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© 1999 American Society for Clinical Oncology Phase II Trial of Doxorubicin and Paclitaxel Plus Granulocyte Colony-Stimulating Factor in Metastatic Breast Cancer: An Eastern Cooperative Oncology Group StudyFrom the Albert Einstein Comprehensive Cancer Center, Montefiore Medical Center, Bronx, NY; Dana-Farber Cancer Institute, Boston, MA; Siouxland Hematology Oncology Association, Sioux City, IA; University of Pretoria, Pretoria, South Africa; and Emory University School of Medicine, Atlanta, GA. Address reprint requests to Joseph A. Sparano, MD, Albert Einstein Comprehensive Cancer Center, Montefiore Medical Center, Department of Oncology–2 South, Room 52, 1825 Eastchester Rd, Bronx, NY 10461-2373; email sparano{at}jimmy.harvard.edu
PURPOSE: Several groups have reported that the combination of doxorubicin plus paclitaxel given as a 3-hour intravenous (IV) infusion for up to eight cycles produces a high response rate (> 80%) and complete response rate (> 20%) in metastatic breast cancer, but is also complicated by a 20% incidence of congestive heart failure (CHF). The purpose of this phase II trial was to evaluate the antineoplastic activity of the regimen in a multi-institutional setting and to reduce the incidence of cardiotoxicity by limiting treatment to a maximum of six cycles. PATIENTS AND METHODS: Fifty-two patients with advanced breast cancer received doxorubicin (60 mg/m2 by IV injection) followed 15 minutes later by paclitaxel (200 mg/m2 by IV infusion over 3 hours) every 3 weeks for four to six cycles. RESULTS: Objective responses occurred in 25 of 48 assessable patients (52%; 95% confidence interval [CI], 38% to 66%), including four complete responses (8%; 95% CI, 0% to 16%). The median cumulative doxorubicin dose given was 240 mg/m2 (range, 132 to 360 mg/m2). Eleven patients (21%) were documented as having a decrease in the LVEF below normal, including three patients (6%; 95% CI, 0% to 12%) who developed CHF. CONCLUSION: The doxorubicin/paclitaxel regimen that we used is unlikely to produce an objective response rate of more than 70% and a complete response rate of more than 20% in patients with metastatic breast cancer, and proved to be excessively cardiotoxic for use in the adjuvant setting.
DOXORUBICIN AND paclitaxel are among the most active cytotoxic agents for the treatment of metastatic breast cancer.1 In the pretaxane era, doxorubicin was considered to be an important component of therapy for metastatic disease. A pooled analysis of five randomized trials performed before the introduction of the taxanes demonstrated that doxorubicin-containing therapy was associated with a statistically significant but clinically modest improvement in time to disease progression (7 v 5 months) and survival (18 v 14 months) when compared with similar regimens that did not include doxorubicin.2 Given their single-agent activity, relative non–cross-resistance, partially nonoverlapping toxicities, and different mechanisms of action, there is clear rationale for combining the taxanes with doxorubicin in patients with advanced breast cancer. Based on these considerations, the Eastern Cooperative Oncology Group (ECOG) initiated a randomized, phase III trial in 739 patients with metastatic breast cancer that compared single-agent doxorubicin (60 mg/m2 as an intravenous [IV] bolus), single-agent paclitaxel (175 mg/m2 as a 24-hour IV infusion), and the combination of doxorubicin (50 mg/m2 as an IV bolus) and paclitaxel (150 mg/m2 as a 24-hour IV infusion beginning 4 hours after doxorubicin) plus granulocyte colony-stimulating factor (G-CSF).3 The trial completed accrual in September 1995, and the findings were presented at the annual meeting of the American Society of Clinical Oncology in May 1997. The doxorubicin/paclitaxel combination produced a significantly higher objective response rate (47%) and median time to treatment failure (8.0 months) than did doxorubicin or paclitaxel used alone (approximately 35% and 6 months for each single agent, respectively), but did not improve survival (between 19 and 22 months for the three groups). The incidence of cardiac toxicity was not different in the combination arm compared with the doxorubicin-alone arm. Given the lack of survival benefit for the combination, this trial provided evidence supporting the use of these agents sequentially rather than in combination.
