [43]. Three different doses were evaluated (10, 20, and 30 mg daily), without significant differences in the response with doses above 10 mg daily. Citalopram was welltolerated, with no difference in adverse events compared to placebo. Escitalopram Similarly, in a trial evaluating two doses of escitalopram (10 and 20 mg daily), hot flashes were reduced by 52% within 8 weeks of escitalopram initiation, compared to 30% with placebo [44]. Adverse events were equivalent between escitalopram and placebo. Sertraline Sertraline 50 mg daily was evaluated against placebo in 3 randomized clinical trials [42,45,46]. These support that sertraline decreases hot flashes to some extent, but not as much as the other above-discussed antidepressants. Sertraline was well-tolerated, with no difference in side effects compared to placebo. Anticonvulsants and other centrally-acting agents Gabapentin In three randomized clinical trials evaluating gabapentin against placebo [47–49], gabapentin decreased hot flashes. In a pooled analysis [35] of individual patient data from these 3 studies, gabapentin reduced hot flashes by 35–38% more than placebo. The largest of these trials enrolled 420 women with breast cancer and randomized them to placebo, gabapentin 300 mg/day or gabapentin 900 mg/day [48]. Of the different doses evaluated, 900 mg daily in three divided doses was more effective (achieving a 46–49% reduction in hot flashes, compared to 31–33% in the 300 mg/day dose). The higher efficacy of 900 mg/day was also noted in the pooled analysis including two additional studies. In another trial, gabapentin was evaluated in patients with inadequate hot flash control with antidepressants [50]. In this trial, patients were randomized to receive both an antidepressant and gabapentin versus being weaned off the antidepressant and receiving gabapentin alone. In this trial, gabapentin decreased hot flashes by 50% regardless of whether or not the antidepressant was continued when gabapentin was started. Of note, in the first week or two, there were more side effects in the group that was weaned from the antidepressant, which were likely related to antidepressant withdrawal. Even though gabapentin appears to be similarly effective to venlafaxine in reducing hot flashes, a randomized trial supports that patients prefer venlafaxine [51]. In this randomized crossover trial of venlafaxine versus gabapentin, in which patient preference was the primary endpoint, 68% of patients preferred venlafaxine, whereas 32% preferred gabapentin. This was despite both agents achieving similar hot flash reduction (66%). Pregabalin Pregabalin was tested in two doses (75 mg or 150 mg twice daily) in a randomized placebo-controlled trial [52]. After 6 weeks of treatment, both doses of pregabalin decreased hot flashes to a similar degree and were more effective than placebo (65% decrease

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with 75 mg twice a day, 71% with 150 mg twice a day, and 50% with placebo). Women noted insomnia, dizziness and weight gain with both doses; in addition, they experienced cognitive dysfunction with the 150 mg twice daily dose. The hot flash reduction with pregabalin appears to be similar to that seen with gabapentin. Zolpidem Zolpidem was evaluated against placebo in a double-blind, randomized clinical trial as an adjunct to SSRI/SNRI for women with hot flashes in association with nighttime awakenings [62]. Patients were randomized to zolpidem vs placebo augmentation. Those who were not taking an SSRI/SNRI were started on venlafaxine concurrently, whereas those who were already on an SSRI/SNRI were continued on that agent. Women on zolpidem augmentation had improved sleep and quality of life. Effect on hot flashes and mood did not differ. Clonidine Older, randomized, placebo-controlled clinical trials have demonstrated that clonidine decreases hot flashes more than placebo [63,64]. However, the efficacy of this approach appears less than what is seen with many of the antidepressant drugs and gabapentinoids discussed above. Additionally, clonidine may be more toxic. Thus, it is not commonly used for treating hot flashes at this time. Progesterone analogs Progesterone analogs have been studied for treatment of hot flashes in women with breast cancer. Admittedly, these are hormonal agents and there have been concerns with regards to treating hot flashes in women with breast cancer with such hormonal agents. This is based, in part, on data that demonstrate that a combined estrogen and progesterone preparation can increase breast cancer risk in patients without breast cancer [25]. While the safety of progesterone alone has not been established in patients with treated breast cancer, it is noteworthy that progesterone analogs were common treatments for metastatic breast cancer in the recent past [65,66]. They are rarely used now because of newer antiestrogen hormonal treatments which have been established over the past decade or longer. Megestrol acetate A placebo-controlled, randomized, double-blind clinical trial illustrated that megestrol acetate, at a dose of 40 mg per day, decreased hot flashes by about 80%, similar to what would be expected with estrogenic therapy [67]. This trial included women with breast cancer and men with prostate cancer. Medroxyprogesterone acetate Medroxyprogesterone acetate is a drug that is closely related to megestrol acetate. It is available as a long-acting depot intramuscular preparation. A randomized trial compared a single dose of medroxyprogesterone acetate to venlafaxine, noting substantially more reduction in hot flashes with medroxyprogesterone acetate [68]. Medroxyprogesterone acetate appeared to be better tolerated than the venlafaxine. Another trial compared to megestrol acetate to medroxyprogesterone acetate, illustrating similar effects with the two drugs [69]. Novel approaches under evaluation Long-acting nitroglycerin A single-arm, dose-escalation trial evaluated the efficacy and tolerability of continuous transdermal nitroglycerin for the treatment of hot flashes [53]. Nineteen pre and postmenopausal women

