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Chemotherapy for older women with early breast cancer
Clinical Oncology (2005) 17: 244–248 doi:10.1016/j.clon.2005.02.002
Overview Chemotherapy for Older Women with Early Breast Cancer R. C. F. Leonard, K. M. Malinovszky South West Wales Cancer Institute and Swansea University Medical School, Swansea, UK ABSTRACT: The incidence of breast cancer increases with age, reaching over 300 per 100 000 in women aged 70–75 years in the UK, increasing to almost 400 per 100 000 in women aged over 85 years. As a healthy 70-year old woman can now expect to live for an average of 15 years, control of breast cancer is likely to significantly affect survival. Variations exist in surgical care, radiotherapy and chemotherapy, depending on age; however, virtually all elderly women with hormone-responsive disease are given adjuvant endocrine therapy, usually tamoxifen. For older women who do not have hormone-responsive cancer, and who have high-risk disease characteristics, questions remain over their best management. Overview data of adjuvant chemotherapy in clinical trials show a significant benefit of chemotherapy for women up to the age of 69 years but, for older women, there are too few data to draw any firm conclusions. When considering treatment options for older women, assessment is critical; functional status and comorbidity are some of the factors linked to shorter survival. Leonard, R. C. F., Malinovszky K. M. (2005). Clinical Oncology 17, 244–248 Ó 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Breast cancer, chemotherapy, older Received: 14 December 2004 Breast Cancer in Older Women
Age is one of the principal risk factors for breast cancer, hence the entry age for screening in the UK is 50 years. The incidence of breast cancer increases with age to over 300 per 100 000 in women over 70 years old. In 1998, 35% (13 674) of new cases in the UK occurred in women aged 70 years or over [1]. Projected population forecasts in Western countries indicate that the proportion of older women aged 60 years and over will increase dramatically over the next 50 years [2,3]. Unless specific lifestyle causes are identified and acted upon, this will inevitably lead to many more older women being diagnosed with breast cancer. A 70-year-old woman of average health in the UK can now expect to live on average for a further 15.1 years [4]. Thus, where comorbid disease is limited, control of breast cancer is more likely to determine survival. However, previous studies have shown that treatment varies according to the woman’s age, and is often less intensive in elderly women independent of comorbidity [5–7]. Data from the EUROCARE II study [2] showed that women diagnosed with breast cancer aged 65–99 years had a relative risk of cancer-related death at 1 year of 1.7
Author for correspondence: R. C. F. Leonard, South West Wales Cancer Institute, Swansea University Medical School, Singleton Hospital, Sketty, Swansea SA2 8QA, UK. Tel: C44-1792-285299; Fax: C44-1792285201; E-mail: [email protected] 0936-6555/05/000000C05 $35.00/0
Accepted: 20 December 2004
compared with women aged 55–64, although this reduced to 1.09 at 5 years. Current standard treatments for early breast cancer include surgery, radiotherapy, endocrine therapy and chemotherapy. Surgical care and radiotherapy vary depending on age [8]; however, virtually all elderly women with hormone-responsive disease are given adjuvant endocrine therapy, usually tamoxifen. For older women who do not have hormone-responsive cancer, and who have high-risk disease characteristics, questions remain over their best management.
Lack of Clinical Trial Data
Clinical trials of adjuvant chemotherapy in elderly people are sparse. A study of participants enrolled in 164 Southwest Oncology Group trials in the USA [9] found that people aged 65 years and over were under-represented in cancer clinical trials. This was especially apparent in breast-cancer trials; despite 49% of women with breast cancer being aged 65 years or over, only 9% of women enrolled in breast-cancer trials were 65 years or older. The findings were similar when trials excluding older women were omitted from the analysis. Because of the lack of reliable trial data, there is a great disparity in the attitudes of clinicians towards the treatment of early breast cancer with cytotoxic chemotherapy in elderly women. The median age for breast cancer is around
Ó 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
CHEMOTHERAPY FOR OLDER WOMEN
65 years and yet, beyond using tamoxifen routinely (and based on latest overview data [10], endocrine therapy is not indicated for the treatment of ER/PgR negative disease), there are no agreed protocols for selecting women for cytotoxic agents. Many oncologists use the lack of data from the overview analyses as evidence of a poor effect of chemotherapy, whereas the reality is that, for women over 70 years, there are so few data that no conclusions can be drawn. A survey of 156 cancer physicians was undertaken to gain an understanding of the perceived barriers to recruitment of older participants [11]. There were concerns over comorbid conditions affecting response to treatment; patients’ lack of understanding of complicated trials leading to poor compliance, and concerns about excessive treatment toxicity and how elderly people would cope with it.
