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Adjuvant chemotherapy in elderly patients with breast cancer: a survey of the Breast International Group (BIG)
Annals of Oncology 15: 207–210, 2004 DOI: 10.1093/annonc/mdh062
Original article
Adjuvant chemotherapy in elderly patients with breast cancer: a survey of the Breast International Group (BIG) L. Biganzoli1*, A. Goldhirsch2, C. Straehle3, M. Castiglione-Gertsch4, P. Therasse5, M. Aapro6, A. Minisini7 & M. J. Piccart1 On behalf of BIG 1
Jules Bordet Institute, Brussels, Belgium; 2European Institute of Oncology, Milan, Italy; 3BIG secretariat, Brussels, Belgium; 4IBCSG Coordinating Center, Bern, Switzerland; 5EORTC Data Center, Brussels, Belgium; 6Multidisciplinary Oncology Institute, Clinique de Genolier, Genolier for the EORTC Task Force Cancer in the Elderly; 7EORTC-IDBBC, Brussels, Belgium Received 8 August 2003; accepted 3 October 2003
cancer patients.
Materials and methods: A questionnaire was circulated among the members of the Breast International Group.
Results: A total of 277 oncologists from 28 countries participated in the survey. Seventy years is the age cutoff commonly used to define a patient as elderly. Biological age and the biological characteristics of the tumor are the most frequently used criteria to propose adjuvant chemotherapy to an elderly patient. Combination therapy with cyclophosphamide, methotrexate and fluorouracil on days 1 and 8 is the most frequently prescribed regimen. Great interest exists in oral chemotherapy. Conclusion: There is interest among those who responded to the survey to validate a comprehensive geriatric assessment for use as a predictive instrument of toxicity and/or activity of anticancer therapy and to evaluate the role of a treatment option that is potentially less toxic and possibly as effective as polychemotherapy. Key words: adjuvant chemotherapy, breast cancer, elderly, geriatric oncology, survey
Introduction Breast cancer is the most common cancer among women, with 1.05 million new cases worldwide in 2000 [1]. Almost half of all cases occur in women aged ≥65 years. The incidence rises with advancing age, which translates into an eight-fold higher mortally rate in elderly women compared to the younger population. Demographic trends suggest that by 2025 the number of elderly women diagnosed with breast cancer in the USA will increase by 72% if incidence rates remain constant [2]. Elderly cancer patients have usually been excluded from clinical trials [3]. The Oxford Overview has shown that polychemotherapy induces a highly significant benefit in terms of relapse and survival rates in breast cancer patients up to the age of 70 years, even if this seems to decrease with increasing age [4]. Unfortunately, only 600 women aged ≥70 years were included in the 47 adjuvant chemotherapy trials analyzed, rendering it impossible to estimate the benefit of chemotherapy in this age group. Even when focusing on the entire postmenopausal population included in clinical trials, an estimation of the benefit from adjuvant chemo-
*Correspondence to: Dr L. Biganzoli, ‘Sandro Pitigliani’ Medical Oncology Unit, Department of Oncology, Hospital of Prato, Piazza dell’ospedale 2, 59100 Prato, Italy. Tel: +39-0574-434334; Fax: +39-0574-29798; E-mail: [email protected] © 2004 European Society for Medical Oncology
therapy becomes arduous. Indeed, the effects of chemotherapy in trials also investigating endocrine therapies is likely to be negligible for postmenopausal women with lower risk of relapse (i.e. nodenegative disease) [5, 6]. On the other hand, for postmenopausal women with endocrine unresponsive disease, chemotherapy is likely to be as effective as in younger women [7]. Medical oncologists are often faced with elderly patients who might ‘theoretically’ benefit from an adjuvant treatment (i.e. women with endocrine unresponsive disease, with doubtful endocrine responsiveness or with a very high risk of relapse), but find themselves unable to base their decision-making on specific and relevant data. Clinical trials are therefore needed to specifically investigate properly tailored treatment regimens for elderly patients. A questionnaire was circulated among the members of the Breast International Group (BIG) to evaluate their attitudes about treating elderly patients with early breast cancer in daily practice and to find out which are for them the most important issues to be evaluated in future clinical trials [8].