reporting at least seven hot flashes per day participated. Patients were started on a 0.1 mg/hour patch applied daily without patchfree periods, and then escalated the dose weekly to 0.2, 0.4, or 0.6 mg/hour as tolerated during a 4-week period, after which the patch was discontinued. Once maximum dose therapy was reached, the average daily hot flash frequency decreased by 54% and the average frequency of moderate-to-severe hot flashes decreased by 69% from baseline. After discontinuing, patients reported an average 23% increase in frequency of any hot flashes, and 96% increase in moderate-to-severe hot flashes. Further data are needed to better establish this mode of treating hot flashes, before this is widely used in clinical practice. Oxybutynin Oxybutynin is an anticholinergic agent that can be taken orally (as short or long-acting formulations) or transdermally. It is approved by the FDA for overactive bladder symptoms, and has also shown efficacy in the treatment of hyperhidrosis [55,70]. There are data that suggest it may be active in the treatment of hot flashes non-responsive to other treatments [56]. In a retrospective review of a prospectively collected database, Sexton et al. identified 52 patients with moderate-to-severe hot flashes that received treatment with oxybutynin, of whom more than 90% had refractory hot flashes and 27% had tried at least 3 previous lines of therapy including SSRIs, SNRIs, gabapentin, clonidine and hormonal therapy. Seventy percent of patients treated with oxybutynin reported substantial hot flash reduction. More than half took treatment for at least six months. Although 62% of patients had mild to moderate side effects, only 12% stopped oxybutynin due to side effects, with dry mouth being the most common one (48%). A subsequent double-blind, placebo-controlled, phase 2 clinical trial evaluated high-dose oxybutynin (15 mg once daily) against placebo among healthy postmenopausal women [71]. At 12 weeks, oxybutynin resulted in significant reductions in frequency and severity of moderate-to-severe VMS compared to placebo. This was at the cost of higher toxicity in the treatment arm (dry mouth: 50%, dyspepsia: 12%, diarrhea: 10%), leading to 7% of patients discontinuing oxybutynin. A randomized, placebocontrolled clinical trial is under development to evaluate safety and efficacy of lower doses of oxybutynin for the treatment of hot flashes. Oxybutynin is primarily metabolized by CYP3A4, and has no known inhibitory effect on CYP2D6. Systematic reviews and pooled analyses of hot flash therapies A metaanalysis evaluated data from published, randomized, double-blind, placebo-controlled trials assessing multiple oral non-hormonal therapies for the treatment of hot flashes in menopausal women [72]. This metaanalysis included 10 trials of antidepressants, 10 trials of clonidine, 6 trials of other prescription medications, and 17 trials of isoflavone extract. In this report, trials evaluating SSRIs, SNRIs, clonidine, and gabapentin provided evidence for efficacy. Overall, the effect was less than what is observed with HRT. A subsequent pooled analysis of individual patient data from 7 double-blind, placebo-controlled studies evaluating several antidepressants and of 3 studies evaluating gabapentin for the treatment of hot flashes demonstrated significant reductions in hot flash scores with paroxetine and venlafaxine over that seen with placebos within 4 weeks of treatment initiation (41% and 33%, respectively) [35]. Fluoxetine and sertraline were associated with less benefit. Gabapentin appeared to perform similarly to paroxetine and venlafaxine, with a reduction in hot flash scores of about 35% more than that seen with a placebo. A third and more recent systematic review evaluated 13 trials of non–hormonal hot flash treatments in breast cancer survivors [73].