By early 1995, however, two other groups had independently reported greater-than-anticipated efficacy and cardiotoxicity with a somewhat different doxorubicin/paclitaxel regimen. Gianni et al4 reported a 94% response rate, a 41% complete response (CR) rate, and a 21% incidence of congestive heart failure (CHF) in 34 patients. Likewise, Dombernowsky et al5 reported an 83% response rate, a 24% CR rate, and a 20% incidence of CHF among 30 patients. The median cumulative doses of doxorubicin in the two trials were 420 mg/m2 (range, 120 to 480 mg/m2) and 369 mg/m2 (range, 114 to 550 mg/m2), respectively. This was a cumulative dose range at which the incidence of CHF should be less than 5%.6 In both studies, doxorubicin (50 to 60 mg/m2) was given as an IV bolus injection either 15 or 30 minutes before or after a 3-hour infusion of paclitaxel (125 to 200 mg/m2). In addition, both reports used the same definition of CHF (grade 2/3 symptoms and objective signs using the New York Heart Association criteria). An even greater proportion of patients had subclinical cardiac damage, as evidenced by a decrease in the left ventricular ejection fraction (LVEF) below normal in 50% of patients treated by Dombernowsky et al.5 Gianni et al7 subsequently demonstrated that the risk of CHF could be reduced to acceptable levels (< 5%) if the cumulative doxorubicin dose was restricted to
These studies prompted our group to consider the following questions: (1) could we preserve the activity of the doxorubicin/paclitaxel regimen and reduce the risk of cardiotoxicity by combining it with the cardioprotective agent dexrazoxane10-12; and (2) could we replicate the high activity of the doxorubicin/paclitaxel regimen in a multi-institutional trial and reduce the risk of cardiac toxicity by limiting the cumulative doxorubicin dose? To address the first question, we completed a phase I trial of the doxorubicin/paclitaxel regimen in conjunction with dexrazoxane and have reported that dexrazoxane does result in cardioprotection without altering the pharmacokinetics of paclitaxel.13 Objective response occurred in eight of 20 patients (40%) with metastatic breast cancer, CR occurred in one patient (5%), and the median response duration was 3 months. To address the second question, we initiated a phase II trial of the doxorubicin/paclitaxel regimen in a manner that was nearly identical to that reported by Gianni et al4 and Dombernowsky et al.5 Our only modification was to restrict the cumulative doxorubicin dose to less than 360 mg/m2 (or
Patient Selection Patients were required to have histologically confirmed adenocarcinoma of the breast with manifestations of progressive regional or metastatic disease that was measurable or assessable. Other requirements included: (1) age  18 years and  70 years; (2) ECOG performance status of 0, 1, or 2; (3) normal organ function (ie, normal total bilirubin and AST twofold the upper limits of normal, neutrophil count 1,500/µL, and platelet count 100,000/µL); (4) no prior chemotherapy for metastases; (5) no prior adjuvant doxorubicin or taxane; (6) no adjuvant chemotherapy within 6 months of the diagnosis of metastatic disease; (7) normal LVEF as measured by radionuclide angiography or echocardiography within 6 weeks of registration; (8) no risk factors of doxorubicin-associated cardiomyopathy6 (ie, no atherosclerotic heart disease, hypertension requiring therapy within 3 months of registration, irradiation to the mediastinum or left chest wall after mastectomy, and age 70 years); (9) not taking drugs known to alter cardiac conduction (ie, digoxin, beta blockers, or calcium channel blockers); (10) no history of irradiation to a field encompassing more than 25% of bone marrow; (11) no symptomatic or untreated brain metastases; (12) no history of thromboembolic disease; (13) no pregnancy, and use of effective contraception if of childbearing potential; and (14) disease-free of prior invasive malignancies for at least 5 years, with the exception of curatively treated squamous cell carcinoma-in-situ of the cervix. All patients were required to provide written informed consent.
