Overview
Etiology
Interventions
Primary Interventions
        Sweats
        Hot flashes
Nonspecific Palliative Interventions

Overview

Sweats and hot flashes are common in cancer survivors, from those in the adjuvant setting to those living with advanced disease. Pathophysiologic mechanisms are complex. Treatment options are broad-based, including hormonal agents, nonhormonal pharmacotherapies, and diverse integrative medicine modalities.[1] Physiologically, sweating mediates core body temperature by producing transdermal evaporative heat loss.[2,3] Sweating occurs in disease states such as fever and in nondisease states such as warm environments, exercise, and menopause. Limited data suggest that sweating occurs in 14% to 16% of advanced cancer patients receiving palliative care, with severity typically rated as moderate to severe.[4-6] Sweating is part of the hot flash complex that characterizes the vasomotor instability of menopause. Hot flashes occur in approximately two thirds of postmenopausal women with a breast cancer history and are associated with night sweats in 44%.[7,8] For most breast cancer and prostate cancer patients, hot flash intensity is moderate to severe. Distressing hot flashes appear to be less frequent in postmenopausal women with nonbreast cancer. Approximately 20% of women without breast cancer seek medical treatment for postmenopausal symptoms, including symptoms related to vasomotor instability. Vasomotor symptoms resolve spontaneously in most patients in this population, with only 20% of affected women reporting significant hot flashes 4 years after the last menses.[9] Unlike the noncancer postmenopausal population, hot flash intensity does not decrease with time in breast cancer survivors. There are no comparable data for women with metastatic breast cancer. Three quarters of men with locally advanced or metastatic prostate cancer treated with orchiectomy experience hot flashes.[10]

Sweats in the cancer patient may be associated with the tumor, its treatment, or unrelated (comorbid) conditions. Sweats are characteristic of certain primary tumor types such as Hodgkin lymphoma, pheochromocytoma, and functional neuroendocrine tumors (i.e., secretory carcinoids). Other causes include fever, menopause, castration (male), drugs, hypothalamic disturbances, and primary disorders of sweating. Causes of menopause include natural menopause, surgical menopause, or chemical menopause, which in the cancer patient may be caused by cytotoxic chemotherapy, radiation, or androgen treatment. Causes of “male menopause” include orchiectomy, gonadotropin-releasing hormone use, or estrogen use. Drug-associated causes of sweats include tamoxifen, opioids, tricyclic antidepressants, and steroids. Distinct from menopausal effects, hormonal therapies, biologic response modifiers, and cytotoxic agents associated with fever secondarily cause sweats.

As with interventions for fever, primary interventions directed at the underlying cause of sweats or hot flashes form the basis of management. In the absence of effective therapy or when onset is delayed, nonspecific palliative interventions are key.

The primary interventions for fever-associated sweats are those directed at the underlying cause of the fever (refer to the Primary Interventions for fever section for more information). Effective antineoplastic therapies control the sweats associated with tumor recurrence or progression. Somatostatin analogues are a primary treatment for flushes and sweats associated with some neuroendocrine tumors.