Materials and methods BIG is a consortium of over 30 co-operative groups with strong academic links based in Europe, Australia, New Zealand, South Africa, South America and Canada that have affiliated centers around the world. BIG functions as a co-
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 17, 2015
Background: To collect oncologists’ experience and opinion on adjuvant chemotherapy in elderly breast
208
Figure 1. Adjuvant chemotherapy regimens used in daily practice. Score: 0, 0% investigators; 10, 100% investigators. CMF 1,8, cyclophosphamide plus methotrexate plus fluorouracil (CMF) given on days 1 and 8.
Results Questionnaires were completed by 277 oncologists, who work mainly in comprehensive cancer centers (41%) or in teaching hospitals (33%). Less than 1% (one physician) of the oncologists who participated in this survey never dealt with elderly cancer patients, while an equal proportion of the participants, 50.7% versus 48.9%, respectively, were scarcely (<20% of their practice) or substantially involved in the care of older patients. Questionnaires were returned from 28 different countries: Australia (11), Austria (five), Belgium (16), Brazil (four), Canada (20), Chile (six), Croatia (one), Czech Republic (one), Egypt (one), France (six), Germany (98), Greece (three), Hungary (one), Israel (four), Italy (23), Peru (two), Poland (13), Portugal (three), Russia (two), Singapore (one), Slovenia (two), South Africa (four), Spain (eight), Sweden (two), Switzerland (12), The Netherlands (12), UK (10) and Yugoslavia (six). The first part of the questionnaire focused on how elderly patients with early breast cancer are approached and treated in daily practice. The following issues were investigated.
Role of chronological age The chronological age used to define a patient as elderly was ≥65, ≥70 and ≥75 years by 13, 62 and 25% of the participants in the survey, respectively. Overall, 43% of those responding to the survey did not believe that patients above a certain age should be denied adjuvant chemotherapy; among those who did favor a cutoff point, the ages were defined at ≥70, ≥75 and ≥80 years by 28, 21 and 8% of the oncologists, respectively.
Criteria considered for proposing adjuvant chemotherapy The following options were given to the participants: biological characteristics of the tumor, patient’s chronological age, patient’s biological age, social conditions, and all the previously mentioned conditions. Multiple answers were allowed. Patient’s biological
age and the biological characteristics of the tumor were the most frequently voted criteria, chosen by 65% and 59% of the participants in the survey, respectively. Patient’s chronological age was considered as one of the criteria for selection by 23% of the surveyed oncologists.
Collaboration with a geriatrician/geriatric assessment (GA) Only 2% of the oncologists collaborate on a regular basis with a geriatrician, while the majority never (48%) or rarely (37%) cooperate with this specialist. No difference was seen in this attitude between oncologists working in comprehensive cancer centers, in which a geriatric department is usually not available, and colleagues practicing in teaching or general hospitals. The survey also investigated whether in clinical practice the oncologists perform any geriatric assessment before proposing adjuvant chemotherapy to an elderly patient. The answers were ‘routinely’ (12%), ‘sometimes’ (29%) and ‘never’ (59%). Among the investigators who perform a GA, the most frequently used instruments are the activities of daily living scale (ADL) (61%), a co-morbidity scale (49%) and the mini-mental state evaluation (38%) [9–11]. Twenty-two per cent of the participants surveyed answered that a GA should be performed routinely. In addition, one-half would be interested in validating the role of the GA as a predictive factor of toxicity/activity of anticancer treatment and of treatment compliance, even though they remain unconvinced about an additive value of GA over classic instruments (i.e. performance status, blood test, assessment of cardiac function) to define the general status of an elderly candidate for adjuvant chemotherapy.
Chemotherapy regimens/primary prophylaxis with growth factors We investigated which adjuvant chemotherapy regimens are most frequently used in clinical practice. The options considered were cyclophosphamide plus methotrexate plus fluorouracil (CMF) given on days 1 and 8 (CMF 1,8), standard anthracycline-based regimens, 3-weekly CMF and personalized regimens defined as single-agent therapy or reduced-dose regimens. The issue of treatment duration was also examined. The results are described in Figure 1. CMF 1,8 every 4 weeks was the most commonly used regimen in the countries surveyed, with the exception of the UK in which 3-weekly CMF is frequently used. Agreement exists on the potentially favorable role of oral chemotherapy in elderly patients.
