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APCCC 2019: Management of Hot Flushes

Basel, Switzerland (UroToday.com) In this session, the important topic of hot flushes caused by androgen deprivation therapy (ADT) was discussed by Dr. Frydenberg. Hot flushes are defined as a subjective feeling of warmth in the upper torso, followed by excessive perspiration. Approximately 80-90% of men on ADT endure hot flushes, with 27% reporting them as the most troublesome side effect. Hot flushes have been associated with patient embarrassment, helplessness, and distress during treatment.1 They can last for the entire duration of treatment and significantly affect quality of life and sleep.2 

The reduction of plasma sex hormones levels from previous normal levels alters the function of brain neurotransmitters such as noradrenaline, serotonin, GABA, dopamine, and beta-endorphins. The thermoregulatory center in the hypothalamus is anatomically close to the LHRH secreting neurons, and by proximity, the thermoregulatory center can be reset. There is a positive correlation between hot flushes and LH surges. Hot flushes have been reported to worsen with longer ADT treatment durations and are also worse in younger men with lower BMI.3

In the next part of his talk, Dr. Frydenberg discussed the various treatment options of hot flushes.

He began with the most basic category of conservative management. This includes:

  • Avoidance of thermogenic stimuli and recommending patients to keep a diary of triggers and to actively avoid them (alcohol, tobacco, caffeine, spicy food)
  • Assessing the degree of bother
  • Application of environment cooling at nighttime (fans, open windows, etc.)
  • Dressing in layers during the day and using open weave fabrics
Another treatment option is ADT manipulation. This includes:

  • Using intermittent androgen deprivation as opposed to continuous androgen deprivation. It is important to remember that hot flushes peak 4 months after the initial LHRH agonist administration and 3 weeks after bilateral orchiectomy. The mean time to cessation of hot flushes observed using intermittent androgen deprivation was 7.6 months4
  • There is data showing that hot flushes with LHRH antagonist are actually worse than with LHRH agonists, but only for the first 3 months and then the rates equalize5
  • The role of anti-androgen monotherapy compared to LHRH agonists is still not entirely clear, with regards to hot flushes
Dr. Frydenberg continued to discuss the various medical treatments available for hot flushes:

  • Estrogens which centrally reduce LH surge can be given in the form of Diethylstilbestrol (DES). The most serious adverse effect is thromboembolism which is dose-dependent.
  • There is a study that showed a possibility to give an alpha agonist instead of LHRH which reduced hot flushes whilst maintaining castrated testosterone6
  • Alpha 2 adrenergic blockers such as clonidine, which can be given orally or transdermally, 1 mg/day. Unfortunately, it has been shown not to be effective and only 30-40% of patients reported partial responses. The most serious side effects include constipation, dizziness, drowsiness, and dry mouth, fatigue, and weakness
  • Progesterone/progestin which results in the reduction of LH surge centrally. There are several options, including cyproterone acetate (Androcur 50 mg daily which can be titrated upwards), medroxyprogesterone (Provera 150-400 mg), megestrol acetate (Megace 20 m BID). Progesterone causes a reduction of hot flushes by 70-80% but it is potentially hepatotoxic and can also cause fatigue as well as gynecomastia7
  • Additional options include selective serotonin reuptake inhibitor (SSRI), and selective serotonin and noradrenaline reuptake inhibitors (SNRI). They have been reported to improve symptoms induced by hot flushes in 60% of patients. Their adverse effects include nausea, anorexia, headaches, and agitation
  • Gabapentinoids – These are gamma-aminobutyric acid analogs, that are usually used for neuropathic pain, but have been reported to reduce hot flushes in 25% of patients. Their side effects include light-headedness and drowsiness8
  • Oxybutynin – used in women with a reported 70% favorable response in a group of women refractory to other treatments9
Dr. Frydenberg also mentioned some complementary treatments that can always be used:

  • Exercise – especially high-intensity aerobics and resistance training
  • Cognitive-behavioral therapy
  • Diet – no benefit has been shown in randomized controlled trials for phytoestrogens
  • Acupuncture – reports of 70-80% reduction in flushes with either dry needling or electro stimulated needling. Moreover, patients maintained less than 50% reduction in their hot flushes 9 months after cessation of treatment in 46% of patients10
Dr. Frydenberg concluded his informative talk emphasizing some important points. Hot flushes are a common and troublesome side effect of ADT. It is imperative that patients avoid known triggers of hot flushes and promote conservative therapies. An intermittent androgen blockade is a good option where appropriate and safe. It is reasonable to consider progesterone and SSRI/SNRI as first-line medical therapy. Lastly, complementary therapies are always recommended (acupuncture and exercise).

Dr. Frydenberg ended his talk stating that this is a significantly under-researched field that could substantially benefit from further research.

Presented by: Mark Frydenberg, MD, Monash University, Melbourne, Australia 

Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New York, USA, Twitter: @GoldbergHanan at the 2019 Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland

References:
1. Ulloa, Erin Winters, Raoul Salup, Stephen G. Patterson, and Paul B. Jacobsen. "Relationship between hot flashes and distress in men receiving androgen deprivation therapy for prostate cancer." Psycho‐Oncology: Journal of the Psychological, Social and Behavioral Dimensions of Cancer18, no. 6 (2009): 598-605.

2. Karling, Pontus, Mats Hammar, and Eberhard Varenhorst. "Prevalence and duration of hot flushes after surgical or medical castration in men with prostatic carcinoma." The Journal of urology 152, no. 4 (1994): 1170-1173.

3. Gonzalez et al. "Course and Moderators of Hot Flash Interference during Androgen Deprivation Therapy for Prostate Cancer: A Matched Comparison." The Journal of Urology. 2015 Sep;194(3):690-5. doi: 10.1016/j.juro.2015.03.026. 

4. Dosani et al. Clin Oncol 2018

5. Sokolakis, I., A. Zarkadoulias, K. Kazanas, P. Georgopoulos, K. Xouplidis, and K. Hatzimouratidis. "S247: Comparing the frequency and severity of hot flashes in prostate cancer patients under androgen deprivation therapy with an LHRH agonist or antagonist." European Urology Supplements 13, no. 7 (2014): e1567.

6. Yu et al. Eur Urol 2015

7. Eaton, A. C., and N. McGuire. "Cyproterone acetate in treatment of post-orchidectomy hot flushes: double-blind cross-over trial." The Lancet 322, no. 8363 (1983): 1336-1337.

8. Bordeleau, Louise, Kathleen I. Pritchard, Charles L. Loprinzi, Marguerite Ennis, Olivera Jugovic, David Warr, Rashida Haq, and Pamela J. Goodwin. "Multicenter, randomized, cross-over clinical trial of venlafaxine versus gabapentin for the management of hot flashes in breast cancer survivors." J Clin Oncol 28, no. 35 (2010): 5147-5152.

9. Sexton, Tracy, Jawaid Younus, Francisco Perera, Lyn Kligman, and Michael Lock. "Oxybutynin for refractory hot flashes in cancer patients." Menopause 14, no. 3 (2007): 505-509.

10. Frisk et al. Eur Urol 2008

Related Content: Watch: APCCC Presentation: The Management of Hot Flushes in Advanced Prostate Cancer
Watch: Interview with Mark Frydenberg, MD: Managing the Complications of Androgen Deprivation Therapy