Originally published as JCO Early Release 10.1200/JCO.2004.02.145 on October 25 2004

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fargeot, P. Articles by Chapelle-Marcillac, I. Search for Related Content PubMed PubMed Citation Articles by Fargeot, P. Articles by Chapelle-Marcillac, I. Related Articles Related Editorial Social Bookmarking                            What's this?

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

From the Centre Georges-François Leclerc, Dijon; Cetre Oscar Lambret, Lille; Institut Claudius Régaud, Toulouse; Clinique Catherine de Sienne; Centre René Gauducheau, Nantes; Centre Jean Perrin, Clermont-Ferrand; Centre Hospitalier André Boulloche, Montbéliard; Centre Antoine Lacassagne, Nice; Centre Paul Strauss, Strasbourg; Centre Hospitalier Louis Pasteur, Colmar; Centre Léon Bérard, Lyon; and Centre Hospitalier de Bretagne Sud, Lorient, France. Dr Chapelle-Marcillac is a consultant in Chatenay-Malabry, France

Address reprint requests to Pierre Fargeot, MD, Département d'Oncologie Médicale, Centre Georges-François Leclerc, 1 rue du Professeur Marion, BP 77980, 21079 Dijon Cedex, France; e-mail: pfargeot{at}dijon.fnclcc.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
PURPOSE: To assess whether an epirubicin (EPI) -based chemotherapy plus hormonal regimen improves disease-free (DFS) in women older than 65 years, with node-positive, operable breast cancer (BC), relative to tamoxifen (TAM) alone.

PATIENTS AND METHODS: A total of 338 patients were randomly assigned after surgery to receive TAM 30 mg/d for 3 years (TAM, n = 164), or EPI 30 mg on days 1, 8, and 15 every 28 days for six cycles plus TAM 30 mg/d for 3 years (EPI-TAM, n = 174). In both arms, patients received radiotherapy, delivered after chemotherapy (CT) in the EPI-TAM group.

RESULTS: The 6-year DFS rates were 69.3% with TAM and 72.6% with EPI-TAM (P = .14). The multivariate analysis shows a relative risk of relapse of 1.93 (95% CI, 1.70 to 2.17) with TAM compared with EPI-TAM (P = .005). The 6-year OS, related to disease progression, was 79.1% and 79.8%, respectively (P = .41). Compliance with CT was good: 96.9% of patients received six cycles. The acute toxicity per patient was mild: grade 2 neutropenia in 5.9%, grade 2 anemia in 2.0%, grade 3 nausea or vomiting in 4.6%, and grade 3 alopecia in 7.2%. Five cases (in five patients) of decreased left ventricular ejection fraction occurred after CT: three after adjuvant CT, and two after anthracycline-based CT for relapse. One patient died as a result of dysrhythmia related to carcinomatous lymphangitis. No secondary leukemia occurred.

CONCLUSION: This study conducted in node-positive elderly patients demonstrates a significant contribution of a weekly EPI regimen in terms of DFS. Moreover, this regimen is safe for hematologic, nonhematologic, and cardiac toxicities.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
Cancer is a disease of the elderly, with more than 60% of cancer cases diagnosed in patients older than the age of 65 years.¹ Despite these demographics, elderly patients are infrequently included in clinical trials, resulting in a paucity of data regarding the effectiveness of standard treatments for many common cancers in the elderly.^2-6 The under-representation of older patients is particularly notable in breast cancer clinical trials.^6-10 In an analysis of the Southwest Oncology Group database for the years 1993 to 1996, 9% of patients in breast cancer clinical trials were 65 years of age or older, although 49% of patients with breast cancer in the general population fit this criterion (P < .001).⁶

Consequently, there are few data regarding the efficacy of chemotherapy in women older than age 70 years. Moreover, there is evidence that in clinical practice, older women with early-stage breast cancer receive adjuvant chemotherapy less frequently than do their younger counterparts,^11-19 and it has been postulated that the poorer 5-year survival in women older than age 75 may be due in part to the decreased use of chemotherapy.¹⁹ Practice pattern variations based on chronological age have persisted when adjusted for baseline demographic factors in several studies, suggesting that age itself, rather than functional or health status, may be a factor in treatment decisions.^12,14,15,17 However, the majority of comparative trials demonstrate that chemotherapy is tolerated equally well by healthy elderly women with breast cancer as by younger women.^20-24

