Lidiando con el Cancer   /   Efectos Secundarios

NCI/PDQ^® Health professionals: Fever, Sweats, and Hot Flashes (PDQ®)

National Cancer Institute
Ultima Vez Modificado: 26 de septiembre del 2012

TABLE OF CONTENTS

• Fever
  • Overview
  • Etiology
  • Assessment
  • Interventions
  • Primary Interventions
    • Infection-associated fever
    • Paraneoplastic fever
    • Drug-associated fever
    • Neuroleptic malignant syndrome
    • Blood productassociated fever
  • Nonspecific Interventions for Palliation of Fever

• Sweats and Hot Flashes
  • Overview
  • Etiology
  • Interventions
  • Primary Interventions
    • Sweats
    • Hot flashes
      • Hormone replacement therapy
      • Other pharmacologic interventions
      • Drug interactions
      • Behavioral methods
      • Integrative approaches
        • Herbs/dietary supplements
        • Acupuncture
      • Prostate cancer
  • Other Pharmacologic Interventions

• Clinical Decision Making in the Management of Fever and Sweats

• Current Clinical Trials

• Changes to This Summary (09/26/2012)

• Questions or Comments About This Summary

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
  • Contact Us

• Get More Information From NCI

Fever

Overview

Normal human body temperature displays a circadian rhythm. Body temperature is lowest in the predawn hours, at 36.1C (97F) or lower, and rises to 37.4C (99.3F) or higher in the afternoon. Normal body temperature is maintained by thermoregulatory mechanisms that balance heat loss with heat production. 1 2 3

Abnormal elevations of temperature result from either hyperthermia or pyrexia (fever). Hyperthermia results from failure of thermal control mechanisms. In fever, thermoregulatory mechanisms are intact, but the hypothalamic set-point is elevated above normal by exogenous or endogenous pyrogens. There are three phases to fever. In the initiation phase, cutaneous vasoconstriction promotes heat retention and shivering generates additional heat. When the new (elevated) set-point is reached, heat production balances heat loss and shivering stops. With lowering of the set-point to normal, cutaneous vasodilatation promotes heat loss to the environment in the form of sweating. These same mechanisms maintain normal core body temperature in afebrile individuals. 1 2 3 4

Response to fever varies with age. In older people, inadequate thermoregulatory mechanisms may contribute to hyperthermia and result in arrhythmias, ischemia, mental status changes, or heart failure from increased metabolic demands. In children between the ages of 6 months and 6 years, febrile convulsions may occur.

In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.

Etiology

The major causes of fever in cancer patients include infection, tumor (also known as paraneoplastic fever), drugs (allergic or hypersensitivity reactions), blood product transfusion, and graft-versus-host disease (GVHD). 2 3 4 5 6 7 8 Infection is a particularly important cause in the neutropenic host, given its high frequency (almost two-thirds of patients) and potentially fatal outcome. Whereas gram-negative infections predominated as the cause of neutropenic fever in cancer patients in the 1970s and early 1980s, gram-positive infections, mainly streptococci and coagulase staphylococci, have predominated since. The increased incidence of staphylococcal and streptococcal infections relates to the use of intravascular devices, severe mucositis due to high-dose chemotherapy, and prophylactic antibiotic therapy with fluoroquinolones. Although fluoroquinolone use has not decreased the morbidity or mortality of neutropenic fever, it has resulted in increased incidence of resistant gram-negative bacteremia. 9 Many consider paraneoplastic fever to be more common in primary tumors such as renal cell carcinomas and lymphomas, but available data suggest that it occurs in tumors of diverse primary sites. 2 Hypersensitivity reactions, pyrogen production, primary cytokine production and tumor necrosis with secondary cytokine production are among the postulated causes of tumor fever. Drug causes of fever include a variety of cytotoxic chemotherapy agents, biologic response modifiers, vancomycin, amphotericin, and multiple other medications. Tumor-associated fevers may be cyclic, occur at a specific time of the day, or be intermittent, alternating with afebrile periods lasting days or weeks. 3 4 Fever pattern does not differentiate drug-associated fever from other causes of fever, except when the temporal relationship is unambiguous. For many drugs, a highly variable lag time between the initiation of the offending agent and the onset of fever masks the causative relationship. 4 6 7 10

