Letrozole: a review of its use in postmenopausal women with breast cancer

Letrozole (Femara), a nonsteroidal, third-generation aromatase inhibitor administered orally once daily, has shown efficacy in the treatment of postmenopausal women with early-stage or advanced, hormone-sensitive breast cancer. In early-stage disease, extending adjuvant endocrine therapy with letrozole (beyond the standard 5-year period of tamoxifen) improved disease-free survival; compared with placebo there was a 43% relative reduction in disease recurrences or new contralateral breast tumours at a median follow-up of 2.4 years. The results of 4 months' neoadjuvant treatment with letrozole or tamoxifen in postmenopausal women with untreated primary disease favour letrozole. In advanced breast cancer, letrozole was superior to tamoxifen as first-line treatment; time to disease progression was significantly longer (9.4 vs 6.0 months, p < 0.0001) and objective response rate was significantly greater with letrozole, but median overall survival was similar between groups. For second-line therapy of advanced breast cancer that had progressed on antiestrogen therapy, letrozole showed efficacy equivalent to that of anastrozole and similar to or better than that of megestrol acetate. Letrozole is generally well tolerated and has a similar tolerability profile to tamoxifen; the most common treatment-related adverse events were hot flushes, nausea and hair thinning. In patients with tumours that had progressed on antiestrogen therapy, letrozole was tolerated as least as well as, or better than, anastrozole or megestrol acetate. In the trial of extended adjuvant therapy, adverse events reported more frequently with letrozole than placebo were hot flushes, arthralgia, myalgia and arthritis. The long-term effects of letrozole on bone mineral density or lipid profile have not been determined and these parameters may require monitoring. In several pharmacoeconomic modelling studies from various public healthcare system perspectives, letrozole was considered a cost effective choice for first-line (vs tamoxifen) or second-line (vs megestrol acetate) treatment for advanced breast cancer in postmenopausal women. In conclusion, letrozole 2.5 mg/day is effective in the treatment of postmenopausal women with early-stage or advanced breast cancer. The efficacy, cost effectiveness and favourable tolerability profile of letrozole are reflected in current treatment guidelines recommending the drug as first-line therapy for advanced breast cancer. Letrozole is superior to tamoxifen for first-line treatment and is at least as effective as standard second-line treatments in disease that has progressed on antiestrogen therapy. For early-stage disease, letrozole is superior to tamoxifen in the neoadjuvant setting, and prolongs disease-free survival when administered after the standard 5-year period of adjuvant tamoxifen therapy.     

Letrozole: a pharmacoeconomic review of its use in postmenopausal women with breast cancer

Letrozole (Femara), an aromatase inhibitor that blocks estrogen synthesis by inhibiting the final step of the estrogen biosynthetic pathway, is approved for use in a wide range of breast cancer settings. Randomised clinical trials in postmenopausal women with hormone-responsive early-stage breast cancer have demonstrated that, as adjuvant therapy, letrozole has greater efficacy than tamoxifen. It is also more effective than placebo as extended adjuvant therapy after completion of tamoxifen therapy in these patients. In women with hormone-responsive advanced breast cancer, letrozole is superior to tamoxifen in prolonging the time to disease progression and time to treatment failure in a first-line setting, and is at least as effective as anastrozole and more effective than megestrol for some endpoints (in one of two trials) in a second-line setting. Letrozole is generally well tolerated, and in a health-related quality-of-life analysis from a large clinical trial, patient well-being with letrozole as extended adjuvant therapy did not differ from that with placebo. Modelled analyses from the UK and the US suggest that, in postmenopausal women with hormone-receptor-positive early-stage breast cancer, letrozole is likely to be a cost-effective alternative to tamoxifen as adjuvant therapy; moreover, using letrozole as extended adjuvant therapy after tamoxifen, rather than no further treatment, is also a cost-effective treatment strategy. Sensitivity analyses have shown these results to be robust. In terms of direct healthcare costs, pharmacoeconomic models suggest that letrozole is a cost-effective alternative to tamoxifen as first-line therapy in postmenopausal women with hormone-responsive advanced breast cancer from the perspectives of the UK NHS, the Canadian and Italian public healthcare systems and the Japanese national health insurance system. Incremental costs per QALY or progression-free year gained over tamoxifen were well within the recommended limits for acceptability of new agents that are more effective and more expensive than existing therapies in the UK, Japan and Canada. Modelled analyses from the UK and Canada have also suggested that letrozole is cost effective as second-line therapy for advanced breast cancer in postmenopausal women who have disease progression following anti-estrogen therapy. In conclusion, letrozole is an effective and well tolerated treatment for postmenopausal women with early-stage or advanced hormone-responsive breast cancer. Pharmacoeconomic analyses from UK and North American perspectives support the use of letrozole in hormone-responsive early-stage breast cancer in both the adjuvant and extended adjuvant settings. In addition, other modelled analyses conducted in a variety of healthcare systems across different countries consistently suggest that letrozole is cost effective in advanced treatment settings.     

