Overview
Etiology
Interventions
Primary Interventions
        Sweats
        Hot flashes
Other Pharmacologic 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.[9] 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] There are no comparable data for women with metastatic breast cancer. Three-quarters of men with locally advanced or metastatic prostate cancer treated with medical or surgical 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, aromatase inhibitors, 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 ¹ 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] 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]

Numerous nonestrogenic, pharmacologic treatment interventions for hot flash management in women with a history of breast cancer and in some men who have undergone androgen deprivation therapy have been evaluated. Options with reported efficacy include androgens, progestational agents, gabapentin, selective serotonin reuptake inhibitors (SSRIs), selective serotonin norepinephrine inhibitors, alpha adrenergic agonists (e.g., methyldopa, clonidine), beta-blockers, and veralipride (an antidopaminergic agent). Inferior efficacy, lack of large definitive studies, and potential side effects limit the use of many of these agents.[19-21]

Agents that have been found to be helpful in large, randomized, placebo-controlled clinical trials include venlafaxine, paroxetine, citalopram, fluoxetine, gabapentin, pregabalin, and clonidine.[19-21] These agents demonstrate a 40% to 60% reduction in hot flash frequency and score (a measure combining severity and frequency).[22] Agents conferring a 55% to 60% reduction in hot flashes are venlafaxine extended release, 75 mg daily;[23] paroxetine, 12.5 mg controlled release [24] or 10 mg daily;[25] gabapentin, 300 mg tid;[26,27] and pregabalin, 75 mg bid.[28] Other effective agents resulting in about a 50% reduction in hot flashes include citalopram, 10 to 20 mg per day;[29] and fluoxetine, 20 mg per day.[20] Clonidine, 0.1 mg transdermal [30] or oral daily,[31] can reduce hot flashes by about 40%.

Agents that have been evaluated in phase II trials but have not shown efficacy include bupropion,[32] aprepitant,[33] and desipramine.[34] In addition, randomized clinical trials with sertraline have not provided convincing evidence of its efficacy in hot flash management.[35,36]

Side effects for antidepressant agents in the doses used to treat hot flashes are minimal in the short term and primarily include nausea, sedation, dry mouth, and appetite suppression or stimulation. In the long term, the prevalence of decreases in sexual function with SSRIs at doses used to treat hot flashes is not known. The anticonvulsants gabapentin and pregabalin can cause sedation, dizziness, and difficulty concentrating, while clonidine can cause dry mouth, sedation, constipation, and insomnia.

Data indicate that if one medication is not helpful for an individual, switching to another medication—whether a different antidepressant or gabapentin—may be worthwhile. In a randomized phase III trial (NCCTG-N03C5 ²) of gabapentin alone versus gabapentin in conjunction with an antidepressant in women who had inadequate control of their hot flashes with an antidepressant alone,[37] 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 produced results equal to those obtained with combined therapy, resulting in the need for fewer medications. Similarly, in a pilot study of women receiving inadequate benefit from venlafaxine for hot flash reduction, switching to open-label citalopram, 20 mg per day, resulted in a 50% reduction in hot flash frequency and score.[38]

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).[39]

In a prospective observational study of 80 women initiating adjuvant tamoxifen therapy for newly diagnosed breast cancer, variant CYP2D6 genotypes and concomitant use of SSRI CYP2D6 inhibitors resulted in reduced endoxifen levels. Variant CYP2D6 genotypes do not produce functional CYP2D6 enzymes.[40] Clinical implications of these changes and of other CYP2D6 genotypes [41] have not yet been elucidated, but the pharmacokinetic interaction between tamoxifen and the newer antidepressants used to treat hot flashes merits further study.[42] 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.[43]

Behavioral interventions as a primary or adjunctive modality may also play a role in hot flash management. Core body temperature has been shown to increase before a hot flash;[44] therefore, interventions to keep body temperature down could improve hot flash management. Some methods of controlling body temperature include the use of loose-fitting cotton clothing, the use of fans and open windows to keep air moving, and behavioral interventions such as stress management. Relaxation training and slow, deep breathing [45,46] have been found to decrease hot flash intensity by as much as 40% to 50% in controlled pilot trials. More research with well-designed control arms is needed to further clarify the main effect of such behavioral treatments as well as the additive and synergistic effects with other treatments. One pilot study also found that self-hypnosis, utilizing cooling suggestions, reduced hot flash scores an average of 68%.[47] Self-hypnosis is being studied further in larger controlled trials as well as in combination with low-dose antidepressants.

