- © 2001 by American Society of Clinical Oncology
Oral Topotecan as Single-Agent Second-Line Chemotherapy in Patients With Advanced Ovarian Cancer
- D. L. Clarke-Pearson,
- L. Van Le,
- T. Iveson,
- C. W. Whitney,
- P. Hanjani,
- G. Kristensen,
- J. H. Malfetano,
- R. A. Beckman,
- G. A. Ross,
- S. R. Lane,
- Mark H. DeWitte and
- S. Z. Fields
- From Duke University Medical Center, Durham, NC; University of North Carolina, Chapel Hill, NC; Medical Center of Delaware, Newark, DE; Abington Memorial Hospital, Abington; SmithKline Beecham Pharmaceuticals, Oaks, PA; Albany Medical College, Albany, NY; Norwegian Radium Hospital, Oslo, Norway; Royal South Hants Hospital, Southampton; and SmithKline Beecham Pharmaceuticals, Harlow, United Kingdom.
- Address reprint requests to Daniel L. Clarke-Pearson, MD, Department of Obstetrics & Gynecology #3079, Duke University Medical Center, Durham, NC 27710-0001; email: clark011{at}mc.duke.edu
Abstract
PURPOSE: To evaluate oral topotecan as single-agent, second-line therapy in patients with ovarian cancer previously treated with a platinum-based regimen.
PATIENTS AND METHODS: Patients (N = 116) received oral topotecan 2.3 mg/m2 daily for 5 days every 21 days. Eligibility criteria included histologic diagnosis of International Federation of Gynecology and Obstetrics stage III or IV epithelial ovarian cancer, bidimensionally measurable disease, prior platinum-containing chemotherapy, age ≥ 18 years, performance status ≤ 2, and life expectancy ≥ 12 weeks.
RESULTS: Overall response rate was 21.6% (25 of 116 patients). Median duration of response was 25.0 weeks; median time to response was 8.4 weeks. Median time to progression was 14.1 weeks; median survival was 62.2 weeks. Grade 4 neutropenia was experienced by 50.4% of patients in 13.4% of courses administered. Grade 4 thrombocytopenia was experienced by 22.1% of patients in 5.1% of courses. Grade 3 or 4 anemia was experienced by 29.2% of patients in 8.5% of courses. Most frequent nonhematologic toxicities were predominantly (> 90%) grade 1 or 2 and included nausea, alopecia, diarrhea, and vomiting.
CONCLUSION: Second-line oral topotecan administered at 2.3 mg/m2 for 5 days every 21 days demonstrated activity in patients with progressive or recurrent ovarian cancer after first-line platinum-based chemotherapy. This activity was comparable to that seen in previous studies with intravenous topotecan. Grade 4 neutropenia was less frequent with oral topotecan than previously reported for intravenous topotecan. Oral topotecan is an active, tolerable, and convenient formulation of an established agent for the second-line treatment of advanced epithelial ovarian cancer and may also facilitate exploring prolonged treatment schedules.
IN THE United States in 1999, 25,200 new cases of ovarian cancer will be diagnosed, and more than 14,500 patients will die of this disease.1 The high mortality is largely related to the absence of symptoms during early-stage disease, with approximately 70% of patients with epithelial cancer of the ovary diagnosed with stage III or IV disease at initial presentation.2 Therapy for advanced ovarian carcinoma (stages III and IV) is maximal surgical cytoreduction followed by systemic chemotherapy. Although ovarian carcinoma is one of the most sensitive cancers to chemotherapy, most individuals with advanced disease ultimately relapse. Given the poor long-term prognosis for patients with advanced ovarian cancer, new therapies are required in the second-line setting; because second line therapy is rarely curative, such agents should be well suited for palliation.
The standard first-line chemotherapy for advanced ovarian cancer now consists of a platinum agent and paclitaxel. In a randomized study comparing two first-line treatments of advanced ovarian cancer, 73% in the cisplatin/paclitaxel group responded to therapy, compared with 60% in the cisplatin/cyclophosphamide group (P = .01).3 Survival was significantly longer (P < .001) in the cisplatin/paclitaxel group (median, 38 v 24 months). The main toxicities caused by cisplatin/paclitaxel treatment were neutropenia, alopecia, emesis/nausea, and peripheral neurotoxicity.
