Fever, Sweats, and Hot Flashes

Summary Type: Supportive care
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about causes and treatment of fever, sweats, and hot flashes in cancer patients.

Fever, Sweats, and Hot Flashes

Fever

Overview

Normal human body temperature displays a circadian rhythm. Body temperature is lowest in the predawn hours, at 36.1°C (97°F) or lower, and rises to 37.4°C (99.3°F) 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 3 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.

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 PDQ summary on Nutrition in Cancer Care for more information, as well as the Nonspecific Interventions for Palliation of Fever section below.)

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 of >38.5°C or 3 elevations >38°C 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 1 of 4 protocols:

1. Aminoglycoside plus antipseudomonal beta-lactam.
2. Combination of 2 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 (>10–14 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 product–associated 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’s lymphoma and cancer patients at risk for thrombocytopenia. Because of the associated risk of Reye’s syndrome, aspirin is not recommended in patients with fever.^4,

¹ Boulant JA: Thermoregulation. In: Machowiak PA, ed.: Fever: Basic Mechanisms and Management. New York, NY: Raven Press, 1991, pp 1-22.

² Dinarello CA, Bunn PA Jr: Fever. Semin Oncol 24 (3): 288-98, 1997.

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.

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.

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.

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.

⁷ Mackowiak PA: Drug fever. In: Machowiak PA, ed.: Fever: Basic Mechanisms and Management. New York, NY: Raven Press, 1991, pp 255-265.

⁸ Huh YO, Lichtiger B: Transfusion reactions in patients with cancer. Am J Clin Pathol 87 (2): 253-7, 1987.

⁹ Marchetti O, Calandra T: Infections in neutropenic cancer patients. Lancet 359 (9308): 723-5, 2002.

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.

¹¹ Pizzo PA: Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med 328 (18): 1323-32, 1993.

¹² Karthaus M, Carratalà J, Jürgens 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.

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.

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.

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.

Sweats

Overview

Physiologically, sweating mediates core body temperature by producing transdermal evaporative heat loss.^1,2 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.^3,4,5 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%.^6,7 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.⁸ 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.^9,

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’s 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.

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

Hot flashes

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;¹⁰ 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.¹¹ 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.^12,13 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.¹⁴ 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.^15,16,

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.¹⁷ Risk associated with progestin use is unknown.¹¹ 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.^{18,19,20,21,22,23,24,25} 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.²⁶ A randomized placebo-controlled trial 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.²⁷ One well-designed randomized, double-blind, placebo-controlled crossover study 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.²⁸ Similarly, two randomized placebo-controlled trials in breast cancer survivors show no benefit of soy over placebo in alleviating hot flashes.^29,30,

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).³¹ 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 enzyme inhibitors.³² Clinical implications of these changes and of other CYP2D6 genotypes ³³ have not yet been elucidated, but the pharmacokinetic interaction between tamoxifen and the newer antidepressants used to treat hot flashes merits further study.³⁴ 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.^35,

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.^36, 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.^37,

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.^38,39 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.^40,

Nonspecific palliative 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. 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 ⁴¹ and sudden death.^42,

¹ Boulant JA: Thermoregulation. In: Machowiak PA, ed.: Fever: Basic Mechanisms and Management. New York, NY: Raven Press, 1991, pp 1-22.

² Dinarello CA, Bunn PA Jr: Fever. Semin Oncol 24 (3): 288-98, 1997.

³ 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.

⁴ Quigley CS, Baines M: Descriptive epidemiology of sweating in a hospice population. J Palliat Care 13 (1): 22-6, 1997 Spring.

⁵ Lichter I, Hunt E: The last 48 hours of life. J Palliat Care 6 (4): 7-15, 1990 Winter.

⁶ 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.

⁷ 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.

⁸ Johnson SR: Menopause and hormone replacement therapy. Med Clin North Am 82 (2): 297-320, 1998.

⁹ Charig CR, Rundle JS: Flushing. Long-term side effect of orchiectomy in treatment of prostatic carcinoma. Urology 33 (3): 175-8, 1989.