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The authors concluded that hot flash reduction with various interventions did not differ by whether patients were taking tamoxifen or aromatase inhibitors, and also concluded that citalopram, venlafaxine, gabapentin and paroxetine had efficacy at the doses mentioned in this manuscript. Among trials comparing pharmacologic to non-pharmacologic treatments, acupuncture appeared to have similar efficacy to gabapentin and venlafaxine. Stellate-ganglion block Given that hot flashes may be centrally mediated, investigators have evaluated the potential effect of stellate ganglion block with a local anesthetic on hot flash relief. After uncontrolled interventions and pilot studies had shown potential benefit [74–77], a randomized clinical trial was conducted [78]. Forty postmenopausal women with moderate to severe VMS were randomized to image-guided sham injection of saline in subcutaneous neck tissues versus stellate ganglion block with bupivacaine. At 6 months, there were no significant differences in overall VMS frequency, but the frequency of moderate to very severe VMS decreased more in the active treatment group compared to the sham injection group (50% reduction in active arm versus 0% reduction in sham arm; p < 0.001), without serious adverse events. Additionally, another trial randomized 20 patients per arm to receive a stellate ganglion block versus treatment with pregabalin 75 mg BID. This trial reported a more hot flash reductions at 3 months in the stellate ganglion block arm (p = 0.006) [79]. Cognitive behavioral strategies Some studies have supported the use of paced respirations and progressive muscle-relaxation training [80–82]. Participation in a yoga program has also shown sustained efficacy in decreasing hot-flash frequency and severity in a randomized clinical trial among breast cancer survivors [83]. Cognitive behavioral strategies, including stress management, relaxation, and deep breathing techniques, have also been explored with mixed results [84–89]. The most promising cognitive behavioral approach at this time is clinical hypnosis with two relatively-recently reported randomized trials, by Elkins et al., supporting that it is beneficial [90,91]. Barton et al., based on Elkins et al. data, conducted a 4-arm clinical trial in women with hot flashes. Women were randomized to a double control arm that received placebos capsules and focused attention training (used as a control for hypnosis), versus venlafaxine capsules and focused attention training, versus placebo capsules and self-hypnosis training/practice, versus venlafaxine and self-hypnosis training/practice. The 3 arms with one or two active treatments had similar hot flash score reductions over 8 weeks; the hypnosis alone arm did significantly better than did the double control arm (p = 0.04) [92]. Complementary and alternative therapies Complementary and alternative therapies are widely used to manage VMS [93,94]. Data are limited regarding the efficacy of the various remedies utilized. Isoflavones and phytoestrogens are plant-based compounds found in foods such as soybeans, chickpeas, and lentils, and are thought to have estrogenic and antiestrogenic properties. Several trials have been designed to evaluate their efficacy in control of hot flashes [95–100]. A review of 11 randomized, controlled trials of soy or isoflavone supplementation found benefit in only three trials that followed patients for at least six weeks [101]. Further, a systematic review considering 43 of such clinical trials found no benefit for any phytoestrogen compounds evaluated, except for genistein, which is thought to possess among the most potent of estrogenic effects [102].

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Black cohosh is another alternative therapy that has been investigated. While small studies have suggested benefit [103,104], this has not been consistently demonstrated. A meta-analysis involving 16 trials and 2023 patients found no difference between black cohosh and placebo in reduction of symptom frequency or severity [105]. Further, safety concerns have been raised regarding the potential for an estrogenic effect on breast tissue, thereby raising concern for disease recurrence in women with breast cancer [106]. Therefore, black cohosh is not commonly recommended for hot flash symptom management. A collection of other substances, such as evening primrose oil [107], flaxseed [108,109], ginseng, dong quai [101], wild yam, and progesterone creams [85] have also been tried without much success. Acupuncture is popular among complementary therapies for a variety of indications, including hot flashes. Acupuncture is a complex intervention, with a significant placebo effect noted in the literature, particularly noted when compared to sham acupuncture. Data are mixed, with one meta-analysis demonstrating inferior efficacy of acupuncture compared to hormonal therapy, no difference compared to sham acupuncture, and superior efficacy compared to no therapy [110]. While many of the studies evaluating acupuncture have suffered from small sample size, one trial randomized 327 patients to acupuncture or sham-control, and found that both groups experienced similar improvement in hot flash symptoms [111]. A recent trial randomized patients to receive electroacupuncture versus gabapentin versus placebo pills/sham acupuncture, and suggested that, with acupuncture, placebo effects were larger and nocebo effects were smaller [112].