Adjuvant Chemotherapy for Breast Cancer
The 1998 overview by the Early Breast Cancer Trialists’ Collaborative Group of adjuvant chemotherapy for women with early breast cancer showed that treatment, in most cases a combination of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), affords a modest, but clinically significant, improvement in survival [10]. This was most apparent in pre-menopausal women with node-positive disease in whom the annual odds of recurrence were reduced by 36%, and odds of death by 25%, with significant further benefit in younger women having anthracycline-containing polychemotherapy. Adjuvant chemotherapy is now accepted as standard treatment in premenopausal and younger post-menopausal women with oestrogen receptor (ER)-negative (and some ER-positive) breast cancer regardless of nodal status. The overview has not, however, established the optimal drugs, doses and schedule for adjuvant chemotherapy. Furthermore, the data showing benefit compared with no treatment indicate statistically significant, albeit diminishing benefits, for post-menopausal women only up to age 69 years. The numbers of women aged over 70 years in the latest unpublished overview [Early Breast Cancer Trialists’ Collaborative Group, 2000] are still only 1200 in total, so that treatment effects are not detectable in the current metaanalysis.
Anthracycline-based Regimens
The anthracyclines are among the most active single agents in the treatment of advanced breast cancer. Anthracyclinebased chemotherapy has been clearly shown to produce higher overall and complete response rates in advanced breast cancer compared with CMF [13]. Direct evidence [14,15] shows that combination chemotherapy containing an anthracycline provides a clinically meaningful benefit in the setting of adjuvant therapy, particularly when there is axillary nodal involvement. In general, it seems that four cycles of anthracycline/cyclophosphamide is used with
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similar expected benefit to six or more cycles of CMF, with the advantage of shortened duration of treatment. Clinical toxicity is similar apart from minor increased risk of cardiac damage and alopecia due to the anthracycline. Myelotoxicity is equivalent. Nevertheless, attention to anthracycline dose is critically important, and ‘low-dose’ anthracycline regimens may produce inferior outcomes compared with CMF [16]. It is also clear, however, that optimal doses and schedules of anthracycline-based polychemotherapy produces clearly superior results to CMF [14,17] or to less intensive or inadequately scheduled anthracycline regimens [15,16,18]. More information is now needed on the potential benefits and risks of chemotherapeutic agents for older people, with reference to patients’ performance status and the likely toxicities of different chemotherapy regimens. Data from other cancer sites, especially lymphoma and colorectal cancer [19,20] suggest that chemotherapy can be safely and effectively given to elderly patients. Current Management of Older Patients with Breast Cancer
Discussion with European and UK oncologists has revealed a wide variation in practice between routine use of chemotherapy in people up to the age of 75 years by some physicians, to a blanket decision not to consider chemotherapy for anyone older than 70 years by others. The extent of endocrine-insensitive disease in elderly people is not clear, but at least 20% of people aged 65 years have ER-negative cancers, and many of these tumours are likely to be of higher grade and may have spread to regional lymph nodes by the time of diagnosis. For these high-risk patients, there is a need to explore whether adjuvant chemotherapy will reduce risk of recurrence and improve overall survival. A study of the management of 2999 post-menopausal women aged 50 years or over [21] found that women aged 75 years and over had more lymph-node-positive disease (62% vs 52%), similar incidence of ER-positive tumours (80%) but were less likely to receive chemotherapy (6.4% vs 35%) than younger women. However, analysis of women aged 65 years and over enrolled in four different CALGB trials (n Z 542), randomised to different doses and schedules of adjuvant treatment [22], found that older women received similar dose-related benefits from chemotherapy in increasing disease-free survival and survival related to breast cancer. The median survival for women aged 65 years and over was 9 years. No data on toxicity were presented in this paper, but a small increase in treatment-related death was reported (1.3% vs 0.4%).
Oestrogen-receptor Status
In the IBCSG trial IX [23], 669 post-menopausal, nodenegative women were studied. Women were randomised to either tamoxifen for 5 years or three cycles of ‘classical’
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CMF followed by 5 years of tamoxifen. Women who were ER-positive (n Z 1217) had no survival benefits with the addition of chemotherapy. However, women who were ER-negative (over half of whom were 60 years or over), randomised to CMF plus tamoxifen, had a statistically significant disease-free survival benefit compared with women taking tamoxifen alone (84% vs 69%). The trend was also significant for overall survival. Another study of node-negative, ER-negative patients (NSABP study B13) [24] showed a survival advantage for women treated with sequential methotrexate and fluorouracil; this benefit was also apparent for older women. A study of 604 post-menopausal women with nodepositive breast cancer by the ICCG [25] found that women receiving tamoxifen plus six cycles of epirubicin improved relapse-free survival compared with women allocated to tamoxifen alone. However, the numbers were too small to determine any differences in response between groups with different ER status. Toxicity
