Table of Contents Purpose of This PDQ Summary Fever
Sweats Clinical Decision Making in the Management of Fever and Sweats Get More Information From NCI Changes to This Summary (02/17/2009) Questions or Comments About This Summary More Information
Purpose of This PDQ Summary
This PDQ cancer information summary provides comprehensive, peer-reviewed information for health professionals about the pathophysiology and treatment of fever, sweats, and hot flashes. This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board.
Information about the following is included in this summary:
- Etiology.
- Assessment.
- Intervention.
This summary is intended as a resource to inform and assist clinicians and other health professionals who care for cancer patients during and after cancer treatment. It does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.
This summary is also available in a patient version, which is written in less technical language, and in Spanish.
Back to Top 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.[1-3]
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.[1-4]
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).[2-8]
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 above 38.5°C or three elevations above 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 one of four protocols:
- Aminoglycoside plus antipseudomonal
beta-lactam.
- Combination of two beta-lactams.
- Vancomycin plus
aminoglycoside and antipseudomonal beta-lactam.
- 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.[12-14]
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 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
-
Boulant JA: Thermoregulation. In: Machowiak PA, ed.: Fever: Basic Mechanisms and Management. New York, NY: Raven Press, 1991, pp 1-22.
-
Dinarello CA, Bunn PA Jr: Fever. Semin Oncol 24 (3): 288-98, 1997.
[PUBMED Abstract]
-
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.
-
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.
-
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]
-
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]
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Mackowiak PA: Drug fever. In: Machowiak PA, ed.: Fever: Basic Mechanisms and Management. New York, NY: Raven Press, 1991, pp 255-265.
-
Huh YO, Lichtiger B: Transfusion reactions in patients with cancer. Am J Clin Pathol 87 (2): 253-7, 1987.
[PUBMED Abstract]
-
Marchetti O, Calandra T: Infections in neutropenic cancer patients. Lancet 359 (9308): 723-5, 2002.
[PUBMED Abstract]
-
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]
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Pizzo PA: Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med 328 (18): 1323-32, 1993.
[PUBMED Abstract]
-
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.
[PUBMED Abstract]
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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]
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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]
-
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]
Back to Top Sweats
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]
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. 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
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;[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]
Other pharmacologic interventions
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. 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 daily.[19-26] A randomized double-blind placebo-controlled trial evaluating the use of controlled-release paroxetine for the treatment of menopausal hot flashes in a general population of women suggests that this SSRI plays a role in hot flash management.[27] A randomized placebo-controlled trial (URCC-U2101) of gabapentin in women with breast cancer suggests that gabapentin in doses of 900 mg per day may be effective in decreasing the frequency and severity of hot flashes.[28] In a randomized phase III trial (NCCTG-N03C5) of gabapentin alone (900 mg daily or 300 mg tid) versus gabapentin in conjunction with an antidepressant in women who had inadequate control of hot flashes with an antidepressant alone, gabapentin use resulted in an approximately 50% median reduction in hot flash frequency and score, regardless of whether the antidepressant was continued. In other words, for women who were using antidepressants exclusively for the management of hot flashes that were inadequately controlled, initiation of gabapentin with discontinuation of the antidepressant did not provide results inferior to those obtained with combined therapy, resulting in the need for fewer medications.[29] An open-label prospective pilot study (n = 30) on the use of levetiracetam for the management of hot flashes in women with a history of breast cancer, as well as those undergoing natural menopause, suggests that it, too, may have a role in the management of hot flashes. While there was a high rate of study withdrawal due to side effects, levetiracetam is not metabolized by the cytochrome P450 system and does not have any known interaction with tamoxifen; therefore, a more critical evaluation of its efficacy is warranted.[30] One well-designed randomized, double-blind, placebo-controlled crossover study (NCCTG-N01CC) of black cohosh in women with a history of breast cancer conducted with a methodology similar to those used with SSRIs shows no evidence of benefit.[31] Similarly, two randomized placebo-controlled trials in breast cancer survivors show no benefit of soy over placebo in alleviating hot flashes.[32,33]
