# Radiation Oncology/Supportive care/Hot flashes

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
Treatment of Hot Flashes

## Hormonal Therapy
### Estrogens

* Estrogen replacement therapy is effective, but its use in BCA patients is not indicated due to an increase in new breast cancer events
* HABITS (1997-2003)
** Randomized. Stopped prematurely for increased risk of breast cancer. 434 women randomized/345 at least one follow-up. DCIS to Stage II BCA. Tamoxifen allowed. Arm 1) Hormone replacement therapy (choice allowed locally) x2 years vs. Arm 2) control. HRT given as estrogen only (21%), continuously combined regimens (46%), sequential regimens (26%), and non-protocol treatments or no HRT (6%). In non-HRT group, 18% exposed to HRT
** 2004 PMID 14962527 -- "HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped." (Holmberg L, Lancet. 2004 Feb 7;363(9407):453-5.) Median F/U 2.1 years
*** Outcome: new breast cancer event HRT 15% vs. non-HRT 5% (SS). LR 6% vs. 1%, DM 6% vs. 3%, contralateral 3% vs. 0.6%
*** Conclusion: Hormone-replacement therapy for menopausal symptoms represents unacceptable risk for new breast cancer events

### Progestins

* Progestins offer significant and long-lasting relief
** Depomedroxyprogesterone acetate (Depo-Provera): IM injection. 400 mg one dose, can consider additional 500 mg at 2 week intervals x2
** Megestrol acetate: 20 mg PO QD
* NCCTG N99C7 (2002-2004) -- Medroxyprogesterone 400 mg IM vs venlafaxine 75 mg PO
** Randomized. 227 patients with bothersome hot flashes. Tamoxifen, raloxifene, and AI allowed, antineoplastics, androgens, and estrogens not allowed. Arm 1) Medroxyprogesterone (MPA) 400 mg IM x1 vs Arm 2) MPA 500 mg IM x3 Q2W vs Arm 3 venlafaxine 37.5 mg QD x 1 week, then 75 mg QD. Due to slow accrual, Arm 2 was discontinued.
** 2006 PMID 16505409 — "Phase III Comparison of Depomedroxyprogesterone Acetate to Venlafaxine for Managing Hot Flashes: North Central Cancer Treatment Group Trial N99C7." (Loprinzi CL, JCO 2006 Mar 20;24(9):1409-14.)
*** Outcome: reduction in hot flashes MPA 79% vs. venlafaxine 55% (SS), reduction by >50% MPA 74% vs. venlafaxine 46% (SS)
*** Toxicity: Better in MPA arm
*** Conclusion: Single MPA dose well tolerated and more effective than venlafaxine
* SWOG 9626 (1998-2000) -- placebo vs. megestrol 20 mg vs. megestrol 40 mg
** 2008 PMID 18375894 -- "Phase III randomized placebo-controlled trial of two doses of megestrol acetate as treatment for menopausal symptoms in women with breast cancer: Southwest Oncology Group Study 9626." (Goodwin JW, J Clin Oncol. 2008 Apr 1;26(10):1650-6.)
** Randomized. 288 women with T1-3N01, at least 10 hot flashes/week. Tamoxifen allowed (85%). Arm 1) placebo vs. Arm 2) megestrol acetate (MA) 20 mg QD vs. Arm 3) MA 40 mg QD x3 months. Success at 3 months defined as >= 75% reduction
*** Outcome: 3 months success placebo 14% vs. MA 20 mg 65% (SS) vs MA 40 mg 48% (SS). 6 months success 77% vs. 81%
*** Conclusion: megestrol significantly reduced hot flashes with durable benefit. MA 20 mg/d is preferred dose
* Italy (1996-1998) -- medroxyprogesterone 500 mg vs. megestrol 40 mg
** Randomized. 71 postmenopausal patients with BCA. Arm 1) depot medroxyprogesterone (MPA) IM 500 mg day 1, 14 and 28 vs. Arm 2) oral megestrol 40 mg QD x6 weeks
** 2002 PMID 12123333 -- "Intramuscular depot medroxyprogesterone versus oral megestrol for the control of postmenopausal hot flashes in breast cancer patients: a randomized study." (Bertelli G, Ann Oncol. 2002 Jun;13(6):883-8.)
*** Outcome: At week 6, hot flash reduction MPA 75% vs. oral megestrol 67% (NS); at week 24, MPA 89% vs. oral megestrol 45% (SS)
*** Toxicity: vaginal dryness, dyspareunia, fatigue, night sweats, but most relatively minor
*** Conclusion: Short cycle of IM MPA injections provide significant and long-lasting relief
* Mayo Clinic (1992-1993) -- placebo vs. megestrol 40 mg
** Randomized, cross-over. 163 patients (97 women with breast CA and 66 men with prostate), with bothersome hot flashes. Arm 1) placebo vs. Arm 2) megestrol 40 mg x4, then crossed over
** 1994 PMID 8028614 -- "Megestrol acetate for the prevention of hot flashes." (Loprinzi CL, N Engl J Med. 1994 Aug 11;331(6):347-52.)
*** Outcome: At 4 weeks, hot flash reduction placebo 21% vs. megestrol 85% (SS), >50% reduction placebo 20% vs. megestrol 74% (SS). Efficacy similar in men and women
*** Toxicity: well tolerated
*** Cross-over portion not analyzed due to longer-term benefit from megestrol in patients initially treated with megestrol vs. placebo
*** Conclusion: Low-dose megestrol well tolerated and efficacious in men and women
** 1998 PMID 9576302 -- "Long term use of megestrol acetate by cancer survivors for the treatment of hot flashes." (Quella SK, Cancer. 1998 May 1;82(9):1784-8.)
*** Retrospective. 132/163 patients. Long-term follow-up for the initial cohort
*** Outcome: 45% continued megestrol >3 years after conclusion of study; 75% utilizing <=20 mg/day
*** Toxicities: chills, appetite stimulation, weight gain, vaginal bleeding, and carpal tunnel
*** Conclusion: Substantial proportion of patients continue to use megestrol; treatment relatively well tolerated