The controversial issue of how best to treat elderly women with early-stage breast cancer has been addressed in recent consensus panel recommendations.^10,25 The 2000 National Institutes of Health Consensus Development Conference Statement and the 2003 St Gallen International Consensus Panel similarly recommend the use of adjuvant tamoxifen (TAM) for all older women with estrogen receptor–positive disease.^10,25 The National Institutes of Health consensus statement recognizes the need for additional data regarding adjuvant chemotherapy in women older than 70 years.¹⁰

Since 1986, the French Adjuvant Study Group (FASG) used epirubicin (EPI) -based chemotherapy as adjuvant treatment of breast cancer. In the metastatic setting, we have demonstrated that EPI was as effective as and less toxic than doxorubicin when administered at equimolar doses.²⁶ On the basis of these results, we considered EPI as our reference anthracycline. Six cycles of fluorouracil 500 mg/m², EPI 50 mg/m², and cyclophosphamide 500 mg/m² every 21 days (FEC 50) was our first standard adjuvant treatment in node-positive breast cancer.²⁷ Thereafter, we demonstrated that FEC 100 (the same regimen with EPI 100 mg/m²) resulted in greater survival than FEC 50.²⁸

Given that elderly patients are considered more likely to suffer toxicities as a result of chemotherapy, we chose to use EPI as a single agent in a weekly schedule, which might lead to a better tolerability profile. In 1991, we decided to initiate an adjuvant phase III trial, FASG 08, in women age 65 years with node-positive breast cancer to evaluate the effectiveness of TAM plus weekly single-agent EPI versus TAM alone, and to determine the tolerability and feasibility of such a regimen in elderly women.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
Patient Population
Between March 1991 and April 2001, 338 women with operable breast cancer, recruited from 19 institutions in France, were enrolled onto the study. The women had all undergone modified radical mastectomy or lumpectomy plus axillary dissection. The study recruited elderly women age 65 years with histologically proven axillary lymph node involvement (at least five axillary lymph nodes resected). No specific recommendation was required regarding hormone receptor status. The main eligibility criteria were WHO performance status 2; normal hematologic (granulocyte count 2,000/µL, platelet count 100,000/µL), hepatic (bilirubin 35 µmol/L), and renal (serum creatinine level 130 µmol/L) functions; and no cardiac dysfunction (baseline left ventricular ejection fraction [LVEF] 50%). LVEF was measured at rest by radioisotopic or echographic methods. Patients were excluded from the study if they had evidence of metastases; a documented history of cardiac disease or previous cancer (except treated basal cell and squamous cell carcinoma of the skin or cancer of the uterine cervix); a serious underlying medical illness or psychiatric disorder; inflammatory or locally advanced breast cancer before surgery; previous radiation therapy, hormonal therapy, or chemotherapy for breast cancer; or if the start of treatment exceeded 42 days from initial surgery for breast cancer.

Potentially eligible patients also underwent bone scan, chest radiograph, abdominal ultrasound or computed tomography scan, and contralateral mammography. Written informed consent was obtained from each patient in a standard procedure at each participating institution according to the French loi Huriet.

Treatment Regimens
Patients were randomly assigned to receive one of the following regimens: TAM 30 mg/d orally for 3 years, or EPI (Pfizer, Milan, Italy) 30 mg, full dose, administered intravenously on days 1, 8, and 15 every 28 days for six cycles plus TAM 30 mg/d orally for 3 years, started at the first chemotherapy cycle (EPI-TAM). The allocated treatment was started within 42 days after initial surgery.

Locoregional radiotherapy was delivered within 6 weeks after initial surgery in the TAM group, and within 30 days after the last chemotherapy cycle in the EPI-TAM group. After mastectomy, radiation to the chest wall, supraclavicular area, and internal mammary chain (and the axillary area if a pN1 tumor was present) was delivered and consisted of 50 Gy in 25 fractions for each target. Patients who underwent lumpectomy received local radiation to the breast that consisted of 55 Gy in 27 fractions plus a complementary breast irradiation of 10 to 15 Gy, and local radiation to the supraclavicular area and internal mammary chain (and axillary area if a pN1 tumor was present), consisting of 50 Gy in 25 fractions for each target.

