Hormone Therapy in Malignancy

Hormone Therapy in Malignancy Discuss the principles, agents, indications and adverse effects of hormone therapy in malignancy, with emphasis on the older patient. (15 marks)

The governing statement. A number of cancers prevalent in the elderly, including breast cancer and prostate cancer, are hormonally responsive. Medications aimed at blocking these hormonal pathways can result in the prevention of recurrence or prolongation of survival.

Why hormone therapy is the geriatrician's most valuable oncological tool. It is oral or depot, non-myelosuppressive, does not cause alopecia, and is given in the outpatient setting. It does not require the marrow reserve that cytotoxic chemotherapy demands. Its toxicity is not acute but cumulative and metabolic — falling on bone, muscle, blood vessel and brain, which is precisely why it needs geriatric supervision.

Five mechanisms of hormonal manipulation. Block synthesis (aromatase inhibitors, abiraterone); block the receptor (tamoxifen, bicalutamide, enzalutamide); degrade the receptor (fulvestrant, elacestrant, imlunestrant); suppress the pituitary–gonadal axis (GnRH agonists and antagonists); and ablate the gland (orchidectomy, oophorectomy — now largely historical).

Tamoxifen. This selective oestrogen receptor modulator reduces the risk of recurrence by 40% and the risk of breast cancer mortality by 31% after primary treatment of oestrogen receptor positive breast cancer. It is an antagonist in the breast but an agonist in bone and endometrium — which is why it protects bone but causes endometrial hyperplasia and carcinoma.

The CYP2D6–paroxetine interaction — a classic examination point. Tamoxifen is converted by cytochrome P450 2D6 into the more potent anti-oestrogen endoxifen. Women who receive the potent 2D6 inhibitor paroxetine together with tamoxifen are at increased risk of death from breast cancer, because less tamoxifen is converted to the active form. This interaction is not seen with other SSRIs. The practical rule: never prescribe paroxetine, fluoxetine or bupropion with tamoxifen — use venlafaxine, citalopram or escitalopram for hot flushes or depression.

Aromatase inhibitors. In postmenopausal women, letrozole, anastrozole and exemestane are the preferred anti-oestrogen therapy. They block the conversion of adrenal androgens to oestrogens by the enzyme aromatase. NICE recommends an aromatase inhibitor in postmenopausal women at medium or high risk of recurrence, reserving tamoxifen for low risk, or where an aromatase inhibitor is contraindicated or not tolerated. Aromatase inhibitors cause arthralgia and increase the risk of osteoporosis. They work only in postmenopausal women.

The comparative toxicity table — memorise this.

Adherence is the hidden problem in the elderly. One-quarter of women are incompletely adherent to their adjuvant hormonal regimen, and older age and an increasing number of co-medications are independent risk factors for non-adherence. An unswallowed tablet has zero efficacy, so adherence must be asked about at every visit rather than assumed.

Duration and extended therapy. Distant recurrences continue at a steady rate for at least 15 years after stopping 5 years of endocrine therapy. The ATLAS trial showed that continuing tamoxifen to 10 rather than 5 years reduced recurrence (RR 0.84) and overall mortality (639 versus 722 deaths). NICE and SIOG therefore recommend considering extension with an aromatase inhibitor after 5 years of tamoxifen, discussing the continuing risk of menopausal symptoms, bone density loss and musculoskeletal pain.

Primary endocrine therapy is not a substitute for surgery. In the Cancer Research UK trial in women over 70, the 5-year risk of local progression was 8% after mastectomy, 18% after breast conservation, but 64% with tamoxifen alone; 10-year survival was 37.7% with surgery plus tamoxifen versus 28.8% with tamoxifen alone. Primary endocrine therapy should only be offered to women with ER-positive tumours who are unfit for or refuse surgery.

Principle. Testosterone fuels prostate cancer growth, so androgen deprivation therapy is the cornerstone of first-line therapy for metastatic prostate cancer, although over time the cancer becomes insensitive to anti-androgen therapy. Surgical castration was used historically; medical castration is now preferred. The castrate level is testosterone below 50 ng/dL.