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 17, 2015
ordinating body for the flow of information among its members. The questionnaire was e-mailed by an officer of the BIG Secretariat to all of its member groups’ key representatives for further circulation among the oncologists affiliated with each group. The questionnaires were returned by fax or e-mail to the BIG Secretariat, after which a descriptive analysis of the collected data was performed.
209 Table 1. Role of oral chemotherapy in the elderly The use of an oral drug as adjuvant chemotherapy is
Agree strongly (%)
Agree (%)
Very interesting—patient can take it at home
37
44
6
11
2
Very interesting—does not require venous access
40
40
8
10
2
Not recommended—patient can stop without informing physician
7
23
14
49
7
Not recommended—patient can forget to take it
7
30
13
43
7
Not recommended—patient may take many other pills
8
26
19
37
10
The advantages exceed possible disadvantages
24
47
14
9
6
Study design/study end point Assuming that polychemotherapy is also a standard adjuvant treatment in elderly patients, we asked the participants to choose one or more of the three following options to be the subject of a trial in healthy elderly women with operable breast cancer: option A, standard chemotherapy versus no chemotherapy; option B, standard chemotherapy versus a treatment that is potentially less toxic and possibly as effective as polychemotherapy, i.e. singleagent chemotherapy; and option C, standard chemotherapy versus a treatment option that is potentially more toxic and considered to be potentially more effective than standard polychemotherapy. The answers indicated that the most adequate study designs were options B and A for 76% and 25% of the respondents, respectively. It was considered important to investigate a no-chemotherapy arm by an additional 7% of the oncologists who responded to the question proposing alternative study designs, i.e. single-agent chemotherapy versus no chemotherapy or a three-arm study of polychemotherapy versus single-agent chemotherapy versus nil. Of note, only 2% of the surveyed participants were interested in exploring option C. The questions on the most appropriate study design for vulnerable women, defined as patients presenting with functional limitations [i.e. Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2] and/or co-
Disagree (%)
Disagree strongly (%)
morbidities (i.e. ≥3 concomitant diseases) were tackled with slightly different options for choice and the corresponding answers were tailored chemotherapy (i.e. single-agent chemotherapy) versus no chemotherapy (62%); same study design as in the healthy patients (13%); and no role for adjuvant chemotherapy in this subgroup of patients (25%). Quality-adjusted survival (44%) and disease-free survival (42%) were considered the most appropriate primary study end points to be evaluated in an elderly-focused adjuvant chemotherapy trial. Overall survival and quality of life have been chosen by 15% and 30% of the respondents, respectively.
Discussion There are limited data from clinical trials to define the optimal use of adjuvant chemotherapy for elderly women, and almost no information is available on which criteria are used to consider these patients as eligible for chemotherapy and how they are routinely treated. BIG’s survey was aimed at obtaining some information on what oncologists assume to be current practice in this field. There was no attempt to perform an audit on what is actually being proposed and administered. There is general agreement among the surveyed oncologists that if chronological age is used as a frame of reference to define the elderly population, the age of 70 years represents an appropriate landmark. No agreement exists, however, on the cut-off age for denying adjuvant chemotherapy to an elderly patient with early breast cancer. Of note, 28% of the surveyed oncologists set this cut-off age at 70 years and 21% at 75 years. This attitude is questionable if we consider that the expected median survival for a 70- and an 80-year-old woman is 15.5 and 9.2 years, respectively [12]. Despite patient’s biological age being the most frequently used criterion to decide whether adjuvant chemotherapy may be proposed, only a minority of oncologists perform a GA. Currently, a comprehensive GA (CGA) may provide the best estimation of an individual’s functional reserve and life expectancy. There is recent evidence that a CGA adds information to the ECOG PS and that some functional scales, i.e. ADL and instrumental ADL,
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 17, 2015
The reasons to support this treatment administration are reported in Table 1. The question about whether primary prophylaxis with hematopoietic colony-stimulating factors is carried out routinely, performed only in frail patients, or never performed was answered positively by 3, 50 and 47% of respondents, respectively. Major differences existed among the countries surveyed. According to the results, primary prophylaxis is almost never or rarely performed by the surveyed oncologists in Australia, the UK and Canada, while in Austria and Germany the vast majority of frail patients received primary growth factor support. The second part of the questionnaire focused on clinical trials and, in particular, on the most appropriate study design and end points to be considered in trials of adjuvant chemotherapy for elderly patients.
