Breast cancer – Treatment Notes for key slides
Slide 1 No notes.
Slide 2 (see case study B and quiz) Cytological or histological confirmation (biopsy) is essential before surgery and histology is also vital after surgery to dictate treatment decisions status of cell surface markers e.g. oestrogen, progesterone and HER2. Surgery: Options are Mastectomy (obliterate the breast) or Lumpectomy (conserve the breast) – most popular. Adjuvant therapy follows surgery to prevent recurrence. Neo-adjuvant therapy is chemotherapy or hormonal therapy to shrink large tumours, facilitating more effective breast-conserving surgery. In primary operable breast cancer primary chemotherapy may facilitate successful breast conserving surgery instead of mastectomy. Current standard of care in most developed countries for early-stage breast cancer is breast conserving surgery, followed by 5-6 weeks post-op radiotherapy – high energy radiation used to eradicate breast cancer cells from a localised field of treatment e.g. breast, chest wall and loco-regional lymph nodes. (Veronesi U, et al. Lancet 2005; 365: 1727-41) Hormonal adjuvant therapy is offered to reduce risk of relapse in patients with endocrine-responsive disease. Aims to deprive tumour cells of the proliferative stimulus of oestrogen by: • Blocking the oestrogen receptor (tamoxifen) • Reducing circulating levels of oestrogenic compounds (either ovarian ablation, most commonly with a gonadotrophin releasing hormone analogue e.g. goserelin, in premenopausal women; or aromatase inhibitors, which block the synthesis of oestrogen, in post-menopausal women) Pre-menopausal women are usually offered tamoxifen with or without suppression of ovarian function. Postmenopausal women usually offered tamoxifen and increasingly aromatase inhibitors. Chemotherapy is offered to reduce risk of relapse in patients with endocrine-unresponsive breast cancer (no expression of both oestrogen and progestogen receptors). Some chemotherapy may also precede endocrine treatment in patients with endocrine-responsive disease who are at high risk of relapse e.g. grade III tumour, HER2-positive, multiple node involvement. Benefits are greater in younger women due to higher incidence of grade III and hormone receptor negative cancers.
Slide 3 (Reference on slide) Summarises recommendations on treatment.
Slide 4 (Reference on slide) Tamoxifen has antagonistic actions in breast cancers, but agonist actions on endometrium, lipids and bone. Side effects of tamoxifen • Venous thromboembolism • Hot flushes • Altered libido • Gastrointestinal upset • Vaginal discharge or dryness
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Menstrual disturbance Endometrial cancer (investigate any reported vaginal bleeding) Weight gain
Slide 5 (Reference on slide) Side effects of aromatase inhibitors • Hot flushes (less than tamoxifen) • Joint and muscle pains • Osteoporosis • Fatigue • Vaginal dryness
Slide 6 (Reference on slide) NICE guidance states: The aim of hormonal therapy is to deprive the tumour cells of the proliferative stimulus provided by oestrogen. This can be achieved by blocking the binding of oestrogen to its receptor in the nucleus of responsive cells, as with tamoxifen. In the UK, 5 years of tamoxifen therapy has become standard adjuvant hormonal treatment for post-menopausal women with early oestrogen-receptor-positive breast cancer. Tamoxifen also provides protection against bone fractures in postmenopausal women and it lowers serum cholesterol levels. However, long-term use of tamoxifen may be associated with vaginal bleeding, endometrial thickening, and increased risk of endometrial cancer and thromboembolic events. • • Aromatase inhibitors act by blocking the conversion of androgens to oestrogens in the peripheral tissues in post-menopausal women, thereby reducing the circulating levels of oestrogens. Because aromatase inhibitors reduce circulating oestrogen levels, a decrease in bone mineral density can be anticipated. SPC warning that women with osteoporosis, or at risk of osteoporosis, should have their bone mineral density formally assessed by bone densitometry at the beginning of treatment and, for anastrozole, at regular intervals thereafter. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and patients treated with an aromatase inhibitor should be carefully monitored. For early disease the recommended duration of treatment with anastrozole is 5 years. Treatment with exemestane should continue until completion of 5 years of combined sequential adjuvant hormonal therapy (tamoxifen followed by exemestane) or until tumour relapse occurs, whichever comes first. Adjuvant treatment with letrozole should continue for 5 years or until tumour relapse occurs, whichever comes first. Following standard adjuvant tamoxifen therapy, treatment with letrozole should continue for 3 years or until tumour relapse occurs, whichever comes first. There are important differences among the clinical trials and licensed indications with the different aromatase inhibitors, particularly in the timing of treatment with an aromatase inhibitor in relation to any previous treatment with tamoxifen. The Committee agreed that there is convincing evidence that all three aromatase inhibitors, within their respective licensed indications, provide clinical benefit over tamoxifen in primary adjuvant or unplanned switch treatment, and over placebo in extended adjuvant treatment. The Committee considered the differences between the clinical trials and agreed that there is insufficient evidence to conclude that any one aromatase inhibitor (used within the licensed indications) or treatment strategy is more clinically effective than another. Aromatase inhibitors are associated with increased fracture risk. They may also be associated with increased cardiovascular risk compared with tamoxifen, but there is still uncertainty about the longterm adverse effects because of the short follow-up in most of the studies. Tamoxifen, but not the aromatase inhibitors, is linked to an increased risk of endometrial cancer and other gynaecological conditions. The Committee considered all the evidence on cost effectiveness of aromatase inhibitors. They concluded that the incremental cost per QALY gained for aromatase inhibitors, compared with tamoxifen, was less than £20,000 for all treatment strategies. They concluded that the licensed strategies for the use of the aromatase inhibitors are cost effective when individually compared with tamoxifen, and that in extended adjuvant treatment letrozole is cost effective compared with placebo. The Committee considered the notion that for primary adjuvant treatment an aromatase inhibitor might be preferable to tamoxifen on the basis of cost effectiveness in women in whom the risk of early recurrence is particularly high. However, because of the lack of definitive evidence on the relative clinical and cost effectiveness of the use of the aromatase inhibitors in different risk groups, 2
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the Committee did not feel able to issue guidance on the relative cost effectiveness of the aromatase inhibitors for the different subgroups. The Committee noted that clarification on the definition of different risk groups, and potentially a consequent variation in treatment strategies, is likely to be reflected in the clinical guideline for early breast cancer currently under development at NICE. Finally, the Committee agreed that the choice of treatment should be made after discussion between the responsible clinician and the woman about the risks and benefits of the options available. It agreed that consideration of the treatment to be adopted should include whether the woman has received tamoxifen as part of her treatment so far, the licensed indications of the individual drugs, the side-effect profiles of the individual drugs and, in particular, the assessed risk of recurrence.
