|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2000 American Society for Clinical Oncology Burdens and Benefits of Adjuvant Cyclophosphamide, Methotrexate, and Fluorouracil and Tamoxifen for Elderly Patients With Breast Cancer: The International Breast Cancer Study Group Trial VIIFrom the Centro di Riferimento Oncologico, Aviano; Ospedali Civili and Fondazione Beretta, Brescia; and European Institute of Oncology, Milan, Italy; International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute and Frontier Science and Technology Research Foundation; and Harvard School of Public Health, Boston, MA; International Breast Cancer Study Group Coordinating Center; and Swiss Group for Clinical Cancer Research, Inselspital, Bern; Kantonsspital; Bürgerspital; and Center for Tumordetection and Prevention, St Gallen; Swiss Group for Clinical Cancer Research, Ospedale San Giovanni, Bellinzona; and Ospedale Civico, Lugano, Switzerland; West Swedish Breast Cancer Study Group, Sahlgrenska University Hospital, Göteborg, Sweden; Australian Cancer Society and University of Sydney, Sydney; Anti-Cancer Council of Victoria, Melbourne; and University of Newcastle, Waratah, Australia; Institute of Oncology, Ljubljana, Slovenia; Groote Schuur Hospital, Cape Town, South Africa; and Madrid Breast Cancer Group, Madrid, Spain. Address reprint requests to Diana Crivellari, MD, Centro di Riferimento Oncologico Aviano, via Pedemontana Occidentale, 12, Aviano, Italy; email sfrustaci{at}ets.it
PURPOSE: Information on the tolerability and efficacy of adjuvant chemoendocrine therapy for older women is limited. We studied these issues using the data collected as part of the International Breast Cancer Study Group Trial VII. PATIENTS AND METHODS: Postmenopausal women with operable, node-positive breast cancer were randomized to receive either tamoxifen alone for 5 years (306 patients) or tamoxifen plus three consecutive cycles of classical cyclophosphamide (100 mg/m2 orally days 1 to 14), methotrexate (40 mg/m2 intravenous days 1 and 8), and fluorouracil (600 mg/m2 intravenous days 1 and 8) every 28 days (CMF; 302 patients). The median follow-up was 8.0 years. RESULTS: Among the 299 patients who received at least one dose of CMF, women 65 years of age or older (n = 76) had higher grades of toxicity compared with women less than 65 years old (n = 223) (P = .004). More women in the older age group compared with the younger women experienced grade 3 toxicity of any type (17% v 7%, respectively), grade 3 hematologic toxicity (9% v 5%, respectively), and grade 3 mucosal toxicity (4% v 1%, respectively). Older patients also received less than their expected CMF dose compared with younger postmenopausal women (P = .0008). The subjective burdens of treatment, however, were similar for younger and older patients based on quality-of-life measures (performance status, coping, physical well-being, mood, and appetite). For older patients, the 5-year disease-free survival (DFS) rates were 63% for CMF plus tamoxifen and 61% for tamoxifen alone (hazards ratio [HR], 1.00; 95% confidence interval [CI], 0.65 to 1.52; P = .99). For younger patients, the corresponding 5-year DFS rates were 61% and 53% (HR, 0.70; 95% CI, 0.53 to 0.91; P = .008), but the test for heterogeneity of CMF effect according to age group was not statistically significant. The reduced effectiveness of CMF among older women could not be attributed to dose reductions according to dose received. CONCLUSION: CMF tolerability and effectiveness were both reduced for older patients compared with younger postmenopausal node-positive breast cancer patients who received tamoxifen for 5 years. The development and evaluation of less toxic and more effective chemotherapy regimens are required for high-risk elderly patients.
