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VA.3 Adjuvant treatment in elderly breast cancer patients – Interim safety analysis of the ICE study
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Critical Reviews in Oncology/Hematology 60 (2006)
possible lower activity of tamoxifen (i.e. overexpression of Her-2, lack of PR expression, etc). As for adjuvant chemotherapy, very few patients in the oldest age groups have been included in clinical trials to date. This paucity of data is the result of exclusion criteria for age in some clinical trials, and physician (or even patient) bias based on the notion that older patients will not benefit from adjuvant chemotherapy, will not tolerate it as well as younger patients, or both. In the Early Breast Cancer Trialists Collaborative Group (EBCTCG) 2005 meta-analysis only very few patients >70 were included, thus failing to show statistically significant benefits of adjuvant chemotherapy in terms of disease recurrence and survival after the age of 70 years. However, an analysis conducted to define a threshold relapse risks above which adjuvant treatment could be worth prescribing in patients aged 65−85 concluded that older breast cancer patients could expect a reduction in relapse fairly similar to that of younger patients. In addition, since some physiologic changes (including reduced glomerular filtration rate, increased susceptibility to myelotoxicity, mucositis, and cardiac and neurotoxicity) are more common in persons aged 65 years and older, age is associated with reduced tolerance to adjuvant chemotherapy with a consequent reduction in dose intensity. In particular, no data are available on the adjuvant treatment of endocrine non responsive tumors in the elderly cohort, partly because most of the time receptor negative tumors represent a relatively small subset in adjuvant studies in the elderly. The CASA (Chemotherapy Adjuvant Study for women at advanced Age) study is a phase III trial evaluating the role of adjuvant pegylated liposomal doxorubicin (PLD, Caelyx® , Doxil® ) for women >66 years with endocrine non-responsive breast cancer, who are not suitable for being offered a “standard chemotherapy regimen”. The trial, coordinated by the International Breast Cancer Study Group (IBCSG), has two individual complementary randomization options which are tailored to the investigator’s decision and/or the patient’s preference about what would constitute an appropriate control treatment group for the individual patient. Option 1, PLD versus nil, is designed for patients who, according to the treating physician and/or to the patient’s preferences, are candidates to receive no adjuvant therapy. Option 2, PLD versus low dose, metronomic cyclophosphamide and methotrexate (CM), is designed for patients who, according to the treating physician and/or to the patient’s preferences, should receive some adjuvant treatment. VA.2 08.50–09.10 Clinical trials in non-Hodgkin’s lymphoma in elderly patients P. Sonneveld, J.J. Doorduijn, P. Lugtenburg. Erasmus MC, Department of Hematology, Rotterdam, The Netherlands Non-Hodgkin’s Lymphomas (NHL) are the most common hematological malignancy with an annual incidence of 20/100.000 in the Netherlands. Among these Diffuse Large B-cell Lymphoma (DLBCL) occurs primarily (>60%) in elderly (>65 yr) patients. The specific role of higher age for the prognosis of patients with DLBCL has been addressed in the Ageadjusted International Prognostic Index (AaIPI). A population-based study in the Netherlands has identified the characteristics of NHL and the clinical outcome in the elderly [1]. Unfortunately, elderly patients have been underrepresented in prospective clinical trials and specific trials in the elderly population are relatively scarce. From 1990 the Dutch Hematologyoncology Group HOVON has conducted a series of prospective clinical trials in elderly patients with aggressive NHL/DLBCL, with the objective to improve the quality of treatment, to increase the response rate and survival and to minimize toxicity. Subsequent trials in >900 patients have investigated the significance of CHOP chemotherapy [2], the role of doseintensity [3], quality of life and health economics [4,5] and immunotherapy added to CHOP (ASH #14, 2005). In addition to other groups which showed superior results with Rituximab plus CHOP [6] or with 2-weekly CHOP [7], HOVON has demonstrated the feasibility and efficacy of 2-weekly CHOP plus Rituximab. New trials will address the relevance of achieving a rapid and durable complete response, the role of maintenance treatment, the dose-intensity of Rituximab and will introduce new, standard diagnostic tools including PET scanning and lymphoma tissue micro-array. The specific requirements and design of clinical trials in elderly patients with NHL will be discussed.