Ageing is associated with a progressive decline in the functional reserve of multiple organ systems, which may lead to increased susceptibility to chemotherapy-related toxicity [26]. A number of studies in clinical trials have shown no increase in toxicity in women older than 65 years [27–29]. As these were retrospective studies, with few women over 75 years, and strict eligibility criteria, they were not typical of the average woman who presents with early breast cancer. But the findings do suggest that age alone is not necessarily a contraindication to chemotherapy. Some specific toxicity concerns, however, deserve further examination. Myelotoxicity
Evidence suggests that the risk of myelosuppression increases with increased age. Analysis of women aged over 65 years in the IBCSG VII trial (tamoxifen G three cycles of CMF in post-menopausal, node-positive breast cancer) [30], found that older women had more Grade 3 toxicities compared with women younger than 65 years (17% vs 7%), and were less likely to receive the planned dose of CMF. Quality-of-life measures were, however, similar. Dees et al. [31] showed that, in adjuvant treatment of breast cancer with doxorubicin and cyclophosphamide, the risk, duration and severity of neutropenia increased with age, particularly after 75 years. Current guidelines do not recommend growth factors as primary prophylaxis for previously untreated patients receiving typical chemotherapy regimens. However, where 40% or more of the patients are expected to experience febrile neutropenia, primary prophylaxis is recommended [32]. Balducci and Lyman [33] suggest that older women (aged 70 years and over) treated with CHOP or similar regimens should be considered as a special high-risk group. The National Cancer Center Network (NCCN) guidelines [34] also indicate that, where older women are due to
receive chemotherapy of similar intensity to CHOP regimens, including adriamycin and cyclophosphamide (AC), there should be routine prophylactic use of growth factors. However, supporting data from prospective randomised-controlled trials are not currently available. Cardiotoxicity
Older women seem to have a greater risk of cardiotoxicity from anthracyclines [35]. This is likely to be due to preexisting chronic injuries linked to hypertension and ischaemia. In the USA, a study of over 7600 people with cancer aged 55 years and over found that 39% had heartrelated problems [3]. The risk of cardiotoxicity from anthracyclines does not seem to be relevant until a cumulative dose equal to 450 mg/m2 of doxorubicin is reached [36]. Although the link between cardiac pathology and anthracycline exposure is established, there is no evidence that a woman with a normal cardiac reserve, regardless of previous therapy, cannot tolerate standard doses of anthracyclines. This may, in future, be modified depending on the adoption of the trastuzumab monoclonal antibody (now in phase III trials as an adjuvant treatment after anthracycline exposure), which is also linked to increased cardiotoxicity. Mucositis
Mucositis occurs more often, is likely to be more severe and last longer in older women [37]. This is likely to be due to increased proliferation of cells in the intestinal mucosa, which makes them more susceptible to damage by chemotherapeutic agents [38]. A study of women receiving adjuvant CMF in the IBCSG VII trial found that 45% of women aged 65 years and over had Grade 1–3 mucosal toxicity compared with 28% of people under 65 years [30]. For Grade 3 mucosal toxicity, the incidence was 4% for the older group compared with 0.9% for people aged under 65 years. Mucositis can have significant morbidity in older women; an early study of 5-fluorouracil and leucovorin showed mucositis-related mortality of nearly 10% in women over 65 years [38], and it is important that it is recognised and treated early. Renal Function
Ageing is associated with a decline in glomerular filtration rate, which can result in delayed excretion, and hence increased toxicity, of some chemotherapeutic agents [39]. For certain cytotoxic drugs excreted via the kidneys, dose reduction according to creatinine clearance levels has been found to be effective, with a marked reduction in myelotoxicity for women aged 65 years and over [40].
Treatment Considerations
When considering treatment options, clinical evaluation of the ageing woman is critically important in judging the
CHEMOTHERAPY FOR OLDER WOMEN
safety and potential for long-term survival, irrespective of the cancer prognosis. Functional status, comorbidity, depression, dementia, history of falls, neglect and abuse have all been linked to shorter survival [41–43]. Ageing effects are highly individualised, and chronologic age is a poor predictor of the extent of physiologic changes in each individual. Few useful laboratory assays are of value; however, clinical tests to assess functional status, comorbidity, social support, cognition, emotional status, nutrition and medication may provide a semi-quantitative profile of value in deciding about fitness to treat. Older women who are being considered for chemotherapy therefore need to be carefully assessed using guidelines developed in geriatric medicine. Comorbidity and functional status may both predict for chemotherapy toxicity. Intervention may be planned for poorly supported women; similarly, nutritional assessment may be of value as well as attending to over-medication. The National Cancer Center Network has produced guidelines to help decision-making for chemotherapy in the older woman [34]. They suggest that (1) women over 70 years should receive some form of geriatric assessment; (2) doses of chemotherapy should be adjusted to glomerular filtration rate in women over 65 years; (3) hemopoietic growth factors should be used prophylactically in women over 70 years; (4) haemoglobin should be maintained above 12 g/l; (5) mucositis should be treated aggressively if eating is affected or diarrhoea develops; (6) consider less toxic alternatives to doxorubicin, when equal effectiveness has been demonstrated, in women over 70 years.
