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Journal of Clinical Oncology, Vol 25, No 24 (August 20), 2007: pp. 3699-3704 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.10.9710 Toxicity of Older and Younger Patients Treated With Adjuvant Chemotherapy for Node-Positive Breast Cancer: The Cancer and Leukemia Group B Experience
From the University of Vermont, Burlington, VT; M.D. Anderson Cancer Center, Houston, TX; Cancer and Leukemia Group B Statistical Center, Durham, NC; North Shore University Hospital, New York University, Manhasset; Pro Health Care Associates, Lake Success; Memorial Sloan Kettering Cancer Center, New York, NY; University California-San Francisco, San Francisco, CA; and the Dana-Farber Cancer Center, Boston, MA Address reprint requests to Hyman B. Muss, MD, University of Vermont and Vermont Cancer Center, 89 Beaumont Ave, Given Bldg E-214, Burlington, VT 05405; e-mail: hyman.muss{at}uvm.edu
Purpose Older node-positive patients treated with newer adjuvant chemotherapy regimens have improvements in relapse-free and overall survival similar to younger patients. We compared toxicity of older and younger patients in three randomized trials of adjuvant chemotherapy. Patients and Methods Toxicity data were available for 93% of 6,642 patients enrolled. The three trials included: Cancer and Leukemia Group B (CALGB) 8541, a comparison of cyclophosphamide, doxorubicin, and fluorouracil in three dose schedules; CALGB 9344: cyclophosphamide and doxorubicin with or without paclitaxel; and CALGB 9741: cyclophosphamide, doxorubicin, and paclitaxel every 2 versus every 3 weeks. National Cancer Institute grade 3 to 5 toxicities were compared among age groups. Results Seven percent of patients (n = 458) were age 65 or older, 3% were 70 or older, 38% were 51 to 64, and 55% were 50 or younger. Twenty-four deaths (0.4%) were attributed to treatment; seven (1.5%) of 486 in patients 65 or older, 10 (0.40%) of 2,480 in patients who were 51 to 64 years, and seven (0.19%) of 3,676 occurred in patients younger than 50. In multivariate analysis, older patients were significantly more likely to have grade 4 hematologic toxicity, to have discontinued treatment for toxicity, or to have died of acute myeloid leukemia/myelodysplastic syndrome. There were no significant differences in grade 3 to 4 nonhematologic toxicity. Conclusion Healthy older patients who met the strict eligibility criteria for these trials had a higher rate of hematologic toxicity and treatment-related deaths than younger patients, but no increase in nonhematologic toxicity. Elderly patients treated with newer adjuvant chemotherapy regimens derive the same benefits from newer chemotherapy regimens as younger patients but should be cautioned about the increased risk of toxicity and treatment-related death.
In affluent nations, breast cancer is a disease associated with aging. In the United States, breast cancer incidence and mortality rates increase with age and about one half of all new breast cancer diagnoses occur in women older than 65.1 Even with the increasing awareness of these statistics, elderly patients continue to have less screening, are less likely to be offered breast conservation and state-of-the-art adjuvant therapies, and are less likely to be entered onto clinical trials when compared with younger patients.2 In addition, undertreatment as defined by not adhering to consensus guidelines, is associated with a higher recurrence rate3 likely resulting in a poorer quality of life and inferior survival. In older women with estrogen receptor–positive early-stage breast cancer, an extensive body of randomized clinical trials data show that endocrine therapy with tamoxifen results in significant improvements in both relapse-free and overall survival.4 Data from trials of aromatase inhibitors also confirm a significant benefit for older patients.5 Chemotherapy data for elderly patients are sparse but in women ages 50 through 69 chemotherapy have been associated with significant improvements in relapse-free and overall survival with proportional benefits of about half that for younger patients.4 Also, recent randomized adjuvant trials have shown that dose-intensive chemotherapy regimens and regimens incorporating taxanes are associated with significant improvements in both relapse-free and overall survival when compared with older regimens such as cyclophosphamide, methotrexate, and fluorouracil (CMF).6 A recent retrospective review of four large cooperative trials using newer more intensive chemotherapy regimens showed that older and younger patients derived the same proportional benefits from the more intensive therapies for both relapse-free and overall survival.7 A major issue in treating elderly patients with chemotherapy is toxicity. Bone marrow reserve and renal function decrease with age, increasing the probability of myelosuppression and the risk of toxicity for renally excreted agents, such as methotrexate.8 Moreover, because older patients have been under-represented in clinical trials9,10 only a small amount of detailed toxicity data are available. These limited data from small trials and retrospective analyses of larger trials indicate that older patients in good health, and who have met the strict eligibility criteria for trial entry, tolerate chemotherapy regimens, including anthracycline-based regimens, about as well as younger patients.11-14 To determine how older patients fared on more aggressive systemic adjuvant chemotherapy regimens, the Cancer and Leukemia Group B (CALGB) retrospectively reviewed toxicity data from three randomized clinical trials of treatments for node-positive breast cancer that accrued patients from 1985 through 1999. These trials compared chemotherapy regimens that differed in treatment intensity, which included anthracyclines and taxanes, and regimens that are still currently used for adjuvant treatment.
