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VA.1 Adjuvant chemotherapy of older women with breast cancer
Faculty abstracts / Critical Reviews in Oncology/Hematology 64 (2007) S11–S28 IVB.2 14.50–15.05 Combining radiation therapy and chemotherapy: feasible in the elderly? J.C. Horiot. Centre de Lutte contre le Cancer GF Leclerc, Dijon, France Data compiled from French tumour registries [1] have confirmed that patients older than 70 years of age are given the best known regimens of radiotherapy in less than 50% of the cases. It is therefore not surprising that less than 10% receive the best known regimens of combined radio-chemotherapy in the same moderately advanced solid tumours. This obviously reduces the chance of cure of such patients. It also seems in total in total contradiction with the principle of equal access to optimal treatment to all patients underlying all national cancer plans. The questions addressed in this presentation will try to clarify the following questions: – Are they some clinical criteria and literature results, which justify the contra-indications of combined chemo-radiotherapy in elderly patients? – As the answer will leave a large number of patients eligible for such combined treatment, which further specific investigations must be done to confirm the indication? – Which medical, physical and psychological management must be done prior to treatment to enhance the chance of treatment tolerance and reduce the risks of acute and late toxicities? – Are they reliable indications per tumour site (head and neck, lung, breast, brain, rectum and anus)? – Are they different options (e.g. neo-adjuvant, concomitant, adjuvant) as well recommended drug and/or radiation regimens dose reductions in case of unacceptable toxicity? – Is there a role for modern radiotherapy techniques such as intensity modulated radiotherapy to reduce the radiotherapy burden and allow a more aggressive combined treatment modality? – Is there room for prospective clinical research when there is no consensus on the indication or optimal combination to propose to the elderly patient? Reference(s) [1] Horiot JC. Radiation Therapy and the Geriatric Oncology Patient. JCO, May 10 2007: 1930–1935.
IVB.3 Can we really omit RT to the breast in the elderly
15.10–15.25
P. Scalliet. Université Catholique de Louvain, Cliniques universitaires Saint Luc, Brussels, Belgium It is tempting to spare elderly women the burden of adjuvant radiotherapy after breast cancer surgery, even if such a treatment would be justified in light of the available clinical evidence. The reason is that evidence-based radiotherapy derives from clinical trials that excluded elderly women, and that breast cancer is often believed to be more indolent at advanced ages. Elderly women have obviously a shorter life expectancy than younger one. Therefore, the need to offer a life-prolonging treatment as postoperative radiotherapy decreases with age. It is certainly true that when life expectancy is shorter than, say 5 years, the benefit in survival disappears. This is not the case for the benefit in local control (prevention of local recurrence) that is already observable 1 year after surgery. Given the psychological burden of a recurrence, as well as the higher cost of salvage therapy, later in life, when new co-morbidities have appeared (or pre-existing one worsened), it seems advisable to aim at maximal local control, disregarding the benefit in absolute survival. The number needed to treat (NNT) for one life saved after 5 years ranges between 10 and 25 (or more). However, the NNT for one recurrence prevented is much lower, around 2 to 5. Also, available data indicate that, apart from the difficulty to daily travel to the radiotherapy department, tolerance to irradiation is independent of age.
S17
The epidemiological evidence, and the few clinical trials recruiting patients over 65 or 70 year of age, all point to the need for postoperative irradiation in a similar set-up as in younger patients to prevent local recurrence (benefit after 1 year already). So far, there is no evidence that a subgroup exist in which radiotherapy can be safely omitted. Therefore, the decision to treat or not to treat should be openly discussed with the patient, addressing risks and benefits of both attitudes. Only in frail patients, with an obviously limited life expectancy (months or at most a few years), can omission of radiotherapy be considered, as the burden of local recurrence is likely not to appear before the patient dies from another cause.