Treatment Plan
All patients were evaluated for response and underwent a repeat measurement of LVEF after cycle 4. If the disease was responding and the LVEF decreased by
Monitoring for Cardiac Toxicity
Schedule for Tumor Evaluation and Criteria for Response ECOG criteria were used to define response.14 Response duration was measured from the day the patient was first documented to have at least 50% tumor volume reduction until the time of disease progression. Time to treatment failure was measured from the date of study entry until the date of progression or relapse, date of death from any cause (even if without documented progression or relapse), or date last known to be responding. Those who were alive and not known to have experienced disease progression were censored at the date last known to be alive.
Statistical Considerations
Patient Characteristics Fifty-three patients were enrolled onto the study between March and December 1996. One patient was taken off study by the treating physician because it was felt that there was not definitive proof of metastatic disease. Four patients were considered ineligible because of failure to meet one of the eligibility criteria, including prior chemotherapy within 6 months of metastases (n = 1), radiation therapy involving more than 25% of marrow-containing bone (n = 1), current use of antihypertensive agents (n = 1), and no evidence of progressive regional or metastatic breast cancer (n = 1). The characteristics of the remaining 48 eligible patients are listed in Table 1. The median age was 51 years (range, 34 to 70 years), 56% had bone metastases, 29% had liver metastases, 63% had at least three sites of metastases, and 25% had undergone prior adjuvant chemotherapy.
Response and Survival Data
Sites of response included the breast (12 of 18; 67%), lymph nodes (20 of 31; 65%), skin (five of nine; 55%), lung (eight of 17; 47%), liver (six of 14; 43%), pleura (three of 12; 25%), bone (two of 27; 7%), and other sites (four of eight; 50%). Response occurred in seven of 18 patients (39%) with less than three disease sites and in 18 of 30 patients (60%) with at least three disease sites.
Cardiac Toxicity
Data regarding cardiac toxicity are listed in Tables 3 and 4. Nine patients (19%) had grade 1 toxicity (LVEF decreased
A total of 47 patients underwent at least two measurements of LVEF, 11 of whom (23%) had a documented decrease in LVEF below normal (Table 4). In eight of 11 patients, the decrease was within 10% (absolute value) below the lower limits of normal. A repeat LVEF demonstrated improvement to a normal value in two of the five patients who had a repeat assessment approximately 3 months later. Of the three patients who had a decrease in LVEF to more than 10% below the lower limit of normal (patients no. 13, 18, and 33), all developed CHF. One patient (no. 13) developed cardiogenic shock (grade 4 toxicity) 3 months after completing six cycles of therapy but received an additional 155 mg/m2 doxorubicin after removal from the study (total dose, 436 mg/m2). The patient died from progressive breast cancer with CHF 3 months later. Two patients developed CHF that was responsive to therapy (grade 3). Patient no. 18 developed CHF 1 month after completing the sixth cycle of therapy, improved with medical therapy, and was alive 16 months later. Patient no. 33 developed CHF approximately 6 weeks after completing the sixth cycle of therapy, responded to medical therapy, and died from progressive breast cancer 13 months later.
