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a Johns Hopkins Medical Institutions, Baltimore, Maryland, USA; b Memorial Sloan-Kettering Cancer Center, New York, New York, USA; c GlaxoSmithKline, Philadelphia, Pennsylvania, USA
Key Words. Myelosuppression • Neutropenia • Noncumulative • Ovarian cancer • Small cell lung cancer • Topotecan
Correspondence: Deborah K. Armstrong, M.D., The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting Blaustein Cancer Research Building, Room 190, 1650 Orleans Street, Baltimore, Maryland 21231, USA. Telephone: 410-614-2743; Fax: 410-955-0125; e-mail: darmstro{at}jhmi.edu
Received December 6, 2004; accepted for publication June 24, 2005.
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LEARNING OBJECTIVES
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Abstract
Introduction
Materials and methods
Results
Discussion
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ABSTRACT |
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2; SCLC; and exposure to both cisplatin (Platinol®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) and carboplatin (Paraplatin®; Bristol-Myers Squibb) (grade 3/4 thrombocytopenia only). The most frequent interventions for hematologic toxicities were RBC transfusions, treatment delays, G-CSF support, and dose reductions. Analysis of neutrophil and platelet nadirs and dosing for each course of therapy showed no apparent evidence of cumulative neutropenia or thrombocytopenia. The risk of grade 3 or 4 anemia was higher during the first four courses of therapy and may need to be more aggressively managed with erythropoietin therapy.
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INTRODUCTION |
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The dose-limiting toxicity for topotecan is myelosuppression, with the most common severe adverse event being noncumulative grade 4 neutropenia [8, 9]. Thus, toxicity is generally managed by treatment delays and dose reductions, and when appropriate, the administration of G-CSF and/or GM-CSF. Guidelines for managing topotecan-related hematologic toxicity have been published previously and include specific recommendations for dose reductions and the use of hematopoietic growth factors [10, 11].
An integrated analysis of the hematologic safety and tolerability of topotecan in patients with SCLC or ovarian cancer has not been previously reported. Based on the previous clinical trial reports, myelosuppression is the predominant toxicity observed in both these populations. The incidences of grade 4 neutropenia, leukopenia, and anemia appear to be slightly higher for patients with ovarian cancer than for patients with SCLC, whereas the incidence of grade 4 (<25 x 109/l) thrombocytopenia is slightly higher in patients with SCLC. Taking into account the different underlying diseases, background clinical conditions, and concomitant medications, the hematologic tolerability profiles for these two patient populations appear to be similar. Therefore, the safety data sets from these two patient populations can be combined to provide a greater overall clinical experience of the tolerability of topotecan. Herein, we report the results of such an integrated safety analysis.
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MATERIALS AND METHODS |
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[1, 4–6, 9, 12–15]. Three noncomparative phase II studies were conducted in patients with epithelial ovarian cancer (studies 012 [12], 033 [1], and 034 [4]) and three were conducted in patients with SCLC (studies 014 [6], 053 [14], and 092 [5]). A randomized, controlled, phase III study (study 039) [9, 13] was conducted in patients with ovarian cancer comparing topotecan with paclitaxel (Taxol®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) at a dose of 175 mg/m2 infused over 3 hours every 21 days. The 61 patients who crossed over to topotecan after progressing on paclitaxel were also included in this analysis. A phase III study comparing topotecan with cyclophosphamide, 1,000 mg/m2, doxorubicin (Adriamycin®; Bedford Laboratories, Bedford, OH, http://www.bedfordlabs.com), 45 mg/m2, and vincristine (Oncovin®; Eli Lilly and Company, Indianapolis, http://www.lilly.com), 2 mg, infused on day 1 every 21 days (CAV) in patients with SCLC was also conducted (study 090) [15].
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Ovarian Cancer Studies
Eligible patients were required to have stage III/IV, histologically confirmed epithelial ovarian carcinoma and a relapse after first-line therapy. Each patient had to have at least one bidimensionally measurable lesion, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score 
2, and adequate bone marrow function (WBC 3.5 x 109 cells per l, neutrophil count 1.5 x 109 cells per l, and platelet count 100 x 109 per l).
