|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2001 American Society for Clinical Oncology Reduced Cardiotoxicity and Preserved Antitumor Efficacy of Liposome-Encapsulated Doxorubicin and Cyclophosphamide Compared With Conventional Doxorubicin and Cyclophosphamide in a Randomized, Multicenter Trial of Metastatic Breast CancerFrom Jewish General Hospital, McGill University, Montreal, Quebec, Canada; Tata Memorial Hospital, Mumbai; MNJ Institute of Oncology, Hyderabad; Cancer Institute, Madras; The Gujarat Cancer and Research Institute, Ahmedabad; Regional Cancer Centre, Trivandrum, India; Sidney Kimmel Cancer Center, San Diego, CA; University Medical Center, Jacksonville, FL; Columbia Comprehensive Cancer Clinic, Columbia, MO; Springfield Clinic, Springfield, IL; University of Maryland Cancer Center, Ellicott City, MD; and The Liposome Company, Princeton, NJ. Address reprint requests to Gerald Batist, MD, Jewish General Hospital, 3755 Cote St Catherine, Montreal, PQ H3T 1E2, Canada; email: gbatist{at}onc.jgh.mcgill.ca
PURPOSE: To determine whether Myocet (liposome-encapsulated doxorubicin; The Liposome Company, Elan Corporation, Princeton, NJ) in combination with cyclophosphamide significantly reduces doxorubicin cardiotoxicity while providing comparable antitumor efficacy in first-line treatment of metastatic breast cancer (MBC). PATIENTS AND METHODS: Two hundred ninety-seven patients with MBC and no prior chemotherapy for metastatic disease were randomized to receive either 60 mg/m2 of Myocet (M) or conventional doxorubicin (A), in combination with 600 mg/m2 of cyclophosphamide (C), every 3 weeks until disease progression or unacceptable toxicity. Cardiotoxicity was defined by reductions in left-ventricular ejection fraction, assessed by serial multigated radionuclide angiography scans, or congestive heart failure (CHF). Antitumor efficacy was assessed by objective tumor response rates (World Health Organization criteria), time to progression, and survival. RESULTS: Six percent of MC patients versus 21% (including five cases of CHF) of AC patients developed cardiotoxicity (P = .0002). Median cumulative doxorubicin dose at onset was more than 2,220 mg/m2 for MC versus 480 mg/m2 for AC (P = .0001, hazard ratio, 5.04). MC patients also experienced less grade 4 neutropenia. Antitumor efficacy of MC versus AC was comparable: objective response rates, 43% versus 43%; median time to progression, 5.1% versus 5.5 months; median time to treatment failure, 4.6 versus 4.4 months; and median survival, 19 versus 16 months. CONCLUSION: Myocet improves the therapeutic index of doxorubicin by significantly reducing cardiotoxicity and grade 4 neutropenia and provides comparable antitumor efficacy, when used in combination with cyclophosphamide as first-line therapy for MBC.
DOXORUBICIN IS recognized as one of the most active drugs for breast cancer, but its clinical utility is limited because of a cumulative dose-dependent cardiac myopathy that can lead to potentially fatal congestive heart failure. The mechanism of doxorubicin cardiotoxicity involves the formation of a stable complex of drug with ferric iron, which reacts with oxygen, forming superoxide anions, hydrogen peroxide, and hydroxyl radicals. These free radicals cause lipid peroxidation.1-4 The injury is initially subclinical, but continued treatment results in progressive myocyte damage leading to cumulative dose-dependent cardiac dysfunction that can manifest during therapy, months after the last anthracycline dose or even years later.5 At increased risk for doxorubicin cardiac toxicity are patients who have received prior radiation that encompassed the heart (eg, mediastinal irradiation)6 or prior adjuvant anthracycline therapy, as well as the elderly7 and/or patients with a history of cardiac disease.8 Because of doxorubicin’s efficacy, significant research has been devoted to reducing the cardiac toxicity of this anthracycline. Myocet (liposome-encapsulated doxorubicin; The Liposome Company, Elan Corporation, Princeton, NJ) was designed to reduce the cardiotoxicity of doxorubicin while preserving its antitumor efficacy. The rationale behind its design is that intravenously injected liposomes cannot escape the vascular space in sites that have tight capillary junctions, such as the heart muscle and gastrointestinal tract. The liposomes generally exit the circulation in tissues and organs lined with cells that are not tightly joined (fenestrated) or areas where capillaries are disrupted by inflammation or tumor growth.9 Thus, Myocet should preferentially direct doxorubicin away from sites of potential toxicity, but leave the tumor exposed. Preclinical studies have demonstrated that Myocet reduces the peak distribution of doxorubicin to the heart and gastrointestinal mucosa, but delivers doxorubicin effectively to tumors.10 In animal models, comparison of the same dose of Myocet and conventional doxorubicin showed that Myocet was associated with significantly less cardiac and gastrointestinal toxicity, while antitumor efficacy was at least comparable to that of the parent molecule.11-16 This phase III, randomized, multicenter trial was designed to test the hypothesis that the combination of Myocet and cyclophosphamide would result in significantly less cardiac toxicity than the same dose and schedule of conventional doxorubicin and cyclophosphamide, while providing comparable antitumor efficacy in first-line treatment of metastatic breast cancer.
