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S38 Late effects of systemic adjuvant therapies in women diagnosed with breast cancer at a young age
S16
Session 10. Adjuvant systemic treatment choice for the individual patient II
1970s established the role of adjuvant chemotherapy, with both showing statistically significant and clinically important reductions in recurrence and, ultimately, mortality. Since these reports, a multitude of investigations from around the world have addressed the three questions raised above. Early subgroup analyses of both the NSABP and Milano studies suggested that premenopausal women were more likely to benefit than older women, although subsequent single study results and meta-analysis have demonstrated that older women do, indeed, benefit. Adjuvant chemotherapy was initially felt to be indicated only in women with positive lymph nodes, but with increasing sophistication, the field has refined our understanding of prognosis and prediction. Increasingly we are able to identify both those patients most likely to need adjuvant chemotherapy (prognosis) and, perhaps, those most likely to benefit from it (prediction). In this regard, web-based, multifactorial calculators, best exemplified by Adjuvant!, permit a patient and her caregiver to estimate her absolute odds of benefit from chemotherapy, thus better informing women in their assessment of benefits and risks (http://www.adjuvantonline.com/index.jsp). The next question is whether there is an optimal regimen, dose, and schedule of adjuvant chemotherapy. The answer is, frankly, “no”. However, clinical research over the last four decades has strongly suggested the following principles: • Combination chemotherapy is superior to single agent. However, ongoing clinical trials, such as CALGB 40101, are re-addressing this issue in women with relatively favorable prognoses using modern chemotherapy, such as paclitaxel. • “Modern” chemotherapy including an anthracycline (doxorubicin [A] or epirubicin [E]) and a taxane appears to be superior to the CMF regimen. However, there may be biologic subgroups of patients for whom either anthracyclines or taxanes are less beneficial, or even inactive. Furthermore, the “best” combination has not been proven. AC appears to be similar to CMF, CEF appears superior to CMF, and AC-T(paclitaxel) or T(docetaxel)AC appears to be superior to AC or CAF, respectively. AC and AT(docetaxel) appear to be quite similar, although T(docetaxel)C appears to be superior to AC. AC-paclitaxel and AC-docetaxel also appear nearly identical. • Multiple cycles of chemotherapy are superior to a single peri-operative course. Furthermore, there appears to be an optimal duration of therapy, although this has not been well-defined. Older studies suggest that 12 is no better than 6 months of CMF, 6 may be slightly better than 3 cycles of CMF, and that 10 cycles of a doxorubicin-based regimen is no better than 5. • For most, if not all, chemotherapy agents there is a dose response curve with increasing benefit up to an optimal dose level, but this curve appears to plateau. Further dose escalation, at least for cyclophosphamide, anthracyclines, and the taxanes, or very high doses of combination therapies which require bone marrow stem cell transplantation, is of little benefit. • Dose-dense chemotherapy (every one or two weeks) may be superior to less frequent scheduling (every three weeks), although this strategy may be class or even agent specific. In summary, it is clear that adjuvant chemotherapy is beneficial for women with early stage breast cancer, and it is clear that selected regimens, based on specific agents, cumulative and cycle-specific dose, and schedule may affect the relative efficacy. It is not clear which patients are most likely to benefit from any adjuvant chemotherapy at all, or from specific strategies. Thus, at this time there is no single standard type or duration of adjuvant chemotherapy, and physicians should choose from regimens that have proven benefit as demonstrated in randomized Phase III trials. The choice of regimen in an individual patient should be based on differential toxicity and patient clinical factors, and arbitrary dose reductions or modification of the regimen should be avoided. Finally, it is also clear that many women will suffer recurrence and death in spite of these enormous advances and that new strategies are needed to further reduce the burden of breast cancer on our patients.