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, which evaluates the impact of hot flashes on a wide variety of daily activities.[48]

Numerous herbs and dietary supplements are popularly used for hot flash reduction. Several of these substances have not been well studied in rigorous clinical trials. Furthermore, the biologic activity of various over-the-counter supplements has yet to be determined. Some of the more well-studied agents include soy phytoestrogen, black cohosh, and vitamin E.

Vitamin E, 400 IU bid, appears to confer a modest reduction in hot flashes that is only slightly better than placebo.[49,50] The reduction in hot flashes is roughly 35% to 40%. Soy has been studied in numerous randomized, placebo-controlled trials, with most of those trials showing that soy was no better than placebo in reducing hot flashes.[51-55] Similarly, trials of black cohosh that have been well designed with a randomized, placebo-controlled arm have also found that black cohosh is no better than placebo in reducing hot flashes.[55-57]

One food product, flaxseed, has been studied in a phase II open-label trial (MC04C9 ³), and promising data indicate that flaxseed may reduce hot flashes.[58] Performed in 30 women, this study showed that ground flaxseed sprinkled in food twice a day, for a total of 40 g per day, resulted in a reduction in hot flash scores of 57%. A large placebo-controlled study (NCCTG-N08C7 ⁴) to further evaluate flaxseed is about to begin.

Other combinations of supplements—including dong quai, milk thistle, red clover, licorice, and chaste tree berry—need more study to clarify their impact on hot flashes and their potential estrogenic activity.[59-62] Women who need or want to avoid estrogen should not take these products until more is known.

Several pilot trials have evaluated the use of acupuncture to treat hot flashes.[63-66] Research in acupuncture is difficult, owing to the lack of novel methodology—specifically, the conundrum of what should serve as an adequate control arm. In addition, the philosophy surrounding acupuncture practice is quite individualized, in that two women experiencing hot flashes would not necessarily receive the same treatment. It would be important to study acupuncture utilizing relevant clinical procedures; so far, acceptable research methods to accomplish this are lacking. Therefore, the data with respect to the effect of acupuncture on hot flashes are quite mixed, with many studies suffering from ineffective control arms. (Refer to the PDQ summary on Acupuncture ⁵ for more information.)

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. With the exception of clonidine, the agents mentioned previously (refer to the Other pharmacologic interventions ⁶ for hot flashes section of this summary) that have been found effective for hot flashes have shown similar rates of efficacy when studied in men. Treatment modalities include estrogens, progesterone, SSRIs, gabapentin 300 mg 3 times per day as an option for men,[67] 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.[68,69] 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.[70]

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. 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 [71] and sudden death.[72]

References

1. Dalal S, Zhukovsky DS: Pathophysiology and management of hot flashes. J Support Oncol 4 (7): 315-20, 325, 2006 Jul-Aug.  [PUBMED Abstract]
   
   
2. Boulant JA: Thermoregulation. In: Machowiak PA, ed.: Fever: Basic Mechanisms and Management. New York, NY: Raven Press, 1991, pp 1-22. 
   
   
3. Dinarello CA, Bunn PA Jr: Fever. Semin Oncol 24 (3): 288-98, 1997.  [PUBMED Abstract]
   
   
4. Ventafridda V, De Conno F, Ripamonti C, et al.: Quality-of-life assessment during a palliative care programme. Ann Oncol 1 (6): 415-20, 1990.  [PUBMED Abstract]
   
   
5. Quigley CS, Baines M: Descriptive epidemiology of sweating in a hospice population. J Palliat Care 13 (1): 22-6, 1997 Spring.  [PUBMED Abstract]
   
   
6. Lichter I, Hunt E: The last 48 hours of life. J Palliat Care 6 (4): 7-15, 1990 Winter.  [PUBMED Abstract]
   
   
7. Couzi RJ, Helzlsouer KJ, Fetting JH: Prevalence of menopausal symptoms among women with a history of breast cancer and attitudes toward estrogen replacement therapy. J Clin Oncol 13 (11): 2737-44, 1995.  [PUBMED Abstract]
   
   
8. 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 82 (9): 1682-91, 1998.  [PUBMED Abstract]
   
   
9. Johnson SR: Menopause and hormone replacement therapy. Med Clin North Am 82 (2): 297-320, 1998.  [PUBMED Abstract]
   
   
10. Charig CR, Rundle JS: Flushing. Long-term side effect of orchiectomy in treatment of prostatic carcinoma. Urology 33 (3): 175-8, 1989.  [PUBMED Abstract]
    