Other etiologies of fever in the cancer patient include drug withdrawal (i.e., opioids, benzodiazepines), neuroleptic malignant syndrome (NMS), obstruction of a viscus (i.e., bladder, bowel, kidney), and tumor embolization. Comorbid medical conditions such as thrombosis, connective tissue disorders, and central nervous system bleeds or strokes may also produce fever. 4 The differential diagnosis of fever in the cancer patient is extensive, and differentiating infection from other causes may be difficult. From a palliative perspective, establishing a fever-specific diagnosis is important, as the specific diagnosis impacts management, comfort, and patient prognosis.

Assessment

Assessment of fever requires careful history taking, medication review, and a physical examination that includes all major body systems. Individuals with suspected infection, especially those with neutropenic fever, should undergo meticulous evaluation of the skin, all body orifices (i.e., mouth, ears, nose, throat, urethra, vagina, rectum), finger stick and venipuncture sites, biopsy sites, and skin folds (i.e., breasts, axilla, groin). Oral assessment includes evaluation of the teeth, gingiva, tongue, floor of the mouth, nasopharynx, and sinuses. The perirectal area is a common source of infection, especially in individuals with leukemia. Vascular access devices (VAD) and other artificial indwelling devices (i.e., percutaneous nephrostomy tubes, biliary drainage tubes, gastrostomy or jejunostomy tubes) are other commonly implicated sources of infection. Urine, sputum, and blood cultures (peripheral and from ports or lumens of VADs) and radiographic imaging with chest radiography as directed by these findings complete the initial evaluation. Individuals undergoing cytotoxic chemotherapy should be instructed to seek immediate medical attention if they develop fever when neutrophil counts are low or declining. Frequent reassessment, including physical examination, is especially important in the neutropenic host, as signs and symptoms of infection may be minimal. Evaluation for recurrent or progressive tumor can be performed at the same time as evaluation for potential infection and other causes of fever. 3

Interventions

The presence of fever is associated with the potential metabolic consequences of dehydration and increased metabolic demand. Effects may be especially pronounced in debilitated cancer patients and include uncomfortable constitutional symptoms such as fatigue, myalgias, diaphoresis, and chills. Potential interventions for fever management include primary interventions directed at the underlying cause, hydration with parenteral fluids or by hypodermoclysis, nutritional support, and nonspecific palliative measures. The specific interventions utilized are determined by the patient's location in the disease trajectory and patient-determined goals of care. Some patients near the end of life may decide not to treat the underlying cause. For example, patients with advanced cancer may decline treatment of pneumonia or other infections but still seek nonspecific palliative measures and hydration to optimize quality of life. Alternatively, others may elect antibiotic therapy for the palliation of symptoms such as cough, fever, dyspnea, or abscess pain. (Refer to the Nonspecific Interventions for Palliation of Fever section of this summary for more information.)

Primary Interventions

Infection-associated fever

Effective antibiotic treatment results in palliation of fever-associated constitutional symptoms, as well as palliation of site-specific symptoms such as cough secondary to pneumonia or localized pain due to abscess formation. For febrile neutropenic patients (granulocyte count <500), immediate initiation of broad-spectrum antibiotic treatment is imperative, as the mortality rate is 70% for patients not receiving antibiotics within 48 hours. For the purposes of neutropenia, fever is defined as a single temperature elevation above 38.5C or three elevations above 38C in a 24-hour period. 4

Since the cause of neutropenic fever is not documented in 50% to 70% of patients, antibiotic use is guided by knowledge of the treating institution's antimicrobial spectrum and antibiotic resistance pattern, as well as the suspected cause. There is no consensus on the particular antibiotic or combination of antibiotics to be used, but empiric antibiotic therapy generally falls into one of four protocols:

1. Aminoglycoside plus antipseudomonal beta-lactam.
2. Combination of two beta-lactams.
3. Vancomycin plus aminoglycoside and antipseudomonal beta-lactam.
4. Monotherapy.