Suggested approach In general, it is reasonable to suggest that most women with milder VMS try non-invasive non-pharmacologic measures, as these are generally well-tolerated and can be efficacious for some patients. In women with more than mild symptoms, pharmacologic measures can be employed. In women in whom nonestrogenic approaches are preferred, clinicians should consider non-hormonal pharmacologic therapy. Along this line, it is reasonable to start with a centrally-acting agent (SSRI, SNRI or anticonvulsant). While both antidepressants and a gabapentinoids appeared to control hot flashes relatively equally well, the randomized cross-over trial that supported that venlafaxine was preferred more than gabapentin, speaks for using an antidepressant agent first [51]. Instead of using venlafaxine, however, it is reasonable to start with citalopram given that the efficacy appears similar between these two antidepressants and citalopram appears to be better tolerated. An additional benefit is that citalopram is less expensive than many other antidepressants. In women receiving tamoxifen who are being considered for anti-VMS pharmacologic therapy, it becomes important to consider the impact of the chosen pharmacologic agent on tamoxifen’s metabolism. For this reason, it is recommended to avoid known potent CYP2D6 inhibitors (paroxetine) and favor drugs with little or no CYP2D6 inhibitory potential (i.e., venlafaxine, desvenlafaxine, escitalopram, gabapentin, pregabalin) in these patients. Other weak-to-moderate inhibitors (such as citalopram) should be used with caution. There does not appear to be much of a role for fluoxetine or sertraline, as they do not appear to work as well as several other studied antidepressant drugs. If other non-estrogenic pharmacologic approaches are desired, clonidine can be tried. The use of a progestational agent could also be considered, understanding that there is debate with regards to its safety in patients with breast cancer. If this approach is desired, a single intramuscular dose of medroxyprogesterone acetate is

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quite reasonable. This certainly would fulfill the goal of short-term hormonal therapy use. While data look quite promising for hypnosis, this technique is not widely available at this time. The available data support that stellate ganglion blocks work, although this is more invasive and might best be employed if other options do not work. At this time, most data do not support the routine use of complementary and/or alternative therapies, although some forms of acupuncture might provide some benefit.

Funding source This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest The authors have the possible conflicts of interest to disclose. Roberto A. Leon-Ferre, MD: none. Neil Majithia, MD: none. Charles L. Loprinzi, MD: Pfizer, Theravance, Competitive Technologies, GEOMC Co LTD, Acetylon, Janssen, Cubist Pharmaceuticals, Coronado Biosciences, Inc., Mitsubishi Tanabe Pharma, Lpath, Mundipharma, Metys, Janssen, QUE Oncology, Inc., and Insys. References [1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7–30. [2] Wilcken N, Hornbuckle J, Ghersi D. Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer. Cochrane Database Syst Rev 2003: CD002747. [3] Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013;381:805–16. [4] Goss PE, Ingle JN, Pritchard KI, Robert NJ, Muss H, Gralow J, et al. Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years. N Engl J Med 2016. [5] Bernhard J, Luo W, Ribi K, Colleoni M, Burstein HJ, Tondini C, et al. Patientreported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): a combined analysis of two phase 3 randomised trials. Lancet Oncol 2015;16:848–58. [6] Group L-aiEBCO. Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptorpositive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials. Lancet 2007;369:1711–23. [7] Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im S-A, Masuda N, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 2016;17:425–39. [8] Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371–88. [9] Francis PA, Regan MM, Fleming GF. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 2015;372:1673. [10] Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, Lang I, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 2014;371:107–18. [11] Freedman RR. Hot flashes: behavioral treatments, mechanisms, and relation to sleep. Am J Med 2005;118(Suppl 12B):124–30. [12] Freedman RR. Physiology of hot flashes. Am J Hum Biol 2001;13:453–64. [13] Casper RF, Yen SS. Neuroendocrinology of menopausal flushes: an hypothesis of flush mechanism. Clin Endocrinol (Oxf) 1985;22:293–312. [14] Shanafelt TD, Barton DL, Adjei AA, Loprinzi CL. Pathophysiology and treatment of hot flashes. Mayo Clin Proc 2002;77:1207–18. [15] Mulley G, Mitchell JR, Tattersall RB. Hot flushes after hypophysectomy. Br Med J 1977;2:1062. [16] Freedman RR, Norton D, Woodward S, Cornelissen G. Core body temperature and circadian rhythm of hot flashes in menopausal women. J Clin Endocrinol Metabol 1995;80:2354–8.

