Adjuvant docetaxel/cyclophosphamide in breast cancer patients over the age of 70: Results of an observational study

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1 Critical Reviews in Oncology/Hematology 80 (2011) Adjuvant docetaxel/cyclophosphamide in breast cancer patients over the age of 70: Results of an observational study Gilles Freyer a,b,, Mario Campone c, Julien Peron a, Thomas Facchini d, Catherine Terret e, Jean-François Berdah f, Jean-Philippe Jacquin g, David Coeffic h, Pierre de Saint Hilaire i, Claire Falandry j a Department of Medical Oncology, Centre Hospitalier Lyon-Sud and Université de Lyon, France b EMR 3738, HCL-University Claude Bernard Lyon, Lyon, France c Centre René Gauducheau, Department of Medical Oncology, Saint Herblain, France d Polyclinique de Courlancy, Department of Medical Oncology, Reims, France e Centre Léon Bérard, Department of Medical Oncology, Lyon, France f Clinique Sainte Marguerite, Department of Medical Oncology, Hyeres, France g Institut de Cancérologie de la Loire. Department of Medical Oncology, Saint-Priest-en-Jarez, France h Institut Daniel Hollard, Department of Medical Oncology, Grenoble, France i Hôpital de la Croix Rousse, Department of Medical Oncology and Gynaecology, Lyon, France j Centre Hospitalier Lyon Sud, Department of Gerontology, Lyon, France Accepted 6 April 2011 Contents 1. Introduction Patients and methods Study design and patient population Data collection and analysis Results Patient characteristics and treatment administered Geriatric assessment Tolerance Discussion Conclusion Conflict of interest statement Role of the funding source Reviewers Acknowledgements References Biographies Abstract This retrospective observational study was designed to describe feasibility and tolerance of adjuvant Taxotere /cyclophosphamide (TC) chemotherapy in women aged over 70 years with early breast cancer. Data including geriatric evaluations were collected from the medical charts of 110 patients from 14 oncology institutions in France who had completed adjuvant systemic TC (91% received at least 4 cycles). Median age was 73 years (range 70 85), 51% of patients had breast conserving surgery, 42% had a tumor smaller than 2 cm and 33% had Corresponding author at: Service d Oncologie Médicale, Centre Hospitalier Lyon Sud, Pierre Benite Cédex, France. Tel.: ; fax: address: gilles.freyer@chu-lyon.fr (G. Freyer) /$ see front matter 2011 Elsevier Ireland Ltd. All rights reserved. doi: /j.critrevonc

2 G. Freyer et al. / Critical Reviews in Oncology/Hematology 80 (2011) positive nodes. Geriatric assessment was performed by oncologists in 88% of patients; 55% were considered fit, 5% had geriatric syndrome and 10% had more than three comorbidities. Neutropenia was reported in 15% of patients, including febrile neutropenia and/or grade 4 in 5% for each. Primary prophylactic G-CSF was given to 49% of patients. In a selected population of elderly patients, 4 cycles of adjuvant TC is feasible without major toxicity, confirming the US Oncology trial data Elsevier Ireland Ltd. All rights reserved. Keywords: Geriatric/aging; Early breast cancer; Docetaxel; Cyclophosphamide; Adjuvant 1. Introduction Life expectancy is increasing with global improvements in health care and living standards and with it comes a consequent worldwide increase in the proportion and numbers of older people. Associated with this is a rising proportion of older women having breast cancer, with more than 50% of reported cases occurring in women over the age of 65, and over 30% in women over 70 [1,2]. Adjuvant chemotherapy has proven to significantly improve survival for women with early breast cancer [3,4]. However, data on the impact of adjuvant systemic chemotherapy in the context of age-related health issues in geriatric populations and on the risk-benefit ratio are limited. Indeed, despite the high proportion of older women suffering from breast cancer, the majority of studies analyzing anticancer treatments include a relatively small proportion of older adults, notably those over the age of 70. In addition, data are rarely analyzed according to age group [5 7]. Therefore, the role of adjuvant chemotherapy in elderly patients has been questioned. Adjuvant therapy and its associated toxicity are particularly important in older patients, the presence of comorbidities such as diabetes or cardiovascular disease or concomitant medications can reduce renal function and bone reserve, and