When multiple-lumen catheters are present, antibiotic therapy should be rotated through each lumen. Bacteriostatic antibiotics (i.e., tetracycline, erythromycin, chloramphenicol) are not beneficial in the absence of granulocytes, which, when given concomitantly, reduce the efficacy of the bactericidal antibiotics. 4 11

Treatment regimens are further modified by the duration of fever and individual patient risk factors such as the presence of central lines or other artificial devices, history of steroid use, and history of injection drug use. Various investigators have developed models predicting risk groups of febrile neutropenia, with implications for management strategies. Therapeutic options under evaluation include early hospital discharge, home intravenous antibiotic therapy, and oral antibiotic regimens. A subset of these studies focus on the pediatric population. Because of rapid changes in the field, the reader is directed to specialized sources for specific management recommendations of febrile neutropenia. 12 13 14

After a specific pathogen is isolated, antibiotic therapy is modified to provide optimal therapeutic response with minimal toxicity. Broad-spectrum coverage must be maintained to prevent secondary bacterial and fungal infections. Antibiotic therapy is usually discontinued after 5 to 7 days provided that the patient's granulocyte count exceeds 500 and the patient remains free of fever and infection. There is no consensus as to appropriate management in cases of persistent granulocytopenia when the patient is afebrile. Some advocate continued therapy, whereas others favor discontinuing antibiotics once the patient stabilizes. Empirical antifungal therapy is often added if a neutropenic patient remains febrile after 1 week of broad-spectrum antibiotics or has recurrent fever, since continued granulocytopenia is usually associated with the development of nonbacterial opportunistic infections, particularly those caused by Candida and Aspergillus. Prolonged therapy (>1014 days) is indicated in the patient with a residual focus of bacterial or mycotic infection. Amphotericin B is usually the agent of choice. Alternative antifungal agents (5-fluorocytosine, miconazole, fluconazole, or itraconazole) are indicated when organisms develop resistance to amphotericin B.

Acyclovir is the drug of choice in the treatment of herpes simplex or varicella zoster viral infection. Ganciclovir has activity against cytomegalovirus. Both agents can be used prophylactically in the management of patients at high risk for these infections. Foscarnet is useful in the treatment of cytomegalovirus and acyclovir-resistant herpes simplex virus.

Paraneoplastic fever

When available, the best management of tumor-associated fevers is treatment of the underlying neoplasm with definitive antineoplastic therapies. In the absence of effective antineoplastic therapy, nonsteroidal anti-inflammatory drugs (NSAIDs) are a mainstay of treatment. Naproxen may preferentially control paraneoplastic fever relative to other NSAIDs or acetaminophen. Response to naproxen has been considered diagnostic of tumor fever; however, efficacy of naproxen and other NSAIDs for infection-related fever is a common clinical observation. Release of tumor fever may respond to treatment with a structurally different NSAID.

Drug-associated fever

The occurrence of fever is predictable for some drugs, such as biologic response modifiers, amphotericin B, and bleomycin. For many other drugs, drug fever is a diagnosis of exclusion. Drug-associated fever responds to cessation of the offending agent, when possible. Fever and related symptoms with biologic response modifier administration is type-, route-, dose-, and schedule-dependent. These factors may sometimes be altered for fever control without sacrificing efficacy. Fever may also be attenuated by the use of acetaminophen, nonsteroidal anti-inflammatory, and steroid premedication. The same may be true for fever associated with some cytotoxic agents and antimicrobials (i.e., amphotericin). 6 7 10 It is common clinical practice to administer meperidine to attenuate severe chills associated with a febrile reaction, although empirical data confirming its efficacy are not available.