Exemestane: a review of its use in postmenopausal women with advanced breast cancer

Exemestane is an orally active irreversible steroidal aromatase inactivator that effectively suppresses in vivo aromatase activity and circulating estrogen levels in postmenopausal women with advanced breast cancer. In clinical trials, tumour responses were elicited by exemestane regardless of disease site, importantly, in patients with visceral disease. In patients with disease refractory to tamoxifen, once daily exemestane 25 mg produced objective response rates of 15 to 28% that were sustained for a median duration of 69 to 76 weeks. In a large comparative study, exemestane and megestrol showed similar clinical efficacy according to objective response and overall success rates. However, the duration of overall success and times to disease progression and treatment failure were significantly prolonged with exemestane compared with megestrol. Additionally, a significant survival advantage for exemestane over megestrol was reported. Exemestane retains efficacy in patients refractory to multiple hormonal therapies. In patients whose disease had progressed after tamoxifen and megestrol, objective response rates of 11 and 13% were reported, and responses were similar regardless of whether megestrol resistance was de novo or acquired. Objective responses also occurred in studies that explored sequential use of exemestane after failure of aminoglutethimide (26% with exemestane 200 mg/day) or other nonsteroidal aromatase inhibitors (6.6% with exemestane 25 mg/day). Additionally, tumour responses (objective response 6.1%, overall success rate 24.7%) were reported in patients who had not responded to their last hormonal treatment. As first-line treatment, once daily exemestane 25 mg elicited objective and overall success rates of 42 and 58%, compared with 16 and 31% for once daily tamoxifen 20 mg. Exemestane was generally well tolerated in clinical trials at once daily dosages up to 600 mg. At the 25 mg recommended once daily dosage, the most commonly occurring adverse events were nausea, hot flushes, fatigue, increased sweating and dizziness. Weight gain occurred in significantly more patients receiving megestrol than among those treated with exemestane. Androgenic events have been reported in a small number of patients receiving once daily exemestane 200 mg, but were rarely reported at the recommended dosage. Conclusions: Exemestane is effective in postmenopausal patients with tamoxifen-refractory advanced breast cancer, prolonging time to disease progression and treatment failure and improving survival compared with megestrol treatment. Moreover, exemestane has an acceptable tolerability profile and a convenient once daily oral dosage regimen. Available data indicate that exemestane maintains its efficacy in patients with visceral metastases and does not show cross-resistance with nonsteroidal aromatase inhibitors. Preliminary data indicate that exemestane is also effective as first-line therapy for advanced breast cancer.     

Fulvestrant: a review of its use in the management of hormone receptor-positive metastatic breast cancer in postmenopausal women

Fulvestrant (Faslodex?) is an intramuscularly administered steroidal estrogen receptor antagonist that is devoid of any known estrogen agonist effects. It is indicated as second-line therapy for the treatment of postmenopausal women with hormone receptor-positive advanced breast cancer who have progressed following prior endocrine therapy. In well designed, randomized clinical trials, regimens of fulvestrant 250 and 500 mg provided effective second-line therapy for postmenopausal women with advanced breast cancer who had progressed following prior endocrine therapy. Moreover, fulvestrant 250 mg monthly (with or without a loading dose) was as effective as aromatase inhibitor therapy. However, fulvestrant is absorbed slowly, and greater steady-state concentrations are achieved more rapidly when using a higher dosage with a loading dose regimen. Consequently, a regimen of fulvestrant 500 mg monthly with a loading dose was significantly more effective than a regimen of 250 mg monthly in postmenopausal women with disease progression. Limited data also indicate a potential role for the fulvestrant 500 mg regimen as first-line therapy. Fulvestrant is generally well tolerated with no additional adverse events noted with the high-dose regimen compared with the 250 mg regimens. Furthermore, the incidence of joint disorders was shown to be significantly lower with fulvestrant 250 mg monthly than with anastrozole. Treatment with fulvestrant is not associated with any clinically significant effects on endometrial thickening, bone-specific turnover markers or sex hormone levels. In conclusion, a monthly regimen of intramuscular fulvestrant 500 mg with a loading dose provides effective and well tolerated second-line therapy for postmenopausal women with advanced breast cancer who have progressed following prior endocrine therapy and is now the approved optimal dose.     