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a second randomisation will be proposed comparing standard 3-weekly administration with accelerated 2-weekly delivery with chemotherapy accompanied by pegylated granulocyte colony-stimulating factor treatment. This proposed second randomisation is identical to that proposed in the TACT 3 trial, and data from the two trials would be combined in the assessment of benefit of acceleration. The chemotherapy schedule has been selected after considerable discussion. Motivation has been based on a desire to keep the regimen short and deliverable. AC is a standard regimen of proven benefit in younger women. We will compare the relative toleration and toxicity of standard 3-weekly AC with GCSF-supported, 2-weekly AC, the latter having the potential advantages of enhancing the efficacy while minimising myelotoxicity and reducing total treatment time. Conclusion
The oncology community has probably been too conservative in its attitudes towards using polychemotherapy in the management of hormone-insensitive early breast cancer in older women. Increasing interest in this problem has derived from greater confidence about the benefit of adjuvant chemotherapy in younger women. This is allied to the universal recognition that we have an ageing population, and many people will live to advanced old age in good health, provided that we are able to control some common diseases with effective and safe interventions. References
Trials for Older Women with Breast Cancer
In the USA, a trial is currently under way for people aged 65 years and over (both men and women) with stage IIA or IIIA disease. It compares one of two standard chemotherapy regimens (CMF or AC) vs oral capecitabine. The choice of standard regimen depends on left-ventricular ejection fraction and patient–doctor choice. This trial includes participants with any hormonal status, and participants with hormone-receptor-positive disease will receive tamoxifen or an aromatase inhibitor for 5 years. In Europe, a slightly different trial of woman with breast cancer aged 70 years and over (Adjuvant Cytotoxic Chemotherapy In Older Women – ACTION) is proposed. The trial will address the unanswered question about the place, if any, of adjuvant chemotherapy in elderly women who have a substantial risk of relapse of breast cancer within 5 years of diagnosis. This will be a prospective, multi-centre randomised trial comparing no chemotherapy and standard treatment in elderly women (age R 70 years) with poor-risk, hormoneinsensitive, primary-breast cancer. For all patients, there must be clinical uncertainty over the benefit of chemotherapy. The chemotherapy design for this study was selected on the basis of establishing a known effective ‘short’ chemotherapy regimen that has been widely used, namely AC, for four cycles. For those women allocated chemotherapy,
1 Cancer Research UK. Breast cancer factsheet. London: Cancer Research UK, 2002. 2 Vercelli M, Quaglia A, Casella C, et al. Relative survival in elderly cancer patients in Europe. Eur J Cancer 1998;34:2264–2270. 3 Yancik R. Cancer burden in the aged: an epidemiologic and demographic overview. Cancer 1997;80:1273–1283. 4 Government Actuary’s Department. Interim life tables: expectation of life based on data for the years 2000–2002. www.gad.gov.uk/ Life_Tables/Interim_life_tables.htm. 5 Yancik R, Ries LG, Yates JW. Breast cancer in ageing women: a population based study in stage, surgery and survival. Cancer 1989; 63:976–981. 6 Bergmann L, Dekker G, van Kerkhoff EHM, Peterse HL, van Dongen JA, van Leeuwen FE. The influence of age and co-morbidity on treatment choice and its effect on survival in elderly patients with breast cancer. Breast Cancer Res Treat 1991;18:189–198. 7 Martin LM, le Pechoux C, Calitchi E, et al. Management of breast cancer in the elderly. Eur J Cancer 1996;30A:590–596. 8 Turner NJ, Haward RA, Mulley GP, Selby PJ. Cancer in old age d is it inadequately investigated and treated? BMJ 1999;319:309–312. 9 Hutchins L, Unger J, Crowley J, Coltman CA, Albain KS. Under representation of patients 65 years of age or older in cancer treatment trials. N Engl J Med 1999;341:2061–2067. 10 Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998;352:930–942. 11 Kornblith AB, Kemeny M, Peterson BL, et al. Survey of oncologists’ perceptions of barriers to accrual of older patients with breast carcinoma to clinical trials. Cancer 2002;95:989–996. 13 A’Hern RP, Smith IE, Ebbs SR. Chemotherapy and survival in advanced breast cancer: the inclusion of doxorubicin in Cooper type regimens. Br J Cancer 1993;67:801–805.
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14 Levine MN, Bramwell VH, Pritchard KI, et al. Randomised trial of intensive cyclophosphamide, epirubicin and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate and fluorouracil CMF in premenopausal women with node-positive breast cancer. J Clin Oncol 1998;16:2651–2658. 15 Moliterni A, Bonadonna G, Valagussa P, Ferrari L, Zambetti M. Cyclophosphamide, methotrexate, and fluorouracil with and without doxorubicin in the adjuvant treatment of resectable breast cancer with one to three positive axillary nodes. J Clin Oncol 1991;9: 1124–1130. 16 Piccart M, Di Leo A, Beauduin M, et al. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol 2001;19:3103–3110. 17 Poole CJ, Earl HM, Dunn L, et al. NEAT [National Epoirubicin Trial] and SCTBG BR9601 [Scottish Cancer Trials Breast Group] phase III adjuvant breast trials show a significant relapse-free and overall survival advantage for sequential ECMF [abstract 13]. Proc Am Soc Clin Oncol 2003;22. 18 Budman DR, Berry DA, Cirrincione CT, et al. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst 1998;90:1205–1211. 19 Fata F, Mirza A, Craig G, et al. Efficacy of adjuvant chemotherapy in elderly patients with colon carcinoma: a 10-year experience of the Geisinger Medical Center. Cancer 2002;94:1931–1938. 20 Sonneveld P, de Ridder M, van der Lelie H, 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;13:2530–2539. 21 Curigliano G, Gennari R, Rotmasz N. Breast cancer in elderly women: features of disease presentation and choice of adjuvant therapies compared with younger postmenopausal patients [abstract 3065]. Proc Am Soc Clin Oncol 2003;22:762. 22 Muss HB, Woolf SH, Berry A, et al. Older women with node positive [NC] breast cancer [BC] get similar benefits from adjuvant chemotherapy [Adj] as younger patients [pts]: The Cancer and Leukemia Group B [CALGB] experience [abstract 11]. Proc Am Soc Clin Oncol 2003;22:4. 23 International Breast Cancer Study Group. Endocrine responsiveness and tailoring adjuvant therapy for postmenopausal lymph-nodenegative breast cancer: a randomized trial. J Natl Cancer Inst 2002; 94:1054–1065. 24 Fisher B, Dignam J, Mamounas EP, et al. Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol 1996;14:1982–1992. 25 Wils JA, Bliss JM, Marty M, et al. Epirubicin plus tamoxifen versus tamoxifen alone in node-positive postmenopausal patients with breast cancer: a randomized trial of the International Collaborative Cancer Group. J Clin Oncol 1999;17:1988–1998.
