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© 1999 American Society for Clinical Oncology Phase II Trial of High-Dose Liposome-Encapsulated Doxorubicin With Granulocyte Colony-Stimulating Factor in Metastatic Breast CancerFrom the Breast Oncology Center, Dana-Farber Cancer Institute, Boston, MA; Ohio State University, Columbus, OH; Maine Center for Cancer Medicine, Portland, ME; The Liposome Company, Inc, Princeton, NJ; and the Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC. Address reprint requests to Charles L. Shapiro, MD, Arthur James Cancer Hospital and Research Institute, Ohio State University, Starling-Loving Hall, 320 W 10th St, Columbus, OH 43210; email shapiro-1{at}medctr.osu.edu
PURPOSE: To estimate the toxicity and response rate of high-dose liposome-encapsulated doxorubicin (TLC D-99, Evacet, The Liposome Company Inc, Princeton, NJ) in patients with advanced breast cancer. PATIENTS AND METHODS: Fifty-two breast cancer patients with bidimensionally measurable metastatic disease and no prior chemotherapy for metastatic disease received a 135 mg/m2 intravenous (IV) bolus of TLC D-99 with 5 µg/kg of granulocyte colony-stimulating factor via subcutaneous injection every 21 days.
RESULTS: The median number of treatment cycles of TLC D-99 was three (range, one to 10 cycles), and the median total cumulative dose of TLC D-99 was 405 mg/m2 (range, 135 to 1,065 mg/m2). Grade IV neutropenia, thrombocytopenia, and mucositis were experienced by 48 (92%), 46 (88%), and 10 (19%) patients, respectively. Twenty (38%) of patients experienced cardiac toxicity: four (8%) experienced a decrease of 20% or more in left ventricular ejection fraction (LVEF) to a final value CONCLUSION: There was no added therapeutic benefit to the dose escalation of TLC D-99 in this study. A high rate of cardiotoxicity was also observed, especially among patients who had received prior adjuvant doxorubicin. This was probably attributable to the dose and schedule of TLC D-99 used in this trial, as well as the patient's lifetime cumulative doxorubicin dose. Administration of high-dose TLC D-99 at 135 mg/m2 every 3 weeks by IV bolus infusion does not warrant further investigation.
IT MAY BE POSSIBLE to improve the therapeutic index of doxorubicin by encapsulating the drug in liposomes. The antitumor activity of liposome-encapsulated doxorubicin has equaled or exceeded that of the free drug in a variety of cell lines.1 When used in vivo, liposome-encapsulated doxorubicin caused less myocardial and gastrointestinal toxicity than standard drug formulations.2,3 In several trials, decreased toxicity, and possibly increased antitumor activity, has been observed in patients with Kaposi's sarcoma, breast cancer, and ovarian cancer treated with several liposome-encapsulated doxorubicin preparations.4-6 Liposome-encapsulated doxorubicin (TLC D-99, Evacet, The Liposome Company, Princeton, NJ) is a formulation that entraps more than 90% of the free drug into 1.0 micron or larger liposomes.7 In patients with metastatic breast cancer, TLC D-99 has been shown to have similar antitumor activity to that of free, unencapsulated doxorubicin but reportedly less myocardial damage when administered as a single agent or in combination with cyclophosphamide and fluorouracil.8,9 The current trial was designed to test the hypothesis that high-dose TLC D-99 yields high complete and overall response rates but with less myocardial and mucosal toxicity than would be seen with similar doses of unencapsulated doxorubicin. The dose used in this trial (135 mg/m2) was based on a prior phase I study.10 Twenty-seven solid tumor patients without prior exposure to anthracyclines received 90 to 165 mg/m2 of TLC D-99 IV bolus every 21 days with granulocyte colony-stimulating factor (G-CSF) 5 µg/kg subcutaneously (SC). The dose-limiting toxicity, determined after the first cycle of therapy, was myelosuppression observed at 165 mg/m2, and the maximum tolerated dose was determined to be 150 mg/m2. No cardiac toxicity was observed in seven patients who received in excess of 500 mg/m2 of TLC D-99. However, repetitive cycles of treatment at 150 mg/m2 were poorly tolerated because of cumulative hematologic toxicity. Therefore, the phase II dose used in the present trial was reduced to 135 mg/m2 to facilitate treatment of patients with multiple cycles.