Don’t know (%)
210
Acknowledgements We would like to thank the members of BIG who participated in this survey. We also thank Ms G. Vogt, Ms N. Santoro and Ms C. Saravia for their assistance.
References 1. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001; 2: 533–543.
2. Alberg AJ, Singh S. Epidemiology of breast cancer in older women: implications for future healthcare. Drugs Aging 2001; 18: 761–772. 3. National Cancer Institute. Facts and figures about cancer clinical trials. http://www.nci.nih.gov/clinicaltrials/facts-and-figures 4. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998; 352: 930–942. 5. International Breast Cancer Study Group (IBCSG). Endocrine responsiveness and tailoring adjuvant therapy for postmenopausal lymph nodenegative breast cancer: a randomized trial. J Natl Cancer Inst 2002; 94: 1054–1065. 6. Hartman AR, Fleming GF, Dillon JJ. Meta-analysis of adjuvant cyclophosphamide/methotrexate/5-fluorouracil chemotherapy in postmenopausal women with estrogen receptor-positive breast cancer. Clin Breast Cancer 2001; 2: 138–143. 7. Cole BF, Gelber RD, Gelber S et al. Polychemotherapy for early breast cancer: an overview of the randomised clinical trials with quality-adjusted survival analysis. Lancet 2001; 358: 277–286. 8. Biganzoli L, Goldhirsch A, Straehle C et al. Breast International Group (BIG) survey of medical oncologist attitudes to the management of elderly patients (pts) with early breast cancer (BC). Ann Oncol 2002; 13 (Suppl 5):105 (Abstr 380P). 9. Katz S, Downs TD, Cash HR, Grotz RC. Progress in development of the index of ADL. Gerontologist 1970; 10: 20–30. 10. Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969; 9: 179– 186. 11. Folstein MF, Folstein SE, McHugh PR. “Mini-Mental State”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–198. 12. Kimmick GG, Balducci L. Breast cancer and aging. Clinical interactions. Hematol Oncol Clin North Am 2000; 14: 213–234. 13. Repetto L, Fratino L, Audisio RA et al. Comprehensive geriatric assessment adds information to Eastern Cooperative Oncology Group performance status in elderly cancer patients: An Italian Group for Geriatric Oncology study. J Clin Oncol 2002; 20: 494–502. 14. Zagonel V, Fratino L, Piselli P et al. The comprehensive geriatric assessment (CGA) predicts mortality among elderly cancer patients (ECP). Proc Am Soc Clin Oncol 2002; 21: 365a (Abstr 1458). 15. Crivellari D, Bonetti M, Castiglione-Gertsch M et al. Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breast cancer: The International Breast Cancer Study Group Trial VII. J Clin Oncol 2000; 18: 1412–1422. 16. Extermann M, Aapro M. Assessment of the older cancer patient. Hematol Oncol Clin North Am 2000; 14: 63–77. 17. Lichtman S, Skirvin JA, Vemulapalli S. Pharmacology of antineoplastic agents in older cancer patients. Crit Rev Oncol Hematol 2003; 46: 101– 114. 18. Colleoni M, Litman HJ, Castiglione-Gertsch M et al. Duration of adjuvant chemotherapy for breast cancer: a joint analysis of two randomised trials investigating three versus six courses of CMF. Br J Cancer 2002; 86: 1705–1714. 19. Fargeot P, Roche H, Bonneterre JM et al. Disease-free survival (DFS) advantage of weekly epirubicin plus tamoxifen vs tamoxifen (Tam) alone as adjuvant treatment of operable, node-positive (N+) elderly breast cancer (BC) patient (pts): 5 year-follow-up results of French adjuvant study group, FASG-08 trial. Proc Am Soc Clin Oncol 2002; 21: 37a (Abstr 145).