26 Balducci L, Hardy CH, Lyman GH. Hemopoietic factors in the older patient. Curr Opin Hematol 2001;8:170–187. 27 Christman K, Muss HB, Case D, Stanley V. Chemotherapy of metastatic breast cancer in the elderly. The Piedmont Oncology Association experience. JAMA 1992;268:57–62. 28 Ibrahim NK, Frye DK, Buzdar AU, Walters RS, Hortobagyi GN. Doxorubicin-based chemotherapy in elderly patients with metastatic breast cancer. Tolerance and outcome. Arch Intern Med 1996;156: 882–888. 29 Ibrahim NK, Buzdar AV, Asmar L, et al. Doxorubicin based adjuvant chemotherapy in elderly breast cancer patients. The M.D. Anderson experience with long term follow up. Ann Oncol 2000;11:1–5. 30 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. 31 Dees EC, O’Reilly S, Goodman SN, et al. A prospective pharmacological evaluation of age-related chemotherapy toxicity in older women. Cancer Invest 2000;18:521–529. 32 Ozer H, Armitage JO, Bennett CL, et al. Update of recommendations for the use of hematopoietic colony-stimulating factors: evidencebased, clinical practice guidelines. J Clin Oncol 2000;8:3558–3585. 33 Balducci L, Lyman GH. Patients aged O70 are at high risk for neutropenic infection and should receive hemopoietic growth factors when treated with moderately toxic chemotherapy [comment]. J Clin Oncol 2001;19:1583–1585. 34 Balducci L, Yates J. General guidelines for the management of older patients with cancer. Oncology [Huntingt] 2000;14:221–227. 35 Allen A. The cardiotoxicity of chemotherapeutic drugs. Semin Oncol 1992;19:529–542. 36 Balducci L, Extermann M. Management of cancer in the older person: a practical approach. Oncologist 2000;5:224–237. 37 Stein BN, Petrelli NJ, Douglas HO, et al. Age and sex are independent predictors of 5-fluorouracil toxicity. Cancer 1995;75:11–17. 38 Balducci L, Corcoran MB. Antineoplastic chemotherapy of the older cancer patient. Hematol Oncol Clin North Am 2000;14:193–212. 39 Cova D, Beretta G, Balducci L. Cancer chemotherapy in the older patient. In: Balducci L, Lyman GH, Ershler WB, eds. Comprehensive geriatric oncology. Amsterdam: Harwood Academic Publishers; 1998: p. 429–442. 40 Gelman RS, Taylor SG. Cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy in women more than 65 years old with advanced breast cancer. The elimination of age trends in toxicity by using doses based on creatinine clearance J Clin Oncol 1984;2: 1406–1414. 41 Reuben DB, Rubenstein LV, Hirsch SH, et al. Value of functional status as a predictor of mortality: results of a prospective study. Am J Med 1992;93:663–669. 42 Santariano WA, Ragland DR. The effect of co-morbidity on 3-year survival of women with primary breast cancer. Ann Intern Med 1994; 120:104–110. 43 Extermann M. Assessment of the older cancer patient. Hematol Oncol Clin North Am 2000;14:63–77.