Study Population Patients 18 years of age or older with histologically confirmed, bidimensionally measurable, metastatic breast cancer were eligible for this study if they had an Eastern Cooperative Oncology Group (ECOG) performance status  2. Patients also had to have adequate bone marrow function (WBC count 3.5 x 109/L, neutrophil count 2.0 x 109/L, hemoglobin 10 g/dL, platelet count 100 x 109/L), liver function ( 1.2 times the upper normal limit for bilirubin and four times the upper normal limit for AST and ALT), and renal function (serum creatinine < 1.5 mg/dL). All patients were required to have a resting left ventricular ejection fraction (LVEF) 50% and no documented history of congestive heart failure (CHF), serious arrhythmia, or myocardial infarction (within 6 months). Cytotoxic therapy for metastatic disease was not permitted; adjuvant chemotherapy, including doxorubicin if the cumulative dose did not exceed 300 mg/m2, was allowed if more than 6 months had elapsed. Prior radiation was permitted if the dose to the mediastinal area did not exceed 35 Gy and no more than 50% of the bone marrow was involved. Patients had to discontinue hormonal therapy for breast cancer before study initiation. Use of investigational agents or chronic use of cytochrome P-450–inducing agents within 4 weeks of study entry was prohibited. Patients with other active neoplasms, except for carcinoma in situ of the cervix or skin cancer (excluding melanoma), were excluded, as were patients with brain metastases or other serious medical risk factors or major organ system dysfunction; life expectancy was to be greater than 3 months. Patients were also ineligible if they had known allergies to anthracyclines or anthracenes, eggs, egg products, granulocyte colony-stimulating factor (G-CSF), or Escherichia coli–derived products. Pregnant or lactating women were excluded. All women were required to have a negative pregnancy test and be postmenopausal, surgically sterilized, or practicing an effective method of birth control. All patients were required to give written informed consent before any study procedures were undertaken. The protocol was approved by an appropriately constituted institutional review board at each participating center and was conducted in accordance with the principles outlined in the Declaration of Helsinki.
Study Treatment
Supportive care, including antiemetics, G-CSF, blood products, and antibiotics were to be administered as needed. Dose escalation was not allowed. Dose of Myocet or doxorubicin was reduced by 10 mg/m2 and cyclophosphamide by 100 mg/m2 for a platelet nadir less than 50,000 cells/µL, absolute neutrophil count (ANC) nadir less than 500 cells/µL on two consecutive counts, onset of grade 4 mucositis, or onset of grade 3 to 4 vomiting despite antiemetics. Restoration of dose was allowed for platelet nadir of
Evaluations Imaging studies required for tumor measurement were performed at baseline, every two cycles, at off-study, and at the 3-month follow-up visit. After a response was achieved, response status was determined every two cycles. If initially abnormal, bone surveys were repeated every two cycles. A physical examination was performed before each cycle. Hematology tests were performed before each cycle, and 96 hours into each cycle. Repeat complete blood counts were performed 24 to 96 hours apart until recovery. Serum biochemistry tests were repeated before each cycle. ECG and MUGA scans were obtained at baseline, and after reaching a lifetime cumulative anthracycline dose of 300 mg/m2, 400 mg/m2, 500 mg/m2, and before each subsequent dose, at off-study, and at the 3-month follow-up visits. Patients were withdrawn from the study for any of the following reasons: disease progression, unacceptable toxicity including cardiotoxicity, noncompliance with the protocol, patient’s request, or at the discretion of the investigator. Serious adverse events, defined as disabling, life-threatening, or fatal events, or those requiring hospitalization, were reported to the sponsor during the study and follow- up period.