## Antidepressants
### Paroxetine (Paxil)

* US Multi-Institutional (2001-2002) -- placebo vs. paroxetine 12.5 vs. paroxetine 25 mg
** 2003 PMID 12783913 -- "Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial." (Stearns V, JAMA. 2003 Jun 4;289(21):2827-34.)
** Randomized. 165 women, functionally menopausal. No hormonal therapy. Arm 1) placebo vs. Arm 2) paroxetine CR 12.5 mg/d vs. Arm 3) paroxetine CR 25 mg/d
*** Outcome: 6 week mean reduction placebo 38% vs. paroxetine 12.5 62% vs. paroxetine 25 65%
*** Toxicity: Not different from placebo (54% vs. 58%)
*** Conclusion: Paroxetine CR may be effective and acceptable alternative
* US Multi-Institutional (1999-2002) -- placebo vs. paroxetine 10 mg vs. paroxetine 20 mg
** Randomized, 2 cross-over studies. 151 women, with or without h/o BCA, not candidate for HRT, with troublesome hot flashes. Arm 1) paroxetine 10 mg x4 weeks then placebo 4 weeks vs. Arm 2) paroxetine 20 mg x4 weeks then placebo 4 weeks vs. Arm 3) placebo x4 weeks then paroxetine 10 mg x4 weeks vs. Arm 4) placebo x4 weeks then paroxetine 20 mg
** 2005 PMID 16192581 -- "Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial." (Stearns V, J Clin Oncol. 2005 Oct 1;23(28):6919-30.)
*** Outcome: Reduction in hot flashes placebo 14% vs. paroxetine 10 46% (SS) vs. paroxetine 20 56% (SS). Also significant benefit in sleep
*** Toxicity: Women more likely to discontinue paroxetine 20 mg
*** Conclusion: Paroxetine effective treatment for hot flashes

