1 Division of Hematology and Oncology, Ohio State University Medical Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH; 2 Comprehensive Cancer Center and Center for Biostatistics, Ohio State University, Columbus, OH, USA
* Correspondence to: Dr C. L. Shapiro, B 405 Starling-Loving, 320 West 10th Avenue, Columbus, OH 43210, USA. Tel: +1-614-293-7530; Fax: +1-614-293-7529; Email: shapiro-1{at}medctr.osu.edu
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Abstract |
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Patients and methods:: Twenty-one patients with no prior chemotherapy for MBC received D-99 (60 or 50 mg/m2) intravenously (i.v.) on day 1 and escalating doses of docetaxel (25, 30 and 35 mg/m2) i.v. on days 1 and 8 in cohorts of three to six patients. Treatment cycles were repeated every 21 days for a maximum of six cycles.
Results:: The maximum tolerated dose (MTD) was 50 mg/m2 of D-99 in combination with 25 mg/m2 of weekly docetaxel. The most common grade 4 toxicity was neutropenia that occurred in 42 (41%) of treatment cycles, with 10 hospitalizations for febrile neutropenia. Serious protocol-defined cardiac events occurred in three (14%) patients, with two (10%; 95% confidence interval [CI] 1% to 30%) developing congestive heart failure (CHF) after a total cumulative anthracycline dose (adjuvant doxorubicin + D-99) of 540 mg/m2.
Conclusions:: D-99 in combination with weekly docetaxel, at the doses and schedule as administered in this trial, is not recommended for phase II testing. Additional trials, using different doses and schedules, are required to evaluate the potential side-effects and efficacy of D-99 and docetaxel.
Key words: liposome encapsulated doxorubicin, cardiotoxicity, breast cancer
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Introduction |
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Patients and methods |
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Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status 2, and the following organ function: platelets
100 000 cells/mm3; absolute neutrophil count
1500 cells/mm3; hemoglobin
10 g/dl; serum creatinine <2.0 mg/dl; and pretreatment left ventricular ejection fraction (LVEF)
50%. Due to the increased risk of side-effects of docetaxel with impaired liver function, the total bilirubin was required to be less than or equal to the upper limit of normal (ULN); AST and ALT
2.5 times ULN if alkaline phosphatase was normal; or alkaline phosphatase
4 times ULN if AST and ALT were normal. Patients were excluded for a known hypersensitivity to taxanes, anthracyclines, polysorbate 80, eggs or eggs products; prior radiotherapy to mediastinal area or internal mammary lymph node exceeding 3500 cGy, or if they received radiation therapy to more than 25% of the bone marrow. Patients with untreated brain metastases were excluded. However, patients with previously treated brain metastases were eligible if they were stable for at least 3 months after surgery and/or radiation and were off steroids. Patients were not required to have bi-dimensionally measurable disease; if measurable disease was present, it was evaluated using standard response criteria (see below). The Institutional Review Board of the Ohio State University approved the study protocol, and written informed consent was obtained from each patient.
Treatment plan
D-99 was provided by Elan Pharmaceuticals, Inc. (Princeton, NJ) in a three-vial set containing liposomes for injection 2 ml (100 mg/ml), doxorubicin hydrochloride powder (50 mg/vial) and buffer for injection 3 ml (sodium carbonate 17.6 mg/ml). The drug was prepared in the pharmacy according to standard manufacturers instructions just before administration. Docetaxel was obtained from commercial sources. D-99 at a dose of 5060 mg/m2 i.v. was administered on day 1 over 60 min by intravenous infusion. Docetaxel 2535 mg/m2 i.v. was administered on days 1 and 8 over 60 min. The docetaxel infusion was started 30 min after completion of D-99 infusion. Patients received dexamethasone 8 mg orally every 12 h for three doses beginning 12 h prior to each docetaxel infusion. Treatment cycles were repeated every 21 days for a maximum of six cycles. The use of granulocyte colony stimulating factor (Neupogen®, G-CSF) or erythropoietin (Procrit®) was at the discretion of the treating physician. Complete blood counts were obtained before and weekly, during each cycle.