For chemotherapy, preventive use of granulocyte colony-stimulating factors and antibiotics was prohibited. Antiemetic treatment was prescribed routinely before each cycle. A cooling cap could be used, according to the usual practice of each institution. An absolute granulocyte count less than 2,000/µL or a platelet count less than 100,000/µL on day 14 led to cancelation of the third injection and reintroduction of the protocol regimen on day 28. If the same conditions occurred on day 28, treatment was interrupted for at least 1 week. Treatment was stopped if hematologic recovery took more than 3 weeks. The EPI dose was reduced by 50% if serum bilirubin levels were 35 to 50 µmol/L, and treatment was stopped if bilirubin levels exceeded 50 µmol/L. The tolerability of chemotherapy was evaluated as follows: a CBC was taken on days 14 and 28, an ECG was taken before each cycle, and nonhematologic toxicity was evaluated during the period between each cycle, according to WHO criteria. The assessment of LVEF was recommended within 3 to 4 weeks after the last chemotherapy cycle.

Patients underwent clinical and biochemical assessments every 6 months during the 5-year follow-up period, and yearly thereafter. A radiologic assessment was performed every year during the 5-year follow-up period, and every 2 years thereafter.

Statistical Analysis
The primary end point was the 5-year disease-free survival (DFS), with a reference rate of 70% for TAM; the foreseen difference was 10% in a bilateral test with = 10% and ß = 20%. All assessable patients were entered onto an intention-to-treat analysis using SPSS software (SPSS, Inc, Chicago, IL). The ² test was used to compare baseline categoric variables and the incidence of adverse events in both groups.²⁹ Continuous variables were compared using analysis of variance.³⁰ Relative dose-intensity was calculated on the basis of the ratio of the drug doses actually delivered in the originally expected time to the expected dose delivered in the expected time.³¹ DFS was defined as the time from random allocation until first relapse (local, regional, and distant). A contralateral breast cancer was considered a new primary malignancy. Overall survival (OS) and specific OS (SpOS) were defined as the time from random assignment until death, irrespective of causality (OS) or related to breast cancer (SpOS). DFS, OS, and SpOS rates were computed according to the Kaplan-Meier method, and survival curves were compared with the log-rank test or the stratified log-rank test, as appropriate.^32,33 The prevalence of the following classic prognostic factors was analyzed: age, surgery, Scarff-Bloom and Richardson grade, pathologic tumor size, number of involved lymph nodes, lymph node capsular rupture, and hormone receptor (HR) status. Cox regression methods were used to determine whether known clinical prognostic variables confounded the treatment effect.³⁴ Statistical analysis was performed in a double-blind fashion both by Pfizer (Saint-Quentin en Yvelines, France) and by an independent biostatistician.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
Patient Characteristics
Three hundred thirty-eight patients were enrolled onto the study. Of these, nine (2.7%) were ineligible because of metastatic disease (n = 7) or concomitant malignant disease (n = 2), and 11 (3.2%) were lost to follow-up after random allocation (Table 1). These patients were excluded from the efficacy analysis (n = 318). The safety and compliance analysis involved all treated patients (n = 321; Table 1). Baseline characteristics were well balanced between both arms (Table 2). Major protocol violations were included in the analysis and were as follows: age younger than 65 years (n = 3; lower range, 60 years), fewer than five axillary nodes resected (n = 1), neutrophil count lower than 2,000/µL (n = 3) or not determined (n = 26), LVEF less than 50% (n = 6), LVEF not measured (n = 125), interval between surgery and treatment onset exceeding 42 days (n = 14), radiotherapy delivered before chemotherapy (n = 2), and wrong treatment arm allocation (n = 4). At the cutoff date for analysis, the median follow-up period was 72 months (range, 6 to 128 months).