[17] Freedman RR, Krell W. Reduced thermoregulatory null zone in postmenopausal women with hot flashes. Am J Obstet Gynecol 1999;181:66–70. [18] Rosenberg J, Larsen SH. Hypothesis: pathogenesis of postmenopausal hot flush. Med Hypotheses 1991;35:349–50. [19] Blum I, Vered Y, Lifshitz A, Harel D, Blum M, Nordenberg Y, et al. The effect of estrogen replacement therapy on plasma serotonin and catecholamines of postmenopausal women. Isr J Med Sci 1996;32:1158–62. [20] Berendsen HH. The role of serotonin in hot flushes. Maturitas 2000;36:155–64. [21] de Zambotti M, Colrain IM, Javitz HS, Baker FC. Magnitude of the impact of hot flashes on sleep in perimenopausal women. Fertil Steril 2014;102(1708– 15):e1. [22] Erlik Y, Tataryn IV, Meldrum DR, Lomax P, Bajorek JG, Judd HL. Association of waking episodes with menopausal hot flushes. JAMA 1981;245:1741–4. [23] Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl H. Methodologic lessons learned from hot flash studies. J Clin Oncol 2001;19:4280–90. [24] Maclennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev 2004:CD002978. [25] Heiss G, Wallace R, Anderson GL, Aragaki A, Beresford SA, Brzyski R, et al. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA 2008;299:1036–45. [26] Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–33. [27] Holmberg L, Iversen OE, Rudenstam CM, Hammar M, Kumpulainen E, Jaskiewicz J, et al. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Natl Cancer Inst 2008;100:475–82. [28] Sismondi P, Kimmig R, Kubista E, Biglia N, Egberts J, Mulder R, et al. Effects of tibolone on climacteric symptoms and quality of life in breast cancer patients—data from LIBERATE trial. Maturitas 2011;70:365–72. [29] Fahlen M, Fornander T, Johansson H, Johansson U, Rutqvist LE, Wilking N, et al. Hormone replacement therapy after breast cancer: 10 year follow up of the Stockholm randomised trial. Eur J Cancer 2013;49:52–9. [30] Coope J, Williams S, Patterson JS. A study of the effectiveness of propranolol in menopausal hot flushes. Br J Obstet Gynaecol 1978;85:472–5. [31] Huang AJ, Subak LL, Wing R, West DS, Hernandez AL, Macer J, et al. An intensive behavioral weight loss intervention and hot flushes in women. Arch Intern Med 2010;170:1161–7. [32] Daley A, Stokes-Lampard H, Thomas A, MacArthur C. Exercise for vasomotor menopausal symptoms. Cochrane Database Syst Rev 2014:CD006108. [33] Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, LaVasseur BI, Barton DL, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 2000;356:2059–63. [34] Loprinzi CL, Sloan JA, Perez EA, Quella SK, Stella PJ, Mailliard JA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 2002;20:1578–83. [35] Loprinzi CL, Sloan J, Stearns V, Slack R, Iyengar M, Diekmann B, et al. Newer antidepressants and gabapentin for hot flashes: an individual patient pooled analysis. J Clin Oncol 2009;27:2831–7. [36] Boekhout AH, Vincent AD, Dalesio OB, van den Bosch J, Foekema-Tons JH, Adriaansz S, et al. Management of hot flashes in patients who have breast cancer with venlafaxine and clonidine: a randomized, double-blind, placebocontrolled trial. J Clin Oncol 2011;29:3862–8. [37] 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;105:161–6. [38] 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. [39] Archer DF, Seidman L, Constantine GD, Pickar JH, Olivier S. A double-blind, randomly assigned, placebo-controlled study of desvenlafaxine efficacy and safety for the treatment of vasomotor symptoms associated with menopause. Am J Obstet Gynecol 2009;200(172):e1–e10. [40] 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. [41] Suvanto-Luukkonen E, Koivunen R, Sundstrom H, Bloigu R, Karjalainen E, Haiva-Mallinen L, et al. Citalopram and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized, 9-month, placebocontrolled, double-blind study. Menopause 2005;12:18–26. [42] 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. [43] Barton DL, LaVasseur BI, Sloan JA, Stawis AN, Flynn KA, Dyar M, et al. Phase III, placebo-controlled trial of three doses of citalopram for the treatment of hot flashes: NCCTG trial N05C9. J Clin Oncol 2010;28:3278–83. [44] Freeman EW, Guthrie KA, Caan B, Sternfeld B, Cohen LS, Joffe H, et al. Efficacy of escitalopram for hot flashes in healthy menopausal women: a randomized controlled trial. JAMA 2011;305:267–74. [45] 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.