Overview Chemotherapy for Older Women with Early Breast Cancer R. C. F. Leonard, K. M. Malinovszky South West Wales Cancer Institute and Swansea University Medical School, Swansea, UK ABSTRACT: The incidence of breast cancer increases with age, reaching over 300 per 100 000 in women aged 70–75 years in the UK, increasing to almost 400 per 100 000 in women aged over 85 years. As a healthy 70-year old woman can now expect to live for an average of 15 years, control of breast cancer is likely to significantly affect survival. Variations exist in surgical care, radiotherapy and chemotherapy, depending on age; however, virtually all elderly women with hormone-responsive disease are given adjuvant endocrine therapy, usually tamoxifen. For older women who do not have hormone-responsive cancer, and who have high-risk disease characteristics, questions remain over their best management. Overview data of adjuvant chemotherapy in clinical trials show a significant benefit of chemotherapy for women up to the age of 69 years but, for older women, there are too few data to draw any firm conclusions. When considering treatment options for older women, assessment is critical; functional status and comorbidity are some of the factors linked to shorter survival. Leonard, R. C. F., Malinovszky K. M. (2005). Clinical Oncology 17, 244–248 Ó 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Breast cancer, chemotherapy, older Received: 14 December 2004 Breast Cancer in Older Women
Age is one of the principal risk factors for breast cancer, hence the entry age for screening in the UK is 50 years. The incidence of breast cancer increases with age to over 300 per 100 000 in women over 70 years old. In 1998, 35% (13 674) of new cases in the UK occurred in women aged 70 years or over [1]. Projected population forecasts in Western countries indicate that the proportion of older women aged 60 years and over will increase dramatically over the next 50 years [2,3]. Unless specific lifestyle causes are identified and acted upon, this will inevitably lead to many more older women being diagnosed with breast cancer. A 70-year-old woman of average health in the UK can now expect to live on average for a further 15.1 years [4]. Thus, where comorbid disease is limited, control of breast cancer is more likely to determine survival. However, previous studies have shown that treatment varies according to the woman’s age, and is often less intensive in elderly women independent of comorbidity [5–7]. Data from the EUROCARE II study [2] showed that women diagnosed with breast cancer aged 65–99 years had a relative risk of cancer-related death at 1 year of 1.7
Author for correspondence: R. C. F. Leonard, South West Wales Cancer Institute, Swansea University Medical School, Singleton Hospital, Sketty, Swansea SA2 8QA, UK. Tel: C44-1792-285299; Fax: C44-1792285201; E-mail: [email protected] 0936-6555/05/000000C05 $35.00/0
Accepted: 20 December 2004
compared with women aged 55–64, although this reduced to 1.09 at 5 years. Current standard treatments for early breast cancer include surgery, radiotherapy, endocrine therapy and chemotherapy. Surgical care and radiotherapy vary depending on age [8]; however, virtually all elderly women with hormone-responsive disease are given adjuvant endocrine therapy, usually tamoxifen. For older women who do not have hormone-responsive cancer, and who have high-risk disease characteristics, questions remain over their best management.
Lack of Clinical Trial Data
Clinical trials of adjuvant chemotherapy in elderly people are sparse. A study of participants enrolled in 164 Southwest Oncology Group trials in the USA [9] found that people aged 65 years and over were under-represented in cancer clinical trials. This was especially apparent in breast-cancer trials; despite 49% of women with breast cancer being aged 65 years or over, only 9% of women enrolled in breast-cancer trials were 65 years or older. The findings were similar when trials excluding older women were omitted from the analysis. Because of the lack of reliable trial data, there is a great disparity in the attitudes of clinicians towards the treatment of early breast cancer with cytotoxic chemotherapy in elderly women. The median age for breast cancer is around
Ó 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
CHEMOTHERAPY FOR OLDER WOMEN
65 years and yet, beyond using tamoxifen routinely (and based on latest overview data [10], endocrine therapy is not indicated for the treatment of ER/PgR negative disease), there are no agreed protocols for selecting women for cytotoxic agents. Many oncologists use the lack of data from the overview analyses as evidence of a poor effect of chemotherapy, whereas the reality is that, for women over 70 years, there are so few data that no conclusions can be drawn. A survey of 156 cancer physicians was undertaken to gain an understanding of the perceived barriers to recruitment of older participants [11]. There were concerns over comorbid conditions affecting response to treatment; patients’ lack of understanding of complicated trials leading to poor compliance, and concerns about excessive treatment toxicity and how elderly people would cope with it.
Adjuvant Chemotherapy for Breast Cancer
The 1998 overview by the Early Breast Cancer Trialists’ Collaborative Group of adjuvant chemotherapy for women with early breast cancer showed that treatment, in most cases a combination of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), affords a modest, but clinically significant, improvement in survival [10]. This was most apparent in pre-menopausal women with node-positive disease in whom the annual odds of recurrence were reduced by 36%, and odds of death by 25%, with significant further benefit in younger women having anthracycline-containing polychemotherapy. Adjuvant chemotherapy is now accepted as standard treatment in premenopausal and younger post-menopausal women with oestrogen receptor (ER)-negative (and some ER-positive) breast cancer regardless of nodal status. The overview has not, however, established the optimal drugs, doses and schedule for adjuvant chemotherapy. Furthermore, the data showing benefit compared with no treatment indicate statistically significant, albeit diminishing benefits, for post-menopausal women only up to age 69 years. The numbers of women aged over 70 years in the latest unpublished overview [Early Breast Cancer Trialists’ Collaborative Group, 2000] are still only 1200 in total, so that treatment effects are not detectable in the current metaanalysis.
