|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 1999 American Society for Clinical Oncology Cardiotoxicity of Epirubicin/Paclitaxel–Containing Regimens: Role of Cardiac Risk FactorsFrom the Divisione di Oncologia Medica and Farmacologia e Chemioterapia, Dipartimento di Oncologia, Ospedale Santa Chiara e Universita, Pisa; and Servizio di Epidemiologia Clinica e Sperimentazioni Cliniche Controllate, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy. Address reprint requests to Alessandra Gennari, MD, Division of Medical Oncology, University Hospital Santa Chiara, 67, Via Roma, 56126 Pisa, Italy; email a.gennari{at}do.med.unipi.it
PURPOSE: To evaluate the incidence of clinically relevant cardiac toxicity after treatment with epirubicin/paclitaxel-containing regimens in patients with metastatic breast cancer and to identify high-risk patients in whom the benefit of chemotherapy may be negated by the occurrence of congestive heart failure (CHF). PATIENTS AND METHODS: A total of 105 patients who were referred for epirubicin/paclitaxel treatment were included in this study. Treatment regimens were as follows: (1) epirubicin 90 mg/m2 plus paclitaxel 135 to 225 mg/m2 over 3 hours (n = 76); and (2) gemcitabine 1,000 mg/m2 on days 1 and 4 plus epirubicin/paclitaxel (n = 29). The occurrence of CHF was detected by physical examination, and left ventricular function was evaluated by bidimensional echocardiography to support the diagnosis. Cardiac risk factors examined in this study included age, prior radiotherapy to the chest, hypertension, and diabetes. RESULTS: No patient experienced CHF while on treatment. Nine patients (9%) developed CHF after cumulative epirubicin doses of 1,080 mg/m2 (n = 4), 720 mg/m2 (n = 2), 630 mg/m2 (n = 1), and 540 mg/m2 (n = 2). One of the two patients who developed CHF after a cumulative epirubicin dose of 540 mg/m2 had received consolidation with high-dose chemotherapy. Median time to appearance of cardiologic symptoms was 3 months after the end of treatment (range, 3 to 6 months). Overall, the incidence of CHF was 13% and 4% in patients with or without cardiac risk factors, respectively. The cumulative risk of developing CHF was estimated as 7.7% at a cumulative doses of 720 mg/m2 and 48.7% at a cumulative dose of 1,080 mg/m2. CONCLUSION: This study shows that the incidence of CHF after an epirubicin/paclitaxel regimen is low up to cumulative epirubicin doses of 990 mg/m2, thus allowing the safe administration of this regimen even in patients who received epirubicin in the adjuvant setting. However, the risk of developing CHF increases when a cumulative dose exceeding 990 mg/m2 is reached, concomitantly with the presence of an additional cardiac risk factor.
ANTHRACYCLINES PLAY a major role in the treatment of advanced breast cancer. The incorporation of anthracyclines in combination regimens has increased the response rates, remission duration, and survival of patients with advanced breast cancer,1 with approximately 20% of patients who achieve a complete response still disease-free 10 years later.2 Moreover, a recently published meta-analysis on adjuvant polychemotherapy showed, relatively to the short follow-up, a moderate superiority for the anthracycline-containing regimens.3 Unfortunately, the clinical value of anthracyclines is uniquely limited by late-onset ventricular dysfunction.4 This cardiomyopathy typically presents within 1 year after the end of treatment and is characterized by a severe prognosis.5,6 This toxicity may limit the recent treatment options aimed at improving the outcome of patients with metastatic breast cancer through the combination of the two most active drugs, ie, anthracyclines and taxanes. The combination of doxorubicin and paclitaxel proved to be very active, with an overall response rate in the range of 90% and a complete response rate as high as 24% to 41%7-9; however, an increased risk of cardiac toxicity became apparent at cumulative doxorubicin doses significantly lower than those recommended when doxorubicin is given alone or in combination with other drugs.10 The enhanced cardiotoxicity of this combination may be explained by the pharmacokinetic interactions between these two drugs; as a matter of fact, paclitaxel causes a nonlinear disposition of doxorubicin, with increased plasma concentrations of doxorubicin and its main metabolite, doxorubicinol, which