Study Outcome Variables
To ensure accuracy and objectivity, each center was required to have its equipment and methodology used for MUGA scans reviewed and certified by a cardiologist at the Core Laboratory at Yale University before enrolling patients. During the trial, all MUGA scans were sent to the Core Laboratory at Yale, where they were read by the same cardiologist blinded to the patient’s treatment. To minimize the risk of CHF, all scans were read in real time and results provided to the site before the next scheduled dose of anthracycline therapy. CHF was determined on the basis of a treatment-blinded review of records from patients for whom the investigator had made a diagnosis of CHF, as well as patients who had a LVEF of All randomized patients were assessed for antitumor efficacy. The primary efficacy parameter was the objective tumor response rate. Complete response (CR) was defined as the complete disappearance of all evidence of disease, including disease-related signs and symptoms, lasting at least 6 weeks. Partial response (PR) was defined as a 50% or greater decrease in the sum of the products of the two longest perpendicular diameters of all measured lesions for at least 6 weeks, with no evidence of progressive disease. Stable disease was defined as no significant change in measurable and nonmeasurable disease. Progressive disease (PD) was defined as a 25% or greater increase in the product of the two longest perpendicular diameters of any measurable lesion or in the estimated size of nonmeasurable disease, or the unequivocal appearance of a new lesion, or reappearance of old lesions. Duration of response, time to disease progression, time to treatment failure, and overall survival were also assessed. The duration of response for patients with a CR or PR was defined as the time from day 1 of treatment to first evidence of PD or death. Time to progression (TTP) was defined as the time from day 1 of treatment to the first evidence of PD or death. The time to treatment failure (TTF) was defined as the time from day 1 of treatment to discontinuation of treatment for an adverse event, lack of efficacy, patient intolerance, onset of cardiac toxicity, first evidence of PD, or death. In determination of TTF and TTP, start of poststudy palliative radiation or chemotherapy was considered to be an event, and start of consolidation radiation, hormonal therapy, or anticancer surgery was censored. Overall survival was defined as the time from day 1 of treatment to death. To ensure consistency and objectivity in assessing antitumor efficacy, an independent medical oncologist at the University of Texas reviewed patient records, including tumor logs, physical examinations, imaging studies, investigator’s comments, and available follow-up information to determine the patient’s best response to treatment as well as the date of disease progression. Rules for assessments were established before data review, and all reviews were conducted blinded to the patient’s treatment. Adverse events were assessed at each visit and were graded according to the National Cancer Institute common toxicity criteria.19
Statistical Methodology All efficacy analyses were conducted on an intent-to-treat basis, stratified by exposure to adjuvant doxorubicin. Safety analyses included all patients who received at least one dose of study medications.
For cardiac toxicity, the primary analysis was the lifetime cumulative dose of doxorubicin at onset of a protocol-defined cardiac event. The time to the first cardiotoxicity end point was also measured from the start of protocol therapy. For both analyses, the two treatment groups were compared using log-rank Cochran-Mantel-Haenzsel statistics was used in comparing the response rates on the two arms. Relative risk of response and the 95% one-sided lower confidence limit were calculated. Relative risk, like hazard ratio, indicates the overall risk (or chance) of experiencing response in one group relative to the other group. Again, a relative risk more than 1 favors the MC arm, and vice versa. A 95% CI was calculated around the difference in objective response rates.20 Distribution of duration of response, time to progression, time to treatment failure, and overall survival were estimated by the Kaplan-Meier product-limit method. In accordance with the International Conference on Harmonization (ICH) guidelines21 for evaluating two active treatments to demonstrate noninferiority, the Kaplan-Meier curves were compared on the basis of the hazard ratio and the associated lower 95% confidence limit. The stratified log-rank statistics were also presented.
Patient Characteristics From December 1994 through March 1998, 297 patients with metastatic breast cancer, and no prior chemotherapy for advanced disease, entered this trial at 48 centers: 142 patients were randomized to receive MC, and 155 patients were randomized to receive AC. The results are reported on the basis of data collected on all 297 patients with follow-up through March 1999. The two treatment groups were balanced at baseline with respect to age, disease-free interval, ECOG performance status, estrogen and progesterone receptor status, and visceral involvement ( Table 1). Prior therapies were well matched between the two groups. Ten percent of patients in each group had received doxorubicin as adjuvant therapy; the median cumulative dose was 240 mg/m2 for both arms ( Table 2). Approximately one third of the patients randomized to each treatment arm had one or more risk factors for doxorubicin cardiac toxicity ( Table 3).
