Summary
Synopsis
Extensive clinical experience, summarised in the recent overview of the Early Breast Cancer Trialists’ Col/aboraliFe 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 post menopausal 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 ratio [$US6ooo per additional quality-adjusted life-year (QAL Y), in 1989 dollars] 5 to 6 times lower than that cited as the cost-acceptability cut-off point in the Us.
While tamoxifen monotherapy is effective in postmenopausal women, the EBCTCG overview findings indicate that a combined regimen of tamoxifen and antineoplastic chemotherapy has superior efficacy in the same patient group. An issue of current interest is whether the added benefit offered by such a regimen can by justified in terms of added toxicity and cost. Data from a decision analysis model indicate that combined therapy has a high incremental cost-utility ratio ($US58 000 per additional QALY, in 1989 dollars) compared with no therapy in postmenopausal women. However, the qualily-oflife 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 benefit. Patient preference data from I 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.
Disease Considerations
According to recent statistics in the US, 1 in 9 women will develop breast cancer, twice the risk recorded in 1940. This equates with approximately 175 500 new cases per annum in the US alone. While a number of risk factors for breast cancer have been identified. few are amenable to intervention. Thus, screening as a means of early detection, locoregional and adjuvant therapy are all used in the management of early breast cancer.
To date, only the direct costs of breast cancer have been evaluated. Estimates show wide variation. One analysis, using a longitudinal data source, estimated the lifetime direct costs of breast cancer to be $US36 926 per patient (1984 dollars). Indirect costs are thought to be around 2 to 2.6 times greater than direct costs in patients with cancer.
As with other cancers. breast cancer has a massive effect on patient quality of life. Patients not only must come to terms with the diagnosis of breast cancer, but also with all the stages of treatment (surgery, radiation therapy and adjuvant therapy). Psychosocial stress experienced by the patient can extend to both partner and family. Fear of recurrence is often a primary concern among those with breast cancer. In the advanced stage of the disease, the patient experiences loss of independence, physical symptoms and a progressively compromised quality of life.
Therapeutic Efficacy and Tolerability
The recent overview conducted by the Early Breast Cancer Trialis’ Collaborative Group (EBCTCG) provides strong evidence that tamoxifen adjuvant therapy improves both disease-free survival and overall survival in women with early breast cancer. Treatment effects are greatest in patients with node-positive disease, those aged over 50 years, and those with estrogen receptor-positive breast cancer. From data generated from individual clinical trials and the EBCTCG overview, tamoxifen is now recommended for adjuvant use in postmenopausal women with early breast cancer, and particularly in those with node-positive, estrogen receptor-positive disease. importantly, in patients aged from 50 to 69 years, the efficacy of combined chemotherapy and tamoxifen exceeded that of either treatment modality alone.
Overall, tamoxifen has a favourable tolerability profile. The most common adverse events associated with tamoxifen treatment are hot flushes, and vaginal bleeding or discharge. Three to 4% of patients withdraw from treatment as a result of adverse events. With the use of increasingly prolonged regimens of tamoxifen, the long term effects of the drug require further investigation. Of concern is the association of tamoxifen with the development of endometrial, ovarian and liver cancers, and thromboembolic complications. Conversely, there are data which suggest that tamoxifen has possible beneficial effects on bone mineral density and cardiovascular risk factors in women.
Quality-of-Life Considerations
Preliminary data concerning Quality of life in patients treated with tamoxifen arc available. In postmenopausal women with node-positive breast cancer, tamoxifen combined with chemotherapy was superior in terms of both Time Without Symptoms and Toxicity (TWiST) and quality-adjusted TWiST (Q-TWiST) to tamoxifen plus prednisone, which in turn was superior to no treatment. However. the fact that tamoxifen was coadministered with prednisone confounded interpretation of the results.
Preliminary results after 15 months of an ongoing study using patient-derived quality-of-life data assessed with the Perceived Adjustment to Chronic Illness Scale. suggest that patients with stage II breast cancer receiving tamoxifen monotherapy fare better at most assessment months than those receiving tamoxifen combined with chemotherapy. A Q-TWiST analysis is required to determine if the greater effort to cope with the disease for patients receiving combined tamoxifen and chemotherapy could be balanced by an improved quality of life related to delayed disease recurrence and improved survival.
Only one study which incorporated a quality-of-life component in patients with node-negative breast cancer has been performed. While overall quality-of-life scores did not differ between patients treated with tamoxifen or placebo, it was suggested that persistent vasomotor symptoms among patients receiving tamoxifen could have an adverse effect on long term compliance.
Pharmacoeconomic Analysis
To date, 2 preliminary pharmacoeconomic evaluations involving the use of tamoxifen in postmenopausal women with node-positive breast cancer have been performed. In the first study, savings of $Can2247 per patient (1987 dollars) were realised as a result of improved disease-free survival after at least 8 year’ follow-up compared with no treatment.
In the second study, data generated from a decision-analysis model indicated that a 5-year regimen of tamoxifen had a favourable incremental cost-utility ratio [$US6000 per additional quality-adjusted life-year (QALY), 1989 dollars] compared with no therapy. The estimated incremental cost-utility ratio of adding chemotherapy to tamoxifen was $US58 000 per additional QAL Y, assuming that the addition of chemotherapy reduced the relapse rate by a further 19% than did tamoxifen alone. The cost-utility ratio was sensitive to the degree of efficacy assigned to the combined regimen. and ranged from $USI9 400 to $US420 000 per additional QALY (1989 dollars) in best and worst case scenarios, respectively.
In the most recent application of the same decision-analysis model, tamoxifen had a low incremental cost-utility ratio ($US4330 to $US11 440 per additional QALY, 1989 dollars) in premenopausal women with receptor-positive tumours. Chemotherapy gave added benefit over tamoxifen again at a low incremental cost-utility ratio ($US9230 to $US11 370 per additional QALY). In this context it is likely that chemotherapy will be favoured over tamoxifen. However, if administered as part of a combined regimen, tamoxifen offered small extra benefits over those seen with chemotherapy alone at favourable cost utility ($US14 750 to $US33 100 per additional QALY).
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Various sections of the manuscript reviewed by: N.K. Aaronson, Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; G. Bonnadonna, Division of Medical Oncology, Instituto Nazionale Tumori, Milan, Italy; B.R. Cassileth, Behavioral Resources Corporation, Chapel Hill, North Carolina, USA; D. Coyle, University of York Centre for Health Economics, York, England; R.G. Gelber, Dana-Farber Cancer Institute, Division of Biostatistics, Boston, Massachusetts, USA; S. Green, Southwest Oncology Group Statistical Center, Fred Hutchinson Research Center, Seattle, Washington, USA; S.F. Hurley, Department of Biostatistics, School of Public Health and Community Medicine, University of Washington, Seatttle. Washington, USA; V.C Jordan, Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin, USA; R.R. Love, University of Wisconsin Clinical Cancer Center, Madison, Wisconsin, USA; C M . Moinpour, Southwest Oncology Group Statistical Center, Fred Hutchinson Research Center, Seattle, Washington, USA; M. Stockler, Department of Medical Oncology, Royal Prince Albert Hospital, Sydney. Australia.
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Bryson, H.M., Plosker, G.L. Tamoxifen. Pharmacoeconomics 4, 40–66 (1993). https://doi.org/10.2165/00019053-199304010-00006
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DOI: https://doi.org/10.2165/00019053-199304010-00006