GnRH agonists and the tumour flare — the most important practical point. The agonists leuprolide and goserelin initially cause release of FSH and LH with a rise in serum testosterone before suppressing gonadotropin secretion. That initial surge may cause increased pain from bone metastases, urinary obstruction, or spinal cord compression if it is already impending. The flare is prevented by giving an androgen receptor antagonist for two weeks before starting the GnRH agonist. In a man with vertebral metastases, omitting this step can cause paraplegia.

Antagonists and receptor blockers. The GnRH antagonist degarelix causes rapid suppression of testosterone without a flare. Androgen receptor antagonists — bicalutamide, flutamide and nilutamide — were traditionally added after failure of first-line androgen deprivation.

Immediate side effects. Hot flushes, erectile dysfunction, gynaecomastia and anaemia, with an increased risk of osteoporosis.

The four long-term geriatric harms of androgen deprivation. Bone — bone loss is 1–4.6% per year on androgen deprivation, with fracture risk increasing by up to 45% over the long term. Seek osteoporosis risk factors (family history, low weight, previous fracture, alcohol, smoking, glucocorticoids, low vitamin D) and prescribe calcium and vitamin D. Bisphosphonates are not recommended routinely — only in established osteoporosis. Muscle — hormone therapy causes an increase in fat mass and sarcopenia, which in the elderly leads to loss of autonomy, falls and fractures. Metabolic and cardiovascular — altered lipid profile, increased insulin resistance and diabetes, and increased prevalence of metabolic syndrome, with increased cardiovascular risk demonstrated in RTOG 92-02. Cognitive — executive cognitive impairment, alongside documented deficits in physical performance and increased falls. Prevention is explicit: modification of diet and lifestyle — walking, an adapted diet and smoking cessation — is needed to reduce the metabolic and cardiovascular impact of hormone therapy.

Endometrial carcinoma. High-dose progestins (medroxyprogesterone acetate, megestrol acetate) and increasingly aromatase inhibitors are used in low-grade, receptor-positive advanced or recurrent disease. This is a well-suited option for the frail older woman who cannot tolerate chemotherapy.

Differentiated thyroid carcinoma. TSH suppression with levothyroxine after thyroidectomy removes the growth stimulus to residual thyroid tissue. In the elderly this must be risk-adapted, because over-suppression causes atrial fibrillation, osteoporosis and heart failure.

Cancer cachexia. Megestrol acetate and medroxyprogesterone improve appetite and weight, but the weight gained is largely fat rather than muscle, they carry a thromboembolic risk, and they do not improve survival.

Two cautions on hormones that cause malignancy. HRT and breast cancer (Million Women Study, 1,084,110 women) — current users had RR 1.66; the risk was highest for combined oestrogen plus progestogen (RR 2.0), then oestrogen alone (RR 1.3) and tibolone (RR 1.45), with a dose–response relationship rising to RR 2.31 after 10 or more years. Some excess risk persisted for more than 10 years after stopping. Testosterone replacement — the effects of long-term replacement on benign prostatic hypertrophy and prostate cancer remain unclear. It is contraindicated in known prostate carcinoma, and supplementation may increase cardiovascular events in those aged 65 and above, especially during the first year. Monitoring of prostate size, PSA and haematocrit is mandatory.

A checklist before starting any endocrine therapy in an older patient. Before an aromatase inhibitor: DEXA and FRAX; calcium (mg/dL) and vitamin D (ng/mL) with supplementation; lipid profile (mg/dL); baseline joint symptoms. Before tamoxifen: history of venous thromboembolism, stroke, cataract or abnormal vaginal bleeding; screen the drug chart for CYP2D6 inhibitors. Before androgen deprivation: DEXA, falls and fracture history; calcium and vitamin D routinely; lipids, fasting glucose or HbA1c, blood pressure and ECG; baseline cognition (Mini-Cog), gait and grip strength. The five rules. (1) Confirm receptor status before prescribing — older women are three times more likely to have receptor testing omitted. (2) Never start a GnRH agonist in a man with impending cord compression without two weeks of anti-androgen cover. (3) Never combine tamoxifen with paroxetine. (4) Every patient on an aromatase inhibitor or androgen deprivation needs calcium, vitamin D and a bone-density plan. (5) Hormone therapy replaces chemotherapy in the frail — it does not replace surgery in the fit.