Cardiotoxicity All MUGA scan data were interpreted and LVEF values were estimated at a core laboratory on a blinded basis. Nine patients (6%) treated with MC developed protocol-defined cardiotoxicity compared with 33 patients (21%) treated with AC (log-rank P = .0001) ( Table 4). Five cases of CHF, all in the AC arm (log-rank P = .02), were observed after cumulative lifetime doses ranging from 360 to 480 mg/m2. Four of the five patients with CHF were anthracycline-naive before this study; one patient had 240 mg/m2 of prior adjuvant doxorubicin. All other patients with cardiotoxicity had an asymptomatic decrease in LVEF of 10 EF units from baseline to a final value less than 50%. The estimated (Kaplan-Meier) median cumulative lifetime dose of doxorubicin at the first occurrence of protocol-defined cardiac toxicity was more than 2,220 mg/m2 for the MC arm versus 480 mg/m2 for the AC arm ( Fig 1). The hazard ratio of 4.8 shows that patients treated with MC were 80% less likely to develop cardiotoxicity relative to patients treated with AC.
Similarly, there was a highly significant difference in the time to onset of cardiotoxicity when measured from the start of protocol therapy. The estimated median onset of protocol-defined cardiotoxicity was more than 22 months for MC versus 10 months for AC (log-rank P = .0003). There was a gradual increase in the median change from baseline LVEF to the last posttreatment LVEF among patients treated with either regimen, but this was more pronounced in the AC-treated group (Table 4). In the subset of patients with recognized risk factors for cardiac toxicity (Table 2), the hazard ratio was increased to 16, indicating that these patients were more than 90% less likely to develop cardiac toxicity with MC relative to AC. Four percent of MC-treated patients developed a protocol-defined cardiac event versus 22% of AC-treated patients. The median lifetime cumulative dose of doxorubicin at onset was 480 mg/m2 for AC versus more than 2,220 mg/m2 for MC (P = .0001) ( Fig 2). Four of the five patients with CHF were in this subgroup with increased risk of cardiac toxicity.
Antitumor Efficacy An independent oncologist assessed responses of all patients, blinded to treatment assignment. A CR or PR was observed in 43% of patients in both treatment groups (Table 5). These observed response rates of 43% for both treatment groups resulted in a post hoc power calculation of more than 80% to detect a one-sided difference of 15%. Among doxorubicin-naive patients the response rates were comparable: 42% in the MC-treated group versus 45% in the AC-treated group. In the small subset of patients (10%) that had received prior doxorubicin, 50% of the MC patients versus 20% of the AC patients achieved an objective response. The stratified 95% CI about the difference in response rates (MC - AC) was -10% to 12%. A lower limit of -10% implies that the probability is less than 2.5% that the MC arm could have a 10% or lower response rate than the AC arm. The response rates by prognostic factors showed a high degree of comparability between the two treatment groups ( Table 6).
The duration of the response was also comparable in the two treatment groups ( Table 7). The median duration was estimated to be 9.6 months in MC patients and 9.1 months for the AC patients (P = .38). Disease progression or death was observed in 80% of the MC-treated group versus 87% of the AC-treated group. TTP was comparable in the two treatment groups ( Fig 3). The median TTP was 5.1 months for the MC patients and 5.5 months for the AC patients with the hazard ratio of 1.03 (P = .82). A hazard ratio of more than 1 favors the MC-treated group and vice versa.
Treatment failure takes into account treatment-limiting toxicity as well as disease progression and death. There was little difference in TTF between the two treatment groups ( Fig 4). The median TTF was 4.6 months for the MC patients versus 4.4 months for the AC patients, with a hazard ratio of 1.14 (P = .30).
With median follow-up of 20 months, there was little difference in the survival curves of the two treatment groups ( Fig 5). The median survival was 19 months in the MC-treated group and 16 months in the AC-treated group, with a hazard ratio of 1.04 (P = .79).
Antitumor efficacy was also comparable in the subset of patients at increased risk for cardiac toxicity. The median survival was 23 months in the MC patients versus 15 months in the AC patients, with a hazard ratio of 1.40 and log-rank P = .21 ( Fig 6).