    
11. Freedman RR, Blacker CM: Estrogen raises the sweating threshold in postmenopausal women with hot flashes. Fertil Steril 77 (3): 487-90, 2002.  [PUBMED Abstract]
    
    
12. Pritchard KI: Hormone replacement in women with a history of breast cancer. Oncologist 6 (4): 353-62, 2001.  [PUBMED Abstract]
    
    
13. Writing Group for the Women's Health Initiative Investigators.: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 288 (3): 321-33, 2002.  [PUBMED Abstract]
    
    
14. Chlebowski RT, Hendrix SL, Langer RD, et al.: Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 289 (24): 3243-53, 2003.  [PUBMED Abstract]
    
    
15. Li CI, Malone KE, Porter PL, et al.: Relationship between long durations and different regimens of hormone therapy and risk of breast cancer. JAMA 289 (24): 3254-63, 2003.  [PUBMED Abstract]
    
    
16. Vassilopoulou-Sellin R, Asmar L, Hortobagyi GN, et al.: Estrogen replacement therapy after localized breast cancer: clinical outcome of 319 women followed prospectively. J Clin Oncol 17 (5): 1482-7, 1999.  [PUBMED Abstract]
    
    
17. Decker DA, Pettinga JE, VanderVelde N, et al.: Estrogen replacement therapy in breast cancer survivors: a matched-controlled series. Menopause 10 (4): 277-85, 2003 Jul-Aug.  [PUBMED Abstract]
    
    
18. Bertelli G, Venturini M, Del Mastro L, et al.: Intramuscular depot medroxyprogesterone versus oral megestrol for the control of postmenopausal hot flashes in breast cancer patients: a randomized study. Ann Oncol 13 (6): 883-8, 2002.  [PUBMED Abstract]
    
    
19. Barton D, Loprinzi CL: Making sense of the evidence regarding nonhormonal treatments for hot flashes. Clin J Oncol Nurs 8 (1): 39-42, 2004.  [PUBMED Abstract]
    
    
20. Loprinzi CL, Stearns V, Barton D: Centrally active nonhormonal hot flash therapies. Am J Med 118 (Suppl 12B): 118-23, 2005.  [PUBMED Abstract]
    
    
21. Loprinzi CL, Barton DL, Sloan JA, et al.: Mayo Clinic and North Central Cancer Treatment Group hot flash studies: a 20-year experience. Menopause 15 (4 Pt 1): 655-60, 2008 Jul-Aug.  [PUBMED Abstract]
    
    
22. Sloan JA, Loprinzi CL, Novotny PJ, et al.: Methodologic lessons learned from hot flash studies. J Clin Oncol 19 (23): 4280-90, 2001.  [PUBMED Abstract]
    
    
23. Loprinzi CL, Kugler JW, Sloan JA, et al.: Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 356 (9247): 2059-63, 2000.  [PUBMED Abstract]
    
    
24. Stearns V, Beebe KL, Iyengar M, et al.: Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA 289 (21): 2827-34, 2003.  [PUBMED Abstract]
    
    
25. 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 23 (28): 6919-30, 2005.  [PUBMED Abstract]
    
    
26. Guttuso T Jr, Kurlan R, McDermott MP, et al.: Gabapentin's effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol 101 (2): 337-45, 2003.  [PUBMED Abstract]
    
    
27. 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 366 (9488): 818-24, 2005 Sep 3-9.  [PUBMED Abstract]
    
    
28. Loprinzi CL, Qin R, Stella PJ, et al.: Pregabalin for hot flashes in women: NCCTG trial N07C1. [Abstract] J Clin Oncol 27 (Suppl 15): A-9513, 2009. 
    
    
29. Barton DL, LaVasseur B, Sloan JA, et al.: A phase III trial evaluating three doses of citalopram for hot flashes: NCCTG trial N05C9. [Abstract] J Clin Oncol 26 (Suppl 15): A-9538, 2008. 
    
