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Sweating in advanced cancer
Correspondence Address: Source of Support: None, Conflict of Interest: None
Sweating (perspiration, diaphoresis, hidrosis) is the secretion of fluid, mainly water and sodium chloride, from the eccrine (sweat) glands onto the skin. Sweating occurs only in humans and apes, and is an important component of the thermoregulatory system. It aids cooling by the evaporation of sweat from the body surface (Pittelkow and Loprinzi 2003). Other mammals must pant, rest, splash with water, or move to a cooler place to lower body temperature. Evaporation of secretions occurs constantly from the skin and the mucous membranes of the mouth and respiratory tract. The basal level of 'insensible' water loss is about 50ml/h, i.e. about 1200ml/24h (Ganong 1979). The maximum possible secretion from 3-4 million glands in the skin is 2-3L/h (Ryan 1996). Sweating typically occurs during and after exercise, when there is a high ambient temperature, or when there is a pyrexia. However, infants and sedentary old people tend to sweat insufficiently, and may develop hyperthermia in these circumstances. Paradoxically, sweating is sometimes cold-induced. Ingestion of spicy food may cause 'gustatory sweating' limited to the lips, nose and forehead. After drinking alcohol, vasodilation may result in sweating. It commonly occurs in response to embarrassment, anxiety, fear, and severe pain. Sweating also occurs at the menopause and after ovarian or testicular ablation in addition to the characteristic hot flushes (Hargrove and Eisenberg 1995). Hyperhidrosis, i.e. inappropriate high-volume sweating, occurs in various disorders. In malignant disease, as with chronic infections, it may occur only at night ('night sweats'), and tends to be paroxysmal whatever time it occurs. If there is associated pyrexia, there is no fixed pattern (Boggs and Frei 1960). Thus it may be continuous, intermittent, remittent, low-grade, hectic, or any combination of these types.
Two types of gland secrete moisture onto the surface of the body:
Apocrine glands develop at puberty and their ducts empty into hair follicles. They occur in the scalp, axillae, around the nipples and in the anogenital area. Secretions contain proteins and complex carbohydrates, and are under adrenergic control (Kirby 1990). The eccrine glands secrete sweat, a watery fluid containing chloride, lactic acid, fatty acids, glycoproteins, mucopolysaccharides and urea, directly onto the skin surface. There are two functionally separate sets of eccrine glands. One set populates the entire skin except the palms and soles and is responsible for thermal regulation; secretion is controlled by cholinergic (muscarinic) postganglionic sympathetic fibres. The other set is confined to the palms, soles and axillae and is controlled by adrenergic fibres. Those on the palms and soles respond mostly to emotion whereas those in the axillae respond to both heat and emotion.
Sweating is particularly associated with Hodgkin's disease and several other types of malignant disease, as well as with any type of widely disseminated malignancy and/or liver metastases. The prevalence in advanced malignancy may be as high as 14-28% (Grond et al. 1994; Quigley and Baines 1997). Most cases are infective or paraneoplastic (Boggs and Frei 1960). Hormonal insufficiency and drugs probably account for most of the rest [Table - 1]. Sweating also occurs as part of a withdrawal syndrome seen after the abrupt discontinuation of various psycho-active drugs, including opioids. Sometimes there is more than one cause, e.g. both liver metastases and morphine. Hypotheses to explain paraneoplastic sweating include:
The pyrogens then induce a prostaglandin cascade which results in pyrexia and consequential sweating (Tabibzadeh et al. 1989; Tsavaris et al. 1990). However, some patients with paraneoplastic sweating do not have an associated pyrexia. Indeed, in one small series, only one patient out of seven was pyrexial (Deaner 2000). A clue to explaining the apparent dissociation between sweating and pyrexia is contained in the following case history.