Abstracts Reference(s) [1] Maartense, E., et al., Elderly patients with non-Hodgkin’s lymphoma: populationbased results in The Netherlands. Ann Oncol, 1998. 9(11): p. 1219−27. [2] Sonneveld, P., et al., Comparison of doxorubicin and mitoxantrone in the treatment of elderly patients with advanced diffuse non-Hodgkin’s lymphoma using CHOP versus CNOP chemotherapy. J Clin Oncol, 1995. 13(10): p. 2530−9. [3] Doorduijn, J.K., et al., CHOP compared with CHOP plus granulocyte colonystimulating factor in elderly patients with aggressive non-Hodgkin’s lymphoma. J Clin Oncol, 2003. 21(16): p. 3041−50. [4] Doorduijn, J., et al., Self-reported quality of life in elderly patients with aggressive non-Hodgkin’s lymphoma treated with CHOP chemotherapy. Eur J Haematol, 2005. 75(2): p. 116−23. [5] Doorduijn, J.K., et al., Economic evaluation of prophylactic granulocyte colony stimulating factor during chemotherapy in elderly patients with aggressive nonHodgkin’s lymphoma. Haematologica, 2004. 89(9): p. 1109−17. [6] Feugier, P., et al., Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol, 2005. 23(18): p. 4117−26. [7] Pfreundschuh, M., et al., Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood, 2004. 104(3): p. 634−41.
VA.3 09.10–09.35 Adjuvant treatment in elderly breast cancer patients – Interim safety analysis of the ICE study G. von Minckwitz. Centre of Gynaecology and Obstetrics, and Breast Clinical Trials Centre, University Women’s Hospital, Frankfurt, Germany Almost 40% of all breast cancers are diagnosed in patients older than 65 years. However, as this age group is strongly under-represented in clinical trials, standard treatment is not very well described. Especially the benefit of adjuvant chemotherapy is uncertain in this age group, as co-mobidities and reduced organ capacities might increase toxicity and reduce relative dose intensity. With Capecitabine a new drug is available that has demonstrated high efficacy in metastatic breast cancer, showed a favorable safety profile with acceptable side effects, and therefore appears suitable especially for older patients. The ICE study started in July 2004 as a prospective, randomized, phase III study of 4 German collaborative groups (AGO, GBG, NOGGO, WSG). Patients older than 64 years with surgically completely excised uni- or bilateral, node positive or high risk node negative (size 2 cm, grade >I, ER and PR negative) breast cancer and adequate organ function are included. Geriatric assessment asks for a Charlson score 2 and includes the VES-13 score for reconfirmation. Patients are randomized to either 6 cycles of Capecitabine 1000 mg/m2 twice daily, days 1−14 q3w or observation. All patients receive Ibandronate, according to their choice either orally 50 mg daily or i.v. 6 mg infusion every 4 weeks for 2 years. Endocrine-sensitive patients also get Anastrozol 1 mg orally for 5 years. A planned interim safety analysis of the first 100 patients treated with Capecitabine revealed the following: Patients were in median 73 years (range 65−87) old, had in 50% positive axillary lymph nodes, in 72% steroid hormone receptor positive tumors, and their elderly performance status was assessed with a median Charlson Score of 0.53. Totally 553 (92.2%) out of 600 planned cycles of Capecitabine were applied. 75 patients received the full planned dose and 12 discontinued treatment. Capecitabine dose was reduced in 38 cycles (6.9%). 47 cycles (8.5%) were not given because of treatment discontinuation. No severe (grade 3−4) hematological toxicity occurred. The main non-hematological toxicities (% grade 3−4 of patients) were hand–foot syndrome (16%), nausea and vomiting (5%), diarrhea (4%), infection without neutropenia (2%), and cough (2%). No treatment-related death occurred. Capecitabine treatment appeared to be feasible in elderly patients with favorable hematological and acceptable non-hematological tolerability. Based on the observed safety profile in the first 100 patients, the ICE study proceeded and has recruited in May 2006 676 of the planned 1400 patients.