lead to a higher risk of mucositis, cardiotoxicity or neurotoxicity. Similarly, life expectancy, functional and nutritional status, cognitive function and living conditions may all impact the outcome of a cancer treatment. In the same way, it is well known that breast cancer in elderly patients is characterized by a disease with less aggressive features. Therefore few elderly patients may be offered chemotherapy compared to younger patients. Yet current data suggest that older patients may derive similar benefit as their younger counterparts, particularly those with hormone receptor negative and lymph node positive tumors [8,9]. The introduction of taxanes in the adjuvant treatment of early breast cancer added further survival benefit while reducing the risk of cardiac toxicity with anthracyclines [10,11]. Current data suggest that the rate of heart failure may increase by 10 0% among women older than 65 years when treated with anthracyclines [12]. Therefore, as the superiority of Taxotere cyclophosphamide (TC) over anthracycline/cyclophosphamide (AC) therapy [11] has been demonstrated, taxane regimens not including anthracyclines may also become widely used for elderly patients. Given that the number of patients over the age of 70 years included in most published studies was relatively small, few data are available of the tolerance of taxane-based regimens in elderly patients. We performed a retrospective observational study in breast cancer clinics across France to describe tolerance in women treated with adjuvant TC chemotherapy in routine clinical care for breast cancer, who were over the age of 70 at the time of chemotherapy administration. We also wished to describe the modalities of geriatric evaluations performed in routine practice in this population of elderly patients. 2. Patients and methods 2.1. Study design and patient population Twenty-five cancer clinics and hospitals (public and private) in France with extensive experience in the treatment of breast cancer patients were invited to participate in this retrospective observational study, 14 of which accepted. Sites were selected to ensure a wide geographic representation throughout France and on the basis of their specialist experience in the treatment of breast cancer. To be eligible, patients had to be at least 70 years old and had to have completed adjuvant chemotherapy with TC within 18 months prior to study entry. Patients who had been treated for metastatic breast cancer or who had received neoadjuvant chemotherapy were excluded from the study. Patient dossiers were reviewed between December 2009 through April 2010 in all participating institutions and all eligible women were included in the study. A total of 110 patients with early breast cancer who were treated with Taxotere /cyclophosphamide in routine practice were identified. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practices. As a non-interventional study, ethical committee approval was not required by the French regulatory authorities at the time of the study. The study was registered with the French National Commission for Data Protection (CNIL) Data collection and analysis Data were retrospectively collected for eligible patients from their medical records. Patient s demographics and breast cancer history data were recorded. TC chemotherapy (dose, modifications and compliance) and supportive treatments were also collected. Date from the following geriatric evaluations were collected when available: a medical evaluation on the basis of co-morbidities and concurrent medications;

3 468 G. Freyer et al. / Critical Reviews in Oncology/Hematology 80 (2011) nutritional status according to body mass index (BMI), and the mini nutritional assessment (MNA screening version) [13] for which a score out of 14 was calculated on the basis of six questions; a functional evaluation was made according to performance status (PS), Activities of Daily Living (ADL) [14] and Instrumental ADL (IADL) [15]; psychocognitive function was tested using the mini mental status (MMS) exam [16] and the geriatric depression scale (GDS, 4 and 30-item tests) [17,18]; a classification was retrospectively made according to the Balducci algorithm (Fit = no geriatric syndrome, significant co-morbidity or depression, MMS >26; Intermediate = no geriatric syndrome, at least three significant co-morbidities, and/or MMS 26, and/or depression, and/or minimal IADL impairment; fragile = geriatric syndrome (including permanent urine loss, osteoporosis with fracture, major denutrition) and/or >3 comorbidities and/or cognitive disorders and/or dependence) [19]. Adverse events as assessed by the treating physicians were collected for each cycle and up to a month after the last treatment administration, as reported in the medical dossier. Toxicity was graded by the physician according to National Cancer Institute Common Toxicity Criteria, version 3 and coded with the Medical Dictionary for Regulatory Activities (MedDRA, version 10). Analysis of data was descriptive (mean and standard deviations for continuous data, frequency and percentages for categorical data, 95% confidence intervals were calculated when relevant). 3. Results 3.1. Patient characteristics and treatment administered Data from 110 patients with operable breast cancer were collected. The majority of patients (n = 79, 73%) were aged years, median age being 73 years (range 70 85). Eighty-one percent of patients had ductal carcinoma. Most patients had a tumor which was estrogen receptor and/or progesterone receptor positive (62% and 40% respectively), and 12% (n = 13) had HER positive tumors (IHC3+ or FISH positive). All patients underwent had undergone primary surgery, with breast conservation for the majority (61 patients, 55%). Hormone therapy was administered to 43 patients (39%) and trastuzumab to 17 (15%). For 46 patients (42%), the tumor was smaller than 2 cm. Thirty-seven patients (33%) had pathological lymph node involvement; 29 (26%) had one to three positive nodes and 8 (7%) had more than 4 nodes involved. In terms of adjuvant systemic chemotherapy (Table 1), most patients received standard doses of docetaxel (75 mg/m 2 ) and cyclophosphamide (600 mg/m 2 ) (85 patients, 77% and 76 patients, 69%, respectively). Of the 110 patients treated, 100 (91%) completed four 3-week cycles of chemotherapy, 17 (15%) received 5 cycles and 16 (14%) had a total of six cycles. Nine patients (8%) stopped adjuvant chemotherapy before cycle 4 due to the occurrence of non-hematological toxicity. Fifty-seven patients (52%) Table 1 Adjuvant docetaxel/cyclophosphamide treatment exposure. N patients (%) (N = 110) Docetaxel 75 mg/m 2 85 (77%) <75 mg/m 2 13 (12%) >75 mg/m 2 12 (11%) Cyclophosphamide 600 mg/m 2 76 (69%) <600 mg/m 2 28 (25%) >600 mg/m 2 6 (6%) N cycles administered 1 3 cycles 105 (95%) 4 cycles 100 (91%) 5 6 cycles 16 (15%) Modifications/reductions Dose 12 (11%) Schedule 7 (6%) were given granulocyte colony-stimulating factor (G-CSF), 54 of whom received primary prophylaxis and three (3%) had erythropoietin, mainly administered from the first cycle. Dose and schedule modifications were introduced for 12 (11%) and seven patients (6%) respectively, and erythropoietin was given as secondary prophylactic treatment to six patients (5%) Geriatric assessment Comprehensive geriatric evaluations were not routinely performed, however of the 110 patients, 97 (88%) underwent evaluations in one or more areas of geriatric assessment, 51 of whom had two or three evaluations (Table 2). For the majority of patients (67%), these evaluations were performed by the oncologist. Seventy-one percent of the study population had one or more co-morbidities when they were diagnosed with breast cancer, with ten patients (11%) having three or more. The most frequent co-morbidities reported were hypertension (51%), hyper-lipidemia (28%), and cardiovascular disease (21%). Patients had a mean BMI of 25.8 ± 5.1 at diagnosis, with 48 patients (44%) being overweight or obese, while only four patients (4%) were underweight. A functional evaluation was performed in 58% of the patient population; in those patients for whom data were available, median Karnofsky PS was 100% and 71% of patients had an ECOG PS. Fortyfive patients (41%) were living with a partner and 37 (34%) lived alone at the time of therapy. Nutritional evaluations were performed in a large proportion of patients (75%). Patients had a mean MNA score of 9.8 ± 4.0 and with only minimal mean weight change over 6 months. Psycho-cognitive tests were rarely performed, with only 15 patients (14%) having data available, all but one of whom had performed an MMS test. A classification into the Balducci categories was performed a posteriori on all 110 included patients, with most patients being evaluated as fit (55%) or intermediate (40%). Six patients (5%) were identified as having a geriatric syndrome (mainly denutrition).