    
30. Goldberg RM, Loprinzi CL, O'Fallon JR, et al.: Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol 12 (1): 155-8, 1994.  [PUBMED Abstract]
    
    
31. Pandya KJ, Raubertas RF, Flynn PJ, 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 132 (10): 788-93, 2000.  [PUBMED Abstract]
    
    
32. Pérez DG, Loprinzi CL, Sloan J, et al.: Pilot evaluation of bupropion for the treatment of hot flashes. J Palliat Med 9 (3): 631-7, 2006.  [PUBMED Abstract]
    
    
33. Bardia A, Thompson S, Atherton PJ, et al.: Pilot evaluation of aprepitant for the treatment of hot flashes. Support Cancer Ther 3 (4): 240-6, 2006.  [PUBMED Abstract]
    
    
34. Barton DL, Loprinzi CL, Atherton P, et al.: Phase II Evaluation of Desipramine for the Treatment of Hot Flashes. Support Cancer Ther 4 (4): 219-24, 2007.  [PUBMED Abstract]
    
    
35. Kimmick GG, Lovato J, McQuellon R, et al.: 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 12 (2): 114-22, 2006 Mar-Apr.  [PUBMED Abstract]
    
    
36. Gordon PR, Kerwin JP, Boesen KG, et al.: Sertraline to treat hot flashes: a randomized controlled, double-blind, crossover trial in a general population. Menopause 13 (4): 568-75, 2006 Jul-Aug.  [PUBMED Abstract]
    
    
37. Loprinzi CL, Kugler JW, Barton DL, 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 25 (3): 308-12, 2007.  [PUBMED Abstract]
    
    
38. Loprinzi CL, Flynn PJ, Carpenter LA, et al.: Pilot evaluation of citalopram for the treatment of hot flashes in women with inadequate benefit from venlafaxine. J Palliat Med 8 (5): 924-30, 2005.  [PUBMED Abstract]
    
    
39. Stearns V, Johnson MD, Rae JM, et al.: Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 95 (23): 1758-64, 2003.  [PUBMED Abstract]
    
    
40. Jin Y, Desta Z, Stearns V, et al.: CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97 (1): 30-9, 2005.  [PUBMED Abstract]
    
    
41. Bonanni B, Macis D, Maisonneuve P, et al.: Polymorphism in the CYP2D6 tamoxifen-metabolizing gene influences clinical effect but not hot flashes: data from the Italian Tamoxifen Trial. J Clin Oncol 24 (22): 3708-9; author reply 3709, 2006.  [PUBMED Abstract]
    
    
42. Goetz MP, Loprinzi CL: A hot flash on tamoxifen metabolism. J Natl Cancer Inst 95 (23): 1734-5, 2003.  [PUBMED Abstract]
    
    
43. This P, De La Rochefordière A, Clough K, et al.: Phytoestrogens after breast cancer. Endocr Relat Cancer 8 (2): 129-34, 2001.  [PUBMED Abstract]
    
    
44. Freedman RR, Woodward S: Core body temperature during menopausal hot flushes. Fertil Steril 65 (6): 1141-44, 1996.  [PUBMED Abstract]
    
    
45. Freedman RR: Hot flashes: behavioral treatments, mechanisms, and relation to sleep. Am J Med 118 (Suppl 12B): 124-30, 2005.  [PUBMED Abstract]
    
    
46. Wijma K, Melin A, Nedstrand E, et al.: Treatment of menopausal symptoms with applied relaxation: a pilot study. J Behav Ther Exp Psychiatry 28 (4): 251-61, 1997.  [PUBMED Abstract]
    
    
47. Elkins G, Marcus J, Stearns V, et al.: Randomized trial of a hypnosis intervention for treatment of hot flashes among breast cancer survivors. J Clin Oncol 26 (31): 5022-6, 2008.  [PUBMED Abstract]
    
    
48. Carpenter JS: The Hot Flash Related Daily Interference Scale: a tool for assessing the impact of hot flashes on quality of life following breast cancer. J Pain Symptom Manage 22 (6): 979-89, 2001.  [PUBMED Abstract]
    
    
49. Barton DL, Loprinzi CL, Quella SK, et al.: Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. J Clin Oncol 16 (2): 495-500, 1998.  [PUBMED Abstract]
    
    
50. Ziaei S, Kazemnejad A, Zareai M: The effect of vitamin E on hot flashes in menopausal women. Gynecol Obstet Invest 64 (4): 204-7, 2007.  [PUBMED Abstract]
    
    
51. 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 18 (5): 1068-74, 2000.  [PUBMED Abstract]
    
    
52. 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 20 (6): 1449-55, 2002.  [PUBMED Abstract]
    
    
53. St Germain A, Peterson CT, Robinson JG, et al.: Isoflavone-rich or isoflavone-poor soy protein does not reduce menopausal symptoms during 24 weeks of treatment. Menopause 8 (1): 17-26, 2001 Jan-Feb.  [PUBMED Abstract]
    