is also deemed as a major determinant of myocardial damage.11,12 Several approaches have been used to avoid or diminish the incidence of doxorubicin-induced cardiotoxicity, including limitation of the amount of drug administered; alternative drug-delivery regimens such as prolonged infusions or liposomal doxorubicin; alternative schedules of administration; use of cardioprotective agents; and the substitution of doxorubicin with other anthracycline analogs, including 4'-epidoxorubicin (epirubicin), which does not eliminate the risk of cardiotoxicity but has been shown to be less cardiotoxic and myelotoxic than the parent compound at equimolar doses.13 We reported on the combination of epirubicin and paclitaxel as first-line chemotherapy for advanced breast cancer, yielding a high level of activity with an overall response rate of 84% and a low incidence of cardiotoxicity, with only 6% of patients developing congestive heart failure (CHF).14 The reduced cardiotoxicity of this combination, as opposed to doxorubicin/paclitaxel treatment, can be explained on the basis of the lower cardiotoxic effects of epirubicin, as well as on the limited interaction of paclitaxel on epirubicin pharmacokinetics; the most relevant alterations observed at the maximum-tolerated dose (MTD) of paclitaxel 200 mg/m2 consisted of a significant increase in epirubicinol plasma levels and area under the concentration-time curve, whereas epirubicin pharmacokinetics, at variance with that observed in the case of doxorubicin, was almost unaffected.15 However, although epirubicin has a lower cardiotoxic potential than doxorubicin, at cumulative doses greater than 1,000 mg/m2, the drug induces cardiac failure in 16% to 35% of patients,16 with an incidence of related death ranging from 20% to 38%.17,18 Therefore, prevention of cardiotoxicity seems to be the ultimate goal even when using a less cardiotoxic anthracycline analog such as epirubicin. In this perspective, the evaluation of preexisting cardiovascular risk factors in the individual patient might be relevant. Although reports are in conflict, the proposed risk factors for anthracycline cardiotoxicity include higher cumulative doses,19 prior chest wall radiotherapy,20,21 childhood or advanced age,22,23 female sex,24 preexisting heart disease, hypertension, and diabetes.25-27 In particular, previous cardiac irradiation and higher cumulative doses of anthracycline have been shown to be independent risk factors for histologically documented cardiac damage in a multivariate analysis.28 Given these premises, the aim of the present study was to evaluate the pattern and patient characteristics of clinically relevant cardiac toxicity after treatment with epirubicin/paclitaxel-containing regimens to identify patients who might be at high risk of developing CHF, in whom the benefit of chemotherapy may be reduced by the occurrence of cardiotoxicity.
Patient Selection All patients with metastatic breast cancer who were referred for treatment protocols that included epirubicin and paclitaxel were included in this study. Treatment was performed as first-line chemotherapy for advanced disease. Patients had to have a baseline resting left ventricular ejection fraction (L-VEF)  50%, as determined by bidimensional echocardiography. Patients with histologically confirmed metastatic disease with at least one bidimensionally measurable lesion were eligible for treatment. Other eligibility criteria included age less than 70 years, Eastern Cooperative Oncology Group performance status  1, and no history of cardiac disease or signs of cardiac abnormality at initial physical examination. Prior adjuvant therapy was allowed if it was stopped at least 6 months before study entry; adjuvant anthracycline-based therapy was allowed if the total cumulative dose was less than 180 or 360 mg/m2 for doxorubicin or epirubicin, respectively, whereas prior endocrine treatment was allowed. Written informed consent was obtained from all patients, and the studies were designed and conducted in accordance with the Declaration of Helsinki and were approved by the Ethics Committee of Pisa University Hospital and the National Ministry of Health.
Treatment Plan Young patients who achieved a response to chemotherapy received high-dose consolidation treatment with thiotepa 600 mg/m2 plus melphalan 140 mg/m2 with peripheral-blood stem-cell support.