A man complained of troublesome sweating. Some months earlier, after the diagnosis of mesothelioma, he noted that his normal temperature had decreased from 37oC to about 35oC. On one occasion, he developed a chest infection and his temperature increased to 37.5oC, but he was told that he could not have an infection because his temperature was 'normal'. He had also noted that, just before the onset of an episode of sweating, his temperature would increase but, using the standard definition of pyrexia (above 38oC), he was still technically apyrexial. Thus, it seems reasonable to postulate that, in some patients, a substance is released by the tumour which lowers the thermal set-point in the hypothalamus. Then, following a tumour-related release of endogenous pyrogen, sweating occurs in an attempt to restore the body temperature to its malignancy-lowered thermal set-point - but in the absence of pyrexia as normally defined. Hypercapnia, plasma osmolality, intravascular volume changes, and dehydration can also impact on the hypothalamic thermoregulatory centre, lowering the thermal set-point and resulting in an increased tendency to sweating (Pittelkow and Loprinzi 2003). Abnormal localised sweating may be associated with lesions of the nervous system [Table - 1]. For example, pressure on the sympathetic chain in the thorax by a lung cancer or mesothelioma may result in ipsilateral hyperhidrosis. In contrast, with a Pancoast tumour, the sympathetic chain subserving the ipsilateral upper quadrant may be damaged, causing regional anhidrosis and compensatory hyperhidrosis on the contralateral side (Pleet et al 1983, Middleton 1976) .
It is useful to have working definitions of mild, moderate and severe sweating, such as:
Although there are several objective tests to determine the pattern and extent of hyperhidrosis (Pittelkow and Loprinzi 2003), these are generally inappropriate in patients with advanced cancer. As with other symptoms, the diagnosis of the cause of the sweating is based largely on probability and pattern recognition. Paraneoplastic sweating is a diagnosis of exclusion. Questions to ask include:
Consider checking the white blood cell count and examining the urine for pus cells. Urine and blood cultures, and a chest radiograph are sometimes also appropriate. At some centres, 'blind' antibiotic therapy is used as a diagnostic test. Guidance about appropriate therapy should be obtained from a microbiologist.
Correct the correctable
if a tricyclic antidepressant or an SSRI is the cause, switch to venlafaxine if morphine is the cause, consider switching to an alternative strong opioid, although this may not be beneficial (Mercadante 1998; Zylicz and Krajnik 2003). [Table - 2] Note that placebo reduces menopausal flushes by a mean of 20-25%. In 20% of women, the reduction will be >50% [Figure - 1] (Loprinzi et al. 2001). Hormonal treatment is equally effective in breast and prostate cancer; the maximum effect comes after 3-4 weeks. However, at many centres, hormonal treatment is no longer the treatment of choice for hot flushes in cancer patients [Figure - 2]. Non-drug treatment
Although local treatment with aluminium chloride hexahydrate (axillae) and formalin or gluteraldehyde (feet) are of value in emotional sweating (Simpson N 1988), they are generally irrelevant in advanced cancer. Such treatments work by blocking or destroying sweat glands. Iontophoresis (Murphy and Harrington 2000), botulinum toxin and surgical approaches such as undercutting the axillary skin, excision and sympathectomy, are also irrelevant (Atkins and Butler 2000; Collin and Whatling 2000). Symptomatic drug treatment Begin by prescribing an antipyretic:
Some people complain of a transient increase in sweating after taking an antipyretic; however, this is part of the process of cooling down. It has been claimed that naproxen is the NSAID of choice for paraneoplastic pyrexia and sweating (Chang 1988). However, a comparison of 250mg b.d. with diclofenac 25mg t.d.s. and indomethacin 25mg t.d.s. in 3 randomly allocated groups of 16 patients demonstrated no significant difference between the three drugs [Figure - 3], although the mean time to response was about 8 hours for naproxen but over 20 hours for the other two drugs (Tsavaris et al. 1990). However, this could reflect the relatively low doses of diclofenac and indomethacin used. What was surprising was the relatively poor response to corticosteroids in dose equivalent to at least 100mg of hydrocortisone/day (Chang 1988). A complete response to naproxen 250-375mg b.d. was seen in 36/39 patients, but in only 6/12 given a corticosteroid [Figure - 4]. It is difficult to explain this. However, a formal controlled trial of the two agents has never been done. Similarly surprising was the observation that, although the antipyretic effect of an NSAID tends to wear off after 1-5 months, further benefit is obtained by switching to an alternative NSAID. However, the duration of benefit with the second- and third-line drugs is generally shorter. If the sweating does not respond to an NSAID, prescribe an antimuscarinic drug:
If an antimuscarinic fails, other options include:
Thalidomide should be the last resort even though the response rate appears to be high (Deaner 2000). This is because of the likelihood of an irreversible painful peripheral neuropathy; it also has a tendency to cause somnolence (Twycross et al. 2002b). [Figure - 5] offers a possible 4-step treatment ladder.
The author thanks Dr Mary Miller for supplying the case history, and for her helpful comments on the article. [Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5] [Table - 1], [Table - 2]
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