Patients Toxicity data were available for 6,174 (93%) of 6,642 patients enrolled on three Cancer and Leukemia Group B (CALGB) randomized clinical trials designed for women with node-positive breast cancer. Toxicity data were obtained from all cycles of treatment. All trials compared at least two chemotherapy regimens that differed by dose level, dose intensity, or regimen, and all included anthracyclines (Table 1).
CALGB 8541 randomly assigned patients to one of three regimens of cyclophosphamide, doxorubicin, and fluorouracil (CAF) that differed in dose duration and dose intensity. Patients treated with moderate or higher dose intensity of CAF had significantly longer disease-free survival (P < .001) and overall survival (P = .004) compared with those treated with lower doses. The details concerning these regimens have been reported previously.15 Eligibility required patients be at least 16 years of age and without serious medical or psychiatric illness. CALGB 9344 (Intergroup 0148) used a 3 x 2 factorial design in which patients were randomly assigned first to one of three dose levels of doxorubicin (60, 75, or 90 mg/m2) and a fixed dose of cyclophosphamide (600 mg/m2) with or without paclitaxel. Eligibility required patients to have adequate bone marrow, liver, and renal function and a normal left ventricular ejection fraction. There were no differences in outcome among patients randomly assigned to the three different dose levels of doxorubicin. Patients randomly assigned to paclitaxel, however, had significantly improved 5-year disease-free survival (P = .0023) and 5-year overall survival (P = .0064). Details of this trial have been previously published.16 Initially, full toxicity reporting was required only for the first 1,500 patients. However, after reaching the criterion number of patients, toxicity reporting was later reinstituted to allow adequate estimation of toxic event rates. For this reason, toxicity data are not available for all patients on this trial. CALGB 9741 used a factorial design that randomly assigned patients to cyclophosphamide, doxorubicin, and paclitaxel administered on either a 2-week (dose dense) or every 3-week schedule, and to either cyclophosphamide and doxorubicin followed by paclitaxel or sequential doxorubicin followed by paclitaxel followed by cyclophosphamide. Eligibility was similar to CALGB 9344 and excluded patients with other serious medical illnesses or severe cardiovascular disease. After 36 months of follow-up, patients on dose-dense therapy had significantly improved disease-free survival (P = .01) and overall survival (P = .013). The details of this trial have been published previously.17 A recent update at a median follow-up of 69 months, a significant benefit persisted for both disease-free and overall survival for patients treated with dose-dense therapy.18
Statistics
Toxicity data were available for 6,174 (93%) of 6,642 patients treated in these three trials. These 6,174 patients form the basis of the current report. Details concerning accrual and trial characteristics are presented in Table 1. Four hundred fifty-eight patients (7%) were 65 years or older (65+) and 144 (3%) were 70 years or older. There were no differences in clinical characteristics among age groups except patients 65 or older were more likely to have  10 positive nodes (24% v 13% v 8% for patients 65+, 51 to 64, and  50 years, respectively) or mastectomy (78% v 71% v 69% for 65+, 51 to 64, and 50 years, respectively).