Study Parameters and Statistical Analysis The primary end point in this study was the assessment of clinical CHF according to the New York Heart Association clinical criteria for cardiac failure.31 The diagnostic criteria for CHF were new onset of dyspnea, presence of peripheral edema, cardiac enlargement or pulmonary congestion on chest radiograph, or pulmonary rales at auscultation. When a patient had clinical symptoms of CHF, reduced L-VEF contributed to the diagnosis, and its assessment was performed by bidimensional echocardiography.
The cumulative probability of developing cardiac toxicity, while taking into account the different number of patients at the various cumulative dose levels of epirubicin, was computed as follows. According to the life-table method, for each cumulative dose level, the number of patients who subsequently experienced cardiac events and had not been treated with higher cumulative doses was divided by the total number of patients treated at that level (including patients who had been treated with higher doses). The resulting dose-specific probabilities of cardiac events for each preexisting cardiac risk factor were pooled to obtain the cumulative probability of cardiac events. The presence of preexisting cardiac risk factors for the development of CHF was analyzed in all patients and included age, hypertension, diabetes, and prior radiotherapy to the chest wall (left or right). The incidence of cardiac events in patients with and without each (and any) potential risk factor was compared by the Mantel-Haenszel
Between June 1994 and March 1999, 105 patients with advanced breast cancer received an epirubicin/paclitaxel-containing regimen: 76 patients were treated with epirubicin 90 mg/m2 plus paclitaxel, 32 of whom entered a dose-finding study and were treated as follows: three received paclitaxel 135 mg/m2, six received paclitaxel 155 mg/m2, six received paclitaxel 175 mg/m2, nine received paclitaxel 200 mg/m2, and eight received paclitaxel 225 mg/m2; 48 additional patients received paclitaxel 200 mg/m2. Twenty-nine patients were recruited for a phase II study on the association of gemcitabine, epirubicin, and paclitaxel. Thirty patients received high-dose chemotherapy with peripheral-blood stem-cell support after six courses of induction chemotherapy.
Patient Characteristics
Cardiotoxicity No patient experienced grade 3 cardiotoxicity while on treatment. Nine patients (9%) eventually developed symptomatic CHF with a decrease in L-VEF well below 50%. Cumulative epirubicin doses in these patients were 1,080 mg/m2 in four patients (360 mg/m2 in the adjuvant setting plus 720 mg/m2), 720 mg/m2 in two patients (one of whom received 360 mg/m2 in the adjuvant setting plus 360 mg/m2), 630 mg/m2 in one patient, and 540 mg/m2 in two patients. One of the two patients who developed CHF after a cumulative epirubicin dose of 540 mg/m2 had received consolidation treatment with high-dose chemotherapy, with a decrease in L-VEF of 12%, and two stopped the administration of epirubicin after cumulative doses of 540 and 630 mg/m2, respectively, because of the occurrence of pericardial effusion; subsequent to this event, they developed CHF during the follow-up period. Median time to appearance of cardiac symptoms was 3 months after the end of treatment (range, 3 to 6 months), and median L-VEF at first clinical signs was 32% (range, 20% to 46%). All patients received timely and appropriate cardiologic therapy that contained digitalis, diuretics, angiotensin-converting enzyme inhibitors, and beta-blockers, with symptomatic relief. However, despite the pharmacologic treatment, L-VEF values did not recover to within normal limits. Six of these patients are still alive and under cardiologic treatment, whereas three have died from progressive breast cancer; no patient died from cardiac failure. The incidence of CHF in the various groups of patients treated with different cumulative epirubicin doses is listed in Table 2. No episode of CHF was observed among the 12 patients treated with epirubicin less than 450 mg/m2, whereas five cases (6.7%) of CHF were observed among 74 patients who had received between 450 and 720 mg/m2. No case of CHF was observed among the 10 patients who received cumulative epirubicin doses between 720 and 990 mg/m2, whereas four of nine patients (44%) who received the maximal cumulative dose of 1,080 mg/m2 developed CHF. The cumulative risk of developing CHF was estimated as 7.7% at a cumulative dose of 720 mg/m2 and 48.7% at a cumulative dose of 1,080 mg/m2.