Topotecan is an antitumor drug with topoisomerase I inhibitory activity. Phase I studies determined a maximum-tolerated dose of 1.5 mg/m2/d given as a 30-minute intravenous (IV) infusion on days 1 through 5 of a 21-day cycle.4 Phase II studies in refractory or relapsed ovarian cancers5-7 demonstrated activity that led to a phase III randomized comparison versus paclitaxel in this setting.8 This latter study demonstrated similar efficacy for topotecan and paclitaxel and led to marketing approval in the United States and Europe for topotecan in the treatment of metastatic carcinoma of the ovary after failure of initial or subsequent chemotherapy.
An oral formulation of topotecan has been developed; it offers a more convenient treatment option than IV topotecan on the schedule of five consecutive days every 21 days. The absolute bioavailability of oral topotecan is 42% (90% confidence interval [CI], 37% to 47%),9 and this is not affected by food9 or by the coadministration of an H2 antagonist.10 In a phase I study of 29 patients with solid tumors, the maximum-tolerated dose of oral topotecan on this schedule was determined to be 2.3 mg/m2/d, and the dose-limiting toxicity was granulocytopenia.11
We conducted a multicenter open-label noncomparative study in the United States and Western Europe to characterize the efficacy, safety, and tolerability of oral topotecan as a single-agent second-line therapy in patients with stage III or IV ovarian cancer who had not responded to or who had relapsed after platinum-based first-line chemotherapy regimens.
PATIENTS AND METHODS
Eligibility
Patients entering this study must have had progressive disease during or after one prior chemotherapy regimen containing a platinum compound. They were required to have at least one lesion that was bidimensionally measurable by computed tomography, magnetic resonance imaging, ultrasound, radiograph, or physical examination. Previously irradiated lesions were not allowed as indicator lesions; however, new lesions in the field of prior radiation therapy were allowed. Other inclusion criteria were at least 4 weeks since prior surgery, hormonal therapy, radiotherapy, or chemotherapy; age ≥ 18 years; life expectancy ≥ 12 weeks; an Eastern Cooperative Oncology Group performance status ≤ 2; adequate bone marrow function (WBC ≥ 3,500/mm3, neutrophils ≥ 1,500/mm3, and platelets ≥ 100,000/mm3); normal liver function (bilirubin ≤ 2.0 mg/dL); and normal renal function (creatinine ≤ 1.5 mg/dL or creatinine clearance > 60 mL/min). Patients who had received more than one previous chemotherapy regimen or any prior topotecan treatment were ineligible. Written informed consent was obtained from each patient before study entry. The study was conducted in accordance with Good Clinical Practices and the Declaration of Helsinki as amended in Hong Kong (1989). The protocol received written unconditional approval by the ethical review committee or institutional review board at each participating site.
Treatment Schedule and Duration
Topotecan was administered orally for 5 consecutive days every 21 days at a starting dose of 2.3 mg/m2/d. The next treatment course was given on schedule if there was no evidence of tumor progression and the following criteria were met: hemoglobin ≥ 9.0 g/dL (after transfusion if necessary), neutrophils ≥ 1,000/μL, and platelets ≥ 100,000/μL. Dose reduction for the following course, in 0.4-mg/m2/d decrements, was required if a patient had manifested any of the following: grade 4 neutropenia with fever or infection or lasting ≥ 7 days, grade 3 neutropenia lasting beyond day 21, grade 4 thrombocytopenia, or grade 3 or 4 nonhematologic toxicity other than alopecia, nausea, or vomiting. The minimum oral dose of topotecan allowed was 1.5 mg/m2/d; if there was more than a 2-week delay at this dose, the patient was withdrawn. Dose escalation for the next course, in 0.4-mg/m2/d increments, was recommended if a patient had no toxicity more than grade 2 during the previous course. The maximum oral dose of topotecan allowed was 3.1 mg/m2/d.