Other Toxicity
We performed a multi-institutional phase II trial of doxorubicin and paclitaxel using a dose and schedule of the combination that had previously been reported by two separate groups to produce an unusually high response rate (83% and 94%) and complete response rate (24% and 41%) in patients with metastatic breast cancer.4,5 Our only modification of the regimen was to restrict the duration of therapy to between four and six cycles (rather than eight cycles), which was intended to reduce the high rate of CHF (20%) that had been reported when eight cycles of therapy were administered. In addition, patients were carefully selected to exclude those with any risk factors for doxorubicin-associated cardiomyopathy. Although we succeed in reducing the risk of CHF, 11 patients (21%) were documented to have a decrease in the LVEF below normal. Furthermore, we observed an objective response rate of only 52% and a CR rate of 8%. Based on the statistical considerations of this trial, it is unlikely that the true CR rate with this regimen exceeds 20% and that the true overall objective response rate exceeds 70%. Our findings raise the question as to whether the difference in efficacy was related to a difference in the duration of treatment with the combination, treatment given after completion of the combination, or patient selection. Gianni et al4 reported that the median time to a CR and partial response was 5 months (or approximately six to eight cycles) and 2 months (or approximately two to four cycles), respectively. In our trial, 46 patients (88%) completed at least four cycles, 23 patients (44%) completed at least five cycles, and 18 patients (35%) completed the maximum of six cycles of the combination therapy. With regard to treatment given after completion of the combination therapy, all patients in our study were offered single-agent paclitaxel in a manner similar to the previous studies. Finally, there were some subtle differences in the characteristics of the patient populations studied. For example, no patient treated by Gianni et al4 had received adjuvant chemotherapy, compared with 25% in our trial and 31% of those treated by Dombernowsky et al.5 Indeed, the response rate and response duration was slightly higher in our study if the analysis was restricted to the 36 patients who had no prior adjuvant chemotherapy (Table 2). The implementation of our study in a multi-institutional setting may have removed subtle elements of patient selection that are inherent in single-institution trials. A review of several other single-institution studies that used a similar doxorubicin/paclitaxel combination showed the objective response rates and CR rates to be relatively high in most but not all studies (Table 6).16-20 However, our findings with the doxorubicin/paclitaxel combination in the current study are very consistent with our previous experience using a slightly different schedule of the combination in trial E1193. Of the 243 patients treated with the combination in that trial, the objective response rate was 47% and the CR rate was 9%.
Although the E1193 trial showed no survival advantage for the doxorubicin/paclitaxel combination compared with single-agent therapy in metastatic breast cancer, the combination was associated with a significant improvement in response rate and median time to treatment failure. Because the combination produced a higher response rate in patients with overtly metastatic disease, it stands to reason that it may also be more effective in curing early-stage disease by more effectively eradicating micrometastatic disease. However, a 24-hour infusion of paclitaxel was used in the E1193 trial, a schedule that is not practical in the adjuvant setting. Furthermore, administration of paclitaxel as a 24-hour infusion is no more effective than a 3-hour infusion in metastatic breast cancer.21 Although the schedule of doxorubicin/paclitaxel that we used in the current study is more practical in the adjuvant setting, in our opinion, the relatively high rate of subclinical cardiac damage renders this regimen less than ideal for testing in early-stage disease. If used in the adjuvant setting outside the context of a clinical trial, paclitaxel should be used sequentially after the completion of doxorubicin, as this has been shown