Estrogen replacement effectively controls hot flashes associated with biologic or treatment-associated postmenopausal states in women. The proposed mechanism of action of estrogen replacement on hot flash amelioration is by raising the core body temperature sweating threshold;[11] however, many women have relative or absolute contraindications to estrogen replacement. Physicians and breast cancer survivors often think there is an increased risk of breast cancer recurrence or de novo breast malignancy with hormone replacement therapies and defer hormonal management of postmenopausal symptoms. Methodologically strong data evaluating the risk of breast cancer associated with hormone replacement therapy in healthy women have been minimal, despite strong basic science considerations suggesting the possibility of such a risk.[12] In May 2002, the Women's Health Initiative (WHI), a large, randomized, placebo-controlled trial of the risks and benefits of estrogen plus progestin in healthy postmenopausal women, was stopped prematurely at a mean follow-up of 5.2 years (±1.3) because of the detection of a 1.26-fold increased breast cancer risk (95% confidence interval [CI], 1.00–1.59) in women receiving hormone replacement therapy. Tumors among women in the hormone replacement therapy group were slightly larger and more advanced than in the placebo group, with a substantial and statistically significant rise in the percentage of abnormal mammograms at first annual screening; such a rise might hinder breast cancer diagnosis and account for the later stage at diagnosis.[13,14] These results are supported by a population-based case-control study suggesting a 1.7-fold (95% CI, 1.3–2.2) increased risk of breast cancer in women using combined hormone replacement therapy. The risk of invasive lobular carcinoma was increased 2.7-fold (95% CI, 1.7–4.3), the risk of invasive ductal carcinoma was increased 1.5-fold (95% CI, 1.1–2.0), and the risk of estrogen receptor–positive/progesterone receptor–positive breast cancer was increased 2.0-fold (95% CI, 1.5–2.7). Increased risk was highest for invasive lobular tumors and in women who used hormone replacement therapy for longer periods of time. Risk was not increased with unopposed estrogen therapy.[15] The very limited data available do not indicate an increased risk of breast cancer recurrence with single-agent estrogen use in patients with a history of breast cancer.[16,17]

Numerous nonestrogenic, pharmacologic treatment interventions for hot flash management in breast cancer patients have been evaluated. Options with reported efficacy include androgens, progestational agents, gabapentin, selective serotonin reuptake inhibitors (SSRIs), alpha adrenergic agonists (e.g., methyl dopa, transdermal clonidine), beta-blockers, veralipride (an antidopaminergic agent), and vitamin E. Inferior efficacy and side effects limit the use of many of these agents. A series of double-blind placebo-controlled trials suggests that low-dose megestrol acetate (i.e., 20 mg by mouth twice a day) and SSRIs are among the more promising agents for hot flash management in this population. Limited data suggest that brief cycles of intramuscular depot medroxyprogesterone acetate also play a role in the management of hot flashes.[18] Risk associated with progestin use is unknown.[12] Venlafaxine, a norepinephrine and serotonin reuptake inhibitor, has been demonstrated to produce a 60% reduction in severity and intensity of hot flashes. The optimal dose indicated in these trials is 75 mg of the extended-release formulation twice a day.[19-26] A randomized double-blind placebo-controlled trial evaluating the use of controlled-release paroxetine for the treatment of menopausal hot flashes in a general population of women suggests that this SSRI plays a role in hot flash management.[27] A randomized placebo-controlled trial (URCC-U2101) of gabapentin in women with breast cancer suggests that gabapentin in doses of 900 mg per day may be effective in decreasing the frequency and severity of hot flashes.[28] In a randomized phase III trial (NCCTG-N03C5) of gabapentin alone (900 mg daily or 300 mg tid) versus gabapentin in conjunction with an antidepressant in women who had inadequate control of hot flashes with an antidepressant alone, gabapentin use resulted in an approximately 50% median reduction in hot flash frequency and score, regardless of whether the antidepressant was continued. In other words, for women who were using antidepressants exclusively for the management of hot flashes that were inadequately controlled, initiation of gabapentin with discontinuation of the antidepressant did not provide results inferior to those obtained with combined therapy, resulting in the need for fewer medications.[29] An open-label prospective pilot study (n = 30) on the use of levetiracetam for the management of hot flashes in women with a history of breast cancer, as well as those undergoing natural menopause, suggests that it, too, may have a role in the management of hot flashes. While there was a high rate of study withdrawal due to side effects, levetiracetam is not metabolized by the cytochrome P450 system and does not have any known interaction with tamoxifen; therefore, a more critical evaluation of its efficacy is warranted.[30] One well-designed randomized, double-blind, placebo-controlled crossover study (NCCTG-N01CC) of black cohosh in women with a history of breast cancer conducted with a methodology similar to those used with SSRIs shows no evidence of benefit.[31] Similarly, two randomized placebo-controlled trials in breast cancer survivors show no benefit of soy over placebo in alleviating hot flashes.[32,33]