R.A. Leon-Ferre et al. / Cancer Treatment Reviews 52 (2017) 82–90 [46] 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. [47] Guttuso Jr 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. [48] Pandya KJ, Morrow GR, Roscoe JA, Zhao H, Hickok JT, Pajon E, et al. Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial. Lancet 2005;366:818–24. [49] Reddy SY, Warner H, Guttuso Jr T, Messing S, DiGrazio W, Thornburg L, et al. Gabapentin, estrogen, and placebo for treating hot flushes: a randomized controlled trial. Obstet Gynecol 2006;108:41–8. [50] Loprinzi CL, Kugler JW, Barton DL, Dueck AC, Tschetter LK, Nelimark RA, et al. Phase III trial of gabapentin alone or in conjunction with an antidepressant in the management of hot flashes in women who have inadequate control with an antidepressant alone: NCCTG N03C5. J Clin Oncol 2007;25:308–12. [51] Bordeleau L, Jugovic O, Ennis M, Pritchard KI, Warr D, Haq R, et al. A randomized crossover trial of venlafaxine (V) versus gabapentin (G) for hot flashes (HF) in breast cancer survivors. ASCO Meeting Abstracts 2010;28:9023. [52] Loprinzi CL, Qin R, Balcueva EP, Flynn KA, Rowland Jr KM, Graham DL, et al. Phase III, randomized, double-blind, placebo-controlled evaluation of pregabalin for alleviating hot flashes, N07C1. J Clin Oncol 2010;28:641–7. [53] Huang AJ, Cummings SR, Schembri M, Vittinghoff E, Ganz P, Grady D. Continuous transdermal nitroglycerin therapy for menopausal hot flashes: a single-arm, dose-escalation trial. Menopause 2016;23:330–4. [54] Wolosker N, de Campos JR, Kauffman P, Puech-Leao P. A randomized placebocontrolled trial of oxybutynin for the initial treatment of palmar and axillary hyperhidrosis. J Vasc Surg 2012;55:1696–700. [55] Costa AS, Leao LEV, Succi JE, Perfeito JAJ, Castelo A, Rymkiewicz E, et al. Randomized trial – oxybutynin for treatment of persistent plantar hyperhidrosis in women after sympathectomy. Clinics 2014;69:101–5. [56] Sexton T, Younus J, Perera F, Kligman L, Lock M. Oxybutynin for refractory hot flashes in cancer patients. Menopause 2007;14:505–9. [57] Bardia A, Novotny P, Sloan J, Barton D, Loprinzi C. Efficacy of nonestrogenic hot flash therapies among women stratified by breast cancer history and tamoxifen use: a pooled analysis. Menopause 2009;16:477–83. [58] Hemeryck A, Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Curr Drug Metab 2002;3:13–37. [59] Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 2003;95:1758–64. [60] Haque R, Shi J, Schottinger JE, Ahmed SA, Cheetham TC, Chung J, et al. Tamoxifen and antidepressant drug interaction among a cohort of 16 887 breast cancer survivors. J Natl Cancer Inst 2016;108:djv337. [61] Stearns V, Slack R, Greep N, Henry-Tilman R, Osborne M, Bunnell C, et al. Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial. J Clin Oncol 2005;23:6919–30. [62] Joffe H, Partridge A, Giobbie-Hurder A, Li X, Habin K, Goss P, et al. Augmentation of venlafaxine and selective serotonin reuptake inhibitors with zolpidem improves sleep and quality of life in breast cancer patients with hot flashes: a randomized, double-blind, placebo-controlled trial. Menopause 2010;17:908–16. [63] Goldberg RM, Loprinzi CL, O’Fallon JR, Veeder MH, Miser AW, Mailliard JA, et al. Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol 1994;12:155–8. [64] Pandya KJ, Raubertas RF, Flynn PJ, Hynes HE, Rosenbluth RJ, Kirshner JJ, et al. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Intern Med 2000;132:788–93. [65] Lundgren S, Gundersen S, Klepp R, Lonning PE, Lund E, Kvinnsland S. Megestrol acetate versus aminoglutethimide for metastatic breast cancer. Breast Cancer Res Treat 1989;14:201–6. [66] Brufman G, Isacson R, Haim N, Gez E, Sulkes A. Megestrol acetate in advanced breast carcinoma after failure to tamoxifen and/or aminoglutethimide. Oncology 1994;51:258–61. [67] Loprinzi CL, Michalak JC, Quella SK, O’Fallon JR, Hatfield AK, Nelimark RA, et al. Megestrol acetate for the prevention of hot flashes. N Engl J Med 1994;331:347–52. [68] Loprinzi CL, Levitt R, Barton D, Sloan JA, Dakhil SR, Nikcevich DA, 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. [69] Bertelli G, Venturini M, Del Mastro L, Bergaglio M, Sismondi P, Biglia N, et al. Intramuscular depot medroxyprogesterone versus oral megestrol for the control of postmenopausal hot flashes in breast cancer patients: a randomized study. Ann Oncol 2002;13:883–8. [70] Wolosker N, de Campos JRM, Kauffman P, Puech-Leao P. A randomized placebo-controlled trial of oxybutynin for the initial treatment of palmar and axillary hyperhidrosis. J Vasc Surg 2012;55:1696–700.