No clear role of the proposed risk factors for cardiotoxicity was observed in our study. Overall, seven (13%) of 54 patients with and two (4%) of 51 patients without cardiac risk factors developed CHF. The characteristics of patients who experienced grade 3 cardiotoxicity are listed in Table 3. Among the seven patients in whom hypertension and/or diabetes represented the only risk factor, no episodes of CHF was noted. These patients received a maximum cumulative epirubicin dose of
The cumulative probability of developing CHF was similar in patients with and without at least one preexisting cardiovascular risk factor up to cumulative epirubicin doses of 990 mg/m2 (cumulative risk, 10% and 12%, respectively; Fig 1). All nine patients with a cumulative epirubicin dose of 1,080 mg/m2 had received radiotherapy to the chest wall. As a consequence, the four cases of cardiotoxicity observed among them (44%, for a cumulative risk of cardiotoxicity of 66% among patients with risk factors) cannot be interpreted because of the lack of a comparison group. After adjustment for cumulative epirubicin dose, no significant difference was observed in the incidence of CHF between patients with and without risk factors (P = .85; Table 3), but the small numbers involved provided very little power for this comparison.
None of the patients who received gemcitabine in association with the epirubicin/paclitaxel regimen developed CHF. Finally, the administration of high-dose chemotherapy with peripheral-blood stem-cell support seems not to increase the incidence of CHF either during treatment and follow-up in this set of patients. In fact, among the 30 patients who received high-dose consolidation treatment, only one developed CHF; this patient showed a significant decrease in L-VEF immediately after transplantation, followed by the appearance of clinical symptoms 6 months later.
Anthracyclines and taxanes have been shown to be the most active single drugs in the treatment of breast cancer. Based on this activity, different combinations of these agents have been evaluated. The association of anthracyclines and paclitaxel as first-line treatment for metastatic breast cancer showed a very promising level of activity, superior to that observed with anthracyclines and paclitaxel as single drugs.32-35 Moreover, this regimen retains its activity in patients who had previously received anthracyclines in the adjuvant setting.14 However, this benefit could be counterbalanced by the occurrence of anthracycline-induced cardiotoxicity, which is among the most severe side effects associated with these drugs. Indeed, cardiac damage results in a major impact on patients' quality of life, requiring hospitalization, medication, and specialist consultation. In addition, the diagnosis and care of cardiac toxicity can be important in terms of health care budget.36 Therefore, a reduction in the risk of this life-threatening toxicity is highly desirable from both the patient and hospital perspective. At present, the most commonly used method to prevent this severe side effect is to limit the cumulative dose of anthracycline administered. This approach might result in discontinuation of anthracycline administration to patients who might tolerate higher doses and might further benefit from therapy; however, in some patients, cardiotoxicity may occur even at low cumulative doses. Further attention on the issue of cardiotoxicity has been raised recently by the observation of a high incidence of symptomatic cardiac failure after treatment with anti—HER-2 antibody, which is potentiated when administered with doxorubicin.37
The substitution of doxorubicin with epirubicin in the paclitaxel-containing regimens might allow patients to tolerate higher doses of the anthracycline. However, in this study, among the nine patients who developed CHF, five had received a cumulative epirubicin dose In our study, among the nine patients who developed CHF, only one had a decrease of L-VEF by more than 15% (grade 2 cardiotoxicity) during treatment. In the remaining eight patients, a rather stable L-VEF was recorded until sudden deterioration was observed with the onset of clinical symptoms of cardiac failure and significant decrease of L-VEF. Among the remaining 96 patients who did not develop CHF, 17 had an asymptomatic decrease of L-VEF that regressed to within normal limits during follow-up. However, the clinical value of the L-VEF evaluation is still controversial. Studies of L-VEF in patients who received doxorubicin have shown that this method has rather low specificity and sensitivity