Many of the SSRIs can inhibit the cytochrome P450 enzymes involved in the metabolism of tamoxifen, which is commonly used in the treatment of breast cancer. When SSRIs are being used, drug-drug interactions should be noted. Tamoxifen, used in the management of breast cancer, is metabolized by the cytochrome P450 enzyme system, specifically CYP2D6. Wild-type CYP2D6 metabolizes tamoxifen to an active metabolite, 4-hydroxy-N-desmethyl-tamoxifen, also known as endoxifen. A prospective trial evaluating the effects of the coadministration of tamoxifen and paroxetine, a CYP2D6 inhibitor, on tamoxifen metabolism, found that paroxetine coadministration resulted in decreased concentrations of endoxifen. The magnitude of decrease was greater in women with the wild-type CYP2D6 genotype than in those with a variant genotype (P = .03).[34] In a prospective observational study of 80 women initiating adjuvant tamoxifen therapy for newly diagnosed breast cancer, variant CYP2D6 genotypes, as well concomitant use of SSRI CYP2D6 inhibitors, resulted in reduced endoxifen levels. Variant CYP2D6 genotypes do not produce functional CYP2D6 enzymes.[35] Clinical implications of these changes and of other CYP2D6 genotypes [36] have not yet been elucidated, but the pharmacokinetic interaction between tamoxifen and the newer antidepressants used to treat hot flashes merits further study.[37] Likewise, the risk of soy phytoestrogen use on breast cancer recurrence and/or progression has not yet been clarified. Soy phytoestrogens are weak estrogens found in plant foods. In vitro models suggest that these compounds have a biphasic effect on mammary cell proliferation that is dependent on intracellular concentrations of phytoestrogen and estradiol.[38]

Behavioral methods as a primary or adjunctive modality may also play a role in hot flash management. Many women with breast cancer demonstrate interest in learning more about behavioral methods and complementary and alternative methods for hot flash management. Relaxation training has been found to decrease hot flash intensity in postmenopausal women in general good health who were randomized to relaxation response training, a placebo intervention group, or a control group.[39] Future research on hot flash management may be aided by the development of psychometrically sound assessment tools such as the Hot Flash Related Daily Interference Scale.[40]

Data regarding the pathophysiology and management of hot flashes in men with prostate cancer are scant. The limited data that exist suggest that hot flashes are related to changes in sex hormone levels that caused instability in the hypothalamic thermoregulatory center analogous to the proposed mechanism of hot flashes that occur in women. As with women with breast cancer, hot flashes impair the quality of life for men with prostate cancer who are receiving androgen deprivation therapy. The vasodilatory neuropeptide, calcitonin gene–related peptide, may be instrumental in the genesis of hot flashes. Treatment modalities include estrogens, progesterone, SSRIs, and cyproterone acetate, an antiandrogen. The latter is not available in the United States. Pilot studies of the efficacy of the SSRIs paroxetine and fluvoxamine suggest these drugs decrease the frequency and severity of hot flashes in men with prostate cancer.[41,42] As for women with hormonally sensitive tumors, there are concerns about the effects of hormone use on the outcome of prostate cancer, in addition to other well-described side effects.[43]

Clinical experience suggests that the H₂ blocker cimetidine may be useful in the management of cancer-associated sweats. Given the vascular action of 5-hydroxytryptamine, somatostatin analogs may play a role in the nonspecific management of sweats. Other recommendations include the use of loose-fitting cotton clothing, fans, and behavioral methods. The use of low-dose thioridazine for the management of sweats in advanced cancer is no longer advocated because of reports of torsade de pointes arrhythmias [44] and sudden death.[45]

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