89

[71] Simon JA, Gaines T, LaGuardia KD. Extended-release oxybutynin therapy for vasomotor symptoms in women: a randomized clinical trial. Menopause 2016;23:1214–21. [72] Nelson HD, Vesco KK, Haney E, Fu R, Nedrow A, Miller J, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA 2006;295:2057–71. [73] Johns C, Seav SM, Dominick SA, Gorman JR, Li H, Natarajan L, et al. Informing hot flash treatment decisions for breast cancer survivors: a systematic review of randomized trials comparing active interventions. Breast Cancer Res Treat 2016;156:415–26. [74] Lipov E, Lipov S, Stark JT. Stellate ganglion blockade provides relief from menopausal hot flashes: a case report series. J Womens Health (Larchmt) 2005;14:737–41. [75] Lipov EG, Joshi JR, Sanders S, Wilcox K, Lipov S, Xie H, et al. Effects of stellateganglion block on hot flushes and night awakenings in survivors of breast cancer: a pilot study. Lancet Oncol 2008;9:523–32. [76] Pachman DR, Barton D, Carns PE, Novotny PJ, Wolf S, Linquist B, et al. Pilot evaluation of a stellate ganglion block for the treatment of hot flashes. Support Care Cancer 2011;19:941–7. [77] Loprinzi CL, Barton DL, Carns PE. Stellate-ganglion block: a new treatment for hot flushes? Lancet Oncol 2008;9:506–7. [78] Walega DR, Rubin LH, Banuvar S, Shulman LP, Maki PM. Effects of stellate ganglion block on vasomotor symptoms: findings from a randomized controlled clinical trial in postmenopausal women. Menopause 2014;21:807–14. [79] Othman AH, Zaky AH. Management of hot flushes in breast cancer survivors: comparison between stellate ganglion block and pregabalin. Pain Med 2014;15:410–7. [80] Germaine LM, Freedman RR. Behavioral treatment of menopausal hot flashes: evaluation by objective methods. J Consult Clin Psychol 1984;52:1072–9. [81] Freedman RR, Woodward S. Behavioral treatment of menopausal hot flushes: evaluation by ambulatory monitoring. Am J Obstet Gynecol 1992;167:436–9. [82] Irvin JH, Domar AD, Clark C, Zuttermeister PC, Friedman R. The effects of relaxation response training on menopausal symptoms. J Psychosom Obstet Gynaecol 1996;17:202–7. [83] Carson JW, Carson KM, Porter LS, Keefe FJ, Seewaldt VL. Yoga of Awareness program for menopausal symptoms in breast cancer survivors: results from a randomized trial. Support Care Cancer 2009;17:1301–9. [84] Rada G, Capurro D, Pantoja T, Corbalan J, Moreno G, Letelier LM, et al. Nonhormonal interventions for hot flushes in women with a history of breast cancer. Cochrane Database Syst Rev 2010:CD004923. [85] Nedrow A, Miller J, Walker M, Nygren P, Huffman LH, Nelson HD. Complementary and alternative therapies for the management of menopause-related symptoms: a systematic evidence review. Arch Intern Med 2006;166:1453–65. [86] Ayers B, Smith M, Hellier J, Mann E, Hunter MS. Effectiveness of group and self-help cognitive behavior therapy in reducing problematic menopausal hot flushes and night sweats (MENOS 2): a randomized controlled trial. Menopause 2012;19:749–59. [87] Mann E, Smith MJ, Hellier J, Balabanovic JA, Hamed H, Grunfeld EA, et al. Cognitive behavioural treatment for women who have menopausal symptoms after breast cancer treatment (MENOS 1): a randomised controlled trial. Lancet Oncol 2012;13:309–18. [88] Saensak S, Vutyavanich T, Somboonporn W, Srisurapanont M. Relaxation for perimenopausal and postmenopausal symptoms. Cochrane Database Syst Rev 2014:CD008582. [89] Duijts SF, van Beurden M, Oldenburg HS, Hunter MS, Kieffer JM, Stuiver MM, et al. Efficacy of cognitive behavioral therapy and physical exercise in alleviating treatment-induced menopausal symptoms in patients with breast cancer: results of a randomized, controlled, multicenter trial. J Clin Oncol 2012;30:4124–33. [90] Elkins G, Marcus J, Stearns V, Perfect M, Rajab MH, Ruud C, et al. Randomized trial of a hypnosis intervention for treatment of hot flashes among breast cancer survivors. J Clin Oncol 2008;26:5022–6. [91] Elkins GR, Fisher WI, Johnson AK, Carpenter JS, Keith TZ. Clinical hypnosis in the treatment of postmenopausal hot flashes: a randomized controlled trial. Menopause 2013;20:291–8. [92] Barton D, Fee-Schroeder K, Linquist B, Keith T, Wolf S, Abboud L, et al. Pilot study of a biobehavioral treatment for hot flashes. Ann Behavioral Med 2013;45 (suppl; abstr A-130). [93] Newton KM, Buist DS, Keenan NL, Anderson LA, LaCroix AZ. Use of alternative therapies for menopause symptoms: results of a population-based survey. Obstet Gynecol 2002;100:18–25. [94] Keenan NL, Mark S, Fugh-Berman A, Browne D, Kaczmarczyk J, Hunter C. Severity of menopausal symptoms and use of both conventional and complementary/alternative therapies. Menopause 2003;10:507–15. [95] Van Patten CL, Olivotto IA, Chambers GK, Gelmon KA, Hislop TG, Templeton E, 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. [96] Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study. Menopause 2000;7:236–42. [97] Quella SK, Loprinzi CL, Barton DL, Knost JA, Sloan JA, LaVasseur BI, et al. Evaluation of soy phytoestrogens for the treatment of hot flashes in breast

