Feeling too hot or cold after breast cancer: Is it just a nuisance or a potentially important prognostic factor?

Figures & data

Figure 1. Quantification of scientific literature pertaining to “feeling cold and cancer” reveals far fewer references than those studying “hot flashes and cancer”. Moreover, literature involving hot flashes and cancer has been steadily increasing in numbers over the past decade while articles pertaining to feeling cold remain infrequent.

Table I.  Thermal dysfunction studies in cancer patients.

Cancer site	Thermal dysfunction	Reference	Year
Breast	DB, PC, CO, RT showed a reduction in hot flashes with 20 mg twice a day of medroxyprogesterone acetate compared to placebo.	[67]	1994
	DB, PC, CO, RT showed that clonidine significantly reduced hot flash frequency and severity however results were only moderate clinically.	[138]	1994
	Phase II trial found that venlafaxine at 12.5 mg twice a day alleviated sweating.	[139]	1998
	PC, CO, RT showed that, although statistically significant, 800 IU/day of vitamin E only showed a marginal improvement in the clinical magnitude of hot flashes.	[140]	1998
	A single patient with recurrent breast cancer reported feeling cold and was found to have elevated levels of IGF-2.	[141]	1999
	Pilot study found 83% of participants chose to continue the experimental paroxetine hydrochloride to reduce hot flashes and warrant further study through a DB, PC, RT.	[142]	2000
	DB, PC, RT determined that venlafaxine reduced hot flashes and found a 61% decrease in median hot flash score in patient's taking 150 mg of venlafaxine for 4 weeks compared to a 27% median decrease in those taking a placebo.	[103]	2000
	BD, PC, RT found that 0.1 mg/day of oral clonidine was effective in reducing hot flashes in patients taking tamoxifen.	[106]	2000
	DB, CO, RT of soya products found no difference in the reduction of hot flashes in women taking 50 mg of soya isoflavones compared to those taking a placebo.	[111]	2000
	RT of black cohosh did not find a significant difference in the reduction of number or intensity of hot flashes.	[102]	2001
	Demonstrated that a short cycle of intramuscular depot medroxyprogesterone acetate injections provided significant and long-lasting relief from postmenopausal hot flashes compared to oral megestrol.	[143]	2002
	DB, PC, CO, RT found that 20 mg/day of fluoxetine modestly improved hot flash symptoms based on unadjusted analysis.	[99]	2002
	Cross-sectional analysis failed to find a significant difference in hot flash quality or triggers in breast cancer survivors compared to healthy women.	[1]	2002
	DB, PC, RT found that beverages containing soya phytoestrogens had no more of an effect on hot flashes in postmenopausal women than a placebo beverage.	[110]	2002
	Group of 13 patients showed a significant decrease in hot flash severity with 20 mg/day of paroxetine.	[144]	2002
	BD, PC, RT in which participants were given paroxetine controlled release had significantly reduced hot flash frequency compared to those given placebo.	[98]	2003
	Cross-sectional study shows that sleep disturbance is not related to hot flashes in menopausal women who were not treated for their hot flashes.	[145]	2004
	CYP2D6 genetic variants may alter the effects of tamoxifen resulting in increased hot flashes than women without this genotype.	[146]	2004
	Tamoxifen treated patients with CYP2D6 *4/*4 genotype have a lower incidence of hot flashes suggesting that this gene is, at least in part, responsible for the metabolism of tamoxifen.	[147]	2005
	Literature review concludes that SSRI, SNRI, clonidine, and gabapentin trials provide evidence for efficacy but are not as effective as estrogen in treatment of hot flashes.	[70]	2006
	DB, PC CO, RT showed that sertraline significantly reduced hot flash severity compared to placebo in patients taking tamoxifen.	[97]	2006
	DB, PC, RT found a significant decrease in hot flash severity in those taking gabapentin compared to those taking a placebo.	[148]	2005
	Intramuscular medroxyprogesterone acetate daily is more effective than oral venlafaxine for treatment of hot flashes.	[105]	2006
	Two DB, PC, RT showed that venlafaxine reduced hot flashes but was not efficient for alleviating other treatment related symptoms such as fatigue and sleep disturbance.	[104]	2007
	DB, RT (Phase III) showed that 37.5 mg twice a day of venlafaxine was significantly more effective in reducing hot flashes compared to 0.075 mg twice a day of clonidine.	[149]	2007
	Hypnosis resulted in a 59% decrease in daily hot flashes, a 70% decrease in weekly hot flashes, and a decrease in the degree to which hot flashes interfered with normal daily activities in a small 16 patient sample.	[150]	2007
	Hot flash frequency was reduced following acupuncture but no significance was found when compared to sham acupuncture.	[151]	2007
	Hot flashes were a better predictor of recurrence than age, hormone receptor status, or even the difference in the stage of the cancer at diagnosis (Stage I versus Stage II).	[2]	2008
	PC, RT showed that a diet high in vegetables, fruit, and fibre and low in fat decreased additional risk of secondary breast cancer events in women without hot flashes compared with that in women with hot flashes, possibly through lowered concentrations of circulating estrogens.	[152]	2009
Prostate	DB, PC, CO, RT showed a reduction in hot flashes with 20 mg twice a day of medroxyprogesterone acetate compared to placebo.	[67]	1994
	Found that radiation therapy combined with 3.6 mg of goserelin (subcutaneously), improves local control and survival in patients with advanced cancer but 62% of participants receiving goserelin experienced hot flashes.	[113]	1997
	Details five individuals who were prescribed sertraline for anxiety and depression, all of whom experienced reductions in their hot flash symptoms.	[100]	1998
	Megestrol acetate use was found to be safe and effective in reducing hot flash symptoms for up to three years.	[114]	1999
	Venlafaxine hydrochloride in doses of 12.5 mg twice a day alleviated hot flashes in men undergoing androgen ablation therapy	[153]	1999
Lung	7% of patients experienced hot flashes that were severe and limiting but these symptoms were limited to women.	[154]	2004
Ovary	Study found a positive association between occurrence of hot flashes and the relative risk of ovarian cancer	[155]	1992
Testes	Men reported feeling cold more often that the general male population.	[122]	2002