Exemestane in postmenopausal women with early or advanced breast cancer: a review

Importance of the field: Inhibition of the aromatase enzyme in postmenopausal women reduces levels of estrogens, which is of therapeutic value in hormone-sensitive breast cancer. Exemestane is a third-generation steroidal irreversible inactivator of the aromatase enzyme used in early and advanced breast cancer for the treatment of postmenopausal women with estrogen-receptor-positive disease.

Areas covered in this review: The scientific literature on exemestane, including published articles and abstracts, was searched from 1988 to the present, and the most significant results are included in the review.

What the reader will gain: The review outlines the pharmacological characteristics of exemestane and the evidence supporting its use in the treatment of postmenopausal women with early or advanced estrogen-receptor-positive breast cancer.

Take home message: Exemestane is an effective and well-tolerated aromatase inhibitor with a defined role in early-stage breast cancer following 2 – 3 years of adjuvant treatment with tamoxifen. Exemestane also has a role in the sequence of hormonal agents employed to control advanced hormone-sensitive breast cancer, in which clinicians may exploit its partial lack of cross-resistance with nonsteroidal aromatase inhibitors.     

Letrozole : in postmenopausal hormone-responsive early-stage breast cancer

Letrozole is a highly selective, nonsteroidal, third-generation aromatase inhibitor approved for first-line and extended adjuvant therapy in postmenopausal women with hormone-responsive, early-stage breast cancer. Binding of letrozole to the haeme component of the cytochrome P450 subunit of aromatase inhibits estrogen biosynthesis throughout the body. As first-line adjuvant therapy in approximate, equals 8000 postmenopausal women with hormone-responsive, early-stage breast cancer, once-daily letrozole 2.5mg significantly prolonged disease-free survival (DFS; primary endpoint) and reduced the risk of relapse at distant sites relative to once-daily tamoxifen 20mg in the ongoing Breast International Group 1-98, double-blind, multinational trial. The median duration of follow-up for this primary core analysis was 25.8 months. Extended adjuvant therapy with once-daily letrozole 2.5mg significantly prolonged DFS relative to placebo treatment at a median follow-up of 30 months (primary endpoint) in the MA-17 trial in approximate, equals 5000 postmenopausal women who were disease free after 4.5-6 years of tamoxifen therapy for hormone-responsive, early-stage breast cancer. Letrozole treatment for up to 5 years was generally well tolerated in this clinical setting. As first-line treatment, relative to tamoxifen, letrozole was associated with a significantly lower incidence of venous thromboembolitic events, vaginal bleeding, hot flushes and night sweating, whereas the incidence of cardiac failure, bone fractures and arthralgia was higher in letrozole recipients.     

Cost effectiveness of letrozole versus anastrozole in postmenopausal women with HR+ early-stage breast cancer

Abstract

Background:

The Breast International Group (BIG) 1-98 and Arimidex, Tamoxifen Alone or in Combination (ATAC) trials demonstrated that, in postmenopausal women with hormone receptor positive (HR+) early-stage breast cancer, 5 years of initial adjuvant endocrine therapy with letrozole or anastrozole is superior to tamoxifen. With expected generic availability of anastrozole in July 2010 and letrozole in June 2011, there may be financial pressures prior to letrozole's generic availability to start treatment-naïve patients on anastrozole vs. letrozole or to switch patients already receiving letrozole to anastrozole.     

Adjuvant use of aromatase inhibitors in postmenopausal women with breast cancer.