Incidence and Severity of Selected Toxicities
In response to NCI guidelines for data reduction hospitalization for febrile neutropenia was only recorded for 1,877 patients on CALGB 9741, and was observed in 6% of patients 65+ and in 3% of patients in each of the lower age groups. Hospitalization for other toxicity on 9741 was seen in 10%, 10%, and 8% of patients 65+, 51 to 64 years, and 50, respectively. For 1,733 patients on CALGB 8541 hospitalization for any toxicity was seen in 20%, 21%, and 21% of patients 65+, 51 to 64, and 50 years, respectively.
Nonhematologic toxicities that were assessed included nausea, vomiting, diarrhea, stomatitis, and neuropathy. Table 3 shows the incidence of grades 3 and 4 severity for each of these toxicities as well as for any nonhematologic toxicity. The incidence of these nonhematologic toxicities varied by regimen and by age (P = .0013). More intense regimens were associated with more grade 3 and 4 nonhematologic toxicity than less intense regimens (20% to 25% v 13% to 18%); however, of the three age categories, women age 51 to 64 had the lowest incidence on the less intense regimens and the highest incidence on the more intense regimens. Women age
Discontinuation of Protocol Therapy for Toxicity A total of 3% of patients (n = 210) who began protocol treatment discontinued it before completion due to toxicity. Two percent of patients age 50, 4% of patients between 51 and 64, and 6% of patients age 65+ discontinued chemotherapy before completion. After adjusting for chemotherapy regimen and study, patients age 65+ were nearly 2.5 times more likely than those patients age 50 to stop treatment early (OR, 2.48; 95% CI, 1.57 to 3.91). The incidence of early termination did not differ among the three trials. Early discontinuation was more frequent on those regimens with more intense chemotherapy (3%, 6% and 7% discontinuation for patients age 50, 51 to 64, and 65+ years, respectively) compared with those with less intense chemotherapy (2%, 3%, and 4% discontinuation for patients 50, 51 to 64, and 65+ years, respectively). However, there was no interaction effect on discontinuing chemotherapy by chemotherapy regimen and age. For each regimen, early discontinuation increased linearly with advancing age (P < .0001).
Cause of Death
New Primary Cancers A total of 342 patients (5.5%) developed 353 new primary cancers. Table 5 presents the number and site of these new malignancies. The most common site was the breast, including ductal carcinoma in situ (143 patients; 2.3%) with similar incidence among the three age categories ( 50, 2.4%; 51 to 64, 2.2%; 65+, 2.0%). The time to development of the new primary (from beginning protocol therapy) was inversely related to age. Of the patients age 50 who developed second primaries, about one half were diagnosed within 5 years of beginning protocol therapy; of those patients age 51 to 64, about one half the new primaries occurred by 4 years; of those patients age 65+, about one half the second primaries developed within 2.5 years.
A total of 35 patients (0.6%) developed AML or MDS. The incidence of AML/MDS increased linearly with advancing age (P < .001); 11 were in patients age 50 years (0.3%; 95% CI, 0.2% to 0.6%), 16 were in patients age 51 to 64 years (0.7%; 95% CI, 0.4% to 1.1%), and eight were in patients age 65+ (1.8%; 95% CI, 0.8% to 3.4%). Of the 35 patients who developed AML/MDS, 20 had received filgrastim (57%). Five who received filgrastim were age 50 years, eight were age 51 to 64 years, and seven were age 65+. Among those who developed AML/MDS, there was a significant relationship (P = .008) between age and doxorubicin dose. Of 11 patients age 50 who developed AML, seven (64%) received total doses of doxorubicin more than 240 mg/m2 while all patients 65+ years who developed AML received a 240 mg/m2 total dose of doxorubicin. Data on breast and/or chest wall radiation use were only available for CALGB 8541 but only four patients in this trial developed AML or MDS, too small a sample size for analyses.