DB, double blind; PC, placebo controlled; RT, randomised trial; CO, cross-over.

Figure 2. Humans must balance the amount of energy they consume, in the form of food, with the amount of energy they expend, through basal metabolism (homeothermy and biological maintenance), thermogenesis, and physical activity. When excess energy is required for one process utilizing energy, less energy is available to sustain other processes.

Figure 3. Summary of therapeutic and physiological influences on the thermoregulatory pathway and hot flashes. Generally, menopause reduces estrogen and progesterone levels. See text for additional details. SSRIs: selective serotonin reuptake inhibitors; SNRIs: serotonin-norepinephrine reuptake inhibitors; SERMs: selective estrogen replacement modulators; AIs: Aromatase Inhibitors; MPA: medroxyprogesterone acetate.

Figure 4. The same cytokines are responsible for metabolic factors leading to cancer growth, fatigue, and temperature dysregulation (fever). High levels of TNF-α and IL-6 affect blood concentration and makeup leading to fatigue (blue). Increases in TNF-α and Il-6 promote metabolic syndrome (green) which induces gluconeogenesis and adipocyte production. These bodily changes lead to an upregulation of various immune regulators that result in cancer development and growth. These cytokines also lead to fever via a PGE-2 dependent pathway (red). Temperature dysregulation (feeling cold) has been related to fatigue and may also be associated with cancer growth. RBC: red blood cell; COX-2: inducible cyclo-oxygenase; PGE2:prostaglandin E2; IGF-1: insulin-like growth factor 1; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; ROS: reactive oxygen species; DNA: deoxyribonucleic acid; VEGF: vascular endothelial growth factor.

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