SCLC Studies
Eligible patients were required to have documented, limited or extensive SCLC with progression at least 60 days (phase II studies) or 90 days (phase III study) after completing first-line chemotherapy and at least one bidimensionally measurable lesion. Other eligibility criteria included an ECOG PS score 2, hemoglobin level 9 g/dl, WBC 3.5 x 109 cells per l, neutrophil count 1.5 x 109 cells per l, and platelet count 100 x 109 per l. Patients with symptomatic brain metastases requiring corticosteroids or pre-existing cardiac disease were ineligible.
Treatment
In all studies, topotecan was administered as a 30-minute i.v. infusion on days 1–5 of a 21-day course at a dose of 1.5 mg/m2 per day. Full doses were administered if the treatment-day neutrophil count was 1.0 x 109 cells per l, the platelet count was 100 x 109 per l, and the hemoglobin level was 9.0 g/dl. Topotecan was reduced by 0.25 mg/m2 per day to a minimum dose of 1.0 mg/m2 for the following criteria: grade 4 neutropenia complicated by fever or infection or lasting 7 days, grade 3 neutropenia lasting beyond day 21 of the treatment course, or grade 4 thrombocytopenia. Use of G-CSF and other blood products and growth factors was left to the discretion of the investigator and in the majority of the studies was not allowed during the first course of therapy.
Safety and Tolerability Assessments
Quantitative hematologic toxicities were assessed using the National Cancer Institute Common Toxicity Criteria (CTC). Qualitative data for hematologic toxicities relating to WBC, neutrophil count, platelet count, and hemoglobin level were summarized by the number and percentage of patients and courses affected. Assessments included time to onset and duration of grade 4 toxicities. Quantitative assessments of hematologic toxicities included calculations of absolute nadirs, percentage change from baseline, and day of nadir occurrence.
Data Handling
Specific baseline, background information and hematologic safety data were pooled across the eight clinical studies to form an integrated database. The data in the integrated database included demographic information, patient disposition, medical history, screening tests, treatment exposure, and hematologic data, including adverse events.
For the safety data, summary statistics are presented to give a general description of the patients studied and an overview of the safety results. Categorical parameters, such as hematologic toxicities, adverse experiences, and febrile neutropenia, are summarized by the number and percentage of patients and courses for each toxicity or adverse experience. Time to onset and duration of toxicity are summarized with medians and ranges. Frequencies and percentages of patients with toxicities >7 days are also presented. Hematologic nadirs are summarized by the following three methods: mean value of each parameter, median value of each parameter, and median day. Computations were performed using SAS® (SAS Institute, Inc., Cary, NC, http://www.sas.com) computer software.
An additional analysis was performed to investigate whether any baseline patient characteristics correlated with a greater risk for either grade 3/4 thrombocytopenia or grade 4 neutropenia during the first course of treatment. Logistic regression was used to model the odds of a specific hematologic toxicity event (e.g., grade 4 neutropenia) as a function of one or more independent variables. For each independent variable in the logistic regression model, the odds ratio was estimated and a p value relative to the null hypothesis of no relationship with the response variable (i.e., an odds ratio of 1) was calculated. Independent variables included: sex (male/female), prior radiation therapy (yes/no), renal impairment (present/absent, defined as CTC grade 1 serum creatinine), liver metastases (present/absent), ECOG PS score (0 or 1/2 or 3), bone metastases (present/absent), prior platinum exposure (carboplatin [Paraplatin®; Bristol-Myers Squibb] only/cisplatin [Platinol®; Bristol-Myers Squibb] only/both carboplatin and cisplatin), disease type (ovarian/lung), and age (in 10-year increments). Backward stepwise regression was performed with a decision criterion of 0.10 for inclusion of variables in the model.
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RESULTS |
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Patient Disposition
Patient disposition, including dose modifications, treatment delays, and discontinuations, is summarized in Table 2. A total of 4,124 courses of topotecan was administered to the 879 patients in the pooled population. Of the 879 patients, 487 (55%) completed four courses of treatment, 308 (35%) completed six courses, and 74 (8%) completed 10 courses. Over the first six courses of therapy, treatment delays were noted in 17%–37% of patient and dose reductions occurred in 3%–22% of patients. The percentage of patients treated at each dose level by course number is presented in Table 2.