16.15–18.00
Parallel Session V A. Breast Cancer VA.1 16.15–16.30 Adjuvant chemotherapy of older women with breast cancer H.B. Muss. Vermont Cancer Center and University of Vermont, Burlington, VT, USA In most of the world the incidence and mortality rates for breast cancer rise dramatically with age and most women who die of breast cancer are 65 years and older. Tumor characteristics in older women are somewhat more favorable than in younger patients but after adjusting for stage, mortality rates are similar. More than 75% of older women have breast cancers that are estrogen (ER) and or progesterone receptor (PR) positive. For these patients endocrine therapy with either tamoxifen or aromatase inhibitors is the treatment of choice. Fifteen-year follow-up from the Early Breast Cancer Trials Collaborative Group (EBCTCG) shows that tamoxifen significantly improves both relapse-free and overall survival in women 70 years and older with ER+ tumors and current data shows that aromatase inhibitors likely be even more effective than tamoxifen in this setting. These data suggest two major questions when considering adjuvant chemotherapy. First, what is the added value of chemotherapy to endocrine therapy in women with hormone-receptor positive tumors, and second, what is the value of chemotherapy alone in women with ER and PR negative breast cancer. Randomized trials of adjuvant chemotherapy vs no adjuvant chemotherapy are few in elders and in the EBCTCG meta-analysis only about 1,200 women >70 years were evaluated in such trials. Similar proportional reductions in breast cancer relapse and mortality rates were found for women 70+ and those 60–69 years. These proportional reductions were small however and support observations that older patients with node negative (N-) ER+ breast cancer derive little to no value when chemotherapy is added to endocrine therapy. Moreover, in most N+, ER+ patients the addition of chemotherapy to endocrine therapy is likely to be very small except in those with a very high risk for tumor recurrence and an estimated survival of at least 5 years. Internet based programs such as Adjuvant! (www.adjuvantonline.com) are of great value in estimating the value of endocrine therapy and the added value of chemotherapy in ER+ patients and factor in life-expectancy and co-morbidity data. For older women with N-, ER+ tumors, analysis of tumor genes can estimate the risk of metastases in women taking tamoxifen and help with chemotherapy decisions (OncotypeDX and others). The major benefit of chemotherapy in elders is in N+, ER and PR- patients and N-, ER and PR- patents with larger, high-grade lesions. In patients with ER- and PR- cancers the proportional reductions in risk of recurrence and death is similar among age groups and accurate estimates of chemotherapy benefit can be made. In a large retrospective review of adjuvant chemotherapy trials in N+ patients performed by North American clinical trial cooperative groups, older and younger women receiving more intensive chemotherapy as compared with less intensive chemotherapy showed similar improvements
S18
Faculty abstracts / Critical Reviews in Oncology/Hematology 64 (2007) S11–S28
in both relapse-free and overall survival but had higher chemotherapyassociated mortality, mainly leukemia. Available data suggests that older patients in fair to good health tolerate standard chemotherapy regimens, including anthracyclines, about as well as younger women. However, myelosuppression is more common and cardiac toxicity may also be higher. The value of chemotherapy in older patients is dependent on comorbidity and life expectancy as well as its potential value in reducing recurrence and breast cancer related mortality. In North America a randomized trial in women 65+ is comparing standard chemotherapy (CMF or AC) with 6 courses of the oral 5-fluorouracil pro-drug, capecitabine. In Europe trials are underway comparing capecitabine with no chemotherapy and liposomal doxorubicin with low dose or no chemotherapy. Participation of older women in breast cancer clinical trials remains poor and further adjuvant trials focusing on chemotherapy and the effes of comorbidity are needed.