in predicting the subsequent occurrence of CHF.38,39 Seven of the nine patients who developed CHF had received prior radiotherapy to the chest wall. However, when adjusting for the cumulative dose received by each patient, no difference in the risk of CHF between patients with and without preexisting cardiac risk factors was observed. In fact, among the nine patients who developed CHF, seven had received prior radiotherapy, but four of them received a cumulative epirubicin dose of 1,080 mg/m2, a dose that was not reached by any of the patients who did not receive radiotherapy to the chest wall. The addition of gemcitabine to the epirubicin/paclitaxel combination was not responsible for enhanced cardiotoxicity. This confirms previous studies with single-agent gemcitabine in which no clear evidence of gemcitabine-induced cardiotoxicity was observed.40 Moreover, pharmacokinetic data obtained from the study with gemcitabine, epirubicin, and paclitaxel compared with data from treatment with epirubicin and paclitaxel showed that the pharmacokinetic interaction between epirubicin and paclitaxel is not further affected by gemcitabine.41 The identification of baseline risk factors that can predict the risk of cardiac toxicity could provide guidelines for reducing the incidence of this complication. However, thus far, the efficacy of dose limitations in accordance to risk factors for the prevention of cardiac toxicity remains to be demonstrated, and our data provide little support for this approach. In conclusion, the present study has shown that the incidence of CHF after an epirubicin/paclitaxel-containing regimen is low after a median follow-up duration of 17 months; however, the risk of developing cardiac failure increases dramatically when a cumulative dose greater than 990 mg/m2 is reached, particularly in patients with another cardiovascular risk factor such as previous radiotherapy to chest wall. This suggests that cardiac damage may become clinically more evident in patients who have already received cardiac injury from radiotherapy. This might be relevant in the adjuvant setting, where an increasing number of patients receive radiotherapy after breast-conserving surgery. However, because of the small number of observations (only nine cases of CHF among 105 patients), no conclusion on the influence of chest irradiation is possible. The occurrence of cardiac failure with the epirubicin/paclitaxel regimen is significantly lower than that observed with doxorubicin/paclitaxel, thus allowing the administration of higher doses of epirubicin. Our data also suggest that the low incidence of CHF that has been observed up to cumulative epirubicin doses of 990 mg/m2 allows the safe administration of this regimen even in patients who may have previously received epirubicin in the adjuvant setting. If an additional cardiovascular risk factor such as prior radiotherapy to the chest wall is present, the reduction of epirubicin-containing courses from eight to six may be advisable. Such an approach seemed not to reduce the therapeutic activity of anthracyclines, at least with the doxorubicin/paclitaxel combination.7 Because no single investigative method allows clinicians to predict the risk of a cardiac event in an individual patient, novel means to analyze the individual risk factors predictive for the development of cardiotoxicity are needed. At present, we are testing an approach with a dedicated software module for the evaluation of the cardiac risk correlated to the planned dose of epirubicin in the individual patient. The devised software model, which is built on a statistical model that takes into account prior experiences, could be useful for providing in quasi—real-time indications on the planned treatment. The potential usefulness of similar systems has been already shown in recently published reports.42-44
Supported in part by the Associazione Italiana Ricerca Cancro, Milan, Italy. We thank Professor Frank Muggia (Kaplan Comprehensive Cancer Center, New York University Medical Center, New York, NY) for helpful discussion and suggestions.
1. A'Hern RP, Smith IE, Ebbs SR: Chemotherapy and survival in advanced breast cancer patients: The inclusion of doxorubicin in Cooper type regimens. Br J Cancer67:801-805, 1993[Medline] 2. Greenberg PAC, Hortobagyi G, Smith TL, et al: Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol14:2197-2205, 1996[Abstract] 3. Early Breast Cancer Trialists' Collaborative Group: Polichemotherapy for early breast cancer: An overview of the randomised trials. Lancet352:930-942, 1998[Medline]
4.