PATIENT AGE PLAYS an important role in the epidemiology and management of breast cancer. Breast tumors are the most common cause of cancer death in women older than 65 years of age, and its incidence increases with age up to age 80, with a plateau between age 80 and 85 years.1 In western countries, approximately 50% to 60% of all new cases are diagnosed in patients older than 65 years and as much as 40% in patients older than 70 years. Life expectancy has increased during the present century, and it has been calculated that a 65-year-old woman has 18.8 more years of expected life, a 75-year-old has 11.9 more years, and an 85-year-old has 6 more years of additional life. It seems particularly important, therefore, to give the best chance of cure even in older women. Adjuvant hormonal treatment with tamoxifen has increased the cure rate of breast cancer both in node-positive and node-negative patients, as shown by the overview of all randomized trials.2 Because hormone therapy is easier to administer and is associated with less toxic effects than chemotherapy, it is the logical first choice in adjuvant treatment, especially in the older group of patients. Between 1978 and 1981, the Ludwig Breast Cancer Study Group (predecessor of the International Breast Cancer Study Group [IBCSG]) conducted a randomized clinical trial in elderly patients (66 to 80 years of age) using 1 year of endocrine therapy with tamoxifen and low-dose prednisone versus no adjuvant treatment.3 At a median follow-up of 16 years, this treatment significantly prolonged disease-free survival (DFS) and overall survival (OS), but most patients still died from cancer, confirming the need to improve therapeutic results. Giving tamoxifen for 5 years rather than for 1 year and adding chemotherapy to tamoxifen4 were considered as possible approaches to achieve this objective. Most clinical trials using adjuvant chemotherapy in breast cancer have set an age limit of 65 or 70 years for the accrual of patients. In the absence of such a limit, they have accrued only occasional elderly patients. (Current clinical trials of adjuvant therapy, however, rarely have upper age limits). The presence of frequently serious comorbid conditions5 has generally limited the use of effective, intensive chemotherapy for these patients. In postmenopausal patients, the combination of chemotherapy (such as cyclophosphamide, methotrexate, fluorouracil [CMF] or CMF-like regimens) and tamoxifen gave conflicting results, with some studies demonstrating a significant advantage at least in terms of DFS.6,7
In 1986, the IBCSG initiated a randomized clinical trial (IBCSG Trial VII) to evaluate the effect of adding combination chemotherapy to 5 years of tamoxifen in postmenopausal women with node-positive operable breast cancer. There was no upper age limit, provided that patients were in good clinical performance status (PS), ie, an Eastern Cooperative Oncology Group (ECOG) PS
Details of the entry criteria and of the trial in general have been described elsewhere.8 Between July 1986 and April 1993, postmenopausal female patients with histologic evidence of axillary nodal involvement were accepted for entry. Postmenopausal status was defined as any of the following: (1) age greater than 52 years with  1 year amenorrhea; (2) age  52 years old with 3 years amenorrhea; (3) age 56 years with hysterectomy but no bilateral oophorectomy; or (4) biochemical evidence of cessation of ovarian function (for doubtful cases). Patients were enrolled after informed consent was conducted according to the guidelines established by local ethical review committees. All patients had to have undergone mastectomy or a breast-conserving procedure and axillary node dissection within 6 weeks of randomization. Radiotherapy was mandatory in cases of breast-conserving surgery and had to be postponed until the end of the initial phase of chemotherapy. Tumor classification according to the International Union Against Cancer had to be T1-T2-T3pN1M0.
Proof of absence of metastases beyond the axilla by physical examination, chest x-ray, mammography of the contralateral breast, and bone scan were required before entry. The presence or absence of a comorbid condition was collected on the on-study form. Because the trial was not devoted to elderly women only, in 1986 we did not plan a formal measurement of comorbidity as is used in many geriatric trials today. Estrogen receptor (ER) analysis was also required at the time of entry. ER concentrations of The randomization was stratified according to ER status, type of surgery, and institution. Patients were randomized to one of four treatment groups: tamoxifen 20 mg/d for 5 consecutive years; tamoxifen plus three early consecutive courses of CMF (cyclophosphamide 100 mg/m2 orally days 1 to 14, methotrexate 40 mg/m2 intravenously days 1 and 8, and fluorouracil 600 mg/m2 intravenously days 1 and 8; all repeated every 28 days) started on the same day as tamoxifen; tamoxifen plus three delayed courses of CMF on months 9, 12, and 15; or tamoxifen plus three early and three delayed courses of CMF. Dosages of CMF were modified for hematologic or mucosal toxicity. Toxicity assessment followed a modified World Health Organization toxicity grading criteria (grade 3 level: WBC < 1,000/µL, platelet count < 50,000/µL, and neutrophil count < 750/µL). Furthermore, toxicity grade was reported as 0 = none, 1 = mild, 2 = moderate, 3 = severe, and 4 = life threatening. To assess different kinds of toxicities, we grouped them as follows: hematologic (leukopenia, anemia, neutropenia, hemorrhage, infection, and thrombocytopenia); mucosal (stomatitis, diarrhea, gastritis, and cystitis); hepatic (hepatotoxicity); other (all other toxicities). The protocol specified follow-up with physical examination and chemistries every 3 months for 2 years, then every 6 months until year 5, then yearly thereafter. Yearly mammography was mandatory. All study records were reviewed centrally by the data management and medical staff. Regular site-visit audits of the original medical records were conducted.