4 G. Freyer et al. / Critical Reviews in Oncology/Hematology 80 (2011) Table 2 Comprehensive geriatric evaluations. N patients (71%) N patients with at least one comorbidity at diagnosis (%) a Hypertension 56 (51%) Hyperlipidemia 31 (28%) Cardiovascular disease 23 (21%) Diabetes 12 (11%) Respiratory disorder 12 (11%) BMI at diagnosis, median (range), kg/m ( ) N patients (%) with BMI < (4%) [ ] 47 (43%) [25 30] 29 (26%) (17%) Functional evaluation at diagnosis, N 64 (58%) patients (%) ECOG performance status, N patients (%) 42 (66%) ECOG 0/1 30 (71%)/12 (29%) Karnofsky performance status, N patients 26 (41%) (%) Median KPS (range) 100% (80 100%) Mean ADL/IADL score (SD) 3.93 (2.89)/4.57 (3.34) Nutritional evaluation, N patients (%) 82 (75%) Mean weight change in kg, 6 months after diagnosis (range) b 0.4 ± 2.8 ( 8.0 to +5.0) Mean MNA (14-point scale) (range) c 9.8 ± 4.0 (4 14) Psycho-cognitive evaluation, N patients (%) 15 (14%) Mean MMS (30-point scale) (range) 27.1 ± 2.8 (23 30) Mean GDS (4-point scale) (range) 0.75 ± 0.8 (0 2.0) Autonomy (partner/alone/care facility), N patients (%) 45 (41%)/ 37 (34%)/ 5 (5%) Balducci at diagnosis, N patients (%) 1 (fit) 60 (55%) 2 (intermediate) 44 (40%) 3 (fragile) 6 (5%) ADL, activities of daily living; IADL, instrumental ADL; BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; KPS, Karnofsky Performance Status; MNA, mini nutritional assessment; MMS, mini mental state; GDS, geriatric depression scale. a N = 109. b N = 70. c N = Tolerance Eighty-seven patients (79%) had at least one adverse event (Table 3). The incidence of hematological AEs was relatively low, with the majority of events being mild to moderate in severity. Thirty-two patients (29%) had anemia, one of whom had a grade 4 episode. Anemia was more frequently reported after the first cycle. Neutropenia was reported in sixteen patients (15%), five of whom had grade 4, and six patients (5%; 95% CI [ %]) had febrile neutropenia (FN), two of whom received G-CSF as primary prophylaxis. Thrombocytopenia was reported in only one patient. The most common non-hematological toxicities were asthenia and gastrointestinal notably nausea (30% of patients), diarrhea (28%) and stomatitis (16%). Myalgia and fever were reported in 13 patients (12%) each and ten patients (9%) had peripheral neuropathy. Severe events were rare; six patients had grade 3 or 4 asthenia (5.5%; 95% CI [ %]) and two had grade 3 anorexia (1.8%; 95% CI [ %]). No deaths were reported during chemotherapy and a total of 12 non-fatal serious adverse events were recorded in ten patients (9.1%; 95% exact CI [4.5%; 16.1%]). All but one patient had recovered from the event at the time of data collection. One patient with four comorbidities (vascular and respiratory disease, sarcoidosis, hypothyroidism) had not recovered from a grade 3 worsening of general status combined with anorexia at the time of data collection. This same patient had two previous serious events (grade 3 back pain and urinary infection). One death was reported during follow-up in a patient due to acute leukemia. 4. Discussion Information on the use of adjuvant chemotherapy with TC is lacking in elderly patients due to the fact that very few patients in the oldest age groups have been included in clinical trials. Current guidelines [20,21] do not set an upper age limit for the use of chemotherapy, but recommend that comorbidities and life expectancy should be considered when making chemotherapy decisions. Elderly patients are considered to be at high risk for chemotherapy-induced toxicities, particularly in those who are vulnerable or fragile. Consequently, limited data are available on the tolerance of adjuvant chemotherapy in patients over 70 years of age. In order to document the tolerance of TC as adjuvant chemotherapy in this subset of the population with early breast cancer and evaluate how these patients are treated routinely in current practice, we conducted a retrospective observational study in a cohort of 110 women aged over 70 years who had received the combination regimen in 14 oncology institutions in France. Analysis of the data collected from the medical charts of these patients showed that this regimen was well tolerated: 91% of the patients completed four cycles of TC, and no patients died during chemotherapy. Compliance to chemotherapy was high (77% of the patients had the complete planned