Among the 160 patients who received EPI, 155 patients (96.9%) received six cycles. Five patients stopped chemotherapy prematurely: one patient after the first cycle presented with vertigo, three patients after the fourth cycle refused to continue the treatment, and one patient after the fifth cycle did not tolerate chemotherapy-induced alopecia. Per cycle delivered, patients received a mean dose of 89 mg (ie, 98.8% of the intended dose), and in 96.5% of cycles, the three scheduled injections were administered. The mean cumulative EPI dose received was 527 mg (intended dose, 540 mg), corresponding to 315 mg/m² when calculated according to the individual body-surface area, with a mean EPI dose-intensity of 13.1 mg/m²/wk. Acute toxicity was evaluated according to WHO criteria (Table 3). Regarding hematologic toxicity, no grade 3 to 4 adverse events occurred in terms of neutropenia and anemia, one patient experienced a noncomplicated grade 3 infection, and no febrile neutropenia occurred. The other adverse effects observed were mild: grade 3 nausea or vomiting in 4.6% of patients without anti–5-hydroxytryptamine-3 prophylaxis, no case of grade 3 to 4 stomatitis, and grade 3 alopecia in 7.2% of patients. No deaths occurred as a result of toxicity.

The delayed cardiac toxicity was defined as the occurrence of a cardiac event before relapse, at least 1 month after chemotherapy completion, or during the follow-up period in the TAM arm. No delayed cardiac toxicity was observed in patients who received TAM, and three decreases in LVEF (1.9%) occurred in those who received chemotherapy. These occurrences were observed between 6 and 12 months after chemotherapy, did not require additional investigations, and none of these patients developed subsequent cardiac disorders.

Finally, three patients presented with cardiac events after the occurrence of a relapse. One patient, in the TAM arm, was treated with doxorubicin (cumulative dose, 500 mg/m²) and died as a result of pulmonary embolism. In the EPI-TAM arm, one patient died as a result of rhythm disorders related to carcinomatous lymphangitis, and one patient presented with a decrease in LVEF after being re-treated with 450 mg/m² of EPI for her metastatic disease.

DFS, OS, and Second Malignancies
Recurrence was evaluated in 318 patients (TAM, n = 155; EPI-TAM, n = 163), of whom 84 had experienced disease relapse at the cutoff date for analysis (46 [29.7%] in the TAM arm, and 38 [23.3%] in the EPI-TAM arm). The 6-year DFS rates were 69.3% (95% CI, 65.2% to 73.4%) with TAM, and 72.6% (95% CI, 68.7% to 76.5%) with EPI-TAM (P = .14; Fig 1). Of note, there were significantly fewer patients who experienced local relapse in the EPI-TAM arm, with a 6-year local DFS of 97.8% compared with 93.2% in the TAM arm (P = .05). The annual incidence of relapse showed that chemoendocrine therapy decreased the risk of relapse during the first 2 years, and reached a plateau around the 3-year mark; in TAM-treated patients, the annual risk of relapse decreased after the second year, then increased after the fifth year (Fig 2). No statistically significant difference was detected in the pattern of recurrences (Table 4). A subset analysis of treatment efficacy according to HR status showed that the difference between TAM alone and chemotherapy plus endocrine therapy was significantly in favor of EPI-TAM in HR-negative patients (P = .01). When adjusted on HR status, there was a significant difference in favor of the EPI-TAM arm (stratified log-rank, P = .03; Table 5). The Cox proportional hazards model showed that initial surgery, number of positive axillary lymph nodes, and HR status were independent prognostic factors (Table 6). In this model, the comparison of treatment demonstrates a significant improvement in disease-free survival with the EPI-TAM combination compared with TAM alone (hazard ratio, 1.93; 95% CI, 1.70 to 2.17; P = .005; Table 5).

View larger version (14K): [in this window] [in a new window]   Fig 1. Six-year disease-free survival: 69.3% (tamoxifen [TAM]) v 72.6% (epirubicin plus TAM [EPI-TAM]); P = .14 (univariate) and P = .005 (multivariate).

View larger version (17K): [in this window] [in a new window]   Fig 2. Annual incidence of relapse. TAM, tamoxifen; EPI-TAM, epirubicin plus TAM.

View larger version (14K): [in this window] [in a new window]   Fig 3. Six-year overall survival: 75.8% (tamoxifen [TAM]) v 75.4% (epirubicin plus TAM [EPI-TAM]); P = .81.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
The treatment of elderly breast cancer patients takes into account several issues: efficacy, compliance, toxicity, and quality of life. To our knowledge, this trial is the only one that was conducted specifically in patients older than 65 years for the treatment of early breast cancer. At the beginning of the 1990s, it was a challenge to initiate an anthracycline-based adjuvant trial in elderly patients, and thus it took 10 years to recruit 338 patients. Statistical data must be interpreted carefully. Nevertheless, we demonstrate that this schedule of EPI-TAM improves disease-free survival relative to TAM alone. A part of this improvement is driven by the reduction in local relapse with chemotherapy plus endocrine therapy. Notably, in this trial initiated in 1991, these results were obtained using EPI and TAM concurrently. The recent observations made by the Southwest Oncology Group strongly suggested that a sequential administration of TAM after chemotherapy improved DFS.³⁵ If this were true, our results could be improved if TAM and EPI are used sequentially. At a median follow-up of 72 months, an OS advantage with the combination regimen was not observed. Given the relatively modest number of deaths, longer follow-up is needed to provide a more reliable analysis of OS.

