(UroToday.com) The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) meeting featured a session on the identification, assessment, and management of side effects of systemic therapies, and a presentation by Dr. Anthony Joshua discussing how we can help our patients with hot flushes. The pathophysiology of side effects secondary to ADT is based on:
- Suppression of testosterone, leading to erectile dysfunction, loss of muscle mass, loss of muscle strength
- Suppression of endogenous estradiol, leading to osteoporosis and increased fracture risk, lipid changes, increased fat deposition, increased insulin resistance, memory loss, and hot flushes
Strikingly, 44-80% of men undergoing ADT have hot flushes. At four months, there is a peak of LHRH, with no useful predictors for who has more severe peaks. At 12 months of ADT, the median time to cessation of hot flushes is 7.6 months, and at 5-8 years, 70% to 40% will continue having hot flushes.
Hot flushes have a significant impact on patients, with 30% of patients reporting hot flushes as the most troublesome effect on therapy. They also lead to sleep disturbances, diminished cognition, and lower quality of life, with up to 55% of patients reporting distress and 11% severe distress. Furthermore, hot flushes can lead to treatment discontinuation and/or abbreviation. Among 64 UK urologic oncologists, the most common therapy recommendations for addressing hot flushes included: lifestyle changes, cyproterone acetate, acupuncture, and herbal medicines:
Cognitive behavioral therapy has increasing evidence for reducing the impact of hot flushes, especially in the first 2 months of treatment, with previous trials showing a 40% reduction in problem rating secondary to hot flushes. There have been single-arm studies for acupuncture showing a 40% reduction in symptoms, which appears to be sustainable. In a cross-over study of 39 women, the EMBR wave heat pump “watch” had an impact on hot flushes interfering with sleep (90% vs 70%).
Dr. Joshua then discussed the PATCH trial, a phase 2/3, randomized, multicenter trial at 52 study sites in the UK. In this trial, men with locally advanced or metastatic prostate cancer were randomly allocated (1:2) to either LHRH agonist according to local practice, or transdermal administration of estradiol patches (four 100 μg patches per 24 h, changed twice weekly, reducing to three patches twice weekly if castrate at 4 weeks). Any grade hot flushes occurred in 86% of men in the LHRH agonist arm versus 35% of men in the transdermal administration of estradiol patches arm, with 3% Grade 3 hot flushes versus 0%, respectively. Moreover, any grade gynecomastia occurred in 38% of men in the LHRH agonist arm versus 86% of men in the transdermal administration of estradiol patches arm, with 0% Grade 3 gynecomastia versus 4%, respectively.
The following table summarizes hormonal management with estradiol:
Other therapies that have previously been tested for ADT hot flushes includes medroxyprogesterone (20 mg BID daily), cyproterone acetate (50-100 mg/day), and venlafaxine (75 mg daily). Dr. Joshua notes that venlafaxine appears effective, but is likely dose-dependent and temporary. Gabapentin studies have been tested at 600 – 900 mg daily. Interestingly, a trial reporting on oxybutynin for hot flushes will be presented at ASCO 2024. Fezolinetant is a neurokinin 3 antagonist that has been tested for hot flush reduction in women, leading to decreased hot flush severity, decreased hot flush frequency, and increased quality of life indices at both 4 and 12-week evaluations.
With any treatment, particularly one aimed at decreasing debilitating symptoms such as hot flushes, there may be challenging side effects:
- Medroxyprogesterone: edema, nausea, chills, headache, mood changes, thrombosis risk
- Cyproterone acetate: fatigue, weight gain, mood changes
- Estrogen: nipple sensitivity, gynecomastia, increase in body fat, thrombosis risk
- Fezolinetant (rare): hepatotoxicity, headache, GI symptoms
- Gabapentin: fatigue
- Oxybutynin: dry mouth, dizziness, constipation
Dr. Joshua also emphasized that there are challenges with trial design, including (i) objective quantification of hot flushes (ie. scales), (ii) objective quantification of bother and impact on quality of life, (iii) large placebo effect, and (iv) hard to fund off label treatments.
Dr. Joshua concluded his presentation discussing how we can help our patients with hot flushes with the following take-home messages:
- The current management of hot flushes is suboptimal
- There is no single solution and there is a need to individualize
- Upcoming data (ASCO, ESMO) may assist with treatment
- Side effects of treatment for hot flushes need vigilance
- Fezolinetant trials are needed
- Comparison and combination studies are needed
Presented by: Anthony M. Joshua, MBBS, PhD, FRACP, Kinghorn Cancer Centre, St. Vincent’s Hospital, Sydney, Australia
Written by: Zachary Klaassen, MD, MSc - Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 Advanced Prostate Cancer Consensus Conference (APCCC) Meeting, Lugano, Switzerland, Thurs, Apr 25 - Sat, Apr 27, 2024.
References:
- Langely RE, Gilbert DC, Duong T, et al. Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomized Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme. Lancet. 2021 Feb 13;397(10274): 581-591.
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