### Venlafaxine (Effexor)

    See also #Randomized comparisons gabapentin vs venlafaxine
* NCCTG N99C7 (2002-2004) -- Medroxyprogesterone 400 mg IM vs venlafaxine 75 mg PO
** Randomized. 227 patients with bothersome hot flashes. Tamoxifen, raloxifene, and AI allowed, antineoplastics, androgens, and estrogens not allowed. Arm 1) Medroxyprogesterone (MPA) 400 mg IM x1 vs Arm 2) MPA 500 mg IM x3 Q2W vs Arm 3 venlafaxine 37.5 mg QD x 1 week, then 75 mg QD. Due to slow accrual, Arm 2 was discontinued.
** 2006 PMID 16505409 — "Phase III Comparison of Depomedroxyprogesterone Acetate to Venlafaxine for Managing Hot Flashes: North Central Cancer Treatment Group Trial N99C7." (Loprinzi CL, JCO 2006 Mar 20;24(9):1409-14.)
*** Outcome: reduction in hot flashes MPA 79% vs. venlafaxine 55% (SS), reduction by >50% MPA 74% vs. venlafaxine 46% (SS)
*** Toxicity: Better in MPA arm
*** Conclusion: Single MPA dose well tolerated and more effective than venlafaxine 75 mg
* US Multi-Institutional (1999) -- placebo vs. venlafaxine 37.5 mg vs. 75 mg vs. 150 mg
** Randomized. 191 patients, h/o BCA or concerned about developing BCA. Tamoxifen, raloxifene and AI allowed. Androgens, estrogens not allowed. Arm 1) placebo vs. Arm 2) venlafaxine 37.5 mg vs. Arm 3) venlafaxine 75 mg vs. Arm 4) venlafaxine 150 mg, taken x4 weeks
** 2000 PMID 11145492 -- "Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial." (Loprinizi CL, Lancet. 2000 Dec 16;356(9247):2059-63.)
*** Outcome: After 4 weeks, median hot flash reduced by placebo 27% vs 37.5 mg 37% vs 75 mg 61% vs. 150 mg 61%
*** Toxicity: mouth dryness, decreased appetite, nausea, constipation worse in 75 mg and 150 mg groups
*** Outcome: Venlafaxine effective, favor 75 mg QD dose

### Fluoxetine (Prozac)

* Mayo Clinic (1998-2000) -- placebo vs. fluoxetine 20 mg
** Randomized, cross-over. 81 patients with h/o BCA or perceived increased risk of BCA, bothersome hot flashes. Tamoxifen or raloxifene allowed. No androgens, estrogens, progestational drugs or chemotherapy. Arm 1) placebo vs. Arm 2) fluoxetine 20 mg x4 weeks. After 4 weeks, cross-over.
** 2002 PMID 11896107 -- "Phase III evaluation of fluoxetine for treatment of hot flashes." (Loprinzi CL, J Clin Oncol. 2002 Mar 15;20(6):1578-83.)
*** Outcome: After 4 weeks (cross-over), hot flash decrease placebo 36% vs. fluoxetine 50% (NS); after cross-over fluoxetine arm better (SS)
*** Conclusion: Fluoxetine 20 mg modestly effective

### Citalopram (Celexa)

* NCCTG -- citalopram 10 mg, 20 mg, 30 mg, vs placebo
** Randomized. 254 postmenopausal women.
** 2010 PMID 20498389 -- "Phase III, Placebo-Controlled Trial of Three Doses of Citalopram for the Treatment of Hot Flashes: NCCTG Trial N05C9." (Barton DL, J Clin Oncol. 2010 July 10;28(20):3278-83.)
*** Reduction in mean hot flash score 23% (placebo), 49%, 50%, 55% (10,20,30 mg). Secondary outcomes superior in 20 mg arm.
*** Citalopram is effective.

#### Escitalopram (Lexapro)

* U. Pennsylvania (2009-10) - escitalopram 10-20 mg vs placebo
** Randomized. 205 menopausal women.
** 2011 PMID 21245182 -- "Efficacy of escitalopram for hot flashes in healthy menopausal women: a randomized controlled trial." (Freeman EW, JAMA. 2011 Jan 19;305(3):267-74.)
*** Escitalopram is effective in reducing hot flashes and is well tolerated.