Safety One patient randomized to AC had nonmeasurable bone disease only, and was withdrawn before the first dose. All other patients received the intended treatment. Therapy was generally well tolerated in both groups ( Table 8). The median number of cycles per patient was six, and the median cumulative dose of anthracycline was 360 mg/m2 in both arms. Twenty-two patients (15%) in the MC arm versus seven patients (5%) in the AC arm received cumulative lifetime doses of doxorubicin in excess of 500 mg/m2.
Myelosuppression was the most frequent and severe adverse side effect on both arms, and was the most common cause of dose reductions and delays. Still, dose reductions and delays were not common; median duration of cycles was 21 days on both arms, and patients achieved 92% of the planned dose intensity. Grade 3 or 4 thrombocytopenia was observed in 22% of the MC patients versus 20% of AC patients. Grade 4 neutropenia, however, was significantly lower in the MC arm, 61% of MC patients versus 75% of AC patients (P = .017). G-CSF was administered in 39% of MC cycles versus 46% of AC cycles. Thirteen patients (9%) on the MC arm compared with 20 patients (13%) on the AC arm developed neutropenic fever requiring IV antibiotics and/or hospitalization. Additionally, fewer RBC transfusions were required with MC (28 transfusions to 19 patients) relative to AC (58 transfusions to 25 patients). With comparable drug exposure, there were no new or unexpected adverse events on the MC arm, and there was no increase in incidence or severity of known doxorubicin adverse effects. The incidence of all grade mucositis/stomatitis was significantly reduced in the MC arm (P = .008); consistent with this, there was also a reduction in the incidence of diarrhea that trended towards statistical significance (P = .08). There was, however, no significant difference in grade 3 or 4 gastrointestinal toxicities ( Table 9). Of note, severe (grade 3 or 4) palmar-plantar erythrodysthesia, which is a dose-limiting toxicity with pegylated liposomal doxorubicin, was not observed with Myocet. There was one death on the MC arm that the investigator considered related to treatment: a patient with extensive lung and bone metastases died with grade 4 neutropenia, pneumonia, and associated multiorgan failure.
Doxorubicin cardiac toxicity begins with the first dose of therapy. The insult may be subclinical initially, but with continued treatment can result in clinical CHF.5 Consequently, it is generally recommended that the lifetime cumulative dose of doxorubicin not exceed 450 mg/m2. This guideline was determined on the basis of a retrospective review suggesting a greater than 5% incidence of clinical CHF at this cumulative dose.7 However, data from more recent prospective trials show that cardiotoxicity occurs earlier, particularly when doxorubicin is used in combination chemotherapy regimens. In a prospective study of cardiac toxicity in patients receiving fluorouracil, doxorubicin, and cyclophosphamide with or without dexrazoxane conducted by Speyer et al,22 the incidence of cardiotoxicity (as defined by significant LVEF changes or CHF) was seen starting at 300 mg/m2. These data are confirmed by two trials of doxorubicin with or without dexrazoxane reported by Swain et al.23 In fact, recent data from prospectively evaluated patients show the probability of developing CHF at 400 mg/m2 to be 4.9%, at 450 mg/m2 to be 7.7%, and at 500 mg/m2 to be 20.5%.24 Additionally, the pediatric population,25,26 patients 65 years of age,7 patients with preexisting heart disease,8 and those with prior mediastinal radiation6 have been reported to be at increased risk for anthracycline-induced CHF. An important potential risk group is the increasing number of patients who are treated with an anthracycline as a component of adjuvant chemotherapy for early breast cancer. Typically, these patients receive four or more courses of doxorubicin at a dose of 60 mg/m2, for a cumulative dose of 240 mg/m2 or higher before being re-treated with doxorubicin for recurrent metastatic tumor. Thus, doxorubicin’s cardiac toxicity can limit a patient’s ability to receive further potentially life-sustaining therapy. This is especially frustrating in instances where the tumor is responding and tolerance to the regimen has been otherwise acceptable. Although other therapies are available, response rates in this setting are relatively modest and limited in duration. Moreover, clinical manifestation of anthracycline cardiac toxicity can occur