As part of the trial, quality-of-life (QOL) data were collected over time.9,10 Patient-rated QOL was assessed using linear analog self-assessment scales for coping (Perceived Adjustment to Chronic Illness Scale [PACIS]. How much effort does it cost you to cope with your illness? none to a great deal), physical well-being (good to lousy), mood (happy to miserable), and appetite (good to none).10 ECOG PS was assessed by the clinician. Baseline QOL was available for the self-reported measures but not for PS (except it had to be Because the delayed chemotherapy treatment groups are not widely used today, we restricted the following analyses to the 302 eligible patients randomized to receive tamoxifen plus three courses of early CMF and the 306 eligible patients randomized to receive tamoxifen alone. To assess differences according to patient age at the time of randomization, we prospectively considered three groups before data analysis: less than 65 years old (436 patients), 65 to 69 years old (119 patients), and 70 years of age or older (53 patients). Because of the small number of patients in the oldest category, we combined the two oldest groups and present analyses comparing patients less than 65 years old with patients 65 years of age or older. Tests for the equality of toxicity grade distributions and QOL assessment distributions were based on the Wilcoxon test.11 Differences in percent of patients with PS = 0 were evaluated using Fisher’s exact test.12 The Kaplan-Meier method13 was used to estimate DFS and OS. DFS was defined as the time from randomization to first relapse (including ipsilateral breast cancer recurrence), second primary tumor (including breast tumor), or death without relapse, whichever occurred first. OS was defined as the time from randomization to death from any cause. Multiple regression analyses using Cox proportional hazards models14 were conducted to adjust for covariates and to test for interaction effects. Covariates included in the models were ER status, nodal status, tumor size, tumor grade, and type of primary surgery. Differences with respect to competing risks were evaluated using the cumulative incidence function method.15 All analyses were conducted using the SAS (SAS institute Inc, Cary, NC), StatXact (CYTEL Software Corporation, Cambridge, MA), and S-PLUS (Mathsoft, Inc, Cambridge, MA) software packages, and all P values were two-sided. The median follow-up was 8.0 years.
Patient Characteristics Table 1 lists patient characteristics according to treatment group and age category. None of the disease-related characteristics was significantly different between older and younger patients. There were, however, trends toward lower grade tumors (P = .08) and more ER-positive tumors (P = .13) among older patients compared with younger patients. As expected, older patients had more comorbid conditions reported than younger (P = .001). Within each age category, the treatment groups were well-balanced with respect to these prognostic factors.
Toxicity Three of the 302 patients randomized to receive CMF did not receive any chemotherapy and have been excluded from the toxicity analyses. Table 2 lists the percent of patients who experienced each degree of toxicity (both overall toxicity and different types) according to age category. There were no grade 4 toxicities. The distributions of grades for both hematologic (P = .0002) and mucosal toxicities (P = .004) were significantly higher for patients 65 years of age or older compared with women under 65 years old. Older women had more grade 3 hematologic toxicity compared with younger women (9.2% v 4.5%, respectively). Leukopenia was the most common hematologic toxicity: rates of grade 3 and grade 2 leukopenia were 4% and 47% for older patients and 1% and 27% for younger patients, respectively. Four percent of older women had grade 3 mucosal toxicity compared with 0.9% of younger women.