Two other adjuvant trials included some patients older than 65 years.^24,36 The International Breast Cancer Study Group trial compared TAM alone with TAM combined with three cycles of cyclophosphamide, methotrexate, and fluorouracil in 608 node-positive, menopausal women, of whom 172 (28%) were age 65 years. Overall, the 5-year DFS was significantly better with chemotherapy plus endocrine therapy (P = .03), whereas no difference was observed in the subgroup of patients 65 years.²⁴ The International Collaborative Cancer Group randomly assigned 604 node-positive, postmenopausal patients (27% age 65 years) between TAM alone and single agent EPI-TAM given at 50 mg/m² on days 1 and 8 every 28 days for six cycles.³⁶ The 5-year DFS was significantly better with the EPI-TAM combination (P = .023), but this trial was not powered to determine the effect of treatment according to age.

In the International Breast Cancer Study Group trial, acute toxicity related to the CMF regimen was significantly more severe in patients age 65 years despite a higher rate of dose reduction. With EPI used as a single agent, acute toxicities and cardiac adverse effects described in both International Collaborative Cancer Group and FASG 08 trials are manageable (Table 7). However, in both trials, no quality-of-life assessment was performed. In elderly patients, impaired renal excretion was one of the main factors affecting toxicity. In the metastatic setting, Gelman et al²¹ used creatinine clearance to calculate doses of cyclophosphamide and methotrexate in the cyclophosphamide, methotrexate, and fluorouracil regimen, but this adjustment resulted in a lower efficacy. With EPI, approximately 11% to 15% of the administered dose is excreted in the urine as unchanged drug or metabolites.³⁷ EPI clearance problems induced by renal dysfunction may become clinically relevant only in patients with severe renal impairment: terminal half-life values were similar between patients with severe renal failure and those with normal function (37 v 39 hours, respectively).³⁷

This study demonstrates the efficacy and feasibility of EPI-based chemotherapy in the elderly and provides a solid basis for future trials in this setting. There are several unanswered questions in the treatment of the elderly, including whether an elderly patient should be defined as 65, 70, or 75 years old. The use of geriatric assessment scales could be helpful to determine patients who could benefit most from adjuvant treatments, and quality of life would need to be taken into consideration in such strategies. Breast cancer in elderly patients will be a growing issue in the years to come, and additional clinical trials are warranted.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
The French participating centers are, in order of institutional accruals: Centre Oscar Lambret, Lille; Institut Claudius Régaud, Toulouse; Centre Georges-François Leclerc, Dijon; Centre Paul Papin, Angers; Centre René Gauducheau, Nantes; Centre Jean Perrin, Clermont-Ferrand; Centre Hospitalier André Boulloche, Montbéliard; Centre Antoine Lacassagne, Nice; Centre Hospitalier Jean Minjoz, Besançon; Centre Hospitalier Louis Pasteur, Colmar; Centre Léon Bérard, Lyon; Centre Hospitalier Edouard Herriot, Lyon; Centre Hospitalier de Bretagne Sud, Lorient; Centre Hospitalier Universitaire Dupuytren, Limoges; Centre Catherine de Sienne, Nantes; Centre Hospitalier Bellevue, Saint-Etienne; and Clinique de l'Océan, Saint-Nazaire.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
The following authors or their family members have 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. Acted as a consultant within the last 2 years: Isabelle Chapelle-Marcillac, Pfizer.

	Acknowledgment

 
We thank Elisabeth Luporsi (Centre Alexis Vautrin, Nancy, France) for her statistical analysis contribution. The Phillips Group Oncology Communications Company provided editorial assistance in the preparation of the manuscript.