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 17, 2015
allow the prediction of survival probability for elderly cancer patients, irrespective of PS and type of cancer [13, 14]. CGAs are far from being performed in daily practice, but it is important to note that the majority of the participants in this survey are convinced about the need to use/validate a CGA as a predictive instrument of toxicity and/or activity of anticancer therapy in the elderly. Elderly patients are mainly treated with chemotherapy regimens that are considered standard for the younger population, and CMF given for six courses is the most frequently used treatment regimen. Yet, concern exists about whether this treatment represents a favorable option in the elderly. In fact, Crivellari et al. [15] showed that CMF tolerability and effectiveness were both reduced for older patients compared with younger women in the context of the International Breast Cancer Study Group Trial VII in which estrogen receptor positive postmenopausal patients were randomized between tamoxifen and tamoxifen plus three cycles of classic CMF. Some of this toxicity may be related to renal clearance, which is an issue also for other agents, such as capecitabine. The evaluation of renal clearance, and in general the pharmacology of cytoxic agents in the elderly is still under investigation [16, 17]. Also questionable is whether elderly patients should receive six cycles of CMF based on the results of a recent joint analysis of two trials that investigated three versus six courses of CMF [18]. Recently, Fargeot et al. [19] have shown that weekly epirubicin prolongs disease-free survival when added to tamoxifen in node-positive patients aged ≥65 years. Great interest exists in evaluating the role of treatments with low toxic profiles, i.e. single-agent chemotherapy, as demonstrated by an ongoing study in the USA and Canada. In this trial, patients aged ≥65 years who present with a carcinoma of the breast >3 cm, or with positive axillary nodes, are randomized to receive either a ‘standard’ polychemotherapy (four courses of doxorubicin–cyclophosphamide or six courses of classic CMF in case of impaired cardiac function) or single-agent capecitabine for six cycles. The results of our survey confirmed that there is significant interest within the oncological community to investigate single-agent, oral treatment options. The BIG survey was also designed to determine the most important issues to be included in a comprehensive approach to the problem. Respondents showed interest in the evaluation of the role of a CGA to predict treatment effectiveness and safety, and in the use of potentially less toxic, yet effective therapies. One or more BIG trials on this subject will be based on the information provided by this survey.
Original article
Adjuvant chemotherapy in elderly patients with breast cancer: a survey of the Breast International Group (BIG) L. Biganzoli1*, A. Goldhirsch2, C. Straehle3, M. Castiglione-Gertsch4, P. Therasse5, M. Aapro6, A. Minisini7 & M. J. Piccart1 On behalf of BIG 1
Jules Bordet Institute, Brussels, Belgium; 2European Institute of Oncology, Milan, Italy; 3BIG secretariat, Brussels, Belgium; 4IBCSG Coordinating Center, Bern, Switzerland; 5EORTC Data Center, Brussels, Belgium; 6Multidisciplinary Oncology Institute, Clinique de Genolier, Genolier for the EORTC Task Force Cancer in the Elderly; 7EORTC-IDBBC, Brussels, Belgium Received 8 August 2003; accepted 3 October 2003
cancer patients.
Materials and methods: A questionnaire was circulated among the members of the Breast International Group.
Results: A total of 277 oncologists from 28 countries participated in the survey. Seventy years is the age cutoff commonly used to define a patient as elderly. Biological age and the biological characteristics of the tumor are the most frequently used criteria to propose adjuvant chemotherapy to an elderly patient. Combination therapy with cyclophosphamide, methotrexate and fluorouracil on days 1 and 8 is the most frequently prescribed regimen. Great interest exists in oral chemotherapy. Conclusion: There is interest among those who responded to the survey to validate a comprehensive geriatric assessment for use as a predictive instrument of toxicity and/or activity of anticancer therapy and to evaluate the role of a treatment option that is potentially less toxic and possibly as effective as polychemotherapy. Key words: adjuvant chemotherapy, breast cancer, elderly, geriatric oncology, survey