Eligible patients had histologically documented primary breast cancer with one or more bidimensional sites of disease measurable by physical examination and/or radiographic evaluation. In the absence of measurable disease, patients with elevated carcinoembryonic antigen, malignant effusion(s), or bone-only disease were not eligible. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of  2 and the following laboratory data: WBC count  3,500/µL, granulocytes 2,000/µL, hematocrit 30%, hemoglobin 10 g/dL, platelets 100,000/µL, serum creatinine < 1.5 mg/dL, AST and ALT less than two times the upper limit of normal, and normal bilirubin, prothrombin time, and partial prothrombin time. Patients were required to have left ventricular ejection fraction (LEVF) 50% by radionuclide ventriculography and no history of congestive heart failure (CHF), angina, myocardial infarction, or serious ventricular arrhythmia. No prior chemotherapy for metastatic disease was permitted, but prior hormone therapy was allowed. Patients were permitted to have prior adjuvant therapy only if the treatment was administered more than 6 months before study entry and the total amount of adjuvant doxorubicin was 300 mg/m2. No prior history of allergy to egg or egg products was permitted. TLC D-99 was provided by The Liposome Company Inc (Princeton, NJ) in a kit consisting of a three-vial system containing TLC D-99 liposomes (100 mg/mL), doxorubicin hydrochloride (50 mg/vial), and buffer (sodium carbonate 17.6 mg/mL). The drug was prepared by the pharmacy before drug administration. The TLC D-99 liposomes are approximately 1.5 microns in size and are composed of egg phosphatidylcholine and cholesterol. The doxorubicin hydrochloride used in this study was a commercially available formulation of a lyophilized powder with lactose and methylparaben in a weight ratio of 1.5 to 1. The liposomes were shaken for 15 seconds and 1.9 mL were withdrawn and injected into a buffer solution of sodium carbonate 17.6 mg/mL at pH 10.8 to 12, and the mixture was shaken for 15 seconds. The doxorubicin hydrochloride was heated in a 55° to 60°C water bath for 10 minutes, shaken vigorously for 15 seconds, and immediately added to the liposome-buffer mix. The vial containing all three components was then vigorously shaken in the inverted position for 15 seconds, and the mixture was heated for 10 minutes in a 55° to 60°C water bath. After 10 minutes of heating, the TLC D-99 mixture was removed from the water bath and shaken again for 15 seconds. Vials were allowed to cool for at least 30 minutes at room temperature before use.
TLC D-99 was administered in a 135 mg/m2 IV bolus over a 60-minute period every 21 days. Forty-eight hours after drug administration, G-CSF was administered by SC injection at a dose of 5 µg/kg per day. G-CSF was continued until the absolute neutrophil count (ANC) was Toxicity was graded using the National Cancer Institute common toxicity criteria. Doses were reduced by 15 mg/m2 in all subsequent cycles for the following reasons: nadir ANC less than 500/µL, episode of fever higher than 101°F with an ANC less than 500/µL, platelet count less than 25,000/µL, grade 4 nausea and/or vomiting, or grade 4 mucositis. After an initial cohort of 22 patients were enrolled, the criteria for dose reductions were modified: subsequent doses were reduced 15 mg/m2 for a sustained nadir ANC less than 500/µL for more than 7 days or a platelet count less than 25,000/µL for more than 7 days. The frequency of dose reductions was similar for the initial 22 patients and the 30 patients who subsequently entered the study. Therefore, the overall frequency of dose reductions for the entire study population were reported.
Patients were removed from study for grade 3 or higher hyperbilirubinemia that was sustained for more than 2 weeks. Patients who developed CHF, angina, myocardial infarction, or serious ventricular arrhythmia were also removed from study. In the absence of clinical symptoms, patients observed to have a Measurable sites of disease were evaluated within 4 weeks before study entry and after every two cycles. The following criteria were used in response assessment: complete response (CR), the disappearance of all signs and symptoms and biochemical changes related to the cancer for a period of more than 6 weeks in which no new lesions appeared; partial response (PR), a reduction of more than 50% in the sum of the products of perpendicular diameters of all measured lesions lasting more than 6 weeks during which no new lesions appear and no existing lesions enlarge; stable disease (SD), a less than 50% reduction or a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions; and progressive disease (PD), an increase of more than 25% in the product of two perpendicular diameters of any measured lesion over the size at study entry, or the appearance of new areas of malignant disease. The trial was designed to detect a true CR rate of 30%. With 30 planned patients, the 95% confidence interval (CI) for the true CR rate of 30% was 17% to 47%. When the criteria for dose reductions were modified after 22 patients had been enrolled, it was decided to treat an additional 30 patients per the amended protocol. Multivariate analysis of risk factors affecting the development of CHF was performed in a stepwise logistic regression model. Using this model, the probability of CHF as a function of age, race, prior radiation therapy to the chest, total cumulative dose of prior adjuvant doxorubicin, and total cumulative dose of TLC D-99 was estimated. Curves of time to treatment failure and overall survival were estimated by the Kaplan-Meier method.