Because there were only six cases of hepatic toxicity (all six in younger women), hepatic toxicities were combined with the category of other toxicities. Other kinds of toxicity were equally distributed in the different age categories (P = .34). Largely because of the differences observed for the hematologic and mucosal category, the worst grade of toxicity of any type was significantly higher for older patients than for younger patients (P = .004). More women 65 years of age or older had at least one grade 3 toxicity compared with patients under 65 years old (17.1% v 7.2%, respectively). Two deaths related to therapy were observed in the CMF arm, one in the younger group (liver cirrhosis) and one in the older group (renal failure). A review of the deaths while under adjuvant CMF on IBCSG studies was recently published.16
QOL
CMF Dose Received The amount of CMF dose actually received was calculated for each patient and compared with the planned CMF dose for that patient. Figure 1 shows the percent of patients who at least received a given percent of protocol-specified CMF dose according to age group. Among the older patient group, 38 (48.1%) of the 79 patients received at least 85% of the protocol-specified CMF dose compared with 144 (64.6%) of the 223 women in the younger patient group (P = .0008 by Wilcoxon test).
DFS Figure 2 shows the Kaplan-Meier plots of DFS for CMF + tamoxifen versus tamoxifen alone for the younger patient group, and Fig 3 shows the DFS treatment comparison for the older patients. Table 4 lists the results of the Cox model multiple regression analyses, showing the treatment comparisons overall and according to age groups. Overall, the addition of CMF to tamoxifen significantly reduced the risk of relapse, with estimated 5-year DFS percents of 62% for chemoendocrine therapy and 56% for endocrine therapy alone (hazards ratio [HR], 0.78; 95% confidence interval [CI], 62% to 97%; P = .03). The treatment effect was statistically significant among patients younger than 65 years at the time of study entry (HR, 0.70; 95% CI, 0.53 to 0.91; P = .008). In contrast, adding CMF to tamoxifen provided little advantage for the older patients (HR, 1.00; 95% CI, 0.65 to 1.52; P = .99). The test for heterogeneity of the CMF effect according to age group was not statistically significant (P = .24).
Some of the reduced effectiveness of CMF might have been caused by the increased risk of death or second primary tumor (not breast) without recurrence in the elderly. In fact, 22 older patients (13%) had such a first event compared with 25 younger patients (6%) (P = .006, competing risk analysis).15 These proportions of patients were split evenly between the two treatment groups (6% in both arms for the younger patients and 13% in both arms for the older patients). Separate analyses are also listed in Table 4 for the ER-positive and the ER-negative cohorts. The randomization was stratified by ER status, which had to be known before patient enrollment onto the trial. The results within ER subgroups were similar with respect to outcome.
OS
DFS According to Dose of CMF Received Table 6 lists the DFS outcome according to age group and percent of expected CMF dose received. Surprisingly, with the older patient population, the patients who received less than 85% of their expected dose did not have a worse DFS than patients who received at least 85% of their expected dose. Thus, the lower effectiveness of CMF observed for the older patients could not be attributed to the higher incidence of dose reductions for this patient group.