VA.2 Hormone therapy in BC patients with co-morbidities
16.35–16.50
D. Crivellari. Centro di Riferimento Oncologico, Aviano, Italy Even if approximately 50% of all new breast cancers occur in women 65 years or older, we have too few evidence-based clinical studies which can guide the clinical decision-making process regarding safety and efficacy of therapies in elderly women, especially in patients with frequent co-morbidities. In the last few years a new concern about this issue has developed. Furthermore,until recently only tamoxifen was the gold standard for the treatment of postmenopausal women with endocrine responsive breast cancer, but now with the advent of the third generation aromatase inhibitors and fulvestrant clinicians should consider patient profiles before choosing between different drugs. The BIG 1-98 adjuvant trial compared 5 years of letrozole with 5 years of tamoxifen in 4922 postmenopausal women with endocrine-responsive early breast cancer and found an absolute 3% increase in disease-free survival (DFS) and an 18% reduction in event risk (AS Coates, Journal of Clinical Oncology, 2007 25:486–492) among those receiving letrozole. More thromboembolic events, endometrial pathology, hot flashes, night sweats, and vaginal bleeding were reported for the tamoxifen group and more bone fractures, arthralgia, low-grade hypercholesterolemia, and cardiovascular events other than ischemia and cardiac failure were reported for letrozole. We wished to explore potential differences in efficacy, treatment completion and adverse events in older women in the trial (D Crivellari, Proc ASCO 2007 abs. 9033). Women were stratified into 3 age groups: ≤64 (n=3127), 65–74 (n=1500), ≥75 years (n=295). As expected in the group of elderly women baseline co-morbidities were different from the groups of younger patients, in particular hypertension increased from 24% in pts ≤ 64 yrs to 41% in pts 65–74 yrs and to 61% in elderly pts treated with letrozole, diabetes requiring treatment increased from 3.5% to 7.3% to 10.9%, cardiac events from 6.4% to12.55% to 23.8%, osteoporosis from 2.5% to 5.1% to 10.9% respectively in the three age groups. In the older group of postmenopausal patients, a patient-profile based approach should be considered therefore, in order to reduce the risk of serious adverse events. In consideration of the increasing population of older women, this analysis suggests that age per se should not unduly affect the choice of adjuvant endocrine therapy.
VA.3 16.55–17.10 Chemotherapy in elderly patients with metastatic breast cancer (MBC) H. Wildiers. Multidisciplinary Breast Unit, University Hospitals Leuven, Belgium Breast cancer is the most commonly diagnosed cancer and leading cause of cancer mortality in women. MBC is treatable but not curable.
Therefore, the main aims in treating elderly patients, like younger patients, with MBC are to maintain quality of life, minimize symptoms from disease, and prolong survival without causing excessive toxicity. Medical oncologists are often reluctant to use chemotherapy in elderly partly because of concern about increased toxicity and poor tolerability, and because of the inability to appropriately select elderly that may benefit from chemotherapy. However, women older than 70 years of age who are treated with chemotherapy for metastatic disease can derive similar benefits to their younger counterparts. Older patients should not be excluded from receiving chemotherapy for advanced breast cancer on the basis of age alone. The use of chemotherapy should be considered in hormone receptor-negative or hormone refractory patients. Preference should be given to chemotherapeutic agents with ’safer’ profiles such as weekly taxane regimens, newer less cardiotoxic anthracycline formulations, capecitabine, gemcitabine, and vinorelbine. These drugs are often used in elderly with adapted doses compared to younger patients, based on pharmacokinetic or pharmacodynamic (toxicity) alterations in this population, but level I evidence on these specific dosing schedules is generally lacking. Monotherapy is generally favoured over combination chemotherapy since the latter is generally associated with increased toxicity and little, if any, survival gain compared to the sequential use of single drugs. Choice of chemotherapy regimens and agents is generally based on extrapolation of efficacy in the younger population and data from single arm phase II studies in elderly, but also individual patient characteristics and drug availability/reimbursement by the health system can play a role. The only randomized phase III study performed in elderly with MBC compared gemcitabine to epirubicin, both in a weekly regimen (Hamberg et al EJC 2007). Toxicity was significant in both arms, and epirubicin was significantly more effective than gemcitabine in terms of response rate (40% vs 16%), TTP (6.1 vs 3.4 months) and OS (19.1 vs 11.8 months). Since chemotherapy in this situation is only palliative, the quality of life is paramount and significant toxicity is generally not acceptable. In principle, dose reductions in the elderly are not systematically recommended, but should be considered based on pharmacological parameters and altered according to observed toxicity. Strict follow-up is essential in this population in particular to avoid over-treatment and debilitating side effects. Particular attention should be paid to supportive care, as older patients are more likely to develop neutropenia than younger patients, and generally have less functional reserve than their younger counterparts. Conclusion: the goals of treating MBC in older patients are not different from those in younger patients. The use of chemotherapy should be considered in patients with hormone receptor-negative, hormone-refractory or life-threatening disease. Choice of chemotherapy regimens and agents is dependent on individual patient characteristics, preferences, and drug availability.
VA.4 Is there an upper age limit in screening?