Patients continued with therapy until disease progression (PD). Patients with stable disease continued on therapy for at least four courses or until the investigator felt that it was in the patient’s best interest to discontinue treatment. Patients with a complete response (CR) or partial response (PR) by World Health Organization criteria12 were allowed to continue with treatment at the discretion of the investigator until disease progression. Follow-up data were obtained every 3 months from date of withdrawal to assess response duration and time to progression for patients who had not progressed before withdrawal, and survival for all patients.
Evaluation of Efficacy
The primary efficacy variables were response rate, duration of response, and time to progression. The secondary efficacy variables were time to response and survival. Standard response criteria were used, and all claimed radiologic responses were reviewed by an independent radiologist. Time to response and time to progression were measured in weeks from the first dose of oral topotecan to a documented response (CR or PR) or documented PD, respectively. Duration of response was measured from the time of initial documented response to the first evidence of DP. Survival was measured from the first dose of oral topotecan to death. All patients who were not evaluated fully for efficacy were considered to be nonresponders.
Safety Assessment
Complete blood cell counts with differentials and platelets were performed at least weekly. Blood chemistries and urinalyses were performed on day 15 of each 21-day treatment cycle. An ECG was performed at screening and at the end of treatment. Qualitative and quantitative hematologic and nonhematologic toxicities were assessed before each cycle according to the National Cancer Institute common toxicity criteria.13 The relationship of adverse events to topotecan treatment was judged by the investigator according to the following categories: not related, unlikely, suspected (reasonable probability), or probable.
The quantitative evaluation of hematologic toxicities included neutropenia, thrombocytopenia, leukopenia, and anemia. Each was expressed with respect to the nadir observed during each course of topotecan administration. Safety data were also tabulated for vital signs, ECG results, body weight changes, and nonhematologic laboratory assessments. All observed changes that were considered adverse experiences were included in the nonhematologic displays. All patients who received at least one dose of oral topotecan were evaluated for safety.
Statistical Analysis
The results of this noncomparative study are presented with descriptive statistics based on the intent-to-treat (ITT) population. The overall response rate (CR plus PR) and its 95% CI were calculated. Descriptive statistics were used to summarize response duration and patients’ baseline demographic and disease characteristics (age, International Federation of Gynecology and Obstetrics stage, histologic grade, and performance status). Traditional Kaplan-Meier survival methods were used to summarize the time-to-event variables of time to response, response duration, time to progression, and survival. Kaplan-Meier estimates were obtained for each of these end points and presented in life-table format with 4-week intervals. The Kaplan-Meier estimates also included the median, first and third quartiles, and number of censored observations. A plot of Kaplan-Meier estimates was made for each end point.
Separate univariate χ2 tests were performed to assess the association of demographic and disease baseline characteristics with the objective response to topotecan as second-line therapy. The potential predictors investigated were presence or absence of a taxane in first-line therapy, response to platinum in first-line therapy (sensitive, resistant, or refractory), age (grouped by < 41 years, 41 to 64 years, and ≥ 65 years), largest tumor diameter (grouped by < 5 cm, 5 to 10 cm, and > 10 cm), prior radiation, presence or absence of baseline renal impairment, presence or absence of ascites, and performance status (0, 1, or 2). The characteristics showing possible association on the basis of the strength of univariate analyses (P < .15) were included in a subsequent multivariate investigation with logistic regression modeling techniques to determine any significant statistical association with response to oral topotecan.
RESULTS
Patient Characteristics
A total of 116 patients were treated with oral topotecan. Patients were primarily white (n = 110; 94.8%). Mean weight was 66.5 kg (range, 43 to 107 kg), and mean body-surface area was 1.71 mg/m2 (range, 1.37 to 2.17 mg/m2). Additional demographic and disease characteristics at baseline for this ITT population are listed in Table 1. All 116 patients had been treated with a first-line regimen that included at least one platinum compound (Table 1). In addition to paclitaxel and cyclophosphamide, eight other chemotherapeutic agents (not listed in Table 1) had been used in first-line chemotherapy, but in fewer than 3% of patients. More than two thirds of the patients had responded to their first-line chemotherapy (81 of 116; 65.6% had CR or PR) but subsequently relapsed. At baseline, 51 of 116 (44.0%) of all patients were considered platinum sensitive, 30 (25.9%) of 116 were considered platinum resistant, and 35 (30.2%) of 116 were considered platinum refractory (Table 1). (Platinum refractory patients were defined as those who did not respond to their first-line platinum-based regimen; platinum-resistant and -sensitive patients responded to their first-line platinum-based regimen and relapsed at less than or greater than 6 months, respectively, from the completion of first-line therapy.)
