Hormonal Cancer Therapy

Hormonal cancer therapy reduces the stimulus that hormones give to hormone-dependent tumours, by lowering hormone production, blocking the receptor, or degrading it. It is used in breast cancer, prostate cancer, endometrial cancer and some other tumours, with long-term daily tablets that are inexpensive and widely available.

Classification. Selective oestrogen receptor modulators (tamoxifen), selective oestrogen receptor degraders (fulvestrant), aromatase inhibitors (anastrozole, letrozole, exemestane), GnRH agonists and antagonists (goserelin, leuprorelin, degarelix), antiandrogens (bicalutamide, enzalutamide, apalutamide, darolutamide), androgen synthesis inhibitors (abiraterone), and progestogens (megestrol, medroxyprogesterone).

• Tamoxifen 20 mg orally daily for 5 to 10 years.
• Anastrozole 1 mg daily, letrozole 2.5 mg daily, or exemestane 25 mg daily for 5 to 10 years; in pre-menopausal women only with ovarian suppression.
• Fulvestrant 500 mg intramuscularly on days 1, 15 and 29, then every 28 days.
• Goserelin 3.6 mg subcutaneously every 28 days or 10.8 mg every 12 weeks; leuprorelin 3.75 mg every month or 11.25 mg every 3 months.
• Bicalutamide 50 mg daily (with a GnRH agonist) or 150 mg daily (monotherapy).
• Abiraterone 1,000 mg daily with prednisolone 5 mg daily (twice daily in some regimens).
• Enzalutamide 160 mg daily; apalutamide 240 mg daily; darolutamide 600 mg twice daily.
• Megestrol 160 mg daily (breast cancer) or medroxyprogesterone.

Differences. Tamoxifen acts in both pre- and postmenopausal women but increases thromboembolic and endometrial cancer risk; aromatase inhibitors work only after menopause and cause bone loss and joint pain.

• Hormone receptor-positive breast cancer: adjuvant therapy for 5 to 10 years; tamoxifen in pre-menopausal women, aromatase inhibitor (or tamoxifen) in postmenopausal women; metastatic disease with an endocrine drug with or without a CDK4 and CDK6 inhibitor.
• Prostate cancer: androgen deprivation by a GnRH agonist or antagonist or by orchidectomy; add an antiandrogen or abiraterone for advanced disease; start an antiandrogen (bicalutamide 50 mg daily) 1 week before the first GnRH agonist injection to prevent tumour flare.
• Endometrial cancer and endometrial stromal sarcoma: progestogens and aromatase inhibitors.
• Castration target: testosterone under 50 ng/dL (1.7 nmol/L).
• Regional: tamoxifen, letrozole, anastrozole and bicalutamide are available as low-cost generics; surgical oophorectomy or orchidectomy are used when injectable suppression is unavailable.

Selection. Confirm oestrogen and progesterone receptor status (positive in 1 percent or more of cells) before treatment; use adherence support, since stopping early lowers survival.

Contraindications. Pregnancy; tamoxifen with previous venous thromboembolism or stroke (caution); aromatase inhibitors in premenopausal women without ovarian suppression; severe liver disease for abiraterone and antiandrogens.

Adverse effects. Hot flushes, vaginal dryness, bone loss and fractures, arthralgia (aromatase inhibitors), thromboembolism and endometrial cancer (tamoxifen), loss of libido and erectile dysfunction, gynaecomastia, metabolic syndrome, cardiovascular risk and reduced bone density (androgen deprivation), mineralocorticoid excess with hypertension, hypokalaemia and oedema (abiraterone), seizures and fatigue (enzalutamide), and hepatotoxicity.

Interactions. Paroxetine and fluoxetine inhibit CYP2D6 and reduce tamoxifen activation (use sertraline or venlafaxine instead); rifampicin and phenytoin lower abiraterone and enzalutamide exposure; warfarin effect rises with tamoxifen.

Special groups.

• Pregnancy: contraindicated; use non-hormonal contraception.
• Breastfeeding: avoid.
• Children: not used.
• Older adults: bone and cardiovascular risks need management.
• Kidney impairment: no adjustment for most.
• Liver impairment: reduce abiraterone and avoid in severe impairment.

Monitoring. Bone density at baseline and every 1 to 2 years with aromatase inhibitors and androgen deprivation, with calcium, vitamin D and a bisphosphonate where indicated; lipids and glucose; blood pressure and potassium with abiraterone; liver enzymes; PSA and testosterone in prostate cancer; and annual gynaecological assessment with tamoxifen for abnormal bleeding.

Referral and escalation. Postmenopausal bleeding on tamoxifen, leg swelling or chest pain (venous thromboembolism), spinal cord compression symptoms during a GnRH agonist flare, pathological fracture, and adrenal insufficiency on abiraterone need urgent assessment.