dose of Taxotere and 69% received the complete planned dose of cyclophosphamide) and dose reductions were seldom performed (11% of patients), and were mainly for logistical reasons. A number of patients received more than the standard four chemotherapy cycles due to a belief held by some French oncologists that four cycles are inadequate. The incidence of side effects recorded during chemotherapy was low and the majority of the adverse events were of mild to moderate intensity. The most common adverse events were asthenia (37% of patients), gastrointestinal (nausea and diarrhea in 29% and 28% of the patients, respectively) and anemia (29% of patients). Docetaxel-related side effects such as myalgia and arthralgia were observed in only 12% and 8% of patients, respectively. Surprisingly no episodes of

5 470 G. Freyer et al. / Critical Reviews in Oncology/Hematology 80 (2011) Table 3 Incidence of toxicity ( 1%) whatever the relationship, by patient and cycle. N patients/cycles with at least one episode of By patient By cycle All grades (N = 110) Grade 3 4 (N = 110) Cycle 1 (N = 110) All cycles (N = 456) Hematologic toxicity a Anemia 29% 1 8% 17% Neutropenia 15% 8% 5% 4% Febrile neutropenia 5% (n =6) 4%(n =4) Thrombocytopenia 1% Non-hematologic toxicity Asthenia 37% 5% 14% 18% Nausea 30% 1% 18% 11% Diarrhea 28% 16% 8% Alopecia 23% 1% 13% 16% Stomatitis 16% 9% 5% Vomiting 13% 6% 4% Myalgia 12% 6% 6% Fever 12% 6% 3% Allergy 10% 1% 5% 3% Peripheral neuropathy 9% 3% Pain back 9% 1% 4% 3% Pain abdominal 8% 2% 5% Arthralgia 8% 4% Taste changes 7% 3% Anorexia 6% 2% Dyspnea 4% 1% a Complete blood cell tests during chemotherapy were performed as per routine institution practice. edema of the lower extremities were reported by the treating physicians. Neutropenia was recorded in 15% (n = 16) of the patients with only nine patients (8%) having experienced a grade 3 or 4 toxicity, six of whom (5%) had febrile neutropenia. Hematological toxicity is one of the limiting toxicities of the TC regimen. In the pivotal US Oncology adjuvant 9375 trial [10,11] evaluating TC versus AC, the incidence of FN was low, however when using a cut-off of 65 years, the TC regimen was associated with a higher rate of FN compared to the AC regimen for the subgroup of patients aged over 65 years (n = 160) compared to younger patients (n = 856) (8% vs. 4% and 4% vs. 2%, respectively). Given that the use of G-CSF as primary prophylaxis was not allowed in this study, the authors attributed these low rates of FN to the widespread use of prophylactic antibiotics and G-CSF as secondary prophylaxis during the conduct of the study. In a trial conducted by Takabatake et al. [22] on a small population of 53 Japanese patients with early breast cancer aged between 20 and 70 years who received 4 cycles of adjuvant TC, chemotherapy was associated with a high incidence of hematological toxicity. When considering the age subgroups, a lower chemotherapy completion rate (40% vs. 100%), a higher rate of dose reduction (40% vs. 4%) and a higher incidence of FN (88% vs. 23%) were reported among patients aged over 65 years compared to younger patients. No prophylactic antibiotics were given in this trial, G-SCF support was required more in the elderly patients (>65 years) than in younger patients (40% vs. 15%). However, no formal conclusion could be drawn on the tolerability of TC in this study in elderly patients since the number of patients aged 65 years or over included in was very small (n = 5). In a pooled analysis of four randomized and prospective German studies performed by Loibl et al. [23], of more than 4500 women with primary breast cancer who received taxane-based regimens, the incidence of leukopenia and neutropenia increased with age, but the incidence of FN was found to be similar between age groups (n = 3160 <60 years, n = 645 between 60 and 64 years, and n = 422 >64 years) for patients receiving docetaxel-based regimen (7.2% vs. 8.1% vs. 8.7%, respectively). The incidences of neutropenia and FN in our cohort of patients were particularly low, notably given that our population was older than those in most published studies with elderly patients. There is currently a general agreement to consider the threshold to define an elderly population as 70 years rather than 65 years. In our cohort, prophylactic G-CSF was used in more than half of the patients (n = 57; 52%) and for