## Antiseizure medications
### Gabapentin

Gabapentin was designed as a simple analogue of GABA that would be sufficiently lipid-soluble to penetrate the blood-brain barrier. It turned out to be an effective anticonvulsant in several animal models but, surprisingly, not by acting on GABA receptors. It main site of action appears to be on T-type calcium channel function, by binding to particular channel subunit, and it inhibits the release of various neurotransmitters and modulators, but eh details remain unclear.
    See also #Randomized comparisons gabapentin vs venlafaxine
* NCCTG N03C5 -- antidepresant + gabapentin vs. gabapentin alone
** Randomized. 188 patients, inadequate hot flash control on an antidepressant. Randomized to Arm 1) antidepressant + addition of gabapentin vs. Arm 2) tapering of antidepressant + addition of gabapentin. Observation x5 weeks
** 2007 PMID 17146104 -- "Phase III trial of gabapentin alone or in conjunction with an antidepressant in the management of hot flashes in women who have inadequate control with an antidepressant alone: NCCTG N03C5." (Loprinzi CL, J Clin Oncol. 2007 Jan 20;25(3):308-12. Epub 2006 Dec 4.)
*** 5-week outcome: antidepressant + gabapentin 54% reduction vs. gabapentin 49% (NS)
*** Conclusion: Gabapentin decreases hot flashes by ~50%, regardless of concurrent antidepressant
* Rochester (2002-4) -- estrogens, gabapentin, vs. placebo
** 2006 PMID 16816054 — "Gabapentin, estrogen, and placebo for treating hot flushes: a randomized controlled trial." (Reddy SY, Obstet Gynecol. 2006 Jul;108(1):41-8.)
*** Randomized, double blind. 60 postmenopausal women w/ moderate to severe hot flashes. Randomized to 1) conjugated estrogens, 2) gabapentin (to 2400 mg/d), or 3) placebo.
*** Hot flash score reduced by 72% (estrogen), 71% (gabapentin), and 54% (placebo) over 12 week period. Difference between arms 1 & 2 not significant.
*** Conclusion: similar efficacy of gabapentin and estrogens
* Rochester (2001-3) -- high dose (900 mg/d) vs low dose (300 mg/d) gabapentin vs placebo
** 2005 PMID 16139656 — "Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial." (Pandya KJ, Lancet. 2005 Sep 3-9;366(9488):818-24.)
*** Randomized, double blind. 420 women with history of breast cancer. Randomized to 1) gabapentin 100 mg TID, 2) gabapentin 300 mg TID, or 3) placebo.
*** Hot flash severity score decreased by 31% (300 mg), 46% (900 mg), and 15% (placebo) over 8 week period; difference between 300 mg and 900 mg doses is S.S.
*** Conclusion: gabapentin is effective at reducing hot flashes at the 900 mg/d dose but not at 300 mg/d.
* Rochester (2000-1) -- low dose gabapentin (900 mg/d) vs placebo
** 2003 PMID 12576259 — "Gabapentin's effects on hot flashes in postmenopausal women: a randomized controlled trial." (Guttuso T Jr, Obstet Gynecol. 2003 Feb;101(2):337-45.)
*** Randomized, double blind. 59 postmenopausal women. Randomized to 1) gabapentin (100 mg TID) or 2) placebo. After 12 week period, pts optionally could enroll in open-label study of gabapentin, titrating up to 2700 mg/d.
*** At 12 weeks, gabapentin associated with 45% reduction in hot flash frequency and 54% reduction in hot flash composite score vs 29% and 31% for placebo. Higher reduction in symptoms with higher dose in open-label study.
*** Conclusion: gabapentin is effective at reducing hot flashes in postmenopausal women

## Pregabalin

* NCCTG/Mayo -- 75 mg BID vs 150 mg BID vs placebo
** 2010 PMID 19901102 -- "Phase III, Randomized, Double-Blind, Placebo-Controlled Evaluation of Pregabalin for Alleviating Hot Flashes, N07C1" (Loprinzi CL, J Clin Oncol. 2010 Feb 1;28(4):641-7.)
*** Randomized. 163 pts. Assessed at week 6.
*** Hot flash score decreased by 50% (placebo), 65% (75mg) and 71% (150mg); SS vs placebo. Pregabalin was well tolerated.
*** Conclusion: pregabalin decreases hot flashes and is well tolerated.