17.15–17.30
J. Fracheboud ∗ ,1 , G. Draisma 1 , S. Otto 1 , A.L.M. Verbeek 2 , H.J. de Koning 1 . 1 Dept. of Public Health, Erasmus MC, Rotterdam; 2 Dept. of Epidemiology and Biostatistics, Radboud University Nijmegen Medical Centre, the Netherlands Purpose of the study: There is only limited evidence on the efficacy of mammography screening in woman aged 70 and over. Whereas in Europe most centrally organized population-based breast cancer screening programmes target women aged 50–69, in the U.S. mammography is also advised for elderly individuals with a sufficiently reasonable life-expectancy. In 1998, the Dutch biennial breast cancer screening programme for women aged 50–69 was extended with the ages 70–75. This decision was based on model analyses that resulted in a reasonable balance between benefits and harms up to at least 75 years. Methods: Since 1998, all women in the Netherlands aged 50–75 are personally invited every second year for a free mammography in one of
IVB.3 Can we really omit RT to the breast in the elderly
15.10–15.25
P. Scalliet. Université Catholique de Louvain, Cliniques universitaires Saint Luc, Brussels, Belgium It is tempting to spare elderly women the burden of adjuvant radiotherapy after breast cancer surgery, even if such a treatment would be justified in light of the available clinical evidence. The reason is that evidence-based radiotherapy derives from clinical trials that excluded elderly women, and that breast cancer is often believed to be more indolent at advanced ages. Elderly women have obviously a shorter life expectancy than younger one. Therefore, the need to offer a life-prolonging treatment as postoperative radiotherapy decreases with age. It is certainly true that when life expectancy is shorter than, say 5 years, the benefit in survival disappears. This is not the case for the benefit in local control (prevention of local recurrence) that is already observable 1 year after surgery. Given the psychological burden of a recurrence, as well as the higher cost of salvage therapy, later in life, when new co-morbidities have appeared (or pre-existing one worsened), it seems advisable to aim at maximal local control, disregarding the benefit in absolute survival. The number needed to treat (NNT) for one life saved after 5 years ranges between 10 and 25 (or more). However, the NNT for one recurrence prevented is much lower, around 2 to 5. Also, available data indicate that, apart from the difficulty to daily travel to the radiotherapy department, tolerance to irradiation is independent of age.
S17
The epidemiological evidence, and the few clinical trials recruiting patients over 65 or 70 year of age, all point to the need for postoperative irradiation in a similar set-up as in younger patients to prevent local recurrence (benefit after 1 year already). So far, there is no evidence that a subgroup exist in which radiotherapy can be safely omitted. Therefore, the decision to treat or not to treat should be openly discussed with the patient, addressing risks and benefits of both attitudes. Only in frail patients, with an obviously limited life expectancy (months or at most a few years), can omission of radiotherapy be considered, as the burden of local recurrence is likely not to appear before the patient dies from another cause.
16.15–18.00
Parallel Session V A. Breast Cancer VA.1 16.15–16.30 Adjuvant chemotherapy of older women with breast cancer H.B. Muss. Vermont Cancer Center and University of Vermont, Burlington, VT, USA In most of the world the incidence and mortality rates for breast cancer rise dramatically with age and most women who die of breast cancer are 65 years and older. Tumor characteristics in older women are somewhat more favorable than in younger patients but after adjusting for stage, mortality rates are similar. More than 75% of older women have breast cancers that are estrogen (ER) and or progesterone receptor (PR) positive. For these patients endocrine therapy with either tamoxifen or aromatase inhibitors is the treatment of choice. Fifteen-year follow-up from the Early Breast Cancer Trials Collaborative Group (EBCTCG) shows that tamoxifen significantly improves both relapse-free and overall survival in women 70 years and older with ER+ tumors and current data shows that aromatase inhibitors likely be even more effective than tamoxifen in this setting. These data suggest two major questions when considering adjuvant chemotherapy. First, what is the added value of chemotherapy to endocrine therapy in women with hormone-receptor positive tumors, and second, what is the value of chemotherapy alone in women with ER and PR negative breast cancer. Randomized trials of adjuvant chemotherapy vs no adjuvant chemotherapy are few in elders and in the EBCTCG meta-analysis only about 1,200 women >70 years were evaluated in such trials. Similar proportional reductions in breast cancer relapse and mortality rates were found for women 70+ and those 60–69 years. These proportional