to reduce the risk of relapse without increasing the risk of cardiomyopathy.22 Although the doxorubicin/paclitaxel regimen as used in this trial may be prohibitively cardiotoxic, several strategies seem to diminish the risk of this complication.23 For example, when using an identical schedule of doxorubicin (60 mg/m2) and paclitaxel (150 to 175 mg/m2) as used in this trial, none of 25 patients developed CHF or had a decrease in LVEF below normal when the cardioprotective agent dexrazoxane was added to the regimen (despite administration of a substantially greater median cumulative doxorubicin dose of 360 mg/m2).13 Other strategies that result in less cardiotoxicity include increasing the interval between the drugs,3 substituting liposomal doxorubicin24,25 or epirubicin26 for doxorubicin, or substituting docetaxel for paclitaxel.27 In fact, Nabholtz et al28 reported that the doxorubicin/docetaxel combination produced a significantly higher response rate (60% v 47%) and median time to progression compared with doxorubicin/cyclophosphamide, but was not associated with an increased risk of CHF (2% v 4%). Unlike paclitaxel, docetaxel has no significant effect of the plasma disposition of doxorubicin, providing an explanation for the lack of increased cardiotoxicity with the doxorubicin/docetaxel combination.29,30 In conclusion, the overall response rate and CR rate that we observed with doxorubicin plus paclitaxel administered as a 3-hour infusion was consistent with our prior experience with doxorubicin and paclitaxel administered in a slightly different manner. Although the use of these agents in combination results in a higher response rate and time to treatment failure in patients with metastatic disease, this does not seem to translate into an improvement in survival. Nevertheless, the higher response rate observed with doxorubicin/taxane combinations suggests that they may result in a greater likelihood of curing early-stage disease when used in the adjuvant setting. Based on the cardiac toxicity profile of these combinations that we and other investigators have observed, the Eastern Cooperative Oncology Group has selected the doxorubicin/docetaxel combination for comparison with doxorubicin/cyclophosphamide in early-stage breast cancer (E2197). Other groups are also evaluating whether these agents are best used concomitantly or sequentially in early-stage disease.
We thank Drs Jeffrey Abrams and Susan Arbuck for supporting the study, Dianne Ingersoll for expert data management, and Amgen (Thousand Oaks, CA) for supplying the G-CSF.
Conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, MD, Group Chair) and supported in part by Public Health Service grants no. CA21076, CA23318, CA21692, and CA21115 from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services, Bethesda, MD. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Presented at the 20th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 5, 1997.
1. Honig SF: Treatment of metastatic disease: Hormonal and chemotherapy, in Harris JR, Lippman ME, Morrow M, Hellman S (eds): Disease of the Breast. Philadelphia, PA, Lippincott-Raven, 1996, 669-734 2. A'Hern RPA Smith IE, Ebbs SR: Chemotherapy and survival in advanced breast cancer: The inclusion of doxorubicin in Cooper type regimens. Br J Cancer67:801-805, 1993[Medline] 3. Sledge GW Jr, Neuberg D, Ingle J, et al: Phase III trial of doxorubicin versus paclitaxel versus doxorubicin plus paclitaxel as first-line therapy for metastatic breast cancer: An Intergroup trial. Proc Am Soc Clin Oncol 16:1a, 1997 (abstr 2) 4. 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] 5. Dombernowsky P, Gehl J, Boesgaard M, et al: Doxorubicin and paclitaxel: A highly active combination in the treatment of metastatic breast cancer. Semin Oncol23:23-27, 1996 (suppl 11) [Medline] 6. Von Hoff DD, Layard MW, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med91:710-717, 1979 7. Gianni L, Dombernowsky P, Sledge, et al: Cardiac function following combination therapy with Taxol and doxorubicin for advanced breast cancer. Proc Am Soc Clin Oncol 17:115a, 1998 (abstr 444) 8. Gianni L, Bigano 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 Oncol 15;1906-1915, 1997