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Note the one-year cost of drugs
Tamoxifen 20mg daily £29.08 Anastrozole 1mg daily £891.28 Letrozole 2.5mg daily £1081.08 Exemestane 25mg daily £1080.40 If all new patients were to take anastrozole instead of tamoxifen, the annual increase in drug costs could be about £22,000/100,000 population. Initial use of letrozole instead of tamoxifen could involve an increase in costs of approximately £27,000/100,000 population per year. Some patients already taking tamoxifen may also switch to an aromatase inhibitor. SPC indications for anastrozole • Treatment of advanced breast cancer in post-menopausal women. Efficacy has not been demonstrated in oestrogen receptor negative patients unless they had a previous positive clinical response to tamoxifen. • Adjuvant treatment of post-menopausal women with hormone receptor positive early invasive breast cancer. • Adjuvant treatment of early breast cancer in hormone receptor positive post-menopausal women who have received 2 to 3 years of adjuvant tamoxifen. SPC indications for exemestane • Aromasin® is indicated for the adjuvant treatment of post-menopausal women with oestrogen receptor positive invasive early breast cancer, following 2–3 years of initial adjuvant tamoxifen therapy. • Aromasin® is indicated for the treatment of advanced breast cancer in women with natural or induced post-menopausal status whose disease has progressed following anti-oestrogen therapy. Efficacy has not been demonstrated in patients with oestrogen receptor negative status. SPC indications for letrozole • Adjuvant treatment of post-menopausal women with hormone receptor positive invasive early breast cancer. • Treatment of early invasive breast cancer in post-menopausal women who have received prior standard adjuvant tamoxifen therapy. • First-line treatment in post-menopausal women with advanced breast cancer. • Advanced breast cancer in post-menopausal women in whom tamoxifen or other anti-oestrogen therapy has failed. Pre-operative therapy in post-menopausal women with localised hormone receptor positive breast cancer, to allow subsequent breast-conserving surgery in women not originally considered candidates for breastconserving surgery. Subsequent treatment after surgery should be in accordance with standard of care.
Slide 7 (Reference on slide) Side effects of chemotherapy • Fatigue and lethargy • Alopecia (temporary) • Nausea and vomiting
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National Prescribing Centre. Anticipated NICE appraisal: Aromatase inhibitors. Planning ahead document. August 2006. Available at www.npc.nhs.uk/secure/planning_ahead/Aromatase_inhibitors.pdf
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Induction of menopause Risk of infection Oral mucositis Diarrhoea Weight gain Specific side effects of certain drugs
Slide 8 (References on slide) Note HER2-positive disease has a worse prognosis than HER2-negative disease. Trastuzumab reduces recurrence and mortality but does not abolish those outcomes. It also causes cardiac effects, mainly heart failure (and NB many patients will have received anthracyclines, which also cause heart damage). Cardiac function should be assessed prior to treatment, and trastuzumab should not be offered to women with: • LVEF of 55% or less • Transmural infarction on ECG • Angina requiring Rx • Poorly controlled hypertension • High risk uncontrolled arrythmias • Valvular disease (clinically significant) • History of CHF Cardiac functional assessments should be repeated every 3 months and trastuzumab stopped if LVEF drops by 10% from baseline AND to below 50%. Re use in early breast cancer, note the NICE comment: “The Committee accepted that trastuzumab had been shown to reduce the risk of recurrence of HER2-positive breast cancers. The Committee was concerned that the short-term follow-up of all the trials meant that there was only limited evidence about gains in overall survival, and whether trastuzumab reduced recurrences or delayed them. However, it heard from clinical specialists that the relationship between prevention of early recurrence and overall survival benefit seen in clinical trials with other breast cancer drugs could be extrapolated to the patient group eligible for trastuzumab. It also heard from clinical specialists that, on this basis, breast cancer recurrence was likely to be reduced rather than delayed. The Committee therefore accepted that measures of disease-free survival could be used as a surrogate for overall survival.” Slide 9 No notes.
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