reductions were small however and support observations that older patients with node negative (N-) ER+ breast cancer derive little to no value when chemotherapy is added to endocrine therapy. Moreover, in most N+, ER+ patients the addition of chemotherapy to endocrine therapy is likely to be very small except in those with a very high risk for tumor recurrence and an estimated survival of at least 5 years. Internet based programs such as Adjuvant! (www.adjuvantonline.com) are of great value in estimating the value of endocrine therapy and the added value of chemotherapy in ER+ patients and factor in life-expectancy and co-morbidity data. For older women with N-, ER+ tumors, analysis of tumor genes can estimate the risk of metastases in women taking tamoxifen and help with chemotherapy decisions (OncotypeDX and others). The major benefit of chemotherapy in elders is in N+, ER and PR- patients and N-, ER and PR- patents with larger, high-grade lesions. In patients with ER- and PR- cancers the proportional reductions in risk of recurrence and death is similar among age groups and accurate estimates of chemotherapy benefit can be made. In a large retrospective review of adjuvant chemotherapy trials in N+ patients performed by North American clinical trial cooperative groups, older and younger women receiving more intensive chemotherapy as compared with less intensive chemotherapy showed similar improvements
S18
Faculty abstracts / Critical Reviews in Oncology/Hematology 64 (2007) S11–S28
in both relapse-free and overall survival but had higher chemotherapyassociated mortality, mainly leukemia. Available data suggests that older patients in fair to good health tolerate standard chemotherapy regimens, including anthracyclines, about as well as younger women. However, myelosuppression is more common and cardiac toxicity may also be higher. The value of chemotherapy in older patients is dependent on comorbidity and life expectancy as well as its potential value in reducing recurrence and breast cancer related mortality. In North America a randomized trial in women 65+ is comparing standard chemotherapy (CMF or AC) with 6 courses of the oral 5-fluorouracil pro-drug, capecitabine. In Europe trials are underway comparing capecitabine with no chemotherapy and liposomal doxorubicin with low dose or no chemotherapy. Participation of older women in breast cancer clinical trials remains poor and further adjuvant trials focusing on chemotherapy and the effes of comorbidity are needed.
VA.2 Hormone therapy in BC patients with co-morbidities
16.35–16.50
D. Crivellari. Centro di Riferimento Oncologico, Aviano, Italy Even if approximately 50% of all new breast cancers occur in women 65 years or older, we have too few evidence-based clinical studies which can guide the clinical decision-making process regarding safety and efficacy of therapies in elderly women, especially in patients with frequent co-morbidities. In the last few years a new concern about this issue has developed. Furthermore,until recently only tamoxifen was the gold standard for the treatment of postmenopausal women with endocrine responsive breast cancer, but now with the advent of the third generation aromatase inhibitors and fulvestrant clinicians should consider patient profiles before choosing between different drugs. The BIG 1-98 adjuvant trial compared 5 years of letrozole with 5 years of tamoxifen in 4922 postmenopausal women with endocrine-responsive early breast cancer and found an absolute 3% increase in disease-free survival (DFS) and an 18% reduction in event risk (AS Coates, Journal of Clinical Oncology, 2007 25:486–492) among those receiving letrozole. More thromboembolic events, endometrial pathology, hot flashes, night sweats, and vaginal bleeding were reported for the tamoxifen group and more bone fractures, arthralgia, low-grade hypercholesterolemia, and cardiovascular events other than ischemia and cardiac failure were reported for letrozole. We wished to explore potential differences in efficacy, treatment completion and adverse events in older women in the trial (D Crivellari, Proc ASCO 2007 abs. 9033). Women were stratified into 3 age groups: ≤64 (n=3127), 65–74 (n=1500), ≥75 years (n=295). As expected in the group of elderly women baseline co-morbidities were different from the groups of younger patients, in particular hypertension increased from 24% in pts ≤ 64 yrs to 41% in pts 65–74 yrs and to 61% in elderly pts treated with letrozole, diabetes requiring treatment increased from 3.5% to 7.3% to 10.9%, cardiac events from 6.4% to12.55% to 23.8%, osteoporosis from 2.5% to 5.1% to 10.9% respectively in the three age groups. In the older group of postmenopausal patients, a patient-profile based approach should be considered therefore, in order to reduce the risk of serious adverse events. In consideration of the increasing population of older women, this analysis suggests that age per se should not unduly affect the choice of adjuvant endocrine therapy.