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal syndrome that may develop during treatment with neuroleptic drugs for conditions such as psychotic disorders, delirium, nausea, and vomiting. It is marked by fever, rigidity, confusion, and autonomic instability, as well as by elevations in white blood cell count, creatinine phosphokinase, and urine myoglobin. NMS should be considered in the differential diagnosis of the delirious patient receiving neuroleptic agents who develops rigidity and whose condition does not improve on neuroleptics (e.g., haloperidol). Treatment of NMS includes discontinuation of neuroleptic agents, supportive measures, and occasionally, administration of bromocriptine or dantrolene. (Refer to the PDQ® summary on Cognitive Disorders and Delirium for more information.)

Blood productassociated fever

Suspected febrile reactions can be minimized by the use of leukocyte-depleted or irradiated blood products, when clinically appropriate. Common clinical practice includes premedication with acetaminophen and diphenhydramine. 8

Nonspecific Interventions for Palliation of Fever

Along with treatment of the underlying cause, comfort measures are helpful in alleviating the distress that accompanies fever, chills, and sweats. During febrile episodes, increasing a patient's fluid intake, removing excess clothing and linens, and tepid water bathing/sponging may provide relief. Results of a pediatric randomized placebo-controlled trial of sponging with ice water, isopropyl alcohol, or tepid water, with or without acetaminophen, demonstrated that all combinations enhanced fever control. Comfort was greatest in children receiving a placebo or sponging, followed by those who received acetaminophen combined with tepid-water sponging. Sponging with either ice water or isopropyl alcohol, with or without acetaminophen, resulted in the greatest discomfort. 15 During periods of chills, replacing wet blankets with warm, dry blankets, keeping patients out of drafts, and adjusting ambient room temperature may also improve patient comfort.

Symptomatic relief of persistent or intermittent fevers can be aided by the use of NSAIDs (e.g., naproxen) or acetaminophen. 15 Aspirin may also be effective in reducing fever but should be used with caution in patients with Hodgkin lymphoma and cancer patients at risk for thrombocytopenia. Because of the associated risk of Reye syndrome, aspirin is not recommended in patients with fever. 4

References:

1. Boulant JA: Thermoregulation. In: Machowiak PA, ed.: Fever: Basic Mechanisms and Management. New York, NY: Raven Press, 1991, pp 1-22. [PUBMED Abstract]
2. Dinarello CA, Bunn PA Jr: Fever. Semin Oncol 24 (3): 288-98, 1997. [PUBMED Abstract]
3. Young LS: Fever and septicemia. In: Rubin RH, Young LS, eds.: Clinical Approach to Infection in the Compromised Host. 2nd ed. New York, NY: Plenum Medical, 1988, pp 75-114. [PUBMED Abstract]
4. Cleary JF: Fever and sweats: including the immunocompromised hosts. In: Berger A, Portenoy RK, Weissman DE, eds.: Principles and Practice of Supportive Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 1998, pp 119-131. [PUBMED Abstract]
5. Knockaert DC, Vanneste LJ, Vanneste SB, et al.: Fever of unknown origin in the 1980s. An update of the diagnostic spectrum. Arch Intern Med 152 (1): 51-5, 1992. [PUBMED Abstract]
6. Mackowiak PA, LeMaistre CF: Drug fever: a critical appraisal of conventional concepts. An analysis of 51 episodes in two Dallas hospitals and 97 episodes reported in the English literature. Ann Intern Med 106 (5): 728-33, 1987. [PUBMED Abstract]
7. Mackowiak PA: Drug fever. In: Machowiak PA, ed.: Fever: Basic Mechanisms and Management. New York, NY: Raven Press, 1991, pp 255-265. [PUBMED Abstract]
8. Huh YO, Lichtiger B: Transfusion reactions in patients with cancer. Am J Clin Pathol 87 (2): 253-7, 1987. [PUBMED Abstract]
9. Marchetti O, Calandra T: Infections in neutropenic cancer patients. Lancet 359 (9308): 723-5, 2002. [PUBMED Abstract]
10. Quesada JR, Talpaz M, Rios A, et al.: Clinical toxicity of interferons in cancer patients: a review. J Clin Oncol 4 (2): 234-43, 1986. [PUBMED Abstract]
11. Pizzo PA: Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med 328 (18): 1323-32, 1993. [PUBMED Abstract]
12. Karthaus M, Carratalí J, Jí¼rgens H, et al.: New strategies in the treatment of infectious complications in haematology and oncology: is there a role for out-patient antibiotic treatment of febrile neutropenia? Chemotherapy 44 (6): 427-35, 1998 Nov-Dec. [PUBMED Abstract]
13. Klastersky J, Paesmans M, Rubenstein EB, et al.: The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 18 (16): 3038-51, 2000. [PUBMED Abstract]
14. Talcott JA, Siegel RD, Finberg R, et al.: Risk assessment in cancer patients with fever and neutropenia: a prospective, two-center validation of a prediction rule. J Clin Oncol 10 (2): 316-22, 1992. [PUBMED Abstract]
15. Steele RW, Tanaka PT, Lara RP, et al.: Evaluation of sponging and of oral antipyretic therapy to reduce fever. J Pediatr 77 (5): 824-9, 1970. [PUBMED Abstract]