	NOTES

 
Supported by grants from Pfizer, France.

Presented as abstract 145 (oral presentation) at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
1. Gianni W, Cacciafesta M, Pietropaolo M, et al: Aging and cancer: The geriatrician's point of view. Crit Rev Oncol Hematol 39:307-311, 2001[Medline]

2. Kennedy AW, Flagg JS, Webster KD: Gynecologic cancer in the very elderly. Gynecol Oncol 32:49-54, 1989[CrossRef][Medline]

3. Yancik R, Ries LA: Aging and cancer in America: Demographic and epidemiologic perspectives. Hematol Oncol Clin North Am 14:17-23, 2000[CrossRef][Medline]

4. Muss HB: The role of chemotherapy and adjuvant therapy in the management of breast cancer in older women. Cancer 74:2165-2171, 1994[CrossRef][Medline]

5. Fentiman IS, Tirelli U, Monfardini S, et al: Cancer in the elderly: Why so badly treated? Lancet 335:1020-1022, 1990[CrossRef][Medline]

6. Hutchins LF, Unger JM, Crowley JJ, et al: Underrepresentation of patients 65 years of age and older in cancer-treatment trials. N Engl J Med 341:2061-2067, 1999[Abstract/Free Full Text]

7. Stewart JA, Foster RS Jr: Breast cancer and aging. Semin Oncol 16:41-50, 1989

8. Early Breast Cancer Trialists' Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 339:1-15, 1992[Medline]

9. Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930-942, 1998[CrossRef][Medline]

10. National Institutes of Health Consensus Development Panel: National Institutes of Health Consensus Development Conference statement: Adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst 93:979-989, 2001[Abstract/Free Full Text]

11. Silliman RA, Guadagnoli E, Weitberg AB, et al: Age as a predictor of diagnostic and initial treatment intensity in newly diagnosed breast cancer patients. J Gerontol 44:46-50, 1989

12. Allen C, Cox EB, Manton KG, et al: Breast cancer in the elderly: Current patterns of care. J Am Geriatr Soc 34:637-642, 1986[Medline]

13. Hillner BE, Penberthy L, Desch CE, et al: Variation in staging and treatment of local and regional breast cancer in the elderly. Breast Cancer Res Treat 40:75-86, 1996[CrossRef][Medline]

14. Hébert-Croteau N, Brisson J, Latreille J, et al: Compliance with consensus recommendations for the treatment of early stage breast carcinoma in elderly women. Cancer 85:1104-1113, 1999[CrossRef][Medline]

15. Mandelblatt JS, Hadley J, Kerner JF, et al: Patterns of breast carcinoma in older women. Cancer 89:561-573, 2000[CrossRef][Medline]

16. Chu J, Diehr P, Feigl P, et al: The effect of age on the care of women with breast cancer in community hospitals. J Gerontol 42:185-190, 1987[Abstract/Free Full Text]

17. Du XL, Key CR, Osborne C, et al: Discrepancy between consensus recommendations and actual community use of adjuvant chemotherapy in women with breast cancer. Ann Intern Med 138:90-97, 2003[Abstract/Free Full Text]

18. Guadagnoli E, Shapiro C, Gurwitz JH, et al: Age-related patterns of care: Evidence against ageism in the treatment of early-stage breast cancer. J Clin Oncol 15:2338-2344, 1997[Abstract/Free Full Text]

19. Bernstein V, Truong P, Speers C, et al: Breast cancer biology, treatment, and survival in elderly women. Proc Am Soc Clin Oncol 20:247, 2001 (abstr 985)

20. 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 Clin Trials 3:369-374, 1980[Medline]

21. Gelman RS, Taylor SG IV: 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 2:1404-1413, 1984[Abstract]

22. 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[Abstract/Free Full Text]

23. 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]

24. 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[Abstract/Free Full Text]

25. Goldhirsch A, Wood WC, Gelber RD, et al: Meeting highlights: Updated international expert consensus on the primary therapy of early breast cancer. J Clin Oncol 21:3357-3365, 2003[Abstract/Free Full Text]

26. French Epirubicin Study Group: A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil and either doxorubicin or epirubicin. J Clin Oncol 6:679-688, 1988[Abstract]