Demographic and Disease Characteristics
Dose Delivery and Intensity
Of the 116 patients treated with oral topotecan, 12 patients (10.3%) were withdrawn because of adverse experiences (including intercurrent illness), and one patient each was withdrawn for protocol violation (0.9%) and loss to follow-up (0.9%). A total of 633 courses of oral topotecan were administered to the 116 patients comprising the ITT population. The median number of courses per patient was four, and the range was one to 25. The target dose of 2.3 mg/m2/d was attained in 354 (55.9%) of 633 courses. Beyond course 1, there were a total of 101 patients and 517 courses. Delays beyond day 21 were experienced by 81 patients (69.8%) and occurred in 237 (45.8%) of courses after course 1. The dose of oral topotecan was reduced in 43 patients (42.6%) in 56 courses (10.8%). The dose of oral topotecan was increased in 32 patients (31.7%) in 45 courses (8.7%). Exposure to study medication is listed in Table 2.
Exposure to Oral Topotecan
Efficacy
Response rate, duration of response, and time to response.
The overall confirmed response rate for patients treated with oral topotecan was 21.6% (25 of 116; estimated 95% CI, 14.1% to 29.0%). All claimed responses were confirmed by independent radiologic review. Of the 25 patients who responded to oral topotecan therapy, seven patients (6.0%) achieved a CR and 18 patients (15.5%) achieved a PR. Among the 91 nonresponders (78.4%), 29 patients (25.0%) had stable disease, 49 patients (42.2%) had PD, and 13 patients (11.2%) were nonassessable. Separate univariate χ2 tests were performed to assess the association of demographic and baseline characteristics with objective response. There were three characteristics that showed possible association on the basis of the strength of the univariate analyses: first-line taxane exposure (P = .07), sensitivity to previous therapy (P = .02), and performance status (P = .11). The subsequent multivariate investigation with logistic regression modeling techniques found that only one of these characteristics, sensitivity to previous therapy, retained a statistical association with the response seen on topotecan (P = .04). Patients who were sensitive to previous therapy were 4.19 times more likely to respond to oral topotecan than those who were refractory (P = .02), whereas resistant patients were 1.58 times more likely to respond to oral topotecan than were refractory patients (P = .56). Response to oral topotecan, classified by sensitivity to first-line therapy that included a platinum-containing compound, is listed in Table 3. Patients who had been refractory or resistant to prior platinum treatment had lower response rates (four of 35, 11.4%; and four of 30, 13.3%, respectively) to second-line oral topotecan treatment than patients who were sensitive to prior platinum treatment (17 of 51; 33.3%). Four of the seven complete responders (57.1%) were sensitive to their first-line platinum-containing chemotherapy, and three were refractory.
Best Response to Oral Topotecan Treatment (N = 116) Classified by Prior Platinum Sensitivity
The median duration of response in the 25 patients with a CR or PR was 25.0 weeks (range, 8.6 to 71.4 weeks; estimated 95% CI, 19.1 to 32.0 weeks). Median time to response was 8.4 weeks (range, 5.0 to 68.0 weeks; estimated 95% CI, 6.1 to 12.0 weeks).
Time to progression and survival.
The estimated median time to progression for all 116 patients was 14.1 weeks (range, 1.0 to 87 weeks; estimated 95% CI, 10.7 to 18.3 weeks; three patients censored; Fig 1). At the time of analysis, 50 of the 116 patients (43.1%) were alive. One patient had a missing date of death, so the value for survival was censored in 51 patients and observed in 65 patients. Median survival for all patients was 62.6 weeks (95% CI, 49.9 to 81.0 weeks), calculated by using the Kaplan-Meier estimation procedure (Fig 2). Time to death ranged from 1.0 to 106.3 weeks, with the latter estimate corresponding to a censored event.