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. Grade 4 neutropenia was experienced by 674 of 864 (78%) patients and associated with 1,565 (39%) of the courses administered. Severe thrombocytopenia was less frequently reported. Grade 4 thrombocytopenia (defined as platelet count <25 x 109/l) was experienced by 27% of patients and was associated with approximately 10% of courses. Grade 3/4 anemia occurred in 37% of patients and 14% of courses. Hematologic toxicities were comparable between patients with ovarian cancer and patients with SCLC. Between these groups, there were similar incidences of grade 4 leukopenia (ovarian, 32.7% of patients and 10.5% of cycles; SCLC, 31.4% of patients and 12.3% of cycles) and grade 4 thrombocytopenia (ovarian, 25.4% of patients and 8.2% of cycles; SCLC, 28.1% of patients and 10.6% of cycles). However, patients with ovarian cancer had a slightly higher incidence of grade 4 neutropenia (ovarian, 81.4% of patients and 38.3% of cycles; SCLC, 74.3% of patients and 39.1% of cycles) and grade 3/4 anemia (ovarian, 40.4% of patients and 15.3% of cycles; SCLC, 33.4% of patients and 13.1% of cycles).
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Across all treatment courses, the median time to onset of grade 4 neutropenia was 10 days, compared with 15 days for grade 4 thrombocytopenia and 13 days for grade 3/4 anemia. The median durations of severe toxicities (grade 3/4 anemia and grade 4 neutropenia or thrombocytopenia) for each course of therapy through course 10 are presented in Table 3
. The median durations were 7 days for grade 4 neutropenia, 5 days for thrombocytopenia (range, 2–7 days), and 7 days for anemia (range, 4–7.5 days).
The median number of days to nadir for hemoglobin and platelets remained constant throughout treatment, but there was some fluctuation in the median number of days to neutrophil nadir. In course 1, the median onset of grade 4 neutropenia was 13 days, and the duration was longer than 1 week in 37% of affected patients. However, in subsequent courses, the median time to onset per course was generally 9 days, with a duration >1 week in 21%–43% of affected patients. Overall, the median nadir values did not decrease with increasing courses of topotecan therapy. The median neutrophil nadirs plotted as a function of treatment course, dose, and G-CSF support are presented in Figure 1. The lowest median neutrophil nadir occurred during course 1 of therapy, in which patients received topotecan at a dose of 1.5 mg/m2 and no G-CSF support. The subsequent use of G-CSF and early discontinuations likely account for the higher nadir values observed in subsequent courses. G-CSF administration resulted in less severe neutrophil nadirs regardless of dose. In contrast, dose reductions of topotecan did not materially alter the leukocyte nadirs. Patients who received topotecan doses <1.25 mg/m2 had median neutrophil nadirs similar to patients who received 1.25 mg/m2 of topotecan regardless of G-CSF support. In this population, there was no evidence of cumulative neutropenia with subsequent courses. The majority of patients receiving topotecan was able to receive doses 1.25 mg/m2 without further dose reduction or G-CSF support.
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and Figure 3, respectively. The median nadir for hemoglobin in patients who received topotecan doses 1.25 mg/m2 without any RBC/erythropoietin support decreased over the first three courses and then reached a plateau at course 4. Of the 862 patients with hemoglobin laboratory values reported during course 1, 192 (22%) received RBC transfusions or erythropoietin, and the median hemoglobin nadir was 9.8 g/dl. During subsequent courses, patients who received <1.25 mg/m2 of topotecan and did not require RBC/erythropoietin support had median hemoglobin nadirs similar to those of patients who received 1.25 mg/m2 of topotecan without RBC/erythropoietin support. After the first or second cycle, the majority of patients was able to receive 1.25 mg/m2 of topotecan without further dose reductions or RBC/erythropoietin support.
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1.25 mg/m2 and no platelet support, the median platelet nadir for course 1 was 67 x 109 per l. Median platelet nadirs were higher for these patients in subsequent courses, stabilizing at a median of approximately 90 x 109 per l for courses 2–10. Of the 862 patients with platelet laboratory values during course 1, 102 received platelet support because of a median platelet nadir of 14 x 109 per l. As expected, the median platelet nadirs for patients who required platelet transfusions and/or dose reductions were lower than those of patients who did not require intervention because of low platelet counts. However, there was no evidence that platelet nadirs worsened over treatment courses.