PURPOSE: Emerging data from clinical trials on the use of aromatase inhibitors in the management of early-stage, hormone-dependent breast cancer in postmenopausal women are reviewed. SUMMARY: Aromatase is the enzyme responsible for the conversion of androgens to estrogens and the only source of estrogens in postmenopausal women. Clinical trials using aromatase inhibitors in the adjuvant treatment of postmenopausal women with breast cancer are few but significant because of their comparative design with tamoxifen given for five years, long regarded as the gold standard for breast cancer treatment. Data from the Anastrozole, Tamoxifen and Combination trial, the MA-17 trial (letrozole compared with placebo), the Italian Tamoxifen Arimidex trial (anastrozole following tamoxifen), and the Intergroup Exemestane Study have shown promising efficacy and safety in the use of these agents. While the optimal aromatase inhibitor for use in the adjuvant setting has not been elucidated, current evidence-based recommendations include using (1) anastrozole as the first adjuvant therapy for five years, (2) tamoxifen for two to three years, then exemestane or anastrozole for the remainder of the five years, and (3) tamoxifen for five years, then letrozole for another five years. CONCLUSION: While their impact on survival has not been determined, aromatase inhibitors are slowly changing the management of early-stage, hormone-dependent breast cancer in postmenopausal women because of improved disease-free survival rates. Their ultimate role in therapy is unknown, but educating patients about the potential risks and benefits will allow them to make informed decisions regarding these data and their breast cancer care.     

Aromatase inhibitors: a new reality for the adjuvant endocrine treatment of early-stage breast cancer in postmenopausal women

Tamoxifen, a selective estrogen receptor modulator (SERM), has been used for many decades as the "gold standard" adjuvant treatment for patients with hormone-receptor-positive early breast cancer. This drug, when administered for 5 years, reduces the risk for recurrence, contralateral breast cancer (BC) and death. The optimal duration of tamoxifen in the adjuvant setting has not been established yet, but it has been demonstrated that 5 years are better than shorter treatment while it is still unclear if a prolongation of the treatment for more than 5 years is worthwhile. In the last few years, third generation aromatase inhibitors (AIs), either steroidal (exemestane) or non-steroidal (anastrozole, letrozole), have shown to be an effective alternative to tamoxifen in postmenopausal patients with BC regardless of its stage. These agents act by blocking the aromatase enzyme which converts androgens into estrogens. The goal of this article was to review the results of recent randomized trials comparing AIs to tamoxifen in postmenopausal women in the adjuvant setting. Two strategies have been utilized: a direct upfront comparison in which both tamoxifen and AIs were given for 5 years or an early switch in which AIs were administered after 2-3 years of tamoxifen for 3-2 years or vice versa. Both strategies have shown a superiority of AIs over tamoxifen and a different safety profile but, the optimal treatment modality has yet to be defined. Moreover, in an attempt to further reduce patients' risk of recurrence after the administration of tamoxifen for 5 years, three trials have evaluated the role of prolonging the adjuvant treatment with AIs for 5 more years in comparison to placebo (late switch). A significant improvement of disease-free survival and of overall survival in the subgroup of node-positive patients, at least in one trial, has been observed with AIs. Despite these important results several unanswered questions remain and the results of ongoing trials will hopefully clarify some of them.     

Trastuzumab: a review of its use in the management of HER2-positive metastatic and early-stage breast cancer

Trastuzumab (Herceptin) is a humanised monoclonal antibody used in the treatment of breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2), which is associated with clinically aggressive disease and a poor prognosis. The addition of intravenous trastuzumab to first-line chemotherapy improved the time to disease progression, objective response rate, duration of response, and overall survival in randomised, multicentre trials in women with HER2-positive metastatic breast cancer. As such, trastuzumab has become the standard of care in this setting, despite its high acquisition cost and potential for cardiac events, and is licensed for use in combination with paclitaxel (Europe and the US) or docetaxel (Europe). In addition, trastuzumab monotherapy is approved for use in patients with HER2-positive metastatic breast cancer who have previously received chemotherapy for their metastatic disease. Recent data from large phase III trials with trastuzumab in the adjuvant setting revealed significant improvements in disease-free and overall survival. Thus, trastuzumab is also rapidly becoming a standard component of adjuvant therapy for patients with HER2-positive early-stage breast cancer.     