27. Fumoleau P, Kerbrat P, Romestaing P, et al: Randomized trial comparing six versus three cycles of epirubicin-based adjuvant chemotherapy in premenopausal, node-positive breast cancer patients: 10-year follow-up results of the French Adjuvant Study Group 01 trial. J Clin Oncol 21:298-305, 2003[Abstract/Free Full Text]

28. Bonneterre J, Roché H, Kerbrat P, et al: French Adjuvant Study Group 05 trial (FEC 50 vs FEC 100): 10-year update of benefit/risk ratio after adjuvant chemotherapy in node-positive, early breast cancer patients. Proc Am Soc Clin Oncol 22:24, 2003 (abstr 93)

29. Snedecor GW, Cochran WG: Statistical Methods (ed 7). Ames, IA, Iowa State University Press, 1980

30. Duncan DB: P-tests and intervals for comparison suggested by the data. Biometrics 31:339-359, 1975[CrossRef]

31. Meyer RM, Browman GP, Samosh ML, et al: Randomized phase II comparison of standard CHOP with weekly CHOP in elderly patients with non-Hodgkin's lymphoma. J Clin Oncol 13:2386-2393, 1995[Abstract/Free Full Text]

32. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef]

33. Peto R, Peto J: Asymptotically efficient rank invariant test procedures. J R Stat Soc A 135:185-198, 1972[CrossRef]

34. Cox DR: Regression models and life-tables. J R Stat Soc B 34:187-202, 1972

35. Albain KS, Green SJ, Ravdin PM, et al: Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: Initial results from Intergroup trial 0100 (SWOG-8814). Proc Am Soc Clin Oncol 21:37, 2002 (abstr 143)

36. Wils JA, Bliss JM, Coombes MG, et al: Epirubicin plus tamoxifen versus tamoxifen alone in node-positive post menopausal patients with breast cancer: A randomized trial of the International Collaborative Cancer Group. J Clin Oncol 17:1988-1998, 1999[Abstract/Free Full Text]

37. Plosker GL, Faulds D: Epirubicin: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cancer chemotherapy. Drugs 45:788-856, 1993[Medline]

38. Launchbury AP, Habboubi N: Epirubicin and doxorubicin: A comparison of their characteristics, therapeutic activity and toxicity. Cancer Treat Rev 19:197-228, 1993[CrossRef][Medline]

39. Torti FM, Bristow MM, Lum BL, et al: Cardiotoxicity of epirubicin and doxorubicin: Assessment by endomyocardial biopsy. Cancer Res 46:3722-3727, 1986[Abstract/Free Full Text]

40. Ewer MS, Benjamin RS: Cardiac complications, in Holland J, Frei E (eds): Cancer Medicine (ed 5). Philadelphia, PA, BC Decker, 2000, pp 2324-2339

41. Fumoleau P, Roché H, Kerbrat P, et al: Cardiac toxicity in operable breast cancer patients after adjuvant chemotherapy with epirubicin: 7-year analysis in 3577 patients of French Adjuvant Study Group trials. San Antonio Breast Cancer Symposium, San Antonio, TX, December 11-14, 2002 (abstr 64)

Submitted February 20, 2004; accepted June 23, 2004.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Editorial

• Adjuvant Chemotherapy for Elderly Women With Hormone Receptor-Positive Breast Cancer: An Old(er) Problem
  Anne Schott and Daniel F. Hayes
  JCO 2004 22: 4660-4662 [Full Text]

This article has been cited by other articles:

				A. Brunello, U. Basso, C. Pogliani, A. Jirillo, C. Ghiotto, H. Koussis, F. Lumachi, M. Iacobone, L. Vamvakas, and S. Monfardini Adjuvant chemotherapy for elderly patients (>=70 years) with early high-risk breast cancer: a retrospective analysis of 260 patients Ann. Onc., August 1, 2005; 16(8): 1276 - 1282. [Abstract] [Full Text] [PDF]

				A. Schott and D. F. Hayes Adjuvant Chemotherapy for Elderly Women With Hormone Receptor-Positive Breast Cancer: An Old(er) Problem J. Clin. Oncol., December 1, 2004; 22(23): 4660 - 4662. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fargeot, P. Articles by Chapelle-Marcillac, I. Search for Related Content PubMed PubMed Citation Articles by Fargeot, P. Articles by Chapelle-Marcillac, I. Related Articles Related Editorial Social Bookmarking                            What's this?