90

[98]

[99]

[100]

[101]

[102]

[103]

[104]

R.A. Leon-Ferre et al. / Cancer Treatment Reviews 52 (2017) 82–90 cancer survivors: A North Central Cancer Treatment Group Trial. J Clin Oncol 2000;18:1068–74. Nikander E, Kilkkinen A, Metsa-Heikkila M, Adlercreutz H, Pietinen P, Tiitinen A, et al. A randomized placebo-controlled crossover trial with phytoestrogens in treatment of menopause in breast cancer patients. Obstet Gynecol 2003;101:1213–20. MacGregor CA, Canney PA, Patterson G, McDonald R, Paul J. A randomised double-blind controlled trial of oral soy supplements versus placebo for treatment of menopausal symptoms in patients with early breast cancer. Eur J Cancer 2005;41:708–14. Levis S, Strickman-Stein N, Ganjei-Azar P, Xu P, Doerge DR, Krischer J. Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: a randomized, double-blind trial. Arch Intern Med 2011;171:1363–9. Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: a review of randomized, controlled trials. Ann Intern Med 2002;137:805–13. Lethaby A, Marjoribanks J, Kronenberg F, Roberts H, Eden J, Brown J. Phytoestrogens for menopausal vasomotor symptoms. Cochrane Database Syst Rev 2013:CD001395. Frei-Kleiner S, Schaffner W, Rahlfs VW, Bodmer C, Birkhauser M. Cimicifuga racemosa dried ethanolic extract in menopausal disorders: a double-blind placebo-controlled clinical trial. Maturitas 2005;51:397–404. Osmers R, Friede M, Liske E, Schnitker J, Freudenstein J, Henneicke-von Zepelin HH. Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms. Obstet Gynecol 2005;105:1074–83.

[105] Leach MJ, Moore V. Black cohosh (Cimicifuga spp.) for menopausal symptoms. Cochrane Database Syst Rev 2012:CD007244. [106] Fritz H, Seely D, McGowan J, Skidmore B, Fernandes R, Kennedy DA, et al. Black cohosh and breast cancer: a systematic review. Integr Cancer Ther 2014;13:12–29. [107] Chenoy R, Hussain S, Tayob Y, O’Brien PM, Moss MY, Morse PF. Effect of oral gamolenic acid from evening primrose oil on menopausal flushing. BMJ 1994;308:501–3. [108] Dodin S, Lemay A, Jacques H, Legare F, Forest JC, Masse B. The effects of flaxseed dietary supplement on lipid profile, bone mineral density, and symptoms in menopausal women: a randomized, double-blind, wheat germ placebo-controlled clinical trial. J Clin Endocrinol Metab 2005;90:1390–7. [109] Pruthi S, Qin R, Terstreip SA, Liu H, Loprinzi CL, Shah TR, et al. A phase III, randomized, placebo-controlled, double-blind trial of flaxseed for the treatment of hot flashes: North Central Cancer Treatment Group N08C7. Menopause 2012;19:48–53. [110] Dodin S, Blanchet C, Marc I, Ernst E, Wu T, Vaillancourt C, et al. Acupuncture for menopausal hot flushes. Cochrane Database Syst Rev 2013:CD007410. [111] Ee C, Xue C, Chondros P, Myers SP, French SD, Teede H, et al. Acupuncture for menopausal hot flashes: a randomized trial. Ann Intern Med 2016;164:146–54. [112] Mao JJ, Bowman MA, Xie SX, Bruner D, DeMichele A, Farrar JT. Electroacupuncture versus gabapentin for hot flashes among breast cancer survivors: a randomized placebo-controlled trial. J Clin Oncol 2015;33:3615–20.