Critical Reviews in Oncology/Hematology 60 (2006)
possible lower activity of tamoxifen (i.e. overexpression of Her-2, lack of PR expression, etc). As for adjuvant chemotherapy, very few patients in the oldest age groups have been included in clinical trials to date. This paucity of data is the result of exclusion criteria for age in some clinical trials, and physician (or even patient) bias based on the notion that older patients will not benefit from adjuvant chemotherapy, will not tolerate it as well as younger patients, or both. In the Early Breast Cancer Trialists Collaborative Group (EBCTCG) 2005 meta-analysis only very few patients >70 were included, thus failing to show statistically significant benefits of adjuvant chemotherapy in terms of disease recurrence and survival after the age of 70 years. However, an analysis conducted to define a threshold relapse risks above which adjuvant treatment could be worth prescribing in patients aged 65−85 concluded that older breast cancer patients could expect a reduction in relapse fairly similar to that of younger patients. In addition, since some physiologic changes (including reduced glomerular filtration rate, increased susceptibility to myelotoxicity, mucositis, and cardiac and neurotoxicity) are more common in persons aged 65 years and older, age is associated with reduced tolerance to adjuvant chemotherapy with a consequent reduction in dose intensity. In particular, no data are available on the adjuvant treatment of endocrine non responsive tumors in the elderly cohort, partly because most of the time receptor negative tumors represent a relatively small subset in adjuvant studies in the elderly. The CASA (Chemotherapy Adjuvant Study for women at advanced Age) study is a phase III trial evaluating the role of adjuvant pegylated liposomal doxorubicin (PLD, Caelyx® , Doxil® ) for women >66 years with endocrine non-responsive breast cancer, who are not suitable for being offered a “standard chemotherapy regimen”. The trial, coordinated by the International Breast Cancer Study Group (IBCSG), has two individual complementary randomization options which are tailored to the investigator’s decision and/or the patient’s preference about what would constitute an appropriate control treatment group for the individual patient. Option 1, PLD versus nil, is designed for patients who, according to the treating physician and/or to the patient’s preferences, are candidates to receive no adjuvant therapy. Option 2, PLD versus low dose, metronomic cyclophosphamide and methotrexate (CM), is designed for patients who, according to the treating physician and/or to the patient’s preferences, should receive some adjuvant treatment. VA.2 08.50–09.10 Clinical trials in non-Hodgkin’s lymphoma in elderly patients P. Sonneveld, J.J. Doorduijn, P. Lugtenburg. Erasmus MC, Department of Hematology, Rotterdam, The Netherlands Non-Hodgkin’s Lymphomas (NHL) are the most common hematological malignancy with an annual incidence of 20/100.000 in the Netherlands. Among these Diffuse Large B-cell Lymphoma (DLBCL) occurs primarily (>60%) in elderly (>65 yr) patients. The specific role of higher age for the prognosis of patients with DLBCL has been addressed in the Ageadjusted International Prognostic Index (AaIPI). A population-based study in the Netherlands has identified the characteristics of NHL and the clinical outcome in the elderly [1]. Unfortunately, elderly patients have been underrepresented in prospective clinical trials and specific trials in the elderly population are relatively scarce. From 1990 the Dutch Hematologyoncology Group HOVON has conducted a series of prospective clinical trials in elderly patients with aggressive NHL/DLBCL, with the objective to improve the quality of treatment, to increase the response rate and survival and to minimize toxicity. Subsequent trials in >900 patients have investigated the significance of CHOP chemotherapy [2], the role of doseintensity [3], quality of life and health economics [4,5] and immunotherapy added to CHOP (ASH #14, 2005). In addition to other groups which showed superior results with Rituximab plus CHOP [6] or with 2-weekly CHOP [7], HOVON has demonstrated the feasibility and efficacy of 2-weekly CHOP plus Rituximab. New trials will address the relevance of achieving a rapid and durable complete response, the role of maintenance treatment, the dose-intensity of Rituximab and will introduce new, standard diagnostic tools including PET scanning and lymphoma tissue micro-array. The specific requirements and design of clinical trials in elderly patients with NHL will be discussed.