Anastrozole: in early breast cancer

Anastrozole, a nonsteroidal selective aromatase inhibitor, has recently been approved in the US and several other countries for the adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer. In the Arimidex, Tamoxifen alone or in Combination (ATAC) trial, anastrazole 1mg was significantly more effective than tamoxifen 20mg or combined treatment (17 and 19% relative risk reduction) for disease-free survival in postmenopausal women with early breast cancer. black triangle Anastrazole was also significantly more effective than tamoxifen for time to tumour recurrence and the odds of a primary contralateral tumour as a first event. During the first 2 years of treatment with anastrozole, tamoxifen or the combination, patient quality of life was similar in all treatment groups. Compared with tamoxifen, anastrozole was associated with a significantly lower incidence of vaginal bleeding, vaginal discharge, hot flushes, endometrial cancer, ischaemic cerebrovascular events, venous thromboembolic events and deep vein thrombosis including pulmonary embolism; tamoxifen was associated with a lower incidence of musculoskeletal disorders and fracture.     

Clodronate: a review of its use in breast cancer.

Like other members of its class, the bisphosphonate clodronate (clodronic acid) inhibits bone resorption. The efficacy of oral clodronate 1600 mg/day in reducing the incidence of skeletal complications and metastasis development has been assessed in several clinical trials in patients with breast cancer. Long term use of oral clodronate significantly reduced the total cumulative incidence of skeletal events (including fractures, hypercalcaemia, and the need for radiotherapy for bone pain) compared with that in placebo recipients in 2 randomised double-blind placebo-controlled studies, each involving >100 patients. Significant differences in favour of clodronate were also seen in the frequency of some individual skeletal events in 1 trial. A nonblind trial in 302 patients considered to be at high risk of developing metastases found that, at a 3-year follow-up, significantly fewer patients who received clodronate for 2 years developed skeletal metastases than those in a control group. Clodronate recipients were also significantly less likely than controls to develop visceral metastases, and had significantly higher survival rates. A smaller double-blind placebo-controlled study in women with recurrent breast cancer found that clodronate significantly decreased the total number of new skeletal metastases, but not the number of patients who developed them. In a nonblind trial in 299 patients with node-positive breast cancer, however, the incidence of skeletal metastases did not differ significantly between patients who received clodronate for 3 years and those in a control group. In addition, clodronate recipients had a significantly greater incidence of nonskeletal metastases (local and visceral), and significantly lower survival rates. Intravenous or oral clodronate has been well tolerated in clinical trials. The most common adverse effects reported were mild gastrointestinal disturbances such as nausea, vomiting and diarrhoea. All these events were transient, and usually resolved without stopping treatment. Conclusions: Clodronate is a well tolerated bisphosphonate, available in both oral and intravenous forms, that significantly reduces the incidence of skeletal complications associated with breast cancer. Further research is needed to establish more clearly its efficacy in reducing metastasis development, to assess its efficacy compared with other bisphosphonates, and to determine which patients will benefit most from treatment. Currently, clodronate is probably most effective in the treatment and prevention of general skeletal complications in patients with breast cancer.     

Docetaxel: a review of its use in metastatic breast cancer

Docetaxel (Taxotere), a cytotoxic taxane, is an antimicrotubule agent effective in the treatment of patients with breast cancer. The clinical profile of docetaxel as an effective cytotoxic agent in the treatment of metastatic breast cancer is well established. As yet, no single standard regimen has been identified as optimal for the treatment of patients with metastatic breast cancer after failure of prior chemotherapy. However, the efficacy of docetaxel monotherapy administered every 3 weeks as a 1-hour infusion is similar to or better than that of doxorubicin, paclitaxel and fluorouracil plus vinorelbine, and better than that of methotrexate plus fluorouracil or mitomycin plus vinblastine. Although docetaxel is associated with neutropenia and other adverse events, its overall tolerability profile is generally acceptable in the majority of patients. Docetaxel, therefore, is an effective option in the treatment of patients with metastatic breast cancer after failure of prior chemotherapy.     