Fig 1. A plot of Kaplan-Meier product limits for time to progression. At the time of this analysis, the values for only three of the 116 patients were censored.
Fig 2. A plot of Kaplan-Meier product limits for survival. At the time of this analysis, survival was censored in 51 patients and observed in 65 patients.
Safety
Hematologic toxicities.
Table 4 lists the frequency of patients and courses with hematologic toxicity; the percentages were tabulated by using 113 patients and 626 courses that had laboratory data available. Severe (grade 4) neutropenia was experienced by 50.4% of the patients and was associated with 13.4% of the courses administered. Severe leukopenia and thrombocytopenia were less frequent; grade 4 leukopenia and grade 4 thrombocytopenia were experienced by 15.9% and 22.1% of patients and associated with approximately 3.2% and 5.1% of courses, respectively. Grade 3 or 4 anemia occurred in 33 patients (29.2%) in 53 courses (8.5%). Analyses of neutrophil, platelet, and hemoglobin nadirs for each course of therapy showed no evidence of cumulative toxicity. The median neutrophil nadir was 1.2 × 109/L (range, 0.0 to 6.6), with median occurrence of nadir on day 15 (range, 3 to 31 days). The median time to onset of grade 4 neutropenia was 14 days (range, 7 to 22 days) with a median duration of 7 days (range, < 1 to 28 days). Grade 4 neutropenia lasted more than 7 days in 30.1% of courses. The highest incidence of grade 4 neutropenia, 37.2%, was during the first course; it decreased to 14.1%, 10.4%, and 7.5% during courses 2 through 4 and remained infrequent through subsequent courses. Prophylactic granulocyte colony-stimulating factor was used to maintain dose-intensity in 2.2% of courses, and treatment granulocyte colony-stimulating factor was given in 2.4% of courses.
Number (%) of Patients and Courses With Grade 3 or 4 Hematologic Toxicity
The incidence of grade 4 thrombocytopenia was highest (19.5% of patients) in course 1 and then remained ≤ 6.3% in subsequent courses. Platelet transfusions were required by nine patients (7.8%) in course 1, but thereafter by only one patient (one of 68; 1.5%) in course 4. RBC transfusions were given to 43.1% of patients in 16.3% of courses. The median time to onset of both severe thrombocytopenia (grade 4) and anemia (grade 3 or 4) was 15 days. The median durations of severe thrombocytopenia and anemia were 7 and 6 days, respectively.
It should be noted that dose reductions of 0.4 mg/m2/d were required for patients with grade 4 neutropenia associated with fever or infection or lasting ≥ 7 days, grade 3 neutropenia lasting beyond day 21 of the treatment course, and grade 4 thrombocytopenia. Per this requirement, 32 patients (31.7%) did have dose reductions in course 2 of treatment.
Infectious complications.
Suspected or documented infection occurred within 2 days of grade 4 neutropenia in 14 of 116 patients (12.1%) and 22 of 633 treatment courses (3.5%). An additional two patients (1.7%) and two courses (0.3%) were associated with sepsis, and one of these patients was withdrawn from the study. There were no deaths caused by sepsis.
Nonhematologic toxicities.
Nonhematologic adverse experiences were reported for 113 (97.4%) of 116 patients in 567 (89.6%) of 633 courses. The most frequently reported nonhematologic toxicities were nausea, alopecia, diarrhea, vomiting, and fatigue. Prophylactic antiemetics were not routinely administered in this study. The majority of nonhematologic adverse experiences reported were mild or moderate (grades 1 and 2). The nonhematologic adverse events that caused more than 1% of patients to be withdrawn were vomiting (five patients; 4.3%), nausea (three patients; 2.6%), and pulmonary embolism (two patients; 1.7%). No patients were withdrawn from the study because of the adverse experience of fatigue. The nonhematologic toxicities that were considered related or possibly related to topotecan treatment and were reported in more than 10% of patients are listed in Table 5.
Related or Possibly Related Nonhematologic Toxicities Occurring in More Than 10% of Topotecan-Treated Patients
Deaths.