Definition of dose limiting toxicity (DLT) and criteria for dose escalation and reductions
Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0. A dose limiting toxicity (DLT) occurring in cycle 1 was defined as follows: any grade 4 neutropenia lasting more than 7 days; febrile neutropenia; or any grade 4 non-hematologic toxicity, grade 3 mucositis or stomatitis lasting more than 3 days; or any other grade 3 non-hematologic toxicity that did not revert to grade 1 or less within 35 days. Cohorts of three to six patients were treated at a given dose level. There was no intra-patient dose escalation. Escalation to the next higher dose level took place only after all three patients had completed the first treatment cycle without evidence of DLT. If there was one DLT among the initial three patients, an additional three patients were treated at the same dose level. If two or less patients out of six experienced DLT, the dose was escalated to the next level. If more than two patients out of three experienced DLT in cycle 1, the dose was not escalated to the next level, and the MTD was defined as the next lower dose level.
Patients were treated until disease progression, unacceptable toxicity, or a maximum of six cycles. There were no dose reductions for D-99. A docetaxel dose reduction of 5 mg/m2 was permitted for grade 4 neutropenic fever, grade 4 anemia or thrombocytopenia, serum bilirubin level 1.2 x ULN, or grade 3 or 4 mucositis. Only one docetaxel dose reduction per patient was permitted. Dose delays of up to 14 days were permitted for grade 3 or 4 non-hematologic toxicity that did not revert to grade 1, or for an absolute neutrophil count (ANC) of
1000/mm3 and or platelet count of
100 000/mm3 on day 1 of a treatment cycle. Patients who did not revert to
grade 1 non-hematologic toxicity or failed to recover ANC >1000/mm3 or platelet count >100 000/mm3 after 14 days were removed from the study.
Tumor evaluation and criteria for response
All patients had imaging studies and/or physical examination measurements for assessment of tumor sites within 14 days before starting treatment. The same imaging modalities were used for response evaluation after every two cycles, as well as at the time of discontinuation of study therapy. In those patients with measurable disease the definitions of response were as follows: complete response (CR) was the disappearance of all evidence of disease lasting at least 4 weeks; partial response (PR) was a 50% decrease in the sum of the products of the two longest perpendicular diameters of all measured lesions lasting at least 4 weeks and no new lesions; stable disease (SD) was a
50% decrease or
25% increase in measurable disease and no new lesions; and progressive disease (PD) was a
25% increase in the product of the two longest perpendicular diameters of any measurable disease lesion, or the appearance of a new lesion.
Monitoring for cardiac toxicity
All patients had an electrocardiogram (ECG) within 1 week of study entry, and a multiple-gated radionuclide angiography acquisition (MUGA) scan to quantitate LVEF within 4 weeks before treatment. Subsequent MUGA scans were required after patients received a total cumulative anthracycline dose (adjuvant doxorubicin and D-99) of 300 mg/m2, 400 mg/m2, and prior to each cycle after patients received a lifetime cumulative anthracycline dose of 500 mg/m2. Cardiac events were defined as follows: a decrease in the baseline LVEF of 20% if the final LVEF was
50%; a decrease in the baseline LVEF
10% if the final LVEF <50%, or any clinical evidence of American Heart Association (AHA) Class III or IV congestive heart failure CHF. Patients were removed from study if they developed any cardiac event.
Statistical methods
Median time to progression and median overall survival were estimated by the KaplanMeier method [12]. Confidence intervals for median time to progression and overall survival were calculated using the BrookmeyerCrowley method [13
]. Exact binomial confidence intervals are reported for all proportions.
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Results |
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Two (10%; 95% CI 1% to 30%) patients developed grade 3 CHF shortly after completion of study treatment. Both patients received adjuvant doxorubicin dose of 240 mg/m2, and total cumulative anthracycline dose (adjuvant doxorubicin + D-99) of 540 mg/m2. Patient 2 presented with acute CHF about 7 weeks after completing all six treatment cycles at the dose level of 50/30. Her pre- and post-treatment LVEF were 59% and 51%, respectively, but at the time she presented with symptomatic CHF, the LVEF was 29%. This patient responded to medical treatment for CHF and subsequent LVEF improved to 62%.