The decision to offer chemotherapy to elderly patients is complex and chemotherapy-related toxicity must be carefully considered. Our data show that elderly patients have significantly higher hematologic toxicity than younger patients, although this did not result in increased mortality. Elderly patients were also more likely to discontinue treatment for toxicity-related reasons, but the percentage of such patients was still small (6%). Surprisingly, grades 3 and 4 nonhematologic toxicity were not higher in the oldest age group but a limitation of this analysis is that detailed data on grades 1 to 2 toxicity were not available; such toxicity could have a major effect on quality of life and activities of daily living. Of note, older patients on these three trials all met strict eligibility criteria that undoubtedly excluded many elderly patients with significant comorbid illness. Thus these results can only be applied to healthy elderly patients and are not generalizable to the population of all elderly patients who have breast cancer. When adjusted for treatment arm and study, increasing age was associated with an increased risk of grade 4 hematologic toxicity. Others have noted increased risks of myelosuppression in elderly patients treated for breast cancer. Crivellari and colleagues noted greater grade 3 but not grade 4 toxicity in patients age 65+ treated with CMF.19 Du and colleagues20 reviewed Medicare claims for adverse effects of chemotherapy from 35,000 women with stages I to IV breast cancer age 65 years or older entered in the Surveillance, Epidemiology, and End Results (SEER) registry from 1991 through 1996. Nine point two percent of older women receiving chemotherapy were hospitalized compared with 0.5% who were not. Forty (1%) of 4,134 women hospitalized for chemotherapy toxicity died of treatment-related complications compared with 0.4% of nonchemotherapy-related admissions. Anthracyclines were used in 32% of chemotherapy-treated patients and were associated with greater toxicity. In our study the incidence of AML/MDS was higher in elderly patients, a similar finding to the population in general.21 Patt and colleagues22 compared the risk of AML in 36,904 patients with nonmetastatic breast cancer in the SEER data registry given chemotherapy or not. The unadjusted risk of developing AML at 10 years was 1.6% for the 4,572 who received chemotherapy compared with 1.1% for those not receiving chemotherapy. Anthracyclines but not taxanes were associated with a significantly higher HR (2.17) for AML. Recent trials have shown that nonanthracycline-containing regimens may be as effective as anthracycline regimens in the adjuvant setting and may be associated with less leukemia and cardiac risk.23 The use of granulocyte colony-stimulating factor was also associated with a significantly increased risk of AML (HR, 2.21). One study of 6,360 patients followed between 1970 and 1999 found 12 patients who developed AML with breast cancer, a 3.5-fold higher risk.24 In our study, an exploratory analysis showed a trend toward an increased risk of AML/MDS in patients receiving filgrastim. However, in CALGB 9741, of the 0.7% of patients with AML/MDS, there was no difference in leukemia risk between patients randomly assigned to filgrastim arms (dose dense) and those who were not.18 Future chemotherapy trials in elderly patients should further explore the possible relationship of G-CSF and leukemia. A major issue in elderly patients is the increased the risk of anthracycline-related cardiac toxicity.25 Some studies of anthracyclines in healthy elderly patients have shown no increased risk12,26 while others have shown an age-related effect.27 Giordano and colleagues28 assessed the long-term cardiac safety of anthracycline-based chemotherapy in 34,621 patients in the SEER registry observed from 1992 through 1999. Of this group, 28,640 received no chemotherapy, 3,253 received nonanthracycline chemotherapy, and 2,728 received anthracyclines. The 5- and 10-year rates of congestive heart failure in a multivariate Cox regression analysis for women age 66 to 70 years was 19% and 47% for the anthracycline cohort, 14% and 33% for the nonanthracycline cohort, and 12% and 28% for the no chemotherapy cohort, respectively. Of note, there was no statistically different risk of CHF for women older than 70 among the three cohorts. In our study, eight cardiac deaths were attributed to treatment. Coding for cardiac toxicity is problematic because investigators cannot be certain