Introduction Breast cancer is the most common cancer among women, with 1.05 million new cases worldwide in 2000 [1]. Almost half of all cases occur in women aged ≥65 years. The incidence rises with advancing age, which translates into an eight-fold higher mortally rate in elderly women compared to the younger population. Demographic trends suggest that by 2025 the number of elderly women diagnosed with breast cancer in the USA will increase by 72% if incidence rates remain constant [2]. Elderly cancer patients have usually been excluded from clinical trials [3]. The Oxford Overview has shown that polychemotherapy induces a highly significant benefit in terms of relapse and survival rates in breast cancer patients up to the age of 70 years, even if this seems to decrease with increasing age [4]. Unfortunately, only 600 women aged ≥70 years were included in the 47 adjuvant chemotherapy trials analyzed, rendering it impossible to estimate the benefit of chemotherapy in this age group. Even when focusing on the entire postmenopausal population included in clinical trials, an estimation of the benefit from adjuvant chemo-
*Correspondence to: Dr L. Biganzoli, ‘Sandro Pitigliani’ Medical Oncology Unit, Department of Oncology, Hospital of Prato, Piazza dell’ospedale 2, 59100 Prato, Italy. Tel: +39-0574-434334; Fax: +39-0574-29798; E-mail: [email protected] © 2004 European Society for Medical Oncology
therapy becomes arduous. Indeed, the effects of chemotherapy in trials also investigating endocrine therapies is likely to be negligible for postmenopausal women with lower risk of relapse (i.e. nodenegative disease) [5, 6]. On the other hand, for postmenopausal women with endocrine unresponsive disease, chemotherapy is likely to be as effective as in younger women [7]. Medical oncologists are often faced with elderly patients who might ‘theoretically’ benefit from an adjuvant treatment (i.e. women with endocrine unresponsive disease, with doubtful endocrine responsiveness or with a very high risk of relapse), but find themselves unable to base their decision-making on specific and relevant data. Clinical trials are therefore needed to specifically investigate properly tailored treatment regimens for elderly patients. A questionnaire was circulated among the members of the Breast International Group (BIG) to evaluate their attitudes about treating elderly patients with early breast cancer in daily practice and to find out which are for them the most important issues to be evaluated in future clinical trials [8].
Materials and methods BIG is a consortium of over 30 co-operative groups with strong academic links based in Europe, Australia, New Zealand, South Africa, South America and Canada that have affiliated centers around the world. BIG functions as a co-
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 17, 2015
Background: To collect oncologists’ experience and opinion on adjuvant chemotherapy in elderly breast
208
Figure 1. Adjuvant chemotherapy regimens used in daily practice. Score: 0, 0% investigators; 10, 100% investigators. CMF 1,8, cyclophosphamide plus methotrexate plus fluorouracil (CMF) given on days 1 and 8.
Results Questionnaires were completed by 277 oncologists, who work mainly in comprehensive cancer centers (41%) or in teaching hospitals (33%). Less than 1% (one physician) of the oncologists who participated in this survey never dealt with elderly cancer patients, while an equal proportion of the participants, 50.7% versus 48.9%, respectively, were scarcely (<20% of their practice) or substantially involved in the care of older patients. Questionnaires were returned from 28 different countries: Australia (11), Austria (five), Belgium (16), Brazil (four), Canada (20), Chile (six), Croatia (one), Czech Republic (one), Egypt (one), France (six), Germany (98), Greece (three), Hungary (one), Israel (four), Italy (23), Peru (two), Poland (13), Portugal (three), Russia (two), Singapore (one), Slovenia (two), South Africa (four), Spain (eight), Sweden (two), Switzerland (12), The Netherlands (12), UK (10) and Yugoslavia (six). The first part of the questionnaire focused on how elderly patients with early breast cancer are approached and treated in daily practice. The following issues were investigated.
Role of chronological age The chronological age used to define a patient as elderly was ≥65, ≥70 and ≥75 years by 13, 62 and 25% of the participants in the survey, respectively. Overall, 43% of those responding to the survey did not believe that patients above a certain age should be denied adjuvant chemotherapy; among those who did favor a cutoff point, the ages were defined at ≥70, ≥75 and ≥80 years by 28, 21 and 8% of the oncologists, respectively.
Criteria considered for proposing adjuvant chemotherapy The following options were given to the participants: biological characteristics of the tumor, patient’s chronological age, patient’s biological age, social conditions, and all the previously mentioned conditions. Multiple answers were allowed. Patient’s biological
age and the biological characteristics of the tumor were the most frequently voted criteria, chosen by 65% and 59% of the participants in the survey, respectively. Patient’s chronological age was considered as one of the criteria for selection by 23% of the surveyed oncologists.