Fifty-two patients from 13 institutions were enrolled onto the trial between March 1994 and September 1995. Eight patients were deemed ineligible: six had unmeasurable disease (five with bone-only disease, one with unmeasurable liver metastasis), one had received in excess of 300 mg/m2 (311 mg/m2) of adjuvant doxorubicin, and one had received concurrent megestrol acetate. These ineligible patients were included in the analyses based on intent to treat. Patient characteristics are described in Table 1. The median age was 56.5 years, and 46 (88%) patients had an ECOG performance status of 1. Twenty-two (42%) patients had received prior adjuvant chemotherapy. This included 12 patients who received doxorubicin in the adjuvant setting. The median total dose of prior adjuvant doxorubicin was 240 mg/m2 (range, 73 to 311 mg/m2).
A total of 200 treatment cycles of TLC D-99 were administered. The median number of treatment cycles was three (range, one to 10 cycles). The median total dose of TLC D-99 was 405 mg/m2 (range, 135 to 1,065 mg/m2), the median duration of treatment was 76 days (range, 15 to 252 days), and the median dose-intensity was 36 mg/m2/wk (range, 18 to 45 mg/m2/wk). Dose reductions were required in 65 treatment cycles in 33% of patients. Doses were reduced because of grade 4 neutropenia with fever (11 cycles, nine patients), grade 4 thrombocytopenia (45 cycles, 19 patients), mucositis (five cycles, four patients), or other toxicities (four cycles, four patients). Forty-seven (90%) patients were removed from study, including 12 with PD, 20 with cardiac toxicity, five with other adverse events, two with SD, and eight who voluntarily withdrew their consent to treatment. Toxicity is described in Table 2. Forty-eight patients (92%) developed grade 4 neutropenia, and 46 (88%) patients developed grade 4 thrombocytopenia. Thirty-two (62%) patients experienced febrile neutropenia. Mucositis was grade 3 in 11 (21%) patients and grade 4 in 10 (19%) patients. Palmar-plantar erythrodysesthesia (hand-foot syndrome) was not observed. Two patients had drug extravasations; however, these were only associated with transient mild irritation at the infusion site.
Twenty (38%) patients experienced cardiac toxicity: four (8%) patients experienced a The probability of CHF related to the lifetime cumulative dose of doxorubicin (adjuvant doxorubicin plus TLC D-99) is described in Fig 1. The 50th percentile for the cumulative risk of developing CHF occurred at a median lifetime cumulative doxorubicin dose of 971 mg/m2. In a multivariate stepwise logistic regression analysis, the risk of developing CHF was significantly associated with the cumulative dose of prior adjuvant doxorubicin (P = .007) and the cumulative dose of TLC D-99 (P = .032), but not with the other tested risk factors in the model.
The assessment of response rate was based on all 52 patients who received at least one cycle. However, eight patients were unavailable for assessment of response according to protocol guidelines: one patient was unavailable after the first cycle due to concurrent illness, six were unassessable because of unmeasurable disease, and one was unassessable because of concurrent megestrol acetate. These patients were included in the response analysis that was based on the intent to treat. CR was observed in three (6%) patients and PR in 21 (40%) patients, for an overall response rate of 46% (95% CI, 32%-61%). SD was observed in 11 (21%) patients and PD in 17 (33%) patients. Among 12 patients who received prior adjuvant doxorubicin, the response rate was 50%, whereas it was 43% among the 40 patients who had not received prior adjuvant doxorubicin. The median duration of response was 7.4 months (95% CI, 6.1 to 19.6 months). The median progression-free survival was 6.1 months (95% CI, 5.4 to 7.5 months), and the median overall survival was 22.1 months (95% CI, 14.4 to 34.7 months) (Figs 2 and 3).