Pawan KS, Iliskovic N: Doxorubicin-induced cardiomiopathy. N Engl J Med339:900-905, 1998 5. Lefrak EA, Pitha J, Rosenheim S, et al: A clinicopathologic analysis of Adriamycin cardiotoxicity. Cancer32:302-314, 1973[Medline] 6. Bristow MR, Billingham ME, Mason JW, et al: Clinical spectrum of anthracycline antibiotic cardiotoxicity. Cancer Treat Rep62:873-879, 1978[Medline] 7. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3 hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: High antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol13:2688-2699, 1995[Abstract]
8.
Gehl J, Boesgard M, Paaske T, et al: Combined doxorubicin and paclitaxel in advanced breast cancer: Effective and cardiotoxic. Ann Oncol7:687-693, 1996 9. Amadori D, Frassineti GL, Zoli W, et al: A phase I/II study of sequential doxorubicin and paclitaxel in the treatment of advanced breast cancer. Ann Oncol23:16-22, 1996 (suppl 11) 10. Valagussa P, Gianni L, Capri G, et al: Three-year follow up in women with metastatic breast cancer after bolus doxorubicin and paclitaxel infused over 3 hours (AT). Proc Am Soc Clin Oncol17:111, 1998 (abstr 429)
11.
Gianni L, Vigano L, Locatelli A, et al: Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer. J Clin Oncol15:1906-1915, 1997 12. Minotti G, Cavaliere AF, Mordente A, et al: Secondary alcohol metabolites mediate iron delocalization in cytosolic fractions of myocardial biopsies exposed to anticancer anthracyclines: Novel linkage between anthracycline metabolism and iron-induced cardiotoxicity. J Clin Invest95:1595-1605, 1995 13. Coukell AJ, Faulds D: Epirubicin: An updated review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of breast cancer. Drugs53:453-482, 1997[Medline]
14.
Conte PF, Baldini E, Gennari A, et al: Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours: A regimen with high activity and low cardiotoxicity in advanced breast cancer. J Clin Oncol15:2510-2517, 1997 15. Danesi R, Conte PF, Del Tacca M, et al: Pharmacokinetic optimization of treatment schedules for anthracyclines and paclitaxel in cancer patients. Clin Pharmacokin9:135-211, 1999
16.
Jain KK, Casper ES, Geller NL, et al: A prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer. J Clin Oncol3:818-826, 1985 17. Nielsen D, Jensen JB, Dombernowsky P, et al: Epirubicin cardiotoxicity: A study of 135 patients with advanced breast cancer. J Clin Oncol8:1806-1810, 1990[Abstract] 18. Ryberg M, Nielsen D, Skovsgaard T, et al: Epirubicin cardiotoxicity: An analysis of 469 patients with metastatic breast cancer. J Clin Oncol16:3502-3508, 1998[Abstract] 19. Legha SS, Benjamin RS, Mackay B, et al: Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med96:133-139, 1982 20. Bristow MR, Mason JW, Billingham ME, et al: Doxorubicin cardiomiopathy: Evaluation by phonocardiography, endomiocardial biopsy, and cardiac catheterization. Ann Intern Med88:168-175, 1978 21. Shapiro CL, Hardenberg PH, Gelamn R, et al: Cardiac effects of adjuvant doxorubicin and radiation therapy in breast cancer patients. J Clin Oncol16:3493-3501, 1998[Abstract] 22. Schaadt B, Kelbaek H: Age and left ventricular ejection fraction identify patients with advanced breast cancer at high risk for development of epirubicin-induced heart failure. J Nucl Cardiol4:494-501, 1997[Medline] 23. Pratt CB, Ransom JL, Evans WE: Age-related Adriamycin cardiotoxicity in children. Cancer Treat Rep6:1381-1385, 1978
24.