This study has examined the toxicity encountered in elderly ( 65 years old) node-positive breast cancer patients who received three cycles of classic CMF chemotherapy compared with younger (< 65 years) postmenopausal breast cancer patients. We found a significant relationship between older age and increased incidence of grade 3 toxicity from adjuvant chemotherapy. There were no grade 4 toxicities, but there were two deaths recorded during chemotherapy, one in each of the two age groups. Toxic effects were increased within each category of toxicity evaluated. Special attention should be given to mucosal toxicities. Older women are at higher risk for diarrhea, cystitis, gastritis, and mucositis of the oral cavity. In younger patients, these toxicities are easily managed, but they can easily be fatal in older patients. For example, fluorouracil-induced diarrhea in an older patient may cause severe dehydration and failure of vascular support and may be a possible cause of death if not quickly treated. Older women may live alone, and if not advised of the risk of mucosal toxicity, they may underevaluate the symptoms and be treated when it may be too late. None of these events were documented in this clinical trial. The drugs that are probably implicated in mucosal toxicity are methotrexate and cyclophosphamide. Assuming that impaired renal excretion of these drugs was the main factor affecting toxicity in the elderly, Gelman and Taylor17 conducted a trial on women with advanced breast cancer aged 65 years or older in which creatinine clearance rather than surface area was used to calculate the initial doses of cyclophosphamide and methotrexate in the CMF combination. Unfortunately, this approach almost halved the response rate, with complete responses decreasing from 24% to 7% and partial responses reduced from 68% to 44%. This study confirmed data from Bonadonna et al18 showing that the original CMF schedule given at reduced doses was associated with decreased efficacy in both metastatic and adjuvant settings. In our study, the prescribed dose of CMF was not adjusted for age, as it had been in the earlier study by Bonadonna et al.18 Our older group of patients was probably overtreated, but the few number of cycles administered, three consecutive CMF courses instead of six (as in the Bonadonna study), limited the toxicity. Other authors19,20 could not confirm a proper tolerance to chemotherapy in the elderly population when CMF was used in the metastatic setting. It is important to stress the fact that patients greater than 70 years old who were treated in these protocols were highly selected, with good PS and few associated comorbid conditions. This fact probably limited the toxicity encountered. In the study by Pritchard et al,21 which was based on 705 postmenopausal patients with node-positive disease, it was concluded that the addition of CMF to tamoxifen added considerable toxicity in these women. It would have been interesting to know how many of the patients experiencing severe toxicity were older than 65 years of age. QOL assessments in terms of PACIS score, physical well-being, mood, appetite, and PS were similar in this study for younger and older patients, indicating a comparable subjective burden of chemotherapy for these two groups. It is well known in geriatric medicine that elderly patients have a tendency to complain less and endure symptoms better.22 This could explain the fact that the excess of objective toxicity in the group of older patients is not reflected in the self-reported measures of QOL. We conclude that with proper care, older women can tolerate CMF chemotherapy. To date, the adjuvant trials that have been conducted specifically in elderly breast cancer patients with node-positive disease have used hormonal therapy alone with tamoxifen. An ECOG trial23 involved 170 patients age 65 years or older randomized between tamoxifen for 2 years or placebo. Median age was 71 years; 32% were 71 to 75 years old, and 21% were older than 75 years. At a median follow-up of 4 years, there was a significant benefit for the tamoxifen arm compared with the placebo arm: DFS was 73% versus 52%, respectively (P = .003). No treatment differences were noted in OS (80% v 74%, respectively; P = .26), but the majority of patients treated initially with placebo received tamoxifen on recurrence. This along with competing causes of death could have attenuated the survival difference. Another trial, conducted by the IBCSG,3 involved 349 patients aged 66 to 80 years (median age, 70 years) randomized to 1 year of tamoxifen and low-dose prednisone versus no adjuvant treatment. A significant advantage in terms of DFS was demonstrated for the tamoxifen plus prednisone group compared with the group that received no adjuvant therapy at a median follow-up of 8 years (36% v 22%, P = .004). The benefit in OS was probably obscured by the competing causes of death. A third trial devoted to elderly patients was the Danish study,24 which, out of 1,650 postmenopausal, node-positive breast cancer patients, involved 509 patients (31%) who were between the ages of 70 to 79 years. They were randomized to tamoxifen for 1 year plus radiation therapy (RT) versus RT alone. At 6 years of median follow-up, recurrence-free survival was 39% in the RT group versus 48% in the RT plus tamoxifen group (P = .0008). Although there were fewer local and distant metastases in patients treated with tamoxifen, a significant increase in OS was not observed.