Management of Hematologic Toxicity
Based on protocol design, the most common interventions for hematologic toxicity were RBC transfusions, treatment delays, G-CSF support, and dose reductions. Fifty-eight percent of patients experienced treatment delays, and 30% experienced dose reductions. Blood-product and growth-factor interventions for hematologic toxicity by treatment course are summarized in Table 4. RBC transfusions were administered to 52% of patients in 22% of courses. Treatment or prophylaxis with G-CSF was administered to 23% of patients in 20% of courses. Prophylactic use of G-CSF was not required and was left to the discretion of the investigator. Platelet transfusions were administered to 15% of patients in 4% of courses. Platelet transfusions were infrequent after course 1 and remained relatively infrequent (5% of patients) and constant throughout subsequent courses of therapy. The number of RBC transfusions remained relatively stable throughout the 10 courses of therapy. The use of erythropoietin increased slightly throughout the 10 courses but never exceeded 8% of patients in any one course.
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Another important potential myeloid toxicity is treatment-related leukemia. There were no cases of secondary leukemia in patients treated in the clinical studies included in this analysis. One case of secondary leukemia possibly attributable to topotecan has been reported in a patient with SCLC who developed acute myeloid leukemia after receiving 27 courses of oral topotecan as first-line therapy. There have been six other reported cases of secondary leukemias in patients treated with topotecan. In each case, the patients had received many other chemotherapy agents known to cause late leukemia (GlaxoSmithKline, data on file).
Risk Factors for Course 1 Hematology Toxicity
Analyses of hematologic toxicity during the first course of therapy identified some significant risk factors among the patient demographic and baseline parameters. For both grade 3/4 thrombocytopenia and grade 4 neutropenia, there were statistically significant greater odds of an event for patients with renal impairment and advanced age. There was a trend toward a greater incidence of these events in women than in men. Renal impairment was associated with a 1.9-fold greater incidence of grade 3/4 thrombocytopenia (p = .014) and a 1.8-fold greater incidence of grade 4 neutropenia (p = .019). Each successive 10-year age group had a 1.34-fold greater incidence of grade 3/4 thrombocytopenia (p = .0002) and a 1.13-fold greater incidence of grade 4 neutropenia (p = .087). In addition, women had a 1.5-fold greater incidence of grade 3/4 thrombocytopenia (p = .091) and 1.4-fold greater incidence of grade 4 neutropenia than men (p = .069).
In addition to these shared baseline risk factors for neutropenia and thrombocytopenia, other risk factors were identified for grade 3/4 thrombocytopenia: prior radiation therapy, higher ECOG PS score, disease type (SCLC), and prior exposure to multiple platinum agents. For the incidence of grade 3/4 thrombocytopenia, patients with prior radiation therapy had a 1.55-fold greater incidence than patients with no prior radiation therapy (p = .044), patients with PS scores 2 had a 2.6-fold greater incidence than patients with PS scores of 0/1 (p < .001), and patients with SCLC had a 2.9-fold greater incidence than patients with ovarian cancer (p < .001). Although prior carboplatin or cisplatin exposure did not correlate with a significantly greater risk for severe thrombocytopenia (p = .544), patients who had prior exposure to both cisplatin and carboplatin had a 2.7-fold greater incidence of grade 3/4 thrombocytopenia than patients with exposure to either cisplatin or carboplatin (p < .001).
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DISCUSSION |
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5% of patients receiving platelet transfusions. In contrast, anemia appeared to increase, with deeper nadirs through course 4, but stabilized thereafter. Fifty-two percent of patients required RBC transfusions. It is difficult to discern whether this was because of topotecan, prior treatment, or the disease in general. Intervention with erythropoietin was infrequent in this analysis, based on the usage patterns during the study period. Active intervention with erythropoietin may be a reasonable consideration, especially for patients with a predisposition for anemia. A multivariate analysis of risk factors for hematologic toxicity during the first course of therapy may provide insight for patient management. Consistent with the updated dosing guidelines based on the renal clearance of topotecan [16], renal impairment was identified as a significant risk factor for grade 3/4 thrombocytopenia and grade 4 neutropenia during the first course of topotecan therapy. Patients in the older age groups also had a higher risk for both toxicities than younger patients. Grade 3/4 thrombocytopenia also had additional significant risk factors, including prior radiation therapy, higher PS score, and prior exposure to both cisplatin and carboplatin. Patients with SCLC had a higher incidence of grade 3/4 thrombocytopenia during the first course than patients with ovarian cancer, perhaps reflecting differences in disease states or treatment histories. However, these correlations have not been examined prospectively in clinical trials. The overall incidences of grade 4 neutropenia and thrombocytopenia decreased in subsequent courses of therapy.