Anthracycline-based Regimens
The anthracyclines are among the most active single agents in the treatment of advanced breast cancer. Anthracyclinebased chemotherapy has been clearly shown to produce higher overall and complete response rates in advanced breast cancer compared with CMF [13]. Direct evidence [14,15] shows that combination chemotherapy containing an anthracycline provides a clinically meaningful benefit in the setting of adjuvant therapy, particularly when there is axillary nodal involvement. In general, it seems that four cycles of anthracycline/cyclophosphamide is used with
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similar expected benefit to six or more cycles of CMF, with the advantage of shortened duration of treatment. Clinical toxicity is similar apart from minor increased risk of cardiac damage and alopecia due to the anthracycline. Myelotoxicity is equivalent. Nevertheless, attention to anthracycline dose is critically important, and ‘low-dose’ anthracycline regimens may produce inferior outcomes compared with CMF [16]. It is also clear, however, that optimal doses and schedules of anthracycline-based polychemotherapy produces clearly superior results to CMF [14,17] or to less intensive or inadequately scheduled anthracycline regimens [15,16,18]. More information is now needed on the potential benefits and risks of chemotherapeutic agents for older people, with reference to patients’ performance status and the likely toxicities of different chemotherapy regimens. Data from other cancer sites, especially lymphoma and colorectal cancer [19,20] suggest that chemotherapy can be safely and effectively given to elderly patients. Current Management of Older Patients with Breast Cancer
Discussion with European and UK oncologists has revealed a wide variation in practice between routine use of chemotherapy in people up to the age of 75 years by some physicians, to a blanket decision not to consider chemotherapy for anyone older than 70 years by others. The extent of endocrine-insensitive disease in elderly people is not clear, but at least 20% of people aged 65 years have ER-negative cancers, and many of these tumours are likely to be of higher grade and may have spread to regional lymph nodes by the time of diagnosis. For these high-risk patients, there is a need to explore whether adjuvant chemotherapy will reduce risk of recurrence and improve overall survival. A study of the management of 2999 post-menopausal women aged 50 years or over [21] found that women aged 75 years and over had more lymph-node-positive disease (62% vs 52%), similar incidence of ER-positive tumours (80%) but were less likely to receive chemotherapy (6.4% vs 35%) than younger women. However, analysis of women aged 65 years and over enrolled in four different CALGB trials (n Z 542), randomised to different doses and schedules of adjuvant treatment [22], found that older women received similar dose-related benefits from chemotherapy in increasing disease-free survival and survival related to breast cancer. The median survival for women aged 65 years and over was 9 years. No data on toxicity were presented in this paper, but a small increase in treatment-related death was reported (1.3% vs 0.4%).
Oestrogen-receptor Status
In the IBCSG trial IX [23], 669 post-menopausal, nodenegative women were studied. Women were randomised to either tamoxifen for 5 years or three cycles of ‘classical’
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CMF followed by 5 years of tamoxifen. Women who were ER-positive (n Z 1217) had no survival benefits with the addition of chemotherapy. However, women who were ER-negative (over half of whom were 60 years or over), randomised to CMF plus tamoxifen, had a statistically significant disease-free survival benefit compared with women taking tamoxifen alone (84% vs 69%). The trend was also significant for overall survival. Another study of node-negative, ER-negative patients (NSABP study B13) [24] showed a survival advantage for women treated with sequential methotrexate and fluorouracil; this benefit was also apparent for older women. A study of 604 post-menopausal women with nodepositive breast cancer by the ICCG [25] found that women receiving tamoxifen plus six cycles of epirubicin improved relapse-free survival compared with women allocated to tamoxifen alone. However, the numbers were too small to determine any differences in response between groups with different ER status. Toxicity
Ageing is associated with a progressive decline in the functional reserve of multiple organ systems, which may lead to increased susceptibility to chemotherapy-related toxicity [26]. A number of studies in clinical trials have shown no increase in toxicity in women older than 65 years [27–29]. As these were retrospective studies, with few women over 75 years, and strict eligibility criteria, they were not typical of the average woman who presents with early breast cancer. But the findings do suggest that age alone is not necessarily a contraindication to chemotherapy. Some specific toxicity concerns, however, deserve further examination. Myelotoxicity
Evidence suggests that the risk of myelosuppression increases with increased age. Analysis of women aged over 65 years in the IBCSG VII trial (tamoxifen G three cycles of CMF in post-menopausal, node-positive breast cancer) [30], found that older women had more Grade 3 toxicities compared with women younger than 65 years (17% vs 7%), and were less likely to receive the planned dose of CMF. Quality-of-life measures were, however, similar. Dees et al. [31] showed that, in adjuvant treatment of breast cancer with doxorubicin and cyclophosphamide, the risk, duration and severity of neutropenia increased with age, particularly after 75 years. Current guidelines do not recommend growth factors as primary prophylaxis for previously untreated patients receiving typical chemotherapy regimens. However, where 40% or more of the patients are expected to experience febrile neutropenia, primary prophylaxis is recommended [32]. Balducci and Lyman [33] suggest that older women (aged 70 years and over) treated with CHOP or similar regimens should be considered as a special high-risk group. The National Cancer Center Network (NCCN) guidelines [34] also indicate that, where older women are due to
receive chemotherapy of similar intensity to CHOP regimens, including adriamycin and cyclophosphamide (AC), there should be routine prophylactic use of growth factors. However, supporting data from prospective randomised-controlled trials are not currently available. Cardiotoxicity
Older women seem to have a greater risk of cardiotoxicity from anthracyclines [35]. This is likely to be due to preexisting chronic injuries linked to hypertension and ischaemia. In the USA, a study of over 7600 people with cancer aged 55 years and over found that 39% had heartrelated problems [3]. The risk of cardiotoxicity from anthracyclines does not seem to be relevant until a cumulative dose equal to 450 mg/m2 of doxorubicin is reached [36]. Although the link between cardiac pathology and anthracycline exposure is established, there is no evidence that a woman with a normal cardiac reserve, regardless of previous therapy, cannot tolerate standard doses of anthracyclines. This may, in future, be modified depending on the adoption of the trastuzumab monoclonal antibody (now in phase III trials as an adjuvant treatment after anthracycline exposure), which is also linked to increased cardiotoxicity. Mucositis
Mucositis occurs more often, is likely to be more severe and last longer in older women [37]. This is likely to be due to increased proliferation of cells in the intestinal mucosa, which makes them more susceptible to damage by chemotherapeutic agents [38]. A study of women receiving adjuvant CMF in the IBCSG VII trial found that 45% of women aged 65 years and over had Grade 1–3 mucosal toxicity compared with 28% of people under 65 years [30]. For Grade 3 mucosal toxicity, the incidence was 4% for the older group compared with 0.9% for people aged under 65 years. Mucositis can have significant morbidity in older women; an early study of 5-fluorouracil and leucovorin showed mucositis-related mortality of nearly 10% in women over 65 years [38], and it is important that it is recognised and treated early. Renal Function
Ageing is associated with a decline in glomerular filtration rate, which can result in delayed excretion, and hence increased toxicity, of some chemotherapeutic agents [39]. For certain cytotoxic drugs excreted via the kidneys, dose reduction according to creatinine clearance levels has been found to be effective, with a marked reduction in myelotoxicity for women aged 65 years and over [40].