Estrogen receptor modulators and down regulators: optimal use in postmenopausal women with breast cancer

Endocrine treatments have been used in breast cancer since 1896, when Beatson reported on the results of oophorectomy for advanced breast cancer. In the second half of the last century, different endocrine-based compounds were developed and, in this review, the role of the selective estrogen receptor modulators (SERMs) and selective estrogen receptor down regulators (SERDs) in the postmenopausal setting are discussed. Tamoxifen is the most investigated and most widely used representative of these agents, and has been introduced in the advanced disease, in the neoadjuvant and adjuvant setting, and for the prevention of the disease. Its role has been challenged in recent years by the introduction of third-generation aromatase inhibitors that have proven higher activities than tamoxifen with different toxicity patterns. Several other SERMs have been investigated, but none have been clearly superior to tamoxifen. SERDs act as pure estrogen antagonists and should compare favourably to tamoxifen. For the time being, they have been used in the treatment of advanced breast cancers and their role in other settings still needs investigation. The increased use of aromatase inhibitors as first-line endocrine therapy has resulted in new discussions regarding the role that tamoxifen and other SERMs or SERDs may play in breast cancer. The sequencing of endocrine therapies in hormone-sensitive breast cancer remains a very important research issue.     

Raloxifene: a review of its use in postmenopausal osteoporosis

Raloxifene is a selective estrogen receptor modulator that partially mimics the effects of estrogens in bone and the cardiovascular system, while functioning as an antiestrogen in endometrial and breast tissue. In randomised placebo-controlled studies involving postmenopausal women or patients with osteoporosis, raloxifene 60 to 150 mg/day was effective in increasing bone mineral density (BMD) over 12- to 36-month periods. At the 60 mg/day recommended dosage, increases of 1.6 to 3.4%, 0.9 to 2.3% and 1.0 to 1.6% were reported in lumbar spine, femoral neck and total hip, respectively, versus < or =0.5% with placebo. Raloxifene 60 or 120 mg/day decreased the risk of vertebral fractures over a 36-month period in postmenopausal patients with osteoporosis. Significant reductions in radiographic fracture risk versus placebo (30 and 50%) occurred regardless of whether patients had existing fractures at baseline. Although raloxifene did not affect the overall incidence of nonvertebral fractures, a reduction in the incidence of ankle fracture was reported in comparison with placebo. In postmenopausal women, raloxifene 60 mg/day significantly reduced serum levels of total and low density lipoprotein cholesterol from baseline, compared with placebo. High density lipoprotein cholesterol and triglyceride levels were unaffected. Raloxifene 60 or 120 mg/day reduced the risk of invasive breast cancer by 76% during a median of 40 months' follow-up in postmenopausal patients with osteoporosis and no history of breast cancer. A relative risk reduction of 90% was reported for estrogen-receptor positive invasive breast cancers; estrogen-receptor negative cancer risk was unaffected by raloxifene. Raloxifene was generally well tolerated in clinical trials at dosages up to 150 mg/day. Adverse events thought to be related to raloxifene treatment were hot flushes and leg cramps. Venous thromboembolism was the only serious adverse event thought to be related to raloxifene treatment and a relative risk of 3.1 compared with placebo treatment was reported in patients with osteoporosis. Vaginal bleeding occurred in < or =6.4% of raloxifene-treated women but was reported by 50 to 88% of those receiving estrogens or hormone replacement therapy (HRT). Raloxifene treatment was not associated with stimulatory effects on the endometrium. CONCLUSIONS: Raloxifene significantly increases BMD in postmenopausal women and reduces vertebral fracture risk in patients with osteoporosis. In clinical trials, raloxifene was generally well tolerated compared with placebo and HRT, although its propensity to cause hot flushes precludes use in women with vasomotor symptoms. In particular, the lack of stimulatory effects on the endometrium and the reduction in invasive breast cancer incidence indicate raloxifene as an attractive alternative to HRT for the management of postmenopausal osteonorosis.     