the majority of them (n = 54; 94.7%), G-CSF was administered from the first cycle of adjuvant chemotherapy, suggesting that growth factors are routinely used in the clinical practice in elderly patients to support an optimal delivery of chemotherapy. Current guidelines [24,25] do not recommend the use of primary G-CSF in patients receiving chemotherapy expect for regimens which induce a febrile neutropenia rate of 10 20%. No clear recommendations exist with regards to elderly patients. Nevertheless, criteria such as age over 65 years, poor performance and nutritional status are generally considered as risk factors that should be taken into account for the use of G-SCF. In a study performed by Balducci et al. [26], comparing the use of CSF (pegfilgrastim) as primary versus secondary prophylaxis in 852 patients aged over 65 years, patients with solid tumors who received primary pro-

6 G. Freyer et al. / Critical Reviews in Oncology/Hematology 80 (2011) phylaxis had a 60% lower incidence of FN across all cycles, a lower incidence of grade 3 or 4 neutropenia (30% of patients vs. 80%) and lower rate of hospitalization for neutropenia (5% of patients vs. 9%). Another observation from our cohort of patients which could explain the good tolerability of the TC regimen was that overall, patients were relatively young; only 30% of the patients were >75 years, the majority of patients had a good performance status, 10% had three or more co-morbidities and only 5% were identified as having a geriatric syndrome at the initiation of the adjuvant chemotherapy (55% of the patients were evaluated as fit and 41% patients were living with a partner). As a surrogate marker of life expectancy, comorbidity represents one of the key elements to consider in treatment selection for elderly patients. The presence of comorbidities is associated with an increased risk of toxicity and mortality in older patients [2,27]. However, co-morbidity is not the sole factor that is important to consider when evaluating elderly patients. A Comprehensive Geriatric Assessment (CGA) [28] which includes an evaluation of all functional, cognitive, social, psychological, and nutritional status and medication in use is usually needed and can be of a great value, particularly in vulnerable patients, and may predict chemotherapy toxicity [29]. However the scarcity of gerontologists and the time needed for CGA completion may make it difficult to perform systematically in older cancer patients. In our cohort of patients, a some elements of a functional evaluation were performed in 58% of the patient. Nutritional evaluations were done in 75% of the patients, while psychocognitive tests were rarely performed (14% of the patients only in our cohort). Collaboration with a geriatrician to perform a CGA is rare in routine practice. Not surprisingly, 67% of the evaluations in our cohort were done by the treating physicians (oncologists). These results suggest that the TC regimen is feasible and safe in this selected and relatively fit population of elderly patients in current practice. Our study has nevertheless some limitations that are worth noting, given the retrospective and observational nature of the study, the reported incidence rate of neutropenia might have been underestimated since weekly blood tests were not performed systematically during chemotherapy, except when the patient had fever to rule out febrile neutropenia, as per routine practice. Despite this limitation, the low incidence of febrile neutropenia suggests that the TC regimen is well tolerated in elderly patients over 70 years. In addition, while analysis of tolerance by age subgroups (older than 85 years vs. younger than 85 years) may be interest, this was not performed given the small number of patients aged more than 85 years. 