Patient 3 developed CHF about 6 weeks after completing six cycles of study treatment at the dose level of 50/25. She also had a history of left-sided postmastectomy chest wall irradiation after her adjuvant chemotherapy. Her pre- and post-study LVEF were 57% and 52%, respectively, but at the time of symptoms of CHF, the LVEF was 30%. In addition, there was evidence of thrombus in the left ventricle and small pericardial effusion. Patient 3 was treated with anticoagulation and was discharged from the hospital on medication for CHF. Ten days after discharge she presented to an emergency room with acute respiratory failure and died. There was no post-mortem examination. Patients 2 and 3 did not receive chemotherapy, hormonal treatment, or any other potential cardiotoxic drug after completing study treatment and before presenting with CHF. In addition, both patients had no evidence of acute myocardial injury by serial enzymes or electrocardiographic changes, or pulmonary embolus at the time of presentation of CHF.
Two additional patients developed cardiac events 4 and 9 months after completion of study therapy, but only after starting another phase I clinical trial of trastuzumab (Herceptin®) and interleukin 12 (IL-12).
Response and survival data
Eight (38%) patients were removed from the study: four (19%) for PD, including one who expired from respiratory failure due to refractory progressive malignant effusions, and four (19%) for DLT. Sixteen patients had bidimensional measurable disease and were evaluable for response (Table 6). The overall response rate for all 21 patients was 29% (95% CI 11% to 52%), and 38% (95% CI 15% to 65%) among the patients with measurable disease. The time to progression (TTP) and overall survival in all patients was 8.8 months (95% CI 3.712.4 months) and 22.2 months (95% CI 15.429.7 months), respectively.
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Discussion |
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Previous studies of D-99 as a single agent or in combination with cyclophosphamide showed 0%2% incidence of CHF. In a phase III trial comparing D-99 with conventional doxorubicin, only two out of 108 (2%) patients treated with 75 mg/m2 D-99 developed CHF [10]. These two patients received a total cumulative anthracycline (adjuvant doxorubicin + D-99) dose of 785 and 1100 mg/m2, respectively. Similarly, in a phase III trial comparing D-99 and cyclophosphamide (MC) with conventional doxorubicin and cyclophosphamide (AC), none of the 142 patients treated with MC developed CHF after receiving a median cumulative anthracycline dose of 360 mg/m2 (range 602220 mg/m2) [11
]. In the only other phase I study of D-99 (6075 mg/m2) and docetaxel (7585 mg/m2) given every 3 weeks, there were no cases of CHF or decline in LVEF sufficient to remove the patients from the study [15
].
The incidence of CHF ranges from 0% to 10% in clinical trials of conventional doxorubicin combined with docetaxel (Table 7) [1620
]. In contrast, no CHF was observed using pegylated liposomal doxorubicin (Doxil®) in combination with docetaxel [21
24
]. There are several possible explanations for the relatively high incidence of CHF observed in this study. First, because of the small trial population, the true proportion of CHF is as low as 1% or as high as 30%. It is also possible that patient 3 developed CHF because she had received postmastectomy chest wall radiation in addition to a total cumulative dose of doxorubicin (adjuvant doxorubicin plus D-99) of 540 mg/m2. In a prospective randomized adjuvant trial, patients with localized breast cancer received 225 or 450 mg/m2 adjuvant doxorubicin, and a portion of them received postmastectomy radiation [25
]. Acute and long-term cardiac events, including CHF and myocardial infarction, were the primary end points of the study. Whereas no increase cardiac events occurred in patients receiving 225 mg/m2 of doxorubicin along with any dose-volume of chest wall radiation, patients who received 450 mg/m2 and moderate or high dose-volumes of chest wall radiation were at significantly higher risks of acute and long-term cardiac events [25
].
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The primary objective of this phase I trial was not to define the response rate for this combination. However, the overall response rate of 29%, and 38% for patients who had measurable disease, was below the response rates observed by other investigators using combinations of conventional or liposomal doxorubicin with docetaxel in similar MBC patients (Table 7). Likewise, the low response rate in this trial is consistent with the 33% response rate in the only other phase I trial of D-99 and docetaxel [15].
D-99 combined with weekly docetaxel as administered in this phase I trial did not show improved cardiac safety and had low antitumor activity in MBC patients without prior chemotherapy for metastases. Phase II testing of this combination is not recommended. Additional trials, using different doses and schedules, are required to evaluate the potential cardiac, as well as other, side-effects and efficacy of D-99 and docetaxel.
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Acknowledgements |
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Received for publication November 11, 2004. Revision received February 2, 2005. Accepted for publication February 3, 2005.
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References |
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