Collaboration with a geriatrician/geriatric assessment (GA) Only 2% of the oncologists collaborate on a regular basis with a geriatrician, while the majority never (48%) or rarely (37%) cooperate with this specialist. No difference was seen in this attitude between oncologists working in comprehensive cancer centers, in which a geriatric department is usually not available, and colleagues practicing in teaching or general hospitals. The survey also investigated whether in clinical practice the oncologists perform any geriatric assessment before proposing adjuvant chemotherapy to an elderly patient. The answers were ‘routinely’ (12%), ‘sometimes’ (29%) and ‘never’ (59%). Among the investigators who perform a GA, the most frequently used instruments are the activities of daily living scale (ADL) (61%), a co-morbidity scale (49%) and the mini-mental state evaluation (38%) [9–11]. Twenty-two per cent of the participants surveyed answered that a GA should be performed routinely. In addition, one-half would be interested in validating the role of the GA as a predictive factor of toxicity/activity of anticancer treatment and of treatment compliance, even though they remain unconvinced about an additive value of GA over classic instruments (i.e. performance status, blood test, assessment of cardiac function) to define the general status of an elderly candidate for adjuvant chemotherapy.
Chemotherapy regimens/primary prophylaxis with growth factors We investigated which adjuvant chemotherapy regimens are most frequently used in clinical practice. The options considered were cyclophosphamide plus methotrexate plus fluorouracil (CMF) given on days 1 and 8 (CMF 1,8), standard anthracycline-based regimens, 3-weekly CMF and personalized regimens defined as single-agent therapy or reduced-dose regimens. The issue of treatment duration was also examined. The results are described in Figure 1. CMF 1,8 every 4 weeks was the most commonly used regimen in the countries surveyed, with the exception of the UK in which 3-weekly CMF is frequently used. Agreement exists on the potentially favorable role of oral chemotherapy in elderly patients.
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 17, 2015
ordinating body for the flow of information among its members. The questionnaire was e-mailed by an officer of the BIG Secretariat to all of its member groups’ key representatives for further circulation among the oncologists affiliated with each group. The questionnaires were returned by fax or e-mail to the BIG Secretariat, after which a descriptive analysis of the collected data was performed.
209 Table 1. Role of oral chemotherapy in the elderly The use of an oral drug as adjuvant chemotherapy is
Agree strongly (%)
Agree (%)
Very interesting—patient can take it at home
37
44
6
11
2
Very interesting—does not require venous access
40
40
8
10
2
Not recommended—patient can stop without informing physician
7
23
14
49
7
Not recommended—patient can forget to take it
7
30
13
43
7
Not recommended—patient may take many other pills
8
26
19
37
10
The advantages exceed possible disadvantages
24
47
14
9
6
Study design/study end point Assuming that polychemotherapy is also a standard adjuvant treatment in elderly patients, we asked the participants to choose one or more of the three following options to be the subject of a trial in healthy elderly women with operable breast cancer: option A, standard chemotherapy versus no chemotherapy; option B, standard chemotherapy versus a treatment that is potentially less toxic and possibly as effective as polychemotherapy, i.e. singleagent chemotherapy; and option C, standard chemotherapy versus a treatment option that is potentially more toxic and considered to be potentially more effective than standard polychemotherapy. The answers indicated that the most adequate study designs were options B and A for 76% and 25% of the respondents, respectively. It was considered important to investigate a no-chemotherapy arm by an additional 7% of the oncologists who responded to the question proposing alternative study designs, i.e. single-agent chemotherapy versus no chemotherapy or a three-arm study of polychemotherapy versus single-agent chemotherapy versus nil. Of note, only 2% of the surveyed participants were interested in exploring option C. The questions on the most appropriate study design for vulnerable women, defined as patients presenting with functional limitations [i.e. Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2] and/or co-
Disagree (%)
Disagree strongly (%)
morbidities (i.e. ≥3 concomitant diseases) were tackled with slightly different options for choice and the corresponding answers were tailored chemotherapy (i.e. single-agent chemotherapy) versus no chemotherapy (62%); same study design as in the healthy patients (13%); and no role for adjuvant chemotherapy in this subgroup of patients (25%). Quality-adjusted survival (44%) and disease-free survival (42%) were considered the most appropriate primary study end points to be evaluated in an elderly-focused adjuvant chemotherapy trial. Overall survival and quality of life have been chosen by 15% and 30% of the respondents, respectively.