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Holmes FA, Madden T, Newman RA, et al: Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer. J Clin Oncol14:2713-2721, 1996 10. Speyer JL, Green MD, Zeleniuch-Jacquotte A, et al: ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J Clin Oncol10:117-127, 1992[Abstract]
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Swain S, Whaley FS, Gerber MC, et al: Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol15:1318-1332, 1997
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Swain S, Whaley FS, Gerber MC, et al: Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy. J Clin Oncol15:1333-1340, 1997
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Sparano JA, Speyer J, Gradishar WJ, et al: Phase I trial of escalating doses of paclitaxel plus doxorubicin and dexrazoxane in patients with advanced breast cancer. J Clin Oncol17:880-886, 1999 14. Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol5:649-655, 1982[Medline] 15. Falkson G, Gelman RS, Pandya KJ, et al: Eastern Cooperative Oncology Group randomized trials of observation versus maintenance therapy for patients with metastatic breast cancer in complete remission following induction treatment. J Clin Oncol16:1669-1679, 1998[Abstract] 16. Martin M, Lluch A, Ojeda B, et al: Paclitaxel plus doxorubicin in metastatic breast cancer: Preliminary analysis of cardiotoxicity. Semin Oncol24:26-30, 1997 (suppl 17) 17. Jovtis S, Mickiewicz E, Di Notto M, et al: No clinical cardiotoxicity associated with Taxol (paclitaxel) + doxorubicin as first-line treatment for metastatic breast cancer. Proc Am Soc Clin Oncol 16:239a, 1997 (abstr 844) 18. Klein JL, Dansey R, Karanes G, et al: Induction chemotherapy with doxorubicin and paclitaxel for metastatic breast cancer. Breast Cancer Res Treat 46: 1997 (abstr 405) 19. Schwartsmann G, Menke CH, Caleffi M, et al: A phase II trial of Taxol, doxorubicin, plus G-CSF in patents with metastatic breast cancer. Proc Am Soc Clin Oncol15:126, 1996 (abstr 168) 20. Cazap E, Ventriglia M, Rubio G, et al: Taxol plus doxorubicin in the treatment of metastatic breast cancer. Proc Am Soc Clin Oncol15:146, 1996 (abstr 248) 21. Peretz T, Sulkes A, Chollet P, et al: A multicenter, randomized study of two schedules of paclitaxel in patients with advanced breast cancer. Eur J Cancer 31A:S75, 1995 (suppl 5) (abstr 345) 22. Henderson IC, Berry D, Demetri G, et al: Improved disease free and overall survival from the addition of sequential paclitaxel but not from the escalation of doxorubicin dose level in the adjuvant chemotherapy of patients with node-positive breast cancer. Proc Am Soc Clin Oncol 17:101a, 1998 (abstr 390a) 23. Sparano JA: Use of dexrazoxane and other strategies to prevent cardiomyopathy associated with doxorubicin-taxane combinations. Semin Oncol25:66-71, 1998 24. Moore MR, Srinivasiah J, Feinberg BA, et al: Phase II randomized trial of doxorubicin plus paclitaxel versus doxorubicin HCL liposome injection (Doxil) plus paclitaxel in metastatic breast cancer. Proc Am Soc Clin Oncol 17:160a, 1998 (abstr 614) 25. Sparano JA, Malik UR, Einzig A, et al: Phase I trial of liposomal doxorubicin (Doxil) and docetaxel (Taxotere) in patients with advanced breast cancer. Breast Cancer Res Treat50:264, 1998 (abstr 235)
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Conte PF, Baldini E, Bennari A, et al: Dose-finding 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 27. Sparano JA, Hu P Schaefer PL, et al: Phase II trial of doxorubicin and docetaxel plus granulocyte-colony stimulating factor in metastatic breast cancer: An Eastern Cooperative Oncology Group study (E1196). Breast Cancer Res Treat50:223, 1998 (abstr 27) 28. Nabholtz JM, Falkson G, Campos D, et al: A phase III trial comparing doxorubicin and docetaxel to doxorubicin and cyclophosphamide as first line chemotherapy for metastatic breast cancer. Proc Am Soc Clin Oncol 18:127a, 1999 (abstr 485) 29. Schuller J, Czejka M, Kletzl H, et al: Doxorubicin and Taxotere: A pharmacokinetic study of the combination in advanced breast cancer. Proc Am Soc Clin Oncol 17:205a 1998 (abstr 790) 30. Bellot R, Robert J, Dieras V, et al: Taxotere does not change the pharmacokinetic profile of doxorubicin and doxorubicinol. Proc Am Soc Clin Oncol 17:221a, 1998 (abstr 853) Submitted March 3, 1999; accepted July 21, 1999.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