## Acupuncture

* Henry Ford Health System (2004-2007) -- acupuncture vs venlafaxine
** Randomized. 50 patients with Stage 0-III breast cancer, pre- or postmenopausal, on TAM or arimidex, ≥ 14 hot flashes/week, finished chemotherapy. Arm 1) acupuncture x12 weeks vs Arm 2) venlafaxine 75 mg QD x12 weeks. Primary outcome hot flash frequency
** 2010 PMID 20038728 -- "Acupuncture versus venlafaxine for the management of vasomotor symptoms in patients with hormone receptor-positive breast cancer: a randomized controlled trial" (Walker EM, J Clin Oncol. 2010 Feb 1;28(4):634-40. Epub 2009 Dec 28.)
*** Outcome: No difference in hot flashes, depressive symptoms, and QoL. By 2 weeks after treatment, venlafaxine group significant increase in hot flashes but no increase for acupuncture group. In addition, acupuncture improved sex drive and well-being
*** Toxicity: Venlafaxine 18 incidences of adverse effects vs none in acupuncture group
*** Conclusion: Acupuncture appears equivalent to drug therapy for vasomotory symptoms due to hormone therapy
* MSKCC (2002-2005) -- acupuncture vs. sham
** Randomized. 72 women with 3+ hot flashes/day. Arm 1) acupuncture vs. Arm 2) sham acupuncture, twice/week x4 weeks. Cross-over at 4 weeks
** 2007 PMID 18065731 -- "Randomized, controlled trial of acupuncture for the treatment of hot flashes in breast cancer patients." (Deng G, J Clin Oncol. 2007 Dec 10;25(35):5584-90.)
*** Outcome: mean reduction acupuncture 2.5 vs. sham 2.6 hot flashes/day (NS), at 6 weeks difference of 0.8 hot flashes/day (NS)
*** Conclusion: No difference between acupuncture and sham, both groups showed reduction

## Hypnosis

* Multi-Institutional -- hypnosis vs control
** Randomized. 51/60 patients. Breast cancer survivors, no detectable disease, hot flashes >14 per week. Arm 1) hypnosis 5 sessions x50 minutes QW vs Arm 2) no treatment. 20% withdrew or lost to follow up
** 2008 PMID 18809612 -- "Randomized Trial of a Hypnosis Intervention for Treatment of Hot Flashes Among Breast Cancer Survivors." (Elkins G, J Clin Oncol. 2008 Sep 22. [Epub ahead of print])
*** Outcome: Hot flashes (frequency x severity score) decreased by 68%. Sleep, and mood significantly better with hypnosis
*** Conclusion: Hypnosis appears to reduce perceived hot flashes, and my have additional benefits such as reduced anxiety, depression, and improved sleep

## Randomized comparisons

* Hamilton, Ontario -- venlafaxine vs gabapentin
** Randomized, cross-over trial. 66 pts (breast cancer survivors). 4 weeks of gabapentin (300 mg TID) vs venlafaxine (75 mg qd). Primary end point: patient preference.
** 2010 PMID 21060031 -- "Multicenter, Randomized, Cross-Over Clinical Trial of Venlafaxine Versus Gabapentin for the Management of Hot Flashes in Breast Cancer Survivors." (Bordeleau L, J Clin Oncol. 2010 Nov 8. [Epub ahead of print])
*** 56 of 66 pts indicated a preference - 68% venlafaxine, 32% gabapentin. 10 pts no response (8 dropped out, 2 no preference).
*** 66% reduction of hot flashes in both arms.
*** Conclusion: Breast cancer survivors prefer venlafaxine over gabapentin for treatment of hot flashes