Of the 116 patients who entered the study, 66 patients (56.9%) had died before the time of this analysis. Of these 66 deaths, 62 were attributed to PD, and all deaths were considered unrelated to topotecan treatment. Only three patients died within 30 days of their last dose of topotecan; two of these deaths were attributed to PD, and one was attributed to cardiopulmonary arrest secondary to a pulmonary embolism unrelated to topotecan therapy. Sixty-three patients (54.3%) died more than 30 days after therapy; 60 deaths were caused by PD, and three deaths were attributed to events not related to topotecan: probable cardiac arrhythmia, presumed suicide, and urosepsis.
Adverse Events Resulting in Withdrawal
Eleven (9.5%) of 116 patients treated with oral topotecan were withdrawn from the study because of one or more adverse events. Five of these 11 patients were withdrawn for serious adverse experiences: two experienced events considered probably related to topotecan (one hospitalized for grade 3 leukopenia and thrombocytopenia, and one for nausea, fatigue, and diarrhea presumed to be neutropenic sepsis).
DISCUSSION
The combination of a platinum analog with paclitaxel has become the standard first-line treatment for advanced ovarian cancer, with response rates of 60% to 80% reported. Although the majority of patients initially respond to chemotherapy, most eventually relapse and die because of DP.2
Because paclitaxel has become a standard component of first-line therapy for patients presenting with stage III or IV carcinoma of the ovary, there is a need for other agents to treat patients who are refractory to or relapse after initial chemotherapy. Agents with activity in second-line ovarian cancer include paclitaxel, oral etoposide, liposomal doxorubicin, and gemcitabine. Response rates have been in the range of 8% to 26%.14-18 Most of these reports are based on small phase II studies without independent verification of response or analysis of prognostic variables.
IV topotecan has demonstrated second-line efficacy comparable to paclitaxel for all categories of platinum sensitivity in a randomized, comparative trial.8 Analysis in this study was ITT and featured independent radiologic confirmation of all claimed responses. It has been estimated that requiring independent confirmation of response may eliminate up to one third of claimed responses.19 The response rate for the 112 patients taking topotecan was 20.5% as compared with 14.0% for the 114 patients taking paclitaxel (P = .138). When patients were stratified by prior platinum sensitivity, response rates for topotecan and paclitaxel were sensitive disease, 30.8% v 22.2%; resistant disease, 18.2% v 13.0%; and refractory disease, 8.8% v 3.0% for topotecan and paclitaxel, respectively. Median times to progression and survival for topotecan and paclitaxel were, respectively, 18.9 v 14.7 weeks (P = .07) and 63.0 v 53.0 weeks (P = .87).
An oral formulation of topotecan, which offers the patient a more convenient regimen than IV topotecan, has been developed. The present open-label phase II advanced ovarian cancer study examined the efficacy, safety, and tolerability of oral topotecan in patients who had relapsed after or were refractory to first-line chemotherapy that had included a platinum compound.
All claimed responses in this study were confirmed by independent radiologic review. By multivariate analysis, the only baseline demographic or disease characteristic that was predictive of second-line response to oral topotecan was sensitivity to first-line therapy. A relationship between responsiveness in first-line and second-line chemotherapy has been evident in many of the studies cited for IV topotecan.6-8
In this study, six responses to oral topotecan, including three CRs, were seen in patients who were refractory or resistant to a platinum/taxane combination. This suggests incomplete non–cross-resistance between oral topotecan and paclitaxel.
The observed response rate of 21.6% in this study is similar to that observed for IV topotecan in the three phase II studies that contributed to its registration in second-line ovarian cancer, which ranged from 13.3% to 16.3%.6,7,20 Moreover, this response rate is similar to that observed for IV topotecan in the randomized phase III comparison versus paclitaxel (20.5%).8 Patients in these prior studies did not have previous taxane therapy. The median times to progression, 14.1 weeks, and median survival, 62.6 weeks, observed in this study are also similar to those seen for IV topotecan in the studies cited above.