Sweats and Hot Flashes

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 5 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

Etiology

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. Women who are extensive metabolizers of tamoxifen related to CYP2D6 may have more severe hot flashes than those who are poor metabolizers. 11 Distinct from menopausal effects, hormonal therapies, biologic response modifiers, and cytotoxic agents associated with fever secondarily cause sweats.

Interventions

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.

Primary Interventions

Sweats

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 analogs are a primary treatment for flushes and sweats associated with some neuroendocrine tumors.

Hot flashes

Hormone replacement therapy

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; 12[Level of evidence: I] 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. 13

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], 1.001.59) 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. 14 15[Level of evidence: I] These results are supported by a population-based case-control study suggesting a 1.7-fold (95% CI, 1.32.2) 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, 1.74.3), the risk of invasive ductal carcinoma was increased 1.5-fold (95% CI, 1.12.0), and the risk of estrogen receptorpositive/progesterone receptorpositive breast cancer was increased 2.0-fold (95% CI, 1.52.7). 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. 16

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. 17 18 A series of double-blind placebo-controlled trials suggests that low-dose megestrol acetate (i.e., 20 mg by mouth twice a day) and selective serotonin reuptake inhibitors (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. 19[Level of evidence: I] Risk associated with progestin use is unknown. 13

Other pharmacologic interventions

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, 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. 20 21 22[Level of evidence: I]

Agents that have been found to be helpful in large, randomized, placebo-controlled clinical trials include venlafaxine, paroxetine, citalopram, fluoxetine, gabapentin, pregabalin, and clonidine. 20 21 22 These agents demonstrate a 40% to 60% reduction in hot flash frequency and score (a measure combining severity and frequency). 23 Agents conferring a 55% to 60% reduction in hot flashes are venlafaxine extended release, 75 mg daily; 24 paroxetine, 12.5 mg controlled release 25 or 10 mg daily; 26 gabapentin, 300 mg tid; 27 28[Level of evidence: I] 29[Level of evidence: II] and pregabalin, 75 mg bid. 30[Level of evidence: I] Other effective agents resulting in about a 50% reduction in hot flashes include citalopram, 10 to 20 mg per day, which was studied in clinical trial NCCTG-N05C9; 31[Level of evidence: I] and fluoxetine, 20 mg per day. 21 Clonidine, 0.1 mg transdermal 32 or oral daily, 33[Level of evidence: I] can reduce hot flashes by about 40%.

