Management of hot flushes in advanced prostate cancer Mark - - PowerPoint PPT Presentation

Management of hot flushes in advanced prostate cancer

Mark Frydenberg AM Professor, Department of Surgery , Monash University Academic Director of Urology, Cabrini Health Melbourne, Australia

• Subjective feeling of warmth , upper torso, followed by excessive

perspiration

• 80-90% of men on ADT, 27% report them as most troublesome side

effect

• Variable sympathy
• Associated with patient distress during treatment, embarrassment

and helplessness Ulloa Psycho-oncology 2009

• Can last for the duration of therapy, effect QOL and sleep quality Karling

et al., J Urol 1994, Nishiyama et al., Int J Urol 2004, Freedman Am J Med 2005, Penson et al., J Urol 2003

• Congenital hypogonadism does not lead to hot flushes
• As such it is not absolute plasma sex hormone level that is critical but

its reduction from previously normal levels that alters the function of brain neurotransmitters such as noradrenalin , serotonin, GABA, dopamine and beta endorphins.

• Thermoregulatory centre in the hypothalamus is anatomically close to

the LHRH secreting neurones and by proximity the thermoregulatory centre can be reset.

• Positive correlation between flushes and LH surges
• Worsens with duration of ADT
• Worse in men of younger age and lower BMI Gonzalez et al., J Urol 2015

Conservative management

• Avoid thermogenic stimuli – keep diary of triggers and avoid them

e.g., alcohol, tobacco, caffeine , spicy foods

• Assess degree of bother , recent study demonstrated that 42% did

not enter trials as not bothersome enough Zarkadoulias et al., Eur Urol 2014

Conservative management

• Environmental cooling at night, fans , open windows
• During day - dress in layers , open weave fabrics e.g., cotton

ADT manipulation

• Intermittent androgen blockade Botrel et al., BMC Urol 2014, Brungs et al., PCPD 2014, Hussain NEJM

2013

• Hot flushes peak 4 months after initial LHRH agonist administration (3

weeks after bilateral orchidectomy)

• Mean time to cessation of flushes with IAB was 7.6 months Dosani et al.,

Clin Oncol 2018

• Studies have shown flushes with LHRH antagonist > agonist but only

for first 3 months then equalises Sokolakis et al., Eur Urol 2014

• Role of anti-androgen monotherapy rather than GnRH agonist? Beckmann

et al., Eur Urol 2019

Medical treatments

• Oestrogens
• Centrally reduces LH surges
• DES 0.25-0.5 mg/day eliminated hot flushes in 70%, 20% had > 50%

reduction

• Also achieved with 0.10 mg/hr transdermal DES Gerber et al., Urology 2000, Atala

Urology 1992, Miller et al., Urology 1992 ;

• SAE thromboembolic and effectiveness and side effects are dose

dependent

• Study using ER alpha agonist GTx758 instead of LHRH reduced hot

flushes whilst maintained drop in testosterone Yu et al., Eur Urol 2015

Medical treatments

• Alpha 2 adrenergic blockers
• Clonidine , oral or transdermal , 1 mg/day, receptors centrally and

peripherally

• Not effective ; 30-40% reported partial responses and another study

no difference to placebo Smith et al., J Urol 1994 Loprinzi, Mynderse et al., J Urol 1994

• SAEs: constipation , dizziness, drowsiness and dry mouth, fatigue and

weakness

Medical treatments

• Progesterone/Progestins
• Reduces LH surges centrally
• Cyproterone acetate (Androcur 50 mg daily and titrate upwards),

medroxyprogesterone (Provera 150-400 mg), megestrol acetate (Megace 20 mg BD) ,

• Reduces hot flushes by 70-80% but potentially hepatotoxic, fatigue

and gynaecomastia Eaton Lancet 1983, Cerveakov et al., Int Urol Nephrol 2000, Loprinzi et al., NEJM 1994,

Thrasher et al., J Urol 2005,

Medical treatments

• SSRI, SNRI anti depressants
• Venlafaxine (Efexor, SNRI) 75 mg per day , Paroxetine (Aropax, SSRI)

used in various doses , usually 10 mg/day

• ~ 60% improved symptoms, > 50% improvement in hot flush score
• SAEs: nausea, anorexia, headaches, agitation ;
• RCTs comparing venlafaxine to progesterones, concluded hormonal

therapies were more effective than SNRI/SSRIs

• Venlafaxine -47%, Cyproterone acetate -94.5%, Medroxyprogesterone

acetate -83.7% Quella et al., J Urol 1999, Irani et al., Lancet Oncol 2010

Medical treatments

• Gabapentinoids – gamma aminobutyric acid analogues, gabapentin

900-2400 mg/day (Neurontin), pregabalin 75-150 mg BD (Lyrica), antiseizure, used for neuropathic pain, 25% reduction in hot flushes – light headedness and drowsiness, Loprinzi et al., J Clin Oncol 2010, Bordeleau et al.,

J Clin Oncol 2010

• Oxybutynin – used in women, 70% favourable response in a group

refractory to other treatments Sexton et al., Menopause 2007

Complementary treatments

• Exercise - some evidence high intensity aerobic and resistance training

helps women reduce flushes during menopause by 40-50%, no data in men

• Cognitive behavioural therapy
• Diet -phytoestrogens/soy – No benefit in RCTs Steams et al., Lancet 2002, Sharma et al., J Urol

2009

• Acupuncture – 70-80% reduction in flushes with either dry needling or

electro-stimulated needling

• Maintained < 50% reduction in flushes 9 months after cessation of

treatment in 46% Frisk et al., Eur Urol 2008

• 89.2% reduction at 6 weeks, maintained at 80.3% at 8 months Ashamalia et al., Int J

Radiat Oncol Biol Phys 2011

Conclusions

• Common and troublesome side effect of ADT
• Avoid triggers
• Promote conservative therapies – fans, light clothes …
• Intermittent androgen blockade where appropriate and safe to do so
• Consider progesterones (cyproterone acetate), and/or SSRI/SNRI

antidepressants as first line medical therapy

• Complementary therapies – acupuncture, exercise
• Significantly under-researched area