Discussion There are limited data from clinical trials to define the optimal use of adjuvant chemotherapy for elderly women, and almost no information is available on which criteria are used to consider these patients as eligible for chemotherapy and how they are routinely treated. BIG’s survey was aimed at obtaining some information on what oncologists assume to be current practice in this field. There was no attempt to perform an audit on what is actually being proposed and administered. There is general agreement among the surveyed oncologists that if chronological age is used as a frame of reference to define the elderly population, the age of 70 years represents an appropriate landmark. No agreement exists, however, on the cut-off age for denying adjuvant chemotherapy to an elderly patient with early breast cancer. Of note, 28% of the surveyed oncologists set this cut-off age at 70 years and 21% at 75 years. This attitude is questionable if we consider that the expected median survival for a 70- and an 80-year-old woman is 15.5 and 9.2 years, respectively [12]. Despite patient’s biological age being the most frequently used criterion to decide whether adjuvant chemotherapy may be proposed, only a minority of oncologists perform a GA. Currently, a comprehensive GA (CGA) may provide the best estimation of an individual’s functional reserve and life expectancy. There is recent evidence that a CGA adds information to the ECOG PS and that some functional scales, i.e. ADL and instrumental ADL,
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 17, 2015
The reasons to support this treatment administration are reported in Table 1. The question about whether primary prophylaxis with hematopoietic colony-stimulating factors is carried out routinely, performed only in frail patients, or never performed was answered positively by 3, 50 and 47% of respondents, respectively. Major differences existed among the countries surveyed. According to the results, primary prophylaxis is almost never or rarely performed by the surveyed oncologists in Australia, the UK and Canada, while in Austria and Germany the vast majority of frail patients received primary growth factor support. The second part of the questionnaire focused on clinical trials and, in particular, on the most appropriate study design and end points to be considered in trials of adjuvant chemotherapy for elderly patients.
Don’t know (%)
210
Acknowledgements We would like to thank the members of BIG who participated in this survey. We also thank Ms G. Vogt, Ms N. Santoro and Ms C. Saravia for their assistance.
References 1. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001; 2: 533–543.
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allow the prediction of survival probability for elderly cancer patients, irrespective of PS and type of cancer [13, 14]. CGAs are far from being performed in daily practice, but it is important to note that the majority of the participants in this survey are convinced about the need to use/validate a CGA as a predictive instrument of toxicity and/or activity of anticancer therapy in the elderly. Elderly patients are mainly treated with chemotherapy regimens that are considered standard for the younger population, and CMF given for six courses is the most frequently used treatment regimen. Yet, concern exists about whether this treatment represents a favorable option in the elderly. In fact, Crivellari et al. [15] showed that CMF tolerability and effectiveness were both reduced for older patients compared with younger women in the context of the International Breast Cancer Study Group Trial VII in which estrogen receptor positive postmenopausal patients were randomized between tamoxifen and tamoxifen plus three cycles of classic CMF. Some of this toxicity may be related to renal clearance, which is an issue also for other agents, such as capecitabine. The evaluation of renal clearance, and in general the pharmacology of cytoxic agents in the elderly is still under investigation [16, 17]. Also questionable is whether elderly patients should receive six cycles of CMF based on the results of a recent joint analysis of two trials that investigated three versus six courses of CMF [18]. Recently, Fargeot et al. [19] have shown that weekly epirubicin prolongs disease-free survival when added to tamoxifen in node-positive patients aged ≥65 years. Great interest exists in evaluating the role of treatments with low toxic profiles, i.e. single-agent chemotherapy, as demonstrated by an ongoing study in the USA and Canada. In this trial, patients aged ≥65 years who present with a carcinoma of the breast >3 cm, or with positive axillary nodes, are randomized to receive either a ‘standard’ polychemotherapy (four courses of doxorubicin–cyclophosphamide or six courses of classic CMF in case of impaired cardiac function) or single-agent capecitabine for six cycles. The results of our survey confirmed that there is significant interest within the oncological community to investigate single-agent, oral treatment options. The BIG survey was also designed to determine the most important issues to be included in a comprehensive approach to the problem. Respondents showed interest in the evaluation of the role of a CGA to predict treatment effectiveness and safety, and in the use of potentially less toxic, yet effective therapies. One or more BIG trials on this subject will be based on the information provided by this survey.