Treatment Considerations
When considering treatment options, clinical evaluation of the ageing woman is critically important in judging the
CHEMOTHERAPY FOR OLDER WOMEN
safety and potential for long-term survival, irrespective of the cancer prognosis. Functional status, comorbidity, depression, dementia, history of falls, neglect and abuse have all been linked to shorter survival [41–43]. Ageing effects are highly individualised, and chronologic age is a poor predictor of the extent of physiologic changes in each individual. Few useful laboratory assays are of value; however, clinical tests to assess functional status, comorbidity, social support, cognition, emotional status, nutrition and medication may provide a semi-quantitative profile of value in deciding about fitness to treat. Older women who are being considered for chemotherapy therefore need to be carefully assessed using guidelines developed in geriatric medicine. Comorbidity and functional status may both predict for chemotherapy toxicity. Intervention may be planned for poorly supported women; similarly, nutritional assessment may be of value as well as attending to over-medication. The National Cancer Center Network has produced guidelines to help decision-making for chemotherapy in the older woman [34]. They suggest that (1) women over 70 years should receive some form of geriatric assessment; (2) doses of chemotherapy should be adjusted to glomerular filtration rate in women over 65 years; (3) hemopoietic growth factors should be used prophylactically in women over 70 years; (4) haemoglobin should be maintained above 12 g/l; (5) mucositis should be treated aggressively if eating is affected or diarrhoea develops; (6) consider less toxic alternatives to doxorubicin, when equal effectiveness has been demonstrated, in women over 70 years.
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a second randomisation will be proposed comparing standard 3-weekly administration with accelerated 2-weekly delivery with chemotherapy accompanied by pegylated granulocyte colony-stimulating factor treatment. This proposed second randomisation is identical to that proposed in the TACT 3 trial, and data from the two trials would be combined in the assessment of benefit of acceleration. The chemotherapy schedule has been selected after considerable discussion. Motivation has been based on a desire to keep the regimen short and deliverable. AC is a standard regimen of proven benefit in younger women. We will compare the relative toleration and toxicity of standard 3-weekly AC with GCSF-supported, 2-weekly AC, the latter having the potential advantages of enhancing the efficacy while minimising myelotoxicity and reducing total treatment time. Conclusion
The oncology community has probably been too conservative in its attitudes towards using polychemotherapy in the management of hormone-insensitive early breast cancer in older women. Increasing interest in this problem has derived from greater confidence about the benefit of adjuvant chemotherapy in younger women. This is allied to the universal recognition that we have an ageing population, and many people will live to advanced old age in good health, provided that we are able to control some common diseases with effective and safe interventions. References
Trials for Older Women with Breast Cancer
In the USA, a trial is currently under way for people aged 65 years and over (both men and women) with stage IIA or IIIA disease. It compares one of two standard chemotherapy regimens (CMF or AC) vs oral capecitabine. The choice of standard regimen depends on left-ventricular ejection fraction and patient–doctor choice. This trial includes participants with any hormonal status, and participants with hormone-receptor-positive disease will receive tamoxifen or an aromatase inhibitor for 5 years. In Europe, a slightly different trial of woman with breast cancer aged 70 years and over (Adjuvant Cytotoxic Chemotherapy In Older Women – ACTION) is proposed. The trial will address the unanswered question about the place, if any, of adjuvant chemotherapy in elderly women who have a substantial risk of relapse of breast cancer within 5 years of diagnosis. This will be a prospective, multi-centre randomised trial comparing no chemotherapy and standard treatment in elderly women (age R 70 years) with poor-risk, hormoneinsensitive, primary-breast cancer. For all patients, there must be clinical uncertainty over the benefit of chemotherapy. The chemotherapy design for this study was selected on the basis of establishing a known effective ‘short’ chemotherapy regimen that has been widely used, namely AC, for four cycles. For those women allocated chemotherapy,
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