Johns Hopkins Medical Institutions, Baltimore, Maryland, USA

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1 The Oncologist Topotecan Dosing Guidelines in Ovarian Cancer: Reduction and Management of Hematologic Toxicity DEBORAH K. ARMSTRONG Johns Hopkins Medical Institutions, Baltimore, Maryland, USA Key Words. Bone marrow/drug effects Drug toxicity Ovarian neoplasms Topotecan LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. Describe the hematologic safety profile of topotecan in patients with relapsed ovarian cancer. 2. List the risk factors for increased hematologic toxicity after topotecan therapy. 3. Discuss topotecan dose determination and the management of hematologic toxicity in higher-risk ovarian cancer patients. CME Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com ABSTRACT Topotecan dosing considerations and alternative dosing schedules to reduce and manage myelosuppression during the treatment of relapsed ovarian cancer were reviewed. The myelosuppression patterns from phase I, II, and III clinical trials were analyzed to evaluate the degree of hematologic toxicity and to determine risk factors predictive of myelosuppression. Additionally, recent publications of alternative topotecan doses and schedules were examined. Extent of prior therapy, prior platinum therapy (particularly carboplatin), advanced age, impaired renal function, and prior radiation therapy were identified as potential risk factors for greater hematologic toxicity after topotecan therapy. Reducing the starting topotecan dose to 1.0 or 1.25 mg/m 2 /day is recommended to reduce the incidence of severe myelosuppression in high-risk individuals receiving topotecan for 5 consecutive days. Hematopoietic growth factors, transfusion therapy, and schedule adjustments may also help manage myelosuppression. Alternative schedules of 3-day or weekly dosing appear to have less myelotoxicity and are currently under evaluation. The clinical aspects of topotecan-related myelosuppression and results from clinical trials indicate that the dose, and possibly the dosing schedule, of topotecan can be modified to reduce hematologic toxicity and improve tolerance without compromising efficacy. Prospective individualization of topotecan dosing may prevent or minimize dose-limiting myelosuppression and allow patients to achieve the maximum topotecan benefit by improving their ability to complete therapy with fewer treatment delays. Ongoing clinical trials evaluating alternative dosing schedules with superior hematologic tolerability may facilitate the inclusion of topotecan in combination regimens for patients with ovarian cancer. Proposed topotecan dosing guidelines to reduce and manage myelosuppression are outlined. The Oncologist 2004;9:33-42 INTRODUCTION Topotecan (Hycamtin ; GlaxoSmithKline, Philadelphia, PA; is a water-soluble, semisynthetic analogue of camptothecin that inhibits the nuclear enzyme topoisomerase I [1, 2]. Topotecan has been approved by the U.S. Food and Drug Administration (FDA) for the treatment 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: ; Fax: ; darmstro@jhmi.edu Received June 11, 2003; accepted for publication November 12, AlphaMed Press /2004/$12.00/0 The Oncologist 2004;9:

2 34 Topotecan Dosing Guidelines of recurrent epithelial ovarian cancer [3] and relapsed small cell lung cancer [4], and has also demonstrated activity in hematologic malignancies [5-7] and solid tumors including non-small cell lung [8, 9], cervical [10-12], and colon cancers [13]. In ovarian cancer, topotecan has demonstrated activity in both platinum- and paclitaxel-resistant tumors, with response rates ranging from 12%-33% [14-19]. In a randomized, phase III study, ovarian cancer patients showed similar response rates with topotecan (21%; n = 112) and paclitaxel (13%; n = 114; p = 0.138) [20, 21]. Approximately half of all patients in both arms of the study had progressed on a platinum-based regimen or had relapsed within 6 months of completing first-line therapy. Topotecan produced responses in 8 of 61 (13%) patients in whom paclitaxel had failed to produce a response. Similarly, paclitaxel produced responses in 5 of 49 (10%) patients in whom topotecan had failed to produce a response [21]. That phase III study, and earlier phase II studies, established topotecan as an important treatment option for patients with either platinum-sensitive or platinumrefractory relapsed ovarian cancer. Toxicities associated with topotecan are more predictable and manageable than those associated with its parent compound (camptothecin) and other chemotherapeutic agents (e.g., carboplatin) used to treat patients with ovarian cancer. Nevertheless, noncumulative reversible myelosuppression is the primary dose-limiting toxicity with topotecan treatment. The FDA-recommended dose of topotecan in recurrent ovarian cancer is 1.5 mg/m 2 by i.v. infusion over 30 minutes on days 1-5 of a 21-day course. Although this dose and schedule of topotecan remain the standard therapy for recurrent ovarian cancer, they are associated with a high incidence of grade 3 or 4 myelosuppression [16, 19]. As a consequence, multiple dose and schedule variations have been evaluated in phase I and II trials [19, 22-31]. Guidelines for managing topotecan-related hematologic toxicities have been published previously and included specific recommendations for dose reductions and the use of hematopoietic growth factors [32, 33]. However, since the publication of those guidelines, the research focus has shifted from treating myelosuppression to preventing myelosuppression through a careful determination of the appropriate initial topotecan dose and administration schedule. HEMATOLOGIC TOXICITY IN TOPOTECAN CLINICAL TRIALS In phase I trials, 3%-25% of the patients treated with the FDA-recommended topotecan dose and schedule developed grade 4 neutropenia or leukopenia [34-36]. Even with doses as high as 2.5 mg/m 2, neutropenia remained the predominant toxicity, whereas thrombocytopenia occurred infrequently and was modest in severity [34]. Patients enrolled in those studies had a number of different diseases and variable treatment histories, and many had been extensively pretreated. However, at the time the phase I trials were conducted, carboplatin, which has a long-term effect on bone marrow reserves, was not widely available. Because most ovarian cancer patients now receive carboplatin as part of their frontline therapy, the risk of myelosuppression associated with topotecan for these patients may be different now than it was for patients treated in the phase I and early phase II studies. In subsequent phase II [16, 17] and III [20] studies of topotecan in patients with ovarian cancer, the incidence of grade 4 neutropenia was higher (81%) than it was in the phase I studies (3%-25%) [33]. Grade 4 thrombocytopenia, which was nearly absent in the phase I studies, occurred in 26% of the 452 patients enrolled in the phase II and III trials. Anemia (hemoglobin level < 8 g/dl) was reported in 40% of patients. In a randomized, phase III study comparing topotecan with paclitaxel in patients with relapsed ovarian cancer, neutropenia and thrombocytopenia were more common in the topotecan arm than in the paclitaxel arm (Table 1) [20]. However, myelosuppression was transient and noncumulative for both treatments, as indicated by the lack of progressively lower hematologic nadirs during successive therapy. During that study, hematologic toxicities were managed with dose reductions and the use of G-CSF. Therefore, although the hematologic toxicities were higher in the topotecan arm, the investigators noted that the myelosuppression was predictable, noncumulative, and manageable. Nonhematologic toxicities were generally mild (grade 1 or 2) on topotecan therapy and did not require pretreatment with corticosteroids or antihistamines, as was the case for paclitaxel. In a recent phase III study comparing topotecan with liposomal doxorubicin, 77% of patients treated with topotecan, 1.5 mg/m 2 /day on days 1-5 of a 21-day course, developed grade 3 or 4 neutropenia, 5% developed sepsis or neutropenic fever, and 34%, 28%, and 50% developed grade 3/4 thrombocytopenia, anemia, and leukopenia, respectively Table 1. Hematologic toxicity of topotecan and paclitaxel in a randomized, phase III comparison Grade 4 Topotecan Paclitaxel toxicity 1.5 mg/m 2 /day a (%) 175 mg/m 2 /day a (%) Leukopenia 34 3 Neutropenia Thrombocytopenia 25 2 Anemia 4 3 a Starting dose. Subsequent doses were reduced based on toxicity. The minimum dose for topotecan was 1.0 mg/m 2 /day. Topotecan dose could be escalated to 2.0 mg/m 2 /day. The minimum dose of paclitaxel was 135 mg/m 2. Data from ten Bokkel Huinink et al. [20].

3 Armstrong 35 [37]. Toxicities were managed by treatment delays, dose reductions, and the administration of G-CSF and/or GM-CSF. Further, topotecan had a significantly better nonhematologic toxicity profile than liposomal doxorubicin. Although topotecan remains a standard therapy for relapsed ovarian carcinoma, it is recognized that a thorough evaluation of each patient s risk for developing myelosuppression should be made, and that dose reductions or treatment schedule adjustments should be considered prospectively for many patients. RISK FACTORS FOR DEVELOPING HEMATOLOGIC TOXICITY The following five factors have been identified as important considerations when determining a patient s risk of developing a hematologic toxicity: extent of prior treatment, prior platinum therapy, greater age, impaired renal function (reduced creatinine clearance), and prior radiation therapy. Specific dosing recommendations for patients identified as high risk for myelosuppression are outlined below. Extent of Prior Treatment Of particular importance in determining a patient s risk of developing topotecan-related myelosuppression is the number of prior myelosuppressive therapies [33]. Phase II trials of topotecan in ovarian cancer patients revealed that heavily pretreated patients appeared to have the highest risk for developing myelosuppression (Fig. 1) [17, 33, 38, 39]. Of those three trials, the highest incidences of neutropenia, thrombocytopenia, 20 neutropenic fever, and treat- 0 ment delays or dose reductions were reported by Kudelka et al. in the study with the most heavily pretreated patient population [17]. Prior Platinum Therapy Most ovarian cancer patients have received agents that can have cumulative myelotoxic effects, Figure 1. The effect on myelosuppressive events of the extent of prior therapy. Data for this figure were obtained from O Reilly et al. [38], Creemers et al. [39], and Kudelka et al. [17]. Reproduced with permission from Armstrong et al. [33]. Patients (%) Patients