S38
Friday, 13 March 2009 Late effects of systemic adjuvant therapies in women diagnosed with breast cancer at a young age
H.J. Burstein1 . 1 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA Adjuvant systemic therapies have particular, long-term side effects in young women, principally related to the anti-estrogen consequences of adjuvant endocrine and chemotherapy treatments. Adjuvant chemotherapy can be toxic to the ovary, contributing to premature menopause and impaired fertility. Endocrine treatments including tamoxifen and ovarian suppression also contribute to menopausal symptoms and are contraindications to pregnancy, and may be associated with other stigmata of menopause including accelerated osteopenia / osteoporosis, sexual dysfunction, weight gain and climacteric symptoms such as hot flashes and night sweats. Clinical experience suggests that young women who experience abrupt changes in hormonal status are at greater jeopardy for more intense menopausal symptoms. Other consequences of cancer diagnosis and treatment, including fatigue, psychosocial distress, cognitive changes, and impaired body image, also appear more prevalent in women diagnosed at younger ages. Younger women may also have unique concerns about fertility preservation and options for child-bearing after breast cancer. Limited data suggest that pregnancy per se does not increase the risk of cancer recurrence, but patients must factor into account that possibility as well as the possible interruption of effective endocrine therapy when weighing such a choice. Very young women are more likely to have hereditary predisposition to breast cancer, and warrant consideration of genetic testing and, when appropriate, prophylactic surgery to reduce the risk of ovarian cancer and second breast cancers. Historically, age has been considered an adverse prognostic factor in breast cancer outcomes. It now seems likely that much if not all of this can be accounted for by the different distributions of breast cancer subsets in younger women, who bear a higher burden of hormone-receptor negative and/or HER2 positive cancers, lack of ovarian suppression with chemotherapy in very young women, and in the past, limited use of adjuvant endocrine therapy in these patients. Thus, there are no differences in surveillance or other follow-up guidelines for women based on age. However, as younger women have fewer more comorbid conditions, and longer life expectancy overall, the long-term consequences of breast cancer loom larger than for many women diagnosed at later ages. Clinicians need to be aware of the special survivorship needs of younger women with early stage breast cancer.
Friday, 13 March 2009
16.00–17.30
Session 10. Adjuvant systemic treatment choice for the individual patient II S39
Treatment of postmenopausal women with hormone responsive breast cancer
E. Winer1 . 1 Dana-Farber − Brigham and Women’s Cancer Center, Harvard Medical School, Boston, USA Over half of all women diagnosed with breast cancer are postmenopausal and have hormone receptor positive disease. Almost all of these women are potential candidates for adjuvant endocrine therapy, and the majority have an excellent overall prognosis. A decade ago, the only treatment available was tamoxifen, which was typically administered for a period of 5 years. Over the course of the past decade, well over 10 randomized trials have addressed the role of the aromatase inhibitors in the treatment of postmenopausal hormonally sensitive breast cancer. These trials have used a variety of distinct strategies including: 1. direct comparison of 5 years of tamoxifen with 5 years of an aromatase inhibitor; 2. cross-over or sequential approaches in which women receive either a 5 year course of tamoxifen or 2−3 years of tamoxifen followed by 2−3 years of an aromatase inhibitor, with randomization occurring either after 2−3 years of tamoxifen or at the time of diagnosis;
Session 10. Adjuvant systemic treatment choice for the individual patient II
1970s established the role of adjuvant chemotherapy, with both showing statistically significant and clinically important reductions in recurrence and, ultimately, mortality. Since these reports, a multitude of investigations from around the world have addressed the three questions raised above. Early subgroup analyses of both the NSABP and Milano studies suggested that premenopausal women were more likely to benefit than older women, although subsequent single study results and meta-analysis have demonstrated that older women do, indeed, benefit. Adjuvant chemotherapy was initially felt to be indicated only in women with positive lymph nodes, but with increasing sophistication, the field has refined our understanding of prognosis and prediction. Increasingly we are able to identify both those patients most likely to need adjuvant chemotherapy (prognosis) and, perhaps, those most likely to benefit from it (prediction). In this regard, web-based, multifactorial calculators, best exemplified by Adjuvant!, permit a patient and her caregiver to estimate her absolute odds of benefit from chemotherapy, thus better informing women in their assessment of benefits and risks (http://www.adjuvantonline.com/index.jsp). The next question is whether there is an optimal regimen, dose, and schedule of adjuvant chemotherapy. The answer is, frankly, “no”. However, clinical research over the last four decades has strongly suggested the following principles: • Combination chemotherapy is superior to single agent. However, ongoing clinical trials, such as CALGB 40101, are re-addressing this issue in women with relatively favorable prognoses using modern chemotherapy, such as paclitaxel. • “Modern” chemotherapy including an anthracycline (doxorubicin [A] or epirubicin [E]) and a taxane appears to be superior to the CMF regimen. However, there may be biologic subgroups of patients for whom either anthracyclines or taxanes are less beneficial, or even inactive. Furthermore, the “best” combination has not been proven. AC appears to be similar to CMF, CEF appears superior to CMF, and AC-T(paclitaxel) or T(docetaxel)AC appears to be superior to AC or CAF, respectively. AC and AT(docetaxel) appear to be quite similar, although T(docetaxel)C appears to be superior to AC. AC-paclitaxel and AC-docetaxel also appear nearly identical. • Multiple cycles of chemotherapy are superior to a single peri-operative course. Furthermore, there appears to be an optimal duration of therapy, although this has not been well-defined. Older studies suggest that 12 is no better than 6 months of CMF, 6 may be slightly better than 3 cycles of CMF, and that 10 cycles of a doxorubicin-based regimen is no better than 5. • For most, if not all, chemotherapy agents there is a dose response curve with increasing benefit up to an optimal dose level, but this curve appears to plateau. Further dose escalation, at least for cyclophosphamide, anthracyclines, and the taxanes, or very high doses of combination therapies which require bone marrow stem cell transplantation, is of little benefit. • Dose-dense chemotherapy (every one or two weeks) may be superior to less frequent scheduling (every three weeks), although this strategy may be class or even agent specific. In summary, it is clear that adjuvant chemotherapy is beneficial for women with early stage breast cancer, and it is clear that selected regimens, based on specific agents, cumulative and cycle-specific dose, and schedule may affect the relative efficacy. It is not clear which patients are most likely to benefit from any adjuvant chemotherapy at all, or from specific strategies. Thus, at this time there is no single standard type or duration of adjuvant chemotherapy, and physicians should choose from regimens that have proven benefit as demonstrated in randomized Phase III trials. The choice of regimen in an individual patient should be based on differential toxicity and patient clinical factors, and arbitrary dose reductions or modification of the regimen should be avoided. Finally, it is also clear that many women will suffer recurrence and death in spite of these enormous advances and that new strategies are needed to further reduce the burden of breast cancer on our patients.