One study compared the efficacy and patient preference of venlafaxine, 75 mg, once daily to gabapentin, 300 mg, 3 times per day for the reduction of hot flashes. Sixty-six women with histories of breast cancer were randomly assigned in an open-label fashion to receive venlafaxine or gabapentin for 4 weeks; after a 2-week washout period, they received the opposite treatment for an additional 4 weeks. Both treatments reduced hot flash scores (severity multiplied by frequency) by about 66%. However, significantly more women preferred venlafaxine over gabapentin (68% vs. 32%, respectively). 34

A study using citalopram to evaluate hot flashes examined how much of a reduction in hot flashes was needed to have a positive impact on activities of daily living and general health-related quality of life. 35 The authors reported that hot flashes had to be reduced at least 46% for women to report significant improvements in the degree of bother they experienced in daily activities.

Agents that have been evaluated in phase II trials but have not shown efficacy include bupropion, 36 aprepitant, 37 and desipramine. 38[Level of evidence: II] Interestingly, these agents do not primarily modulate serotonin. In addition, randomized clinical trials with sertraline have not provided convincing evidence of its efficacy in hot flash management. 39 40 41[Level of evidence: I]

If nighttime hot flashes or night sweats are a particular problem without causing much bother during daytime, strategies to simultaneously improve sleep and hot flashes are in order. Limited data exist related to effective treatments that can target both symptoms. One pilot trial evaluated mirtazapine (a tetracyclic antidepressant that mainly impacts serotonin) for hot flashes because it is often prescribed for sleep difficulties. Twenty-two women were titrated up to 30 mg per day of mirtazapine at bedtime over a 3-week period; then they could choose 15 mg or 30 mg at bedtime daily for the fourth week. Hot flashes were reduced about 53% in this nonrandomized trial, and women were statistically significantly satisfied with their hot flash control. 42 However, only 16 of the 22 women stayed on the agent for the entire study period because of excessive grogginess. Therefore, although this agent could be further studied in a larger randomized trial, it would be particularly important to evaluate the risk/benefit ratio.

Trazodone is another possible agent to use for nighttime hot flashes, based on clinical experience. Trazodone, an atypical antidepressant that is often used as a sleeping aid, has anecdotally been shown to be particularly helpful in patients with nocturnal hot flashes. Doses range from 50 mg to 300 mg. Clinical experience suggests that trazodone can help patients fall asleep and can control hot flashes during the night, helping them to stay asleep. Trazodone is a tricyclic antidepressant and, as such, would not be expected to have a great impact on hot flashes: one open-label pilot trial conducted with a tricyclic antidepressant, desipramine, as a proof-of-principle study did not show a benefit. 38 However, this study has not been replicated. The effect of trazodone on sleep may be so profound that hot flashes are not bothersome; this hypothesis needs further study.

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. 27 28 30[Level of evidence: I] Patients respond as individuals to both the efficacy and the toxicity of various medications. Therefore, careful assessment and tailored treatment chosen collaboratively by provider and health care consumer are needed.

Data indicate that if one medication is not helpful for an individual, switching to another medicationwhether a different antidepressant or gabapentinmay be worthwhile. In a randomized phase III trial (NCCTG-N03C5) of gabapentin alone versus gabapentin in conjunction with an antidepressant in women who had inadequate control of their hot flashes with an antidepressant alone, 43[Level of evidence: I] 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. 44

Drug interactions

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). 45[Level of evidence: II]

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. 46[Level of evidence: II] Since this study was published, several researchers have been evaluating the clinical implications of this finding. 47; 48 49 50[Level of evidence: II] One study followed more than 1,300 women for a median of 6.3 years and concluded that women who were poor metabolizers or heterozygous extensive/intermediate metabolizers (hence, less CYP2D6 activity) had higher rates of recurrence, worse event-free survival, and worse disease-free survival than did women who were extensive metabolizers. 49 Similarly, a retrospective cohort study of more than 2,400 women in Ontario who were being treated with tamoxifen and had overlapping treatment with an SSRI has been completed. Authors concluded that women who concomitantly used paroxetine and tamoxifen had an increased risk of death that was proportionate to the amount of time they used these agents together. 50[Level of evidence: II] Clinical implications of these changes and of other CYP2D6 genotypes 51 have not yet been elucidated, but the pharmacokinetic interaction between tamoxifen and the newer antidepressants used to treat hot flashes merits further study. 52 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. 53