An apparent lack of cumulative toxicity with topotecan has been reported previously. Goldwasser et al. [17], in a study of 21 heavily pretreated patients with ovarian cancer, concluded that treatment with topotecan at a dose of 1.25 mg/m2 per day as a 30-minute i.v. infusion for 5 days every 3 weeks is feasible without prophylactic G-CSF support. In that study, the severity of topotecan-induced grade 4 thrombocytopenia was maximal (43% of patients) in the first course but decreased without dose reduction to 15% and 19% of patients in the second and third courses, respectively. Möbus et al. [18] conducted a retrospective study of long-term therapy with topotecan in 33 patients with recurrent ovarian cancer who received a total of 343 courses of topotecan, an average of more than 10 courses per patient. The incidences of hematologic toxicities in that study were as expected but, as with the current analysis, showed no evidence of being cumulative. The percentages of patients with blood transfusions and growth factor support did not vary over all courses of therapy. Möbus et al. [18] concluded that long-term therapy with topotecan is feasible and may be conducted without an apparently higher risk for cumulative hematologic toxicities.
Many of the agents used in the front-line and salvage treatment of patients with advanced ovarian cancer or SCLC are associated with cumulative and/or irreversible toxicities that pose challenges in long-term planning [19]. The irreversible effects associated with some of these therapies may render patients less tolerant of subsequent treatments and can lead to fewer treatment options with each remission and disease relapse. For example, in patients with recurrent ovarian cancer, cumulative renal tubule toxicity [20, 21] and neurotoxicity associated with cisplatin as first-line therapy may eliminate the option for retreatment with a platinum agent at relapse. Moreover, both cisplatin and carboplatin produce myelotoxicity that may be cumulative. Indeed, the current analysis identified that prior exposure to multiple platinum agents was associated with a significantly greater incidence of grade 3/4 thrombocytopenia during the first course of therapy. Furthermore, severe myelotoxicity and greater incidences of secondary myelodysplasia and leukemia are associated with prolonged and cumulative etoposide (Etopophos®, VePesid®; Bristol-Myers Squibb) treatment in patients with ovarian cancer [23]. Cumulative liposomal doxorubicin and paclitaxel exposure also lead to a greater risk for patient morbidity because of cardiotoxicity [24] and neuropathy [25], respectively. When selecting a chemotherapy regimen, the potential for patients to experience cumulative toxicities must be carefully considered.
In conclusion, the dose-limiting toxicity with topotecan in this integrated safety analysis was myelosuppression. However, hematologic adverse events were predictable and could be managed in most patients. Furthermore, the magnitude of reductions in neutrophils, RBCs, and platelets from baseline appeared to be greatest after the initial course of therapy and then began to lessen or stabilize over ensuing courses. Neutropenia was noncumulative. After the first or second course, the rate of neutropenia per course was relatively low and in line with other standard chemotherapy regimens used for the treatment of recurrent ovarian cancer and SCLC. In this analysis, there was no evidence to suggest that thrombocytopenia was cumulative with topotecan therapy. The risk for grade 3 or 4 anemia was higher during the first four courses of therapy and may need to be more aggressively managed with erythropoietin therapy. Dose reductions, dose delays, and RBC transfusions were the most common interventions for hematologic toxicity. The majority of grade 3 or 4 hematologic episodes occurred during the first or second course, likely because modest (to 1.25 mg/m2 or more) dose adjustments were sufficient in ensuring that subsequent courses of therapy were well tolerated. The generally manageable hematologic toxicity profile of topotecan suggests that topotecan may be safely administered for multiple courses or, potentially, until disease progression. These results suggest that topotecan may be safely administered to patients whose disease warrants extended therapy. These data are of particular importance to patients with stable disease and to other patients for whom extended therapy might be indicated.
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| This Article Has Been Cited by Other Articles Markman, Maurie. Topotecan as Second-Line Therapy for Ovarian Cancer: Dosage Versus Toxicity. The Oncologist 2005;10:695-697. Penson, Richard T., Seiden, Michael V. Topotecan: Weighing in When There Are Many Options. The Oncologist 2005;10:698-700.
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ACKNOWLEDGMENT |
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