    
54. Nikander E, Kilkkinen A, Metsä-Heikkilä M, et al.: A randomized placebo-controlled crossover trial with phytoestrogens in treatment of menopause in breast cancer patients. Obstet Gynecol 101 (6): 1213-20, 2003.  [PUBMED Abstract]
    
    
55. Newton KM, Reed SD, LaCroix AZ, et al.: Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern Med 145 (12): 869-79, 2006.  [PUBMED Abstract]
    
    
56. Osmers R, Friede M, Liske E, et al.: Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms. Obstet Gynecol 105 (5 Pt 1): 1074-83, 2005.  [PUBMED Abstract]
    
    
57. 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 24 (18): 2836-41, 2006.  [PUBMED Abstract]
    
    
58. Pruthi S, Thompson SL, Novotny PJ, et al.: Pilot evaluation of flaxseed for the management of hot flashes. J Soc Integr Oncol 5 (3): 106-12, 2007.  [PUBMED Abstract]
    
    
59. Liu J, Burdette JE, Xu H, et al.: Evaluation of estrogenic activity of plant extracts for the potential treatment of menopausal symptoms. J Agric Food Chem 49 (5): 2472-9, 2001.  [PUBMED Abstract]
    
    
60. Tamir S, Eizenberg M, Somjen D, et al.: Estrogenic and antiproliferative properties of glabridin from licorice in human breast cancer cells. Cancer Res 60 (20): 5704-9, 2000.  [PUBMED Abstract]
    
    
61. Lau CB, Ho TC, Chan TW, et al.: Use of dong quai (Angelica sinensis) to treat peri- or postmenopausal symptoms in women with breast cancer: is it appropriate? Menopause 12 (6): 734-40, 2005 Nov-Dec.  [PUBMED Abstract]
    
    
62. Rotem C, Kaplan B: Phyto-Female Complex for the relief of hot flushes, night sweats and quality of sleep: randomized, controlled, double-blind pilot study. Gynecol Endocrinol 23 (2): 117-22, 2007.  [PUBMED Abstract]
    
    
63. Borud EK, Alraek T, White A, et al.: The Acupuncture on Hot Flushes Among Menopausal Women (ACUFLASH) study, a randomized controlled trial. Menopause 16 (3): 484-93, 2009 May-Jun.  [PUBMED Abstract]
    
    
64. Hervik J, Mjåland O: Acupuncture for the treatment of hot flashes in breast cancer patients, a randomized, controlled trial. Breast Cancer Res Treat 116 (2): 311-6, 2009.  [PUBMED Abstract]
    
    
65. Vincent A, Barton DL, Mandrekar JN, et al.: Acupuncture for hot flashes: a randomized, sham-controlled clinical study. Menopause 14 (1): 45-52, 2007 Jan-Feb.  [PUBMED Abstract]
    
    
66. Borud EK, Alraek T, White A, et al.: The effect of TCM acupuncture on hot flushes among menopausal women (ACUFLASH) study: a study protocol of an ongoing multi-centre randomised controlled clinical trial. BMC Complement Altern Med 7: 6, 2007.  [PUBMED Abstract]
    
    
67. Loprinzi CL, Dueck AC, Khoyratty BS, et al.: A phase III randomized, double-blind, placebo-controlled trial of gabapentin in the management of hot flashes in men (N00CB). Ann Oncol 20 (3): 542-9, 2009.  [PUBMED Abstract]
    
    
68. Loprinzi CL, Barton DL, Carpenter LA, et al.: Pilot evaluation of paroxetine for treating hot flashes in men. Mayo Clin Proc 79 (10): 1247-51, 2004.  [PUBMED Abstract]
    
    
69. Nishiyama T, Kanazawa S, Watanabe R, et al.: Influence of hot flashes on quality of life in patients with prostate cancer treated with androgen deprivation therapy. Int J Urol 11 (9): 735-41, 2004.  [PUBMED Abstract]
    
    
70. Spetz AC, Zetterlund EL, Varenhorst E, et al.: Incidence and management of hot flashes in prostate cancer. J Support Oncol 1 (4): 263-6, 269-70, 272-3; discussion 267-8, 271-2, 2003 Nov-Dec.  [PUBMED Abstract]
    
    
71. Cowap J, Hardy J: Thioridazine in the management of cancer-related sweating. J Pain Symptom Manage 15 (5): 266, 1998.  [PUBMED Abstract]
    
    
72. Glassman AH, Bigger JT Jr: Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry 158 (11): 1774-82, 2001.  [PUBMED Abstract]