Behavioral methods

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; 54 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 as well as the use of fans and open windows to keep air moving. Based on the theory that serotonin may be involved as a central hot flash trigger, behavioral interventions such as stress management may modulate serotonin, causing a decrease in hot flashes. Relaxation training and slow, deep breathing 55 56 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%. 57[Level of evidence: I] 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. 58

Integrative approaches

Herbs/dietary supplements

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 and is far from standardized. Some of the more well-studied agents include soy phytoestrogen, black cohosh, and vitamin E.

Vitamin E, 400 IU twice a day, appears to confer a modest reduction in hot flashes that is only slightly better than that seen with placebo. The reduction in hot flashes is roughly 35% to 40%. 59 60[Level of evidence: I]

Soy has been a dietary supplement of interest for decreasing menopausal symptoms and breast cancer for some time. The interest comes primarily from association studies of a high-soy diet and decreased breast cancer/menopausal symptoms in Asia. Soy is an isoflavone, which is part of a much larger class of plant compounds called flavonoids. Three types of isoflavones are found in soy products:

• Genistein
• Daidzein
• Glycitein

Isoflavones are often referred to as phytoestrogens or plant-based estrogens because they have been shown, in cell line and animal studies, to have the ability to bind with the estrogen receptor. 61

There is confusion about the safety of these plant-based estrogens because these agents can have properties that can cause estrogen-like effects in some cells, causing them to proliferate (divide and grow); while in other cells, isoflavones can stop or block estrogen effects, causing unwanted cells to not grow or even die. There is continuing debate about the following questions: 62

• What doses and types of soy inhibit estrogen as a growth factor?
• Under what circumstances does soy inhibit estrogen as a growth factor?
• In what doses or circumstances does soy promote estrogen-related growth?

Definitive answers to these questions are not known, but phytoestrogens continue to be investigated for chemopreventive properties. On the other hand, soy has been well studied in numerous randomized, placebo-controlled trials for its effects on reducing hot flashes. 63 64 65 66 67[Level of evidence: I] Most of those trials show that soy is no better than a placebo in reducing hot flashes. 68[Level of evidence: I] 69 Currently, there are no compelling data that would inspire the use of soy for hot flash management.

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 a placebo in reducing hot flashes. 67 70 71[Level of evidence: I] Black cohosh used to be thought of as having estrogenic properties, but it is now known that it acts on serotonin receptors, as discussed at the Workshop on the Safety of Black Cohosh in Clinical Studies. One study evaluated black cohosh, red clover, estrogen and progesterone, and placebo in a randomized, double-blind trial. 72[Level of evidence: I] Each treatment arm was small (n = 22); however, over 12 months, hot flashes were reduced 34% by black cohosh, 57% by red clover, 63% by placebo, and 94% by hormone therapy. Of note, adherence rates were reported to be about 89% over the four groups during this long-term study. At 12 months, physiologic markers such as endometrial thickness, estradiol, estrone, follicle-stimulating hormone, sex hormonebinding globulin, and liver function tests were not statistically different for those on either red clover or black cohosh, compared with those on placebo. However, because these groups were small, the power for this secondary analysis was not reported, and it was likely underpowered to detect important differences.

Flaxseed is a plant that is part of the genus Linum, native to the area around the eastern Mediterranean and India. Flaxseed is a rich source of lignans and omega 3 fatty acids. Lignans found in flaxseed are called secoisolariciresinol diglucoside (SDG) and alpha-linolenic acid (ALA). Flaxseed is also a source of fiber. Lignans are a type of phytoestrogen (plant estrogen) that, like soy, is thought to have estrogen agonist-antagonist effects as well as antioxidant properties. Lignans are converted by colonic bacteria to enterodiol and enterolactone, which are metabolites believed to have important physiological properties such as decreasing cell proliferation and inhibiting aromatase, 5-alpha reductase, and 17-beta hydroxysteroid activity. Cell line studies have shown properties of aromatase inhibition with enterolactone but less so with enterodiol. 73 It is thought that these properties can reduce the risk of hormone-sensitive cancers. 74 75 76 In addition, studies have shown that flaxseed can reduce estrogen levels through excretion in the urine. 77 78