VA.3 16.55–17.10 Chemotherapy in elderly patients with metastatic breast cancer (MBC) H. Wildiers. Multidisciplinary Breast Unit, University Hospitals Leuven, Belgium Breast cancer is the most commonly diagnosed cancer and leading cause of cancer mortality in women. MBC is treatable but not curable.
Therefore, the main aims in treating elderly patients, like younger patients, with MBC are to maintain quality of life, minimize symptoms from disease, and prolong survival without causing excessive toxicity. Medical oncologists are often reluctant to use chemotherapy in elderly partly because of concern about increased toxicity and poor tolerability, and because of the inability to appropriately select elderly that may benefit from chemotherapy. However, women older than 70 years of age who are treated with chemotherapy for metastatic disease can derive similar benefits to their younger counterparts. Older patients should not be excluded from receiving chemotherapy for advanced breast cancer on the basis of age alone. The use of chemotherapy should be considered in hormone receptor-negative or hormone refractory patients. Preference should be given to chemotherapeutic agents with ’safer’ profiles such as weekly taxane regimens, newer less cardiotoxic anthracycline formulations, capecitabine, gemcitabine, and vinorelbine. These drugs are often used in elderly with adapted doses compared to younger patients, based on pharmacokinetic or pharmacodynamic (toxicity) alterations in this population, but level I evidence on these specific dosing schedules is generally lacking. Monotherapy is generally favoured over combination chemotherapy since the latter is generally associated with increased toxicity and little, if any, survival gain compared to the sequential use of single drugs. Choice of chemotherapy regimens and agents is generally based on extrapolation of efficacy in the younger population and data from single arm phase II studies in elderly, but also individual patient characteristics and drug availability/reimbursement by the health system can play a role. The only randomized phase III study performed in elderly with MBC compared gemcitabine to epirubicin, both in a weekly regimen (Hamberg et al EJC 2007). Toxicity was significant in both arms, and epirubicin was significantly more effective than gemcitabine in terms of response rate (40% vs 16%), TTP (6.1 vs 3.4 months) and OS (19.1 vs 11.8 months). Since chemotherapy in this situation is only palliative, the quality of life is paramount and significant toxicity is generally not acceptable. In principle, dose reductions in the elderly are not systematically recommended, but should be considered based on pharmacological parameters and altered according to observed toxicity. Strict follow-up is essential in this population in particular to avoid over-treatment and debilitating side effects. Particular attention should be paid to supportive care, as older patients are more likely to develop neutropenia than younger patients, and generally have less functional reserve than their younger counterparts. Conclusion: the goals of treating MBC in older patients are not different from those in younger patients. The use of chemotherapy should be considered in patients with hormone receptor-negative, hormone-refractory or life-threatening disease. Choice of chemotherapy regimens and agents is dependent on individual patient characteristics, preferences, and drug availability.
VA.4 Is there an upper age limit in screening?
17.15–17.30
J. Fracheboud ∗ ,1 , G. Draisma 1 , S. Otto 1 , A.L.M. Verbeek 2 , H.J. de Koning 1 . 1 Dept. of Public Health, Erasmus MC, Rotterdam; 2 Dept. of Epidemiology and Biostatistics, Radboud University Nijmegen Medical Centre, the Netherlands Purpose of the study: There is only limited evidence on the efficacy of mammography screening in woman aged 70 and over. Whereas in Europe most centrally organized population-based breast cancer screening programmes target women aged 50–69, in the U.S. mammography is also advised for elderly individuals with a sufficiently reasonable life-expectancy. In 1998, the Dutch biennial breast cancer screening programme for women aged 50–69 was extended with the ages 70–75. This decision was based on model analyses that resulted in a reasonable balance between benefits and harms up to at least 75 years. Methods: Since 1998, all women in the Netherlands aged 50–75 are personally invited every second year for a free mammography in one of