¹⁰ Freedman RR, Blacker CM: Estrogen raises the sweating threshold in postmenopausal women with hot flashes. Fertil Steril 77 (3): 487-90, 2002.

¹¹ Pritchard KI: Hormone replacement in women with a history of breast cancer. Oncologist 6 (4): 353-62, 2001.

¹² 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.

¹³ 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.

¹⁴ 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.

¹⁵ 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.

¹⁶ 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.

¹⁷ 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.

¹⁸ Loprinzi CL, Michalak JC, Quella SK, et al.: Megestrol acetate for the prevention of hot flashes. N Engl J Med 331 (6): 347-52, 1994.

¹⁹ Quella SK, Loprinzi CL, Sloan JA, et al.: Long term use of megestrol acetate by cancer survivors for the treatment of hot flashes. Cancer 82 (9): 1784-8, 1998.

²⁰ Loprinzi CL, Pisansky TM, Fonseca R, et al.: Pilot evaluation of venlafaxine hydrochloride for the therapy of hot flashes in cancer survivors. J Clin Oncol 16 (7): 2377-81, 1998.

²¹ Quella SK, Loprinzi CL, Sloan J, et al.: Pilot evaluation of venlafaxine for the treatment of hot flashes in men undergoing androgen ablation therapy for prostate cancer. J Urol 162 (1): 98-102, 1999.

²² Loprinzi CL, Kugler JW, Sloan JA, et al.: Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 356 (9247): 2059-63, 2000.

²³ Stearns V, Isaacs C, Rowland J, et al.: A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil) in controlling hot flashes in breast cancer survivors. Ann Oncol 11 (1): 17-22, 2000.

²⁴ Loprinzi CL, Sloan JA, Perez EA, et al.: Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 20 (6): 1578-83, 2002.

²⁵ Weitzner MA, Moncello J, Jacobsen PB, et al.: A pilot trial of paroxetine for the treatment of hot flashes and associated symptoms in women with breast cancer. J Pain Symptom Manage 23 (4): 337-45, 2002.

²⁶ 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.

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.

²⁸ 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.

²⁹ 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.

³⁰ 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.

³¹ 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.

³² 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.

³³ 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.

³⁴ Goetz MP, Loprinzi CL: A hot flash on tamoxifen metabolism. J Natl Cancer Inst 95 (23): 1734-5, 2003.

³⁵ This P, De La Rochefordière A, Clough K, et al.: Phytoestrogens after breast cancer. Endocr Relat Cancer 8 (2): 129-34, 2001.

³⁶ Irvin JH, Domar AD, Clark C, et al.: The effects of relaxation response training on menopausal symptoms. J Psychosom Obstet Gynaecol 17 (4): 202-7, 1996.

³⁷ 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.

³⁸ 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.

³⁹ 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.

⁴⁰ 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.

⁴¹ Cowap J, Hardy J: Thioridazine in the management of cancer-related sweating. J Pain Symptom Manage 15 (5): 266, 1998.

⁴² Novartis Pharmaceuticals Corporation.: Important Drug Warning. Washington, DC: Food and Drug Administration, 2000. Available online. Last accessed April 23, 2007.

Clinical Decision Making in the Management of Fever and Sweats

Effective management strategies for fever and sweats are limited by the paucity of data about symptom epidemiology and contributing pathophysiologies in the advanced cancer patient. Notwithstanding, careful history taking and physical examination can be used to develop a plan for diagnostic evaluation that is consistent with the patient’s location in the disease spectrum and goals of care. For some patients, improved quality of life outweighs potential survival advantages. Fever, sweats, and hot flashes detract from quality of life in a significant number of patients with cancer or a history of cancer. Management strategies require an understanding of the underlying causes and pathophysiologic mechanisms, as well as knowledge of the patient's goals of care. Treatment interventions include pharmacologic, physical, dietary, and behavioral modalities.^1,

¹ Zhukovsky DS: Fever and sweats in the patient with advanced cancer. Hematol Oncol Clin North Am 16 (3): 579-88, viii, 2002.

Changes to This Summary (04/25/2007)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Sweats

Added text to state that the clinical implications of other CYP2D6 genotypes have not yet been elucidated (cited Bonanni et al. as reference 33).

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