Trastuzumab: a pharmacoeconomic review of its use in early breast cancer

Trastuzumab (Herceptin) is a monoclonal antibody approved for the treatment of breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2). Well designed clinical trials in women with early breast cancer have demonstrated that 1 years' therapy with adjuvant intravenous trastuzumab (a loading dose followed by 6 mg/kg every 3 weeks or 2 mg/kg weekly) significantly improves disease-free survival and overall survival compared with observation (subsequent to chemotherapy) or chemotherapy alone in women with HER2-positive disease. In the HERA trial, disease-free survival was estimated to improve by 6.3% at 3 years in the trastuzumab group compared with the observation group. Trastuzumab is generally well tolerated. The most common adverse events are infusion-related symptoms, such as fever and chills, which usually occur with administration of the first dose. Cardiotoxicity occurs in a small proportion of patients receiving trastuzumab, particularly when coadministered with anthracyclines, and cardiac assessment is recommended for all patients at baseline and at 3-monthly intervals. In modelled cost-effectiveness analyses based on data from clinical trials in patients with HER2-positive early breast cancer, adjuvant trastuzumab was predicted to be cost effective from a healthcare payer or societal perspective in several countries. Incremental costs per QALY or life-year gained with trastuzumab administered subsequent to or concurrent with chemotherapy compared with chemotherapy alone were consistently within accepted local thresholds for cost effectiveness. Sensitivity analyses demonstrated that these results remained generally robust to plausible changes in key model assumptions. In conclusion, in patients with HER2-positive early breast cancer, the addition of adjuvant trastuzumab is clinically effective in improving disease-free survival. Available pharmacoeconomic data from several countries, despite some inherent limitations, support the use of adjuvant trastuzumab for 1 year as a cost-effective treatment relative to chemotherapy alone in this patient population.     

Tamoxifen: a review of pharmacoeconomic and quality-of-life considerations for its use as adjuvant therapy in women with breast cancer

Extensive clinical experience, summarised in the recent overview of the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), have confirmed that tamoxifen reduces the rate of both disease recurrence and mortality when administered as adjuvant therapy in women with early breast cancer. Tamoxifen is now established as the preferred adjuvant agent in postmenopausal women; in particular, patients with node-positive, estrogen receptor-positive breast cancer have the most to gain from tamoxifen therapy. Data from a decision-analysis model indicated that tamoxifen monotherapy had a cost-utility ration {$US6000 per additional quality-adjusted life-year (QALY), in 1989 dollars} 5 to 6 times lower than that cited as the cost-acceptability cut-off point in the US. While tamoxifen monotherapy is effective in postmenopausal women, the EBCTCG overview findings indicate that a combined regimen of tamoxifen and antineoplastic chemotherapy has superior efficacy in the same patient group. An issue of current interest is whether the added benefit offered by such a regimen can be justified in terms of added toxicity and cost. Data from a decision-analysis model indicate that combined therapy has a high incremental cost-utility ratio ($US58 000 per additional QALY, in 1989 dollars) compared with no therapy in postmenopausal women. However, the quality-of-life measures TWiST (Time Without Symptoms and Toxicity) and Q-TWiST (quality-adjusted TWiST) indicate that the early toxicity associated with a combined regimen appears to be justified given the superior long term benefits. Patient preference data from 1 study further indicate that the degree of benefit offered by a combined regimen would be acceptable to the majority (73%) of patients. Other areas where pharmacoeconomic analyses may help define more closely the optimal use of adjuvant tamoxifen is in patients at low risk of developing metastatic disease and in determining the optimal duration of therapy. Both areas require further clinical data. In conclusion, tamoxifen adjuvant monotherapy has a low cost-utility ratio in postmenopausal women with node-positive, estrogen receptor-positive breast cancer. Combined therapy in the same patient group has a high cost-utility ratio compared with no therapy but quality-of-life and patient preference data suggest that the costs may be justified. Firm conclusions relating to the use of the drug in other patient subgroups and the optimal duration of therapy await further research.     

Goserelin: a review of its use in the treatment of early breast cancer in premenopausal and perimenopausal women

Goserelin (Zoladex), a gonadotropin-releasing hormone analogue, reduces plasma/serum estrogen levels in pre- or perimenopausal women (to postmenopausal levels), and is indicated in hormone receptor-positive early breast cancer in this population group. Adjuvant goserelin monotherapy has similar efficacy to adjuvant chemotherapy in pre- or perimenopausal women with early, hormone receptor-positive breast cancer. Furthermore, the addition of goserelin to adjuvant chemotherapy appeared to offer an advantage over chemotherapy alone in younger patients. Fewer patients remained amenorrheic after goserelin therapy than after chemotherapy. Complete endocrine blockade provided by the addition of tamoxifen to therapy including goserelin appears to improve outcomes. Thus, goserelin offers a valuable addition to the currently available options for treating pre- or perimenopausal women with hormone therapy-responsive early breast cancer, particularly for women wishing to regain ovarian function after treatment.