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).[34] In a prospective observational study of 80 women initiating adjuvant tamoxifen therapy for newly diagnosed breast cancer, variant CYP2D6 genotypes, as well concomitant use of SSRI CYP2D6 inhibitors, resulted in reduced endoxifen levels. Variant CYP2D6 genotypes do not produce functional CYP2D6 enzymes.[35] Clinical implications of these changes and of other CYP2D6 genotypes [36] have not yet been elucidated, but the pharmacokinetic interaction between tamoxifen and the newer antidepressants used to treat hot flashes merits further study.[37] Likewise, the risk of soy phytoestrogen use on breast cancer recurrence and/or progression has not yet been clarified. Soy phytoestrogens are weak estrogens found in plant foods. In vitro models suggest that these compounds have a biphasic effect on mammary cell proliferation that is dependent on intracellular concentrations of phytoestrogen and estradiol.[38]
Behavioral methods
Behavioral methods as a primary or adjunctive
modality may also play a role in hot flash management. Many women with breast
cancer demonstrate interest in learning more about behavioral methods and
complementary and alternative methods for hot flash management. Relaxation
training has been found to decrease hot flash intensity in postmenopausal women
in general good health who were randomized to relaxation response training, a placebo
intervention group, or a control group.[39]
Future research on hot flash management may be aided by the development of psychometrically sound assessment tools such as the Hot Flash Related Daily Interference Scale.[40]
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 gene–related peptide, may be instrumental in the genesis of hot flashes. Treatment modalities include estrogens, progesterone, SSRIs, gabapentin 300 mg 3 times per day as an option for men,[41] 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.[42,43] 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.[44]
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 [45] and sudden death.[46]
References
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Dalal S, Zhukovsky DS: Pathophysiology and management of hot flashes. J Support Oncol 4 (7): 315-20, 325, 2006 Jul-Aug.
[PUBMED Abstract]
-
Boulant JA: Thermoregulation. In: Machowiak PA, ed.: Fever: Basic Mechanisms and Management. New York, NY: Raven Press, 1991, pp 1-22.
-
Dinarello CA, Bunn PA Jr: Fever. Semin Oncol 24 (3): 288-98, 1997.
[PUBMED Abstract]
-
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]
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Quigley CS, Baines M: Descriptive epidemiology of sweating in a hospice population. J Palliat Care 13 (1): 22-6, 1997 Spring.
[PUBMED Abstract]
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Lichter I, Hunt E: The last 48 hours of life. J Palliat Care 6 (4): 7-15, 1990 Winter.
[PUBMED Abstract]
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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]
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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]
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Johnson SR: Menopause and hormone replacement therapy. Med Clin North Am 82 (2): 297-320, 1998.
[PUBMED Abstract]
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Charig CR, Rundle JS: Flushing. Long-term side effect of orchiectomy in treatment of prostatic carcinoma. Urology 33 (3): 175-8, 1989.
[PUBMED Abstract]
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Freedman RR, Blacker CM: Estrogen raises the sweating threshold in postmenopausal women with hot flashes. Fertil Steril 77 (3): 487-90, 2002.
[PUBMED Abstract]
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Pritchard KI: Hormone replacement in women with a history of breast cancer. Oncologist 6 (4): 353-62, 2001.
[PUBMED Abstract]
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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]
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Back to Top 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]
References
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Zhukovsky DS: Fever and sweats in the patient with advanced cancer. Hematol Oncol Clin North Am 16 (3): 579-88, viii, 2002.
[PUBMED Abstract]
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Back to Top Changes to This Summary (02/17/2009)
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
Revised text to state that three-quarters of men with locally advanced or metastatic prostate cancer treated with medical or surgical orchiectomy experience hot flashes.
Revised text to include aromatase inhibitors as a drug-associated cause of sweats.
Revised text to state that the optimal dose of venlafaxine to reduce the severity and intensity of hot flashes is 75 mg of the extended-release formulation daily.
Revised text to include gabapentin 300 mg 3 times per day as a treatment option for men with prostate cancer who experience hot flashes (cited Loprinzi et al. as reference 41).
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