S38
Friday, 13 March 2009 Late effects of systemic adjuvant therapies in women diagnosed with breast cancer at a young age
H.J. Burstein1 . 1 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA Adjuvant systemic therapies have particular, long-term side effects in young women, principally related to the anti-estrogen consequences of adjuvant endocrine and chemotherapy treatments. Adjuvant chemotherapy can be toxic to the ovary, contributing to premature menopause and impaired fertility. Endocrine treatments including tamoxifen and ovarian suppression also contribute to menopausal symptoms and are contraindications to pregnancy, and may be associated with other stigmata of menopause including accelerated osteopenia / osteoporosis, sexual dysfunction, weight gain and climacteric symptoms such as hot flashes and night sweats. Clinical experience suggests that young women who experience abrupt changes in hormonal status are at greater jeopardy for more intense menopausal symptoms. Other consequences of cancer diagnosis and treatment, including fatigue, psychosocial distress, cognitive changes, and impaired body image, also appear more prevalent in women diagnosed at younger ages. Younger women may also have unique concerns about fertility preservation and options for child-bearing after breast cancer. Limited data suggest that pregnancy per se does not increase the risk of cancer recurrence, but patients must factor into account that possibility as well as the possible interruption of effective endocrine therapy when weighing such a choice. Very young women are more likely to have hereditary predisposition to breast cancer, and warrant consideration of genetic testing and, when appropriate, prophylactic surgery to reduce the risk of ovarian cancer and second breast cancers. Historically, age has been considered an adverse prognostic factor in breast cancer outcomes. It now seems likely that much if not all of this can be accounted for by the different distributions of breast cancer subsets in younger women, who bear a higher burden of hormone-receptor negative and/or HER2 positive cancers, lack of ovarian suppression with chemotherapy in very young women, and in the past, limited use of adjuvant endocrine therapy in these patients. Thus, there are no differences in surveillance or other follow-up guidelines for women based on age. However, as younger women have fewer more comorbid conditions, and longer life expectancy overall, the long-term consequences of breast cancer loom larger than for many women diagnosed at later ages. Clinicians need to be aware of the special survivorship needs of younger women with early stage breast cancer.
Friday, 13 March 2009
16.00–17.30
Session 10. Adjuvant systemic treatment choice for the individual patient II S39
Treatment of postmenopausal women with hormone responsive breast cancer
E. Winer1 . 1 Dana-Farber − Brigham and Women’s Cancer Center, Harvard Medical School, Boston, USA Over half of all women diagnosed with breast cancer are postmenopausal and have hormone receptor positive disease. Almost all of these women are potential candidates for adjuvant endocrine therapy, and the majority have an excellent overall prognosis. A decade ago, the only treatment available was tamoxifen, which was typically administered for a period of 5 years. Over the course of the past decade, well over 10 randomized trials have addressed the role of the aromatase inhibitors in the treatment of postmenopausal hormonally sensitive breast cancer. These trials have used a variety of distinct strategies including: 1. direct comparison of 5 years of tamoxifen with 5 years of an aromatase inhibitor; 2. cross-over or sequential approaches in which women receive either a 5 year course of tamoxifen or 2−3 years of tamoxifen followed by 2−3 years of an aromatase inhibitor, with randomization occurring either after 2−3 years of tamoxifen or at the time of diagnosis;