The recent results reported by the Early Breast Cancer Trialists’ Collaborative Group overview2 showed that a longer duration of hormonal treatment (5 years of tamoxifen) gives a highly significant reduction in recurrence and improved survival for women with ER-positive (or unknown ER status) tumors. Such reduction was of similar magnitude in women both younger and older than 50 years (47% and 45% recurrence reduction, respectively; 30% and 20% mortality reduction, respectively). In the group of older patients ( Up to now, therefore, at least for women whose primary tumors have functional hormonal receptors, tamoxifen alone is of substantial value.2 An unanswered question is the value of tamoxifen in women with hormone receptor–negative tumors. In fact, among the 2,000 women in the overview with ER-poor and progesterone receptor–poor tumors, tamoxifen had no apparent effect on recurrence or mortality rates (1% in both cases), whereas in ER-poor, progesterone receptor–positive tumors (602 women) there was a recurrence reduction of 23% (P = .05) and mortality reduction of 9% (not significant). In these cases, the antineoplastic activity of tamoxifen may be caused by a functional ER that is not detectable. Preclinical data support the observation that the synthesis of effective progesterone receptor requires a biologically functional ER. Alternatively, as hypothesized by others, tamoxifen may enhance the production of transforming growth factor beta, a substance that opposes tumor growth from the tumor stroma.25
Three consecutive early courses of CMF added to tamoxifen compared with tamoxifen alone, as used in this trial, significantly improved 5-year DFS (64% v 57%; P = .01)8 on the overall group of postmenopausal patients. The chemotherapy treatment effect was observed to be reduced for older patients, but the test for heterogeneity between older and younger women was not statistically significant. Given the relatively few patients In 1990, Fisher et al27 published the results of a National Surgical Adjuvant Breast and Bowel Project trial (NSABP B-16) in node-positive postmenopausal patients who were randomized among tamoxifen alone, four cycles of doxorubicin, cyclophosphamide, and tamoxifen, or 17 cycles of melphalan, fluorouracil, and tamoxifen. At 3 years of median follow-up, a better DFS was found for patients treated with doxorubicin, cyclophosphamide, and tamoxifen when compared with those receiving tamoxifen alone (84% v 67%; P = .004). Unfortunately, it was not specified how many treated patients were older than 65 or 70 years of age. Thus, in contrast to several trials that used long-term chemotherapy (six or more cycles), two trials of tamoxifen combined with short-term chemotherapy (three cycles of CMF, as in our trial, or four cycles of doxorubicin and cyclophosphamide, as in NSABP B-16) showed a superior outcome for the chemoendocrine therapy regimen compared with tamoxifen alone. CMF regimens are usually preferred in older women because of concern about cardiotoxicity from anthracycline-containing combinations. However, it should be noted that the trials that demonstrated a significant benefit for the addition of CMF to tamoxifen used classical CMF,28 as originally designed and studied by Bonadonna.18 In conclusion, whether the addition of chemotherapy to tamoxifen provides significant clinical benefit in node-positive elderly subgroups of patients is not yet completely clarified because of the few patients randomized in clinical trials. However, available data support little impact of chemotherapy in this subset of patients. Further studies in the adjuvant setting are needed for the elderly population of postmenopausal patients.
We thank the patients, physicians, nurses, and data managers who participate in the International Breast Cancer Study Group trials.
Initial support provided by the Ludwig Institute for Cancer Research, the Cancer League of Ticino, and the Swiss Cancer League. We further acknowledge the continuing support for central coordination, data management, and statistics provided by the Swedish Cancer League, Australian Cancer Society, Sydney, Australia; Australian-New Zealand Breast Cancer Trials Group (National Health and Medical Research Council grant nos. 880513 and 910420), the Frontier Science and Technology Research Foundation, the Swiss Group for Clinical Cancer Research, Bern, Switzerland; the United States National Cancer Institute (grant nos. CA-06516 and CA-75362), Bethesda, MD; and the American-Italian Cancer Foundation (grant no. 101-98).
1. Chu C, Tarone RE, Kessler LG, et al: Recent trends in U.S. breast cancer incidence, survival and mortality rates. National Cancer Inst 88:1571-1579, 1996 2. Early Breast Cancer Trialists’ Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomized trials. Lancet 351:1451-1467, 1998[Medline] 3. Castiglione M, Gelber RD, Goldhirsch A: Adjuvant systemic therapy for breast cancer in the elderly: Competing causes of mortality. J Clin Oncol 8:519-526, 1990[Abstract] 4. Early Breast Cancer Trialists’ Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic or immune therapy: 133 randomized trials, 31,000 recurrences and 24,000 deaths among 75.000 women. Lancet 319:1-15, 71-84, 1992
5.