Lipshultz SE, Lipsitz SR, Mone SM, et al: Female sex and drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med332:1738-1743, 1995 25. Von Hoff DD, Layard MW, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med91:710-717, 1979 26. Praga C, Beretta G, Vigo PL, et al: Adriamycin cardiotoxicity: A survey of 1273 patients. Cancer Treat Rep63:827-834, 1979[Medline] 27. Minow RA, Benjamin RS, Lee EF: Adriamycin cardiomyopathy: Risk factors. Cancer39:1397-1402, 1977[Medline] 28. Torti FM, Bristow MR, Howes AE: Reduced cardiotoxicity of doxorubicin delivered on a weekly schedule: Assessment by endomyocardial biopsy. Ann Intern Med99:745-749, 1983 29. Gennari A, Salvadori B, Tognoni A, et al: Rapid intravenous premedication with dexamethasone prevents hypersensivity reactions to paclitaxel. Ann Oncol7:977-979, 1996 30. Ganz WI, Sridhar KS, Ganz SS, et al: Review of tests for monitoring doxorubicin-induced cardiomiopathy. Oncology53:461-470, 1996[Medline] 31. Criteria Committee of the New York Heart Association: Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels (ed 8). Boston, MA, Little Brown, 1979 32. Seidman AD: The emerging role of paclitaxel in breast cancer therapy. Clin Cancer Res1:247-256, 1996[Medline] 33. Seidman AD, Reichman BS, Crown JPA, et al: Paclitaxel as second and subsequent therapy for metastatic breast cancer: Activity independent of prior anthracycline response. J Clin Oncol13:1152-1159, 1995[Abstract] 34. Awada A, Paridaens R, Bruning P, et al: Doxorubicin or Taxol as first line chemotherapy for metastatic breast cancer: Results of an EORTC-IDBBC/ECSG randomized trial with crossover (EORTC 10923). Breast Cancer Res Treat46:23, 1997 (abstr 2) [Medline] 35. Sledge GW, Neuberg D, Ingle J, et al: Phase III trial of doxorubicin vs paclitaxel vs doxorubicin + paclitaxel as first line therapy for metastatic breast cancer: An intergroup trial. Proc Am Soc Clin Oncol 16:1a, 1997 (abstr 2) 36. Dranitsaris G, Tran TM: Economic analyses of toxicity secondary to anthracycline-based breast cancer chemotherapy. Eur J Cancer 31A:2174-2180, 1995 37. Slamon D, Leyland-Jones B, Shak S, et al: Addition of Herceptin TM (Humanized anti-HER2 antibody) to first line chemotherapy for HER2 overexpressing metastatic breast cancer (HER2/MBC) markedly increases anticancer activity: A randomized, multinational controlled phase III trial. Proc Am Soc Clin Oncol 17:98a, 1998 (abstr 377) 38. McKillop JH, Bristow MR, Goris ML, et al: Sensitivity and specificity of radionuclide ejection fraction in doxorubicin cardiotoxicity. Am Heart J106:1048-1056, 1983[Medline] 39. Alexander J, Dainiak N, Berger HJ, et al: Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography. N Engl J Med300:278-283, 1979[Abstract] 40. Aapro MS, Martin C, Hatty S: Gemcitabine: A safety review. Anticancer Drugs9:191-201, 1998[Medline] 41. Danesi R, Fogli S, Donati S, et al: Pharmacokinetics of gemcitabine, epirubicin, paclitaxel and their metabolites in advanced breast cancer patients. Proc Am Soc Clin Oncol 18:208a, 1999 (abstr 797) 42. Kentala E, Pyykkö I, Auramo Y, et al: Neural networks in neurotologic expert systems. Acta Otolaryngol Suppl (Stockh)529:127-129, 1997 43. Reategui EB, Campbell JA, Leao BF: Combining a neural network with case-based reasoning in a diagnostic system. Artif Intell Med9:5-27, 1997[Medline] 44. Armoni A: Use of neural networks in medical diagnosis. MD Comput2:100-104, 1998 Submitted February 16, 1999; accepted July 12, 1999.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
2 statistic, which takes into account the differing number of patients at each cumulative dose level. Patients who received anthracyclines in the adjuvant setting were entered at the corresponding cumulative dose. 