as to the relationship of treatment and cardiac damage in individual patients who develop heart failure several years after anthracycline treatment. Besides cardiotoxicity and secondary leukemias, other potential chemotherapy toxicities in elderly patients are also of concern. These include loss of cognitive function,29 a decrease in quality of life and loss of physical function,19,30 and muscle weakness.31 Several clinical trials of adjuvant chemotherapy that are underway in both the United States and Europe will address these issues. One such trial, CALGB/Cancer Trials Support Unit 49907, randomly assigns women age 65 or older to standard chemotherapy (cyclophosphamide and doxorubicin or CMF) or capecitabine. This trial has now completed accrual and captures detailed toxicity, quality of life, functional, and comorbidity data. Moreover, should oral therapy prove as effective as standard chemotherapy, it will offer a major option for treatment of older patients.32 Other intriguing options include the use of low-dose intravenous anthracyclines.33 The use of adjuvant chemotherapy in elderly patients with breast cancer is still a major area of investigation. Although some question the value of chemotherapy in elderly patients, our previous data from patients with node-positive breast cancer who were treated with state-of-the-art chemotherapy regimens suggested that elderly patients derived similar benefits to younger patients.7 Improvements in relapse-free and overall survival associated with more aggressive chemotherapy regimens were similar for all age groups. For women older than 65, a 42% reduction in relapse rate and a 27% reduction in the overall mortality rate were associated with more intensive as opposed to less intensive chemotherapy. However, because the elderly patients experienced greater toxicity than the younger patients, consideration of the risks and benefits of chemotherapy must be carefully weighed and discussed with each patient.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Hyman B. Muss, Amgen Stock: Hyman B. Muss, Amgen Honoraria: Marc L. Citron, Amgen Research Funds: N/A Testimony: N/A Other: N/A
Conception and design: Hyman B. Muss, Donald A. Berry, Larry Norton, Eric P. Winer, Clifford A. Hudis Administrative support: Donald A. Berry, Constance Cirrincione, Eric P. Winer, Clifford A. Hudis Provision of study materials or patients: Hyman B. Muss, Daniel R. Budman, I. Craig Henderson, Marc L. Citron, Larry Norton, Eric P. Winer, Clifford A. Hudis Collection and assembly of data: Donald A. Berry, Constance Cirrincione, Larry Norton Data analysis and interpretation: Hyman B. Muss, Donald A. Berry, Constance Cirrincione, Daniel R. Budman, I. Craig Henderson, Marc L. Citron, Larry Norton, Eric P. Winer, Clifford A. Hudis Manuscript writing: Hyman B. Muss, Donald A. Berry, Constance Cirrincione, Daniel R. Budman, I. Craig Henderson, Marc L. Citron, Larry Norton, Eric P. Winer, Clifford A. Hudis Final approval of manuscript: Hyman B. Muss, Donald A. Berry, Constance Cirrincione, Daniel R. Budman, I. Craig Henderson, Marc L. Citron, Larry Norton, Eric P. Winer, Clifford A. Hudis
Supported by Grants No. CA77406, CA33601, CA35279, CA60138, CAII028, CA77651, CA32291. Presented in abstract format at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Yancik R: Population aging and cancer: A cross-national concern. Cancer J 11:437-441, 2005[Medline] 2. Kimmick GG, Peterson BL, Kornblith AB, et al: Improving accrual of older persons to cancer treatment trials: A randomized trial comparing an educational intervention with standard information: CALGB 360001. J Clin Oncol 23:2201-2207, 2005 3. Hebert-Croteau N, Brisson J, Latreille J, et al: Compliance with consensus recommendations for systemic therapy is associated with improved survival of women with node-negative breast cancer. J Clin Oncol 22:3685-3693, 2004 4. Early Breast Cancer Trialists’ Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005[CrossRef][Medline] 5. Witherby SM, Muss HB: Special issues related to breast cancer adjuvant therapy in older women. Breast 14:600-611, 2005[CrossRef][Medline] 6. Perez E, Muss HB: Optimizing adjuvant chemotherapy in early-stage breast cancer. Oncology (Williston Park) 19:1759-1767, 2005[Medline] 7. Muss HB, Woolf S, Berry D, et al: Adjuvant chemotherapy in older and younger women with lymph node-positive breast cancer. JAMA 293:1073-1081, 2005 8. Lichtman SM, Skirvin JA: Pharmacology of antineoplastic agents in older cancer patients. Oncology (Huntingt) 14:1743-1755, 2000[Medline] 9. Hutchins LF, Unger JM, Crowley JJ, et al: Underrepresentation of patients 65 years of age or older in cancer- treatment trials. N Engl J Med 341:2061-2067, 1999 10. Sateren WB, Trimble EL, Abrams J, et al: How sociodemographics, presence of oncology specialists, and hospital caner programs affect accrual to cancer treatment trials. J Clin Oncol 20:2109-2117, 2002 11. Begg CB, Cohen JL, Ellerton J: Are the elderly predisposed to toxicity from cancer chemotherapy? An investigation using data from the Eastern Cooperative Oncology Group. Cancer Clinical Trials 3:369-374, 1980[Medline] 12. Dees EC, O'Reilly S, Goodman SN, et al: A prospective pharmacologic evaluation of age-related toxicity of adjuvant chemotherapy in women with breast cancer. Cancer Invest 18:521-529, 2000[Medline] 13. Ibrahim NK, Frye DK, Buzdar AU, et al: Doxorubicin-based chemotherapy in elderly patients with metastatic breast cancer: Tolerance and outcome. Arch Intern Med 156:882-888, 1996 14. Christman K, Muss HB, Case LD, et al: Chemotherapy of metastatic breast cancer in the elderly: The Piedmont Oncology Association experience. JAMA 268:57-62, 1992 15. 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 90:1205-1211, 1998 16. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976-983, 2003 17. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup trial C9741/Cancer and Leukemia Group B trial 9741. J Clin Oncol 21:1431-1439, 2003 18. Hudis C, Ciron M, Berry D, et al: Five year follow-up of INT C9741: Dose-dense (DD) chemotherapy (CRx) is safe and effective. Breast Cancer Res Trt 94:20s–21s, 2005 (suppl 1) 19. 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 18:1412-1422, 2000 20. Du XL, Osborne C, Goodwin JS: Population-based assessment of hospitalizations for toxicity from chemotherapy in older women with breast cancer. J Clin Oncol 20:4636-4642, 2002 21. Devesa S: The burden of cancer in the elderly, in Muss HB, Hunter CP, Johnson KA, (eds): Treatment and Management of Cancer in the Elderly. New York, Taylor & Francis Group, 2006, pp 7-28 22. Patt DA, Duan Z, Hortobagyi G, et al: Acute myeloid leukemia (AML) in older women after adjuvant breast cancer therapy. J Clin Oncol 24:17s, 2006 (abstr 560) 23. Jones SE, Savin MA, Holmes FA, et al: Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 24:5381-5387, 2006 24. Renella R, Verkooijen HM, Fioretta G, et al: Increased risk of acute myeloid leukaemia after treatment for breast cancer. Breast 15:614-615, 2006[CrossRef][Medline] 25. Von Hoff DD, Layard MW, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91:710-717, 1979 26. Ibrahim NK, Hortobagyi GN, Ewer M, et al: Doxorubicin-induced congestive heart failure in elderly patients with metastatic breast cancer, with long-term follow-up: The M.D. Anderson experience. Cancer Chemother Pharmacol 43:471-478, 1999[CrossRef][Medline] 27. Fumoleau P, Roche H, Kerbrat P, et al: Long-term cardiac toxicity after adjuvant epirubicin-based chemotherapy in early breast cancer: French Adjuvant Study Group results. Ann Oncol 17:85-92, 2006 28. Giordano SH, Pinder M, Duan Z, et al: Congestive heart failure (CHF) in older women treated with anthracycline (A) chemotherapy (C). J Clin Oncol 24:8s, 2006 (abstr 521)[CrossRef] 29. Hurria A, Goldfarb S, Rosen C, et al: Effect of adjuvant breast cancer chemotherapy on cognitive function from the older patient's perspective. Breast Cancer Res Treat 98:343-348, 2006[CrossRef][Medline] 30. Hurria A, Hurria A, Zuckerman E, et al: A prospective, longitudinal study of the functional status and quality of life of older patients with breast cancer receiving adjuvant chemotherapy. J Am Geriatr Soc 54:1119-1124, 2006[CrossRef][Medline] 31. Extermann M, Boler I, O'Neill E, et al: Muscle weakness is a significant problem in older patients receiving chemotherapy. J Clin Oncol 24:479s, 2006 (abstr 8545) 32. Biganzoli L, Goldhirsch A, Straehle C, et al: Adjuvant chemotherapy in elderly patients with breast cancer: A survey of the Breast International Group (BIG). Ann Oncol 15:207-210, 2004 33. Fargeot P, Bonneterre J, Roche H, et al: Disease-free survival advantage of weekly epirubicin plus tamoxifen versus tamoxifen alone as adjuvant treatment of operable, node-positive, elderly breast cancer patients: 6-year follow-up results of the French adjuvant study group 08 trial. J Clin Oncol 22:4622-4630, 2004[Medline] Submitted January 28, 2007; accepted June 15, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