Preliminary results of several randomized comparisons between IV and oral topotecan are also consistent with the hypothesis that the overall activity is similar between the two formulations. IV and oral formulations of topotecan have been compared in a randomized phase III study in second-line ovarian cancer after platinum therapy.21 Final results showed a statistically nonsignificant numeric advantage in overall response rate for IV topotecan (M. Gore, manuscript in preparation). A randomized phase II comparison of IV and oral formulations of topotecan has been performed in second-line therapy of small-cell lung cancer.22 In this study (n = 106), oral topotecan demonstrated a numeric advantage compared with IV topotecan in all efficacy parameters (21.3% v 14.8% response rate; median time to progression, 14.9 v 13.1 weeks; median survival, 31.4 v 25.7 weeks). Whether the differences in outcome between these ovarian and small-cell studies are statistical fluctuations or reflect disease-specific properties of the two topotecan formulations is unclear.
As with IV topotecan, neutropenia is the dose-limiting toxicity of oral topotecan. However, the incidence of grade 4 neutropenia in this study, 50.4% of patients and 13.4% of courses, was lower than previously reported with IV topotecan: 79.3% of patients and 36% of courses in the randomized comparative study versus paclitaxel.8,23 This reduced incidence of grade 4 neutropenia is also consistent with the results of the randomized comparisons between formulations.21,22 Thus, in the preliminary report from the randomized phase III comparison in second-line ovarian patients, course incidence of grade 4 neutropenia was 19.6% of 144 courses for oral topotecan and 57.4% of 141 courses for IV topotecan. Similarly, in the randomized phase II comparison in small-cell lung cancer, the incidence of grade 4 neutropenia was again lower on the oral arm (12.8% of 206 courses) compared with the IV arm (34.0% of 210 courses). Grade 4 thrombocytopenia occurred in 22.1% of patients and 5.1% of courses, and grade 3 or 4 anemia occurred in 27.9% of patients and 8.5% of courses. These values approximate those observed for IV topotecan in the randomized phase III study versus paclitaxel.8,23
Thrombocytopenia becomes a colimiting toxicity when an attempt is made to further escalate oral topotecan dosing.11 The major differences in pharmacokinetic profile between the two formulations are a lower peak level and area under the curve with oral topotecan.9,24 The lower peak may explain the differential sparing of neutrophils by the oral formulation, in that a high peak level may be required to overcome the small molecule efflux pumps expressed on their surface.
In contrast to an ovarian cancer study of IV topotecan reported by McGuire et al,25 fatigue was not considered a major toxicity and caused no patients to be withdrawn. This may be caused in part by a smaller median number of courses per patient in this study compared with the median number of courses6 per patient in the study by McGuire et al.25
In two separate randomized phase III comparative studies of IV versus oral topotecan in ovarian cancer, the overall incidence of fatigue was similar between the two treatment arms. The overall incidence of fatigue in 131 patients treated with IV topotecan was 38.2%; the overall incidence of fatigue in 135 patients treated with oral topotecan was 37.0% (SmithKline Beecham, data on file).
In conclusion, we report that oral topotecan at a starting dose of 2.3 mg/m2 given daily for 5 days every 21 days demonstrated comparable activity to that previously observed for IV topotecan in patients with progressive or recurrent ovarian cancer. An independently confirmed response rate of 21.6% was achieved. Grade 4 neutropenia occurred less frequently than is often seen with the IV formulation. Other hematologic and nonhematologic toxicities were similar to historical experience with IV topotecan. The oral formulation is convenient and is facilitating the ongoing investigation of more prolonged administration schedules. Further study of oral topotecan as a single agent, in combination, or as a radiosensitizer is warranted.
Acknowledgments
Supported by grants from SmithKline Beecham Pharmaceuticals.
ACKNOWLEDGMENT
We thank Linda H. Schneider, PhD, and Earl L. Jenkins for their contributions with manuscript preparation.
Footnotes
-
G.A.R., S.R.L., and M.H.D. are employees of SmithKline Beecham Pharmaceuticals. R.A.B. and S.Z.F. were employees of SmithKline Beecham Pharmaceuticals.
- Received May 8, 2000.
- Accepted February 9, 2001.