Prior single-institution phase I studies reported that approximately two-fold higher dose escalation of unencapsulated doxorubicin was associated with high overall and complete response rates, but was also associated with dose-limiting cardiac and mucosal toxicity.11,12 TLC D-99 had been shown to reduce cardiac and mucosal toxicity in mice and dogs.2,3 Endomyocardial biopsies have been performed in a limited number of patients receiving TLC D-99. The results of these studies showed less myocardial damage than was observed in historical controls receiving the same cumulative doses of unencapsulated doxorubicin (V. Valero, personal communication, August, 1998).9,13,14 Recently a randomized trial of 216 patients with metastatic breast cancer compared single-agent TLC D-99 to unencapsulated doxorubicin (The Liposome Company, personal communication, August, 1998).15,16 In an interim analysis, there was no significant difference in response rates between the treatment arms, but cardiac, mucosal, and gastrointestinal toxicity were found to be significantly less frequent in the TLC D-99–treated patients. The reduced cardiac, gastrointestinal, and mucosal toxicity observed in the conventional dose range made it feasible to test higher doses of TLC D-99 to see whether there was a clinically meaningful dose-response relationship. However, the overall response rate of 46% observed in this trial was only marginally better than that of conventional doses of unencapsulated doxorubicin. Four large randomized trials in which single-agent doxorubicin was administered at doses of 60 or 75 mg/m2 reported overall response rates of 27% to 34%.17-20 The overall response rate of 46% observed in this trial does not justify the high overall incidence of toxicity, particularly cardiac toxicity. There are several possible explanations for the high frequency of cardiac toxicity observed in this trial. Myocardial damage attributable to doxorubicin is thought, in part, to be the result of free radical generation.21 Liposome encapsulation alters the pharmacokinetics such that there is decreased uptake of doxorubicin into the heart muscle, and overall slower release of the drug. This is considered the basis of the cardioprotection afforded by TLC D-99 when administered at conventional doses.22-25 However, when TLC D-99 is given by IV bolus at approximately two-fold higher dose escalation, the peak levels of the free drug may exceed the threshold at which myocardial damage is likely to occur. There was no limit to the total amount of TLC D-99 patients received in this study, provided they met the criteria for retreatment based on an assessment of the resting LVEF. Determination of resting LVEF by radionuclide ventriculography is the generally accepted way to monitor patients receiving doxorubicin to prevent cardiomyopathy, although endomyocardial biopsy is considered the most sensitive method to detect early myocardial damage.26-29 However, the sensitivity of the resting LVEF for predicting the risk of CHF was only 53% in a prospective study that included endomyocardial biopsy.30 In another study, there was no correlation between resting LVEF and the results of endomyocardial biopsy.14 To detect subclinical myocardial damage from doxorubicin, the use of exercise radionuclide ventriculography has been advocated when the resting LVEF is in the normal range.30,31 Neither endomyocardial biopsy nor exercise radionuclide ventriculography was used in this study, and the sole reliance on the resting LVEF may have led to the high incidence of CHF. The incidence of doxorubicin-related cardiomyopathy is related to the lifetime cumulative dose.32 As there was no limit on the total lifetime cumulative dose, it is not surprising that 13% of study patients developed CHF. In a phase I trial of 27 patients with soft tissue sarcoma, the dose of TLC D-99 was escalated between 75 to 120 mg/m2 every 2 weeks with G-CSF support.33 The cumulative dose of TLC D-99 was limited to 600 mg/m2, and no prior doxorubicin was permitted. Unlike our study, patients on this trial did not experience any significant decline in resting LVEF, and no patient developed CHF. This suggests that either the total lifetime dose, the prior doxorubicin, or both may have contributed to the high frequency of cardiac toxicity observed in this study. At the time of the design of this study, the question of whether there was a clinically meaningful dose-response relationship for doxorubicin or other anthracyclines was unknown. Randomized trials in advanced disease and in the adjuvant setting suggest that administering lower than conventional doses of doxorubicin are associated with a lower therapeutic efficacy.34,35 However, there is more uncertainty regarding the value of administering higher than conventional doses, in part because of their substantive toxicity.11,12 Only modest dose escalations of anthracyclines have been possible in the few randomized trials that have been designed to specifically address the dose-response hypothesis, and the results have been inconclusive.36-38 Recently, the preliminary results of a large randomized adjuvant trial showed no benefit to escalating the dose of doxorubicin in combination with cyclophosphamide.39 The reduced cardiac, gastrointestinal, and mucosal toxicity of TLC D-99 at conventional doses made it feasible to test whether there was a dose-response relationship. However, the hypothesis on which this trial was based—specifically, that high-dose TLC D-99 would lead to high complete response rates with less cardiac and mucosal toxicity—was proven incorrect. The dose and schedule of TLC D-99 used in this trial do not warrant further clinical investigation.
The following individuals are members of the TLC D-99 Study Group: J. Bull, University of Texas Health Science Center, Houston, TX; E. Dickman, Meridia Hilcrest Hospital, Mayfield Heights, OH; R. Gams, Arthur James Cancer Hospital and Research Institute, Columbus, OH; G. Gross, East Texas Medical Center, Tyler, TX; W. Heim, Hematology and Oncology Association of the Northeastern Physicians' Organization, Scranton, PA; D. Henry, Graduate Hospital, Philadelphia, PA; A. Keller, Cancer Care Associates, Tulsa, OK; T. Lynch, Massachusetts General Hospital, Boston, MA; M. Moore, Cancer Specialists of Georgia, Decatur, GA; R. Smith, Shadyside Hospital Oncology Service, Pittsburgh, PA; and R. Winer; Tulane Medical Center, New Orleans, LA.
Presented in part at the American Society of Clinical Oncology Meeting, Philadelphia, PA, May 18-21, 1996.
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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