even after therapy has been discontinued.5 Roughly a quarter of the patients with advanced breast cancer will survive for more than 3 years, and the damage to the heart may become clinically expressed before that tumor, itself, limits life expectancy. The inability of a patient with a relapse to receive additional doxorubicin therapy could represent the loss of an important therapeutic option to suppress and control the tumor. Doxorubicin cardiac toxicity remains an important treatment-limiting problem in preparing therapeutic strategies for some patients with advanced breast cancer. Because of the importance of doxorubicin in the treatment of breast cancer, considerable research has been undertaken to reduce its associated cardiac toxicity. Dexrazoxane, an iron-chelating agent, has shown the ability to reduce the cardiac toxicity associated with doxorubicin; however, protection is not complete, and use of dexrazoxane is associated with increased myelotoxicity that can be severe.23 Additionally, because of the concern of possible tumor protection, dexrazoxane is not indicated for use until a cumulative dose of 300 mg/m2 of doxorubicin has been administered, even though it is recognized that injury to the myocardium begins with the first dose.27 Administration of doxorubicin as a continuous infusion over 96 hours has been reported to be less cardiotoxic, although its safety and efficacy have not been established in the treatment of breast cancer.28 Additionally, this schedule is not widely accepted because it requires (1) a central venous catheter, which increases the risk of complications including thrombosis, extravasation, and infection; and (2) a pump, which is very inconvenient for the patient. Epirubicin, an analog of doxorubicin when used on a milligram-per-milligram basis, is associated with less cardiac toxicity.29 More recent studies using much higher doses of epirubicin obviate its cardiac-sparing effect. Thus, despite three decades of research, current approaches to deliver the antitumor efficacy of doxorubicin with reduced risk of cardiotoxicity are not sufficient. Myocet is a unique liposomal formulation of doxorubicin that alters the biodistribution of this anthracycline.9 Pharmacokinetic studies from blood samples taken from 10 patients treated with Myocet and cyclophosphamide and 10 patients treated with conventional doxorubicin and cyclophosphamide in this trial show that the doxorubicin in Myocet is bioavailable, metabolized, and excreted in a manner similar to that for conventional doxorubicin but at a slower rate (data on file, The Liposome Company, Princeton, NJ). Studies in dogs show similar pharmacokinetics to humans. In dogs, after a single IV dose of 1.5 mg/kg, higher levels of Myocet relative to conventional doxorubicin persist in the circulation. Concentrations are up to 3 logs greater at 6 hours, but the difference diminishes at 24 hours.10 This feature distinguishes Myocet from Doxil (Alza, Montvale, NJ),30 a pegylated liposomal formulation of doxorubicin that persists in circulation significantly longer and is associated with dose-limiting palmar-plantar erythrodysthesia. Whole-body autoradiography studies in dogs show that both peak and overall concentrations of doxorubicin in myocardial tissue after Myocet are reduced by 30% to 40% relative to conventional doxorubicin.10 This diminished myocardial exposure resulted in significant reduction in cardiotoxicity, assessed both functionally and histologically.11,12 Similarly, lower peak levels of doxorubicin in gastrointestinal mucosa resulted in less gastrointestinal toxicity. In contrast to the heart muscle and gastrointestinal tract, which have tight capillary junctions, confocal microscopy showed that Myocet is persistently and pervasively accumulated in the tumor. In five murine tumor models13-16 and a SCID mouse model bearing a human breast tumor xenograft (MX-1),31 Myocet was shown to have antitumor activity at least as great as that of conventional doxorubicin. Phase I/II clinical trials showed that Myocet, administered at a starting dose of 60 or 75 mg/m2 as a 1-hour IV infusion every 3 weeks, had a favorable safety profile relative to what would be expected with the same dose and schedule of conventional doxorubicin. Results of three phase II trials of Myocet at doses of 60 or 75 mg/m2 in patients with metastatic breast cancer show that the drug had promising antitumor activity either as a single agent or in combination with cyclophosphamide and fluorouracil. Objective