Satariano WA, Ragland DR: The effect of comorbidity on 3-year survival of women with primary breast cancer. Ann Intern Med 120:104-110, 1994 6. Taylor SG, Kalish LA, Olson JE, et al: Adjuvant CMFP versus CMFP plus tamoxifen versus observation alone in postmenopausal node-positive breast cancer patients: Three-year results of an Eastern Cooperative Oncology Group Study. Oncol 3:144-154, 1985 7. Goldhirsch A, Gelber R: Adjuvant treatment for early breast cancer: The Ludwig breast cancer studies. NCI Monogr 1:55-70, 1986 8. International Breast Cancer Study Group: Effectiveness of adjuvant chemotherapy in combination with tamoxifen for node-positive postmenopausal breast cancer patients. Oncol 15:1385-1394, 1997 9. Hürny C, Bernhard J, Coates AS, et al: Impact of adjuvant therapy on quality of life in women with node-positive operable breast cancer. Lancet 347:1279-1284, 1996[Medline]
10.
Bernhard J, Hürny C, Coates AS, et al: Quality of life assessment in patients receiving adjuvant therapy for breast cancer: The IBCSG approach. Ann Oncol 8:825-835, 1997 11. Hollander M, Wolfe DA: Nonparametric Statistical Methods. New York, NY,John Wiley & Sons, 1973 12. Kendall M, Stuart A: The Advanced Theory of Statistics (vol 2). New York, NY, Macmillan Publishing Company Inc, 1979 13. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 14. Cox DR: Regression models and life-tables (with discussion). (Methodol) 34:187-220, 1972 15. Gray RJ: A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141-1154, 1988 16. Colleoni M, Price KN, Castiglione-Gertsch M, et al: Mortality during adjuvant treatment of early breast cancer with cyclophosphamide, methotrexate, and fluorouracil. Lancet 354:130-131, 1999[Medline] 17. Gelman RS, Taylor SG: Cyclophsphamide, methotrexate, and 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] 18. Bonadonna G, Valagussa P, Rossi A, et al: Ten-year experience with CMF based adjuvant chemotherapy in resectable breast cancer. Breast Cancer Res Treat 5:95-115, 1985[Medline] 19. 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. Controlled Clin Trials 3:369-374, 1980
20.
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
21.
Pritchard KI, Paterson AHC, Fine S, et al: Randomized trial of cyclophosphamide, methotrexate and fluorouracil chemotherapy in postmenopausal women with node-positive estrogen and/or progesterone receptor positive breast cancer: A report of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 15: 2302-2311, 1997 22. Horan MA: Presentation of disease in old age, in Tallis R, Fillit H, Brocklehurst JC (eds): Textbook of Geriatric Medicine and Gerontology (ed 5). Churchill Livingstone, Edinburgh,United Kingdom, 1998 23. Cummings FJ, Gray R, Davis TE, et al: Tamoxifen versus placebo: Double blind adjuvant trial in elderly women with stage II breast cancer. NCI Monogr 1:119-123, 1986 24. Mouridsen HT, Andersen AP, Brincker H, et al: Adjuvant tamoxifen in postmenopausal high-risk breast cancer patients: Present status of Danish Breast Cancer Cooperative Group Trials. NCI Monograph 1:115-118, 1986
25.
Butta A, MacLennon K, Flanders KC, et al: Induction of transforming growth factors in human breast cancer "in vivo" following tamoxifen. Cancer Res 52:4261-4264, 1992 26. Early Breast Cancer Trialists’ Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomized trials. Lancet 352:930-942, 1998[Medline] 27. Fisher B, Redmond C, Legault-Poisson S, et al: Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of node-positive breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: Results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol 8:1005-1018, 1990[Abstract]
28.
Goldhirsch A, Coates AS, Colleoni M, et al: Adjuvant chemoendocrine therapy in postmenopausal breast cancer: Cyclophosphamide, methotrexate and fluorouracil dose and schedule may make a difference. J Clin Oncol 16:1358-1362, 1998 Submitted May 18, 1999; accepted October 28, 1999.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