Abstracts Reference(s) [1] Maartense, E., et al., Elderly patients with non-Hodgkin’s lymphoma: populationbased results in The Netherlands. Ann Oncol, 1998. 9(11): p. 1219−27. [2] Sonneveld, P., et al., Comparison of doxorubicin and mitoxantrone in the treatment of elderly patients with advanced diffuse non-Hodgkin’s lymphoma using CHOP versus CNOP chemotherapy. J Clin Oncol, 1995. 13(10): p. 2530−9. [3] Doorduijn, J.K., et al., CHOP compared with CHOP plus granulocyte colonystimulating factor in elderly patients with aggressive non-Hodgkin’s lymphoma. J Clin Oncol, 2003. 21(16): p. 3041−50. [4] Doorduijn, J., et al., Self-reported quality of life in elderly patients with aggressive non-Hodgkin’s lymphoma treated with CHOP chemotherapy. Eur J Haematol, 2005. 75(2): p. 116−23. [5] Doorduijn, J.K., et al., Economic evaluation of prophylactic granulocyte colony stimulating factor during chemotherapy in elderly patients with aggressive nonHodgkin’s lymphoma. Haematologica, 2004. 89(9): p. 1109−17. [6] Feugier, P., et al., Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol, 2005. 23(18): p. 4117−26. [7] Pfreundschuh, M., et al., Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood, 2004. 104(3): p. 634−41.
VA.3 09.10–09.35 Adjuvant treatment in elderly breast cancer patients – Interim safety analysis of the ICE study G. von Minckwitz. Centre of Gynaecology and Obstetrics, and Breast Clinical Trials Centre, University Women’s Hospital, Frankfurt, Germany Almost 40% of all breast cancers are diagnosed in patients older than 65 years. However, as this age group is strongly under-represented in clinical trials, standard treatment is not very well described. Especially the benefit of adjuvant chemotherapy is uncertain in this age group, as co-mobidities and reduced organ capacities might increase toxicity and reduce relative dose intensity. With Capecitabine a new drug is available that has demonstrated high efficacy in metastatic breast cancer, showed a favorable safety profile with acceptable side effects, and therefore appears suitable especially for older patients. The ICE study started in July 2004 as a prospective, randomized, phase III study of 4 German collaborative groups (AGO, GBG, NOGGO, WSG). Patients older than 64 years with surgically completely excised uni- or bilateral, node positive or high risk node negative (size 2 cm, grade >I, ER and PR negative) breast cancer and adequate organ function are included. Geriatric assessment asks for a Charlson score 2 and includes the VES-13 score for reconfirmation. Patients are randomized to either 6 cycles of Capecitabine 1000 mg/m2 twice daily, days 1−14 q3w or observation. All patients receive Ibandronate, according to their choice either orally 50 mg daily or i.v. 6 mg infusion every 4 weeks for 2 years. Endocrine-sensitive patients also get Anastrozol 1 mg orally for 5 years. A planned interim safety analysis of the first 100 patients treated with Capecitabine revealed the following: Patients were in median 73 years (range 65−87) old, had in 50% positive axillary lymph nodes, in 72% steroid hormone receptor positive tumors, and their elderly performance status was assessed with a median Charlson Score of 0.53. Totally 553 (92.2%) out of 600 planned cycles of Capecitabine were applied. 75 patients received the full planned dose and 12 discontinued treatment. Capecitabine dose was reduced in 38 cycles (6.9%). 47 cycles (8.5%) were not given because of treatment discontinuation. No severe (grade 3−4) hematological toxicity occurred. The main non-hematological toxicities (% grade 3−4 of patients) were hand–foot syndrome (16%), nausea and vomiting (5%), diarrhea (4%), infection without neutropenia (2%), and cough (2%). No treatment-related death occurred. Capecitabine treatment appeared to be feasible in elderly patients with favorable hematological and acceptable non-hematological tolerability. Based on the observed safety profile in the first 100 patients, the ICE study proceeded and has recruited in May 2006 676 of the planned 1400 patients.