response rates ranged from 43%32 with single-agent therapy to 73%33 with the three-drug combination. The improved therapeutic index for Myocet predicted by the preclinical data and indicated by the phase I/II clinical trials was confirmed in this phase III, randomized, multicenter trial. Statistically significantly fewer patients treated with Myocet in combination with cyclophosphamide experienced cardiac toxicity defined by reductions in LVEF or clinical CHF. The five cases of CHF all occurred in the AC arm, and they occurred after cumulative lifetime doses of doxorubicin of 360 to 480 mg/m2. Kaplan-Meier analyses show that the median cumulative dose of doxorubicin at the onset of cardiac toxicity was 480 mg/m2 with AC, which is consistent with the recent literature. In contrast, the median cumulative dose of doxorubicin at the onset of cardiac toxicity in the MC arm was estimated to be more than 1,800 mg/m2 (P = .0001). In addition to a reduction in cumulative cardiac toxicity, patients treated with Myocet also had no more acute and often dose-limiting toxicities associated with doxorubicin and cyclophosphamide. This improved safety profile was achieved with full preservation of antitumor efficacy whether assessed by response rates, time to progression, time to treatment failure, or overall survival. Response rates were 43% in both arms. Relative risk was 1.01 with one-sided 95% lower bound of 0.81. All the hazard ratios for the time-to-event parameters were more than 1, in favor of the MC arm, with lower bound of one-sided 95% confidence limits more than 0.80, satisfying the ICH guidelines for noninferiority. In the subset of patients with recognized risk factors for this potentially debilitating or lethal toxicity, the hazard ratio for the onset of cardiac toxicity was increased to 16. The survival curves for this high-risk subset of patients suggest that the ability to give higher cumulative doses of this anthracycline may have a beneficial effect on survival. Thus, the data from this randomized, controlled, clinical trial demonstrate that substitution of Myocet for conventional doxorubicin can significantly reduce the cumulative cardiac toxicity associated with this anthracycline and cyclophosphamide combination, while providing comparable antitumor efficacy. A less cardiotoxic and equally efficacious doxorubicin will fulfill an important medical need, especially with the introduction of new therapies for breast cancer such as trastuzumab34 and certain schedules of paclitaxel,35 which are associated with increased risk for doxorubicin cardiac toxicity, as well as the increasing use of doxorubicin as part of adjuvant therapy.
APPENDIX
Supported by a grant from The Liposome Company, Elan Corporation, Princeton, NJ.
Presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999.
1. Doroshow JH: Effect of anthracycline antibiotics on oxygen radical formation in rat heart. Cancer Res 43: 460-472, 1983
2.
Rajagopalan S, Politi PM, Sinha BK, et al: Adriamycin-induced free radical formation in the perfused rat heart: Implications for cardiotoxicity. Cancer Res 48: 4766-4769, 1988 3. Jackson JA, Reeves JP, Muntz KH, et al: Evaluation of free radical effects and catecholamine alterations in adriamycin cardiotoxicity. Am J Pathol 117: 140-153, 1984[Abstract]
4.
Myers CE, McGuire WP, Liss RH, et al: Adriamycin: The role of lipid peroxidation in cardiac toxicity and tumor response. Science 197: 165-167, 1977 5. Billingham ME, Mason JW, Bristow MR, et al: Anthracycline cardiomyopathy monitored by morphologic changes. Cancer Treat Rep 62: 865-872, 1978[Medline] 6. Praga C, Beretta G, Vigo PL, et al: Adriamycin cardiotoxicity: a survey of 1273 patients. Cancer Treat Rep 63: 827-834, 1979[Medline] 7. Von Hoff DD, Layard MW, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91: 710-717, 1979 8. Bristow MR: Anthracycline cardiotoxicity, in Bristow MR (ed): Drug-Induced Heart Disease. New York NY, Elsevier, 1980, pp 191-215 9. Tardi PG, Boman NL, Cullis PR: Liposomal doxorubicin. J Drug Target 4: 129-140, 1996[Medline] 10. Kanter PM, Klaich G, Bullard GA, et al: Preclinical toxicology study of liposome encapsulated doxorubicin (TLC D-99) given intraperitoneally to dogs. In Vivo 8: 975-982, 1994 11. Kanter PM, Bullard GA, Pilkiewicz FG, et al: Preclinical toxicology study of liposome encapsulated doxorubicin (TLC D-99): Comparison with doxorubicin and empty liposomes in mice and dogs. In Vivo 7: 85-95, 1993 12. Kanter PM, Bullard GA, Ginsberg RA, et al: Comparison of the