On the basis of preliminary data testing flaxseed for its effect on hot flashes and related endpoints, 79 80[Level of evidence: I] an open-label pilot study was conducted to evaluate 40 g of flaxseed in decreasing hot flashes. This study of 30 women showed a 57% reduction in hot flash scores and a 50% reduction in hot flash frequency over a 6-week period. 81 However, a follow-up phase III, randomized, controlled trial conducted by the North Central Cancer Treatment Group with 188 women failed to show any benefit of 410 mg of lignans in a flaxseed bar over placebo. 82[Level of evidence: I]

Many plants and natural products are touted as wonderful remedies for hot flashes. Some of these products are plant phytoestrogens, and some have unknown properties. The agents include dong quai, milk thistle, red clover, licorice, and chaste tree berry. There is incomplete understanding of the biology of these agents and whether taking them would impact breast cancer risk or recurrence in a negative or positive way. Data suggest that these plants have different effects, dependent not only on the dose used but also on a woman's hormone environment when she takes them. Little is known about these agents, and caution with respect to taking themif a woman is to avoid estrogen supplementationis needed. 83 84 85 86

Acupuncture

Several pilot trials have evaluated the use of acupuncture to treat hot flashes. 87 88 89 90[Level of evidence: I] Research in acupuncture is difficult, owing to the lack of novel methodologyspecifically, 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. Therefore, as concluded in at least one review, there is not a body of evidence to definitively delineate the role or practice of acupuncture for hot flashes. 91 (Refer to the Vasomotor symptoms section in the PDQ® summary on Acupuncture for more information.)

Prostate cancer

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 generelated 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 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, 92 and cyproterone acetate, an antiandrogen. The latter is not available in the United States.

One large, multisite study from France 93 randomly assigned men who were taking leuprorelin for prostate cancer to receive venlafaxine, 75 mg; cyproterone acetate (an antiandrogen), 100 mg; or medroxyprogesterone acetate, 20 mg, when they reported at least 14 hot flashes per week. All three treatments significantly reduced hot flashes, with cyproterone resulting in a 100% median reduction, medroxyprogesterone resulting in a 97% reduction, and venlafaxine resulting in a 57% reduction at 8 weeks. More adverse events were reported with cyproterone acetate, including one serious adverse event (dyspnea) attributable to the drug. Venlafaxine was not associated with any serious adverse events and overall had a 20% adverse event rate attributable to the drug. Medroxyprogesterone was the most well tolerated, with an adverse event rate of 12%, but with one serious event, urticaria. The most frequent side effects for all agents were related to gastrointestinal issues: nausea, constipation, diarrhea, and abdominal pain. 93

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. 94 95 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. 96

Other Pharmacologic Interventions

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 97 and sudden death. 98

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. [PUBMED Abstract]
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. Lynn Henry N, Rae JM, Li L, et al.: Association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort. Breast Cancer Res Treat 117 (3): 571-5, 2009. [PUBMED Abstract]
12. Freedman RR, Blacker CM: Estrogen raises the sweating threshold in postmenopausal women with hot flashes. Fertil Steril 77 (3): 487-90, 2002. [PUBMED Abstract]
13. Pritchard KI: Hormone replacement in women with a history of breast cancer. Oncologist 6 (4): 353-62, 2001. [PUBMED Abstract]
14. 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]
15. 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]
16. 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]
17. 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]
18. 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]
19. 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]
20. 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]
21. Loprinzi CL, Stearns V, Barton D: Centrally active nonhormonal hot flash therapies. Am J Med 118 (Suppl 12B): 118-23, 2005. [PUBMED Abstract]
22. 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