5. Conclusion This retrospective and observational study confirms that the adjuvant TC regimen can be safely administered as adjuvant treatment for early breast cancer in women over 70 years, in routine practice for elderly patients with long residual life expectancy and no major co-morbidities. Clinical trials evaluating the tolerability of adjuvant chemotherapy in elderly patients are needed. Conflict of interest statement Professor Gilles Freyer acts as a consultant for Sanofi- Aventis France. All other authors declare no conflict of interest. Role of the funding source This work was in part supported by a grant from Sanofi- Aventis France for the design of the study, the collection and analysis of the data. Reviewers Arti Hurria M.D., Director of Cancer and Aging Research Program, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, United States. Sibylle Loibl, M.D., German Breast Group, Medicine and Research, Martin-Behaim-Str. 12, D Neu-Isenburg, Germany. Acknowledgements We would like to thank all the following physicians who included patients in this study: Dr M.A Mouret-Renier (Centre de Lutte Contre le Cancer d Auvergne Jean Perrin, Clermont-Ferrand), Dr D. Jaubert (Clinique Tivoli, Bordeaux), Dr C. Villanueva (CHU Besançon), Dr D. Spaeth (Centre d Oncologie, Nancy), Dr N. Jovenin (Institut Godinot, Reims) and Dr P. Laplaige (Polyclinique de Blois). References [1] Jemal A, Clegg LX, Ward E, et al. Annual report to the nation on the status of cancer, , with a special feature regarding survival. Cancer 2004;101(1):3 27. [2] Yancik R, Ries LA. Cancer in older persons: an international issue in an aging world. 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Probabilities of death from breast cancer and other causes among female breast cancer patients. J Natl Cancer Inst 2004;96: [28] Extermann M, Hurria A. Comprehensive geriatric assessment for older patients with cancer. J Clin Oncol 2007;25: [29] Maas HA, Janssen-Heijnen ML, Olde Rikkert MG, Machteld Wymenga AN. Comprehensive geriatric assessment and its clinical impact in oncology. Eur J Cancer 2007;43: Biographies Gilles Freyer M.D.; Ph.D. is a senior medical oncologist in the Medical Oncology Department of the Centre Hospitalier Lyon-Sud, France and Professor of Oncology at Lyon-Sud University Hospital, a position he has held since Professor Freyer obtained his M.D. in 1994, achieved his specialization in Medical Oncology in 1995 and completed degrees in psychophysiology and clinical pharmacology at the University of Lyon I in 1995 and 1996, respectively. He obtained a Masters in Human Biology from the University of Lyon I in 1996 and completed a specialization in bioethics at the University of Paris V Necker in In 2000, he obtained a Ph.D. in population pharmacokinetics from the University of Lyon I. Professor Freyer is a member of the International Scientific Committee of INCa (French National Cancer Institute) and has led the elderly women clinical trials program of the GINECO group. He is the coordinator of numerous national phase I III clinical trials and is an investigator in several international and national phase I III trials. He is the Director of the EA 3738 laboratory at the University of Lyon I which is focussed on research in Therapeutic targeting in oncology PK/PD analyses and modelling. Professor Freyer has published widely in national and international peer-reviewed scientific journals. He was in charge of the elderly women session at the 4th Ovarian World Consensus Conference in June, 2010 (Vancouver, Canada). Mario Campone M.D.; Ph.D. is a senior medical oncologist at Centre René Gauducheau and President of the Medical Commission on Breast Cancer. Julien Peron is currently completing his medical degree and speciliazation in medical oncology. He obtained a Masters in Infectiology and Immunology in 2008 and in Biostatistics and Modelling in He is currently a fellow in the medical oncology department of the Centre Hospitalier Lyon Sud. Thomas Facchini M.D. is a senior medical oncologist at the Polyclinique de Courlancy. Formerly, he was the head of Oncology Department of Thionville-Metz Hospital. Catherine Terret M.D.; Ph.D. is a senior medical oncologist at Centre Léon Bérard, involved in the regional geronto-oncologic collaborative network. Jean-François Berdah M.D. is a senior medical oncologist at Clinique Sainte Marguerite, Hyères.

8 G. Freyer et al. / Critical Reviews in Oncology/Hematology 80 (2011) Jean-Philippe Jacquin M.D. is a senior medical oncologist at the Institut de Cancérologie de la Loire. David Coeffic M.D. is a senior medical oncologist at Institut Daniel Hollard, Grenoble. Pierre de Saint Hilaire M.D. is a senior surgeon, responsible for gynecology at the Hospital de la Croix Rousse. Claire Falandry M.D.; Ph.D. is a senior geriatrician in the department of gerontology at Lyon Sud Hospital. She obtained her specialization in medical oncology and became Assistant Professor at the Lyon-Sud School of Medicine.