cardiotoxic effects of liposomal doxorubicin (TLC D-99) versus free doxorubicin in beagle dogs. In Vivo 7: 17-26, 1993 13. Nayar R, Mayer LD, Masin D, et al: Antitumor activity of liposomal encapsulated doxorubicin in different murine tumor models: Implications for mechanisms of action. Proc Am Assoc Cancer Res 31: 429, 1990 (abstr 2549) 14. Ostro MJ: Liposomes: From the bench to the marketplace—Doxorubicin as an example, in Lopez-Berestein G, Fidler IJ (eds): Liposomes in the Therapy of Infectious Diseases and Cancer. New York, NY, Alan R. Liss, 1989, pp 155-163 15. Mayer LD, Bally MB, Cullis PR, et al: Comparison of free and liposome encapsulated doxorubicin tumor drug uptake and antitumor efficacy in the SC115 murine mammary tumor. Cancer Lett 53: 183-190, 1990[Medline] 16. Balazsovits JAE, Mayer LD, Bally MB, et al: Analysis of the effect of liposome encapsulation on the vesicant properties, acute and cardiac toxicities, and antitumor efficacy of doxorubicin. Cancer Chemother Pharmacol 23: 81-86, 1989[Medline] 17. Alexander J, Dainiak N, Berger HJ, et al: Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography. N Engl J Med 300: 278-283, 1979[Abstract] 18. Choi BW, Berger HJ, Schwartz PE, et al: Serial radionuclide assessment of doxorubicin cardiotoxicity in cancer patients with abnormal resting left ventricular performance. Am Heart J 106: 638-643, 1983.[Medline] 19. National Cancer Institute: Common Toxicity Criteria. National Institutes of Health, Bethesda, MD 20. Bland M: Introduction to Medical Statistics. London, United Kingdom, Oxford University Press, 1995, pp 119-126 21. International Conference on Harmonization: Guidance on statistical principles for clinical trials. 63 Federal Register 179, 1998 22. Speyer JL, Green MD, Zeleniuch-Jacquotte A, et al: ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J Clin Oncol 10: 117-127, 1992[Abstract]
23.
Swain SM, Whaley FS, Gerber MC, et al: Cardioprotection with dexrazoxane for doxorubicin containing therapy in advanced breast cancer. J Clin Oncol 15: 1318-1332, 1997 24. Pharmacia and Upjohn Company: Adriamycin RDF (doxorubicin hydrochloride for injection, USP), in Physicians’ Desk Reference ( ed 54 ). Montvale NJ, Medical Economics Company, 2000, pp 2408-2410 25. Lipshultz SE, Colan SD, Gelber RD, et al: Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 324: 808-815, 1991[Abstract] 26. Krischer JP, Epstein S, Cuthbertson DD, et al: Clinical cardiotoxicity following anthracycline treatment for childhood cancer: The Pediatric Oncology Group experience. J Clin Oncol 15: 1544-1552, 1997[Abstract]
27.
Swain SM, 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 Oncol 15: 1333-1340, 1997 28. Legha SS, Benjamin RS, Mackay B, et al: Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 19: 133-139, 1982 29. Ryberg M, Nielsen D, Skovsgaard T, et al: Epirubicin cardiotoxicity: An analysis of 469 patients with metastatic breast cancer. J Clin Oncol 16: 3502-3508, 1998[Abstract] 30. Alza Corporation: Doxil (doxorubicin HCl liposome injection), in Physicians’ Desk Reference ( ed 54 ). Montvale NJ, Medical Economics Company, 2000, pp 508-511 31. Roberts P, Janoff AS, Mayhew E: Doxorubicin fluorescence in a human breast carcinoma (MX-1), after treatment with liposome-associated or free doxorubicin. Proc Am Assoc Cancer Res 41: 522, 2000 (abstr 3327) 32. Batist G, Saletan S, Panasci L, et al: High response rate and visceral organ targeting by liposomal doxorubicin (TLC D-99) in metastatic breast cancer. Presented at 15th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, 1992 (abstr)
33.
Valero V, Buzdar AU, Theriault RL, et al: Phase II trial of liposome-encapsulated doxorubicin, cyclophosphamide, and fluorouracil as first-line therapy in patients with metastatic breast cancer. J Clin Oncol 17: 1425-1434, 1999 34. Genentech, Inc: Herceptin (trastuzumab), in Physicians’ Desk Reference ( ed 54 ). Montvale NJ, Medical Economics Company, 2000, pp 1115-1117 35. Perez EA: Paclitaxel and cardiotoxicity. J Clin Oncol 16: 3481-3482, 1998 (editorial)[Medline] Submitted May 25, 2000; accepted November 9, 2000.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
2 test. The Cox proportional hazards model was used to estimate the hazard ratio and its 95% confidence interval (CI). The hazard ratio indicates the overall risk of experiencing an event in one group relative to the other group. In this report, a hazard ratio more than 1 suggests that the result of the particular parameter favors the MC-treated patients. 
