Abstract

Background:

To collect oncologists’ experience and opinion on adjuvant chemotherapy in elderly breast 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 cut-off 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.

Received 8 August 2003; accepted 3 October 2003

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 chemotherapy 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. node-negative 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-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.

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 cut-off 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%) co-operate 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%) [911]. 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. 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.

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. single-agent 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-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, 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.

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.

*

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: lbiganzoli@usl4.toscana.it

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.

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.

Table 1.

Role of oral chemotherapy in the elderly

The use of an oral drug as adjuvant chemotherapy is Agree strongly (%) Agree (%) Don’t know (%) Disagree (%) Disagree strongly (%) 
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 
The use of an oral drug as adjuvant chemotherapy is Agree strongly (%) Agree (%) Don’t know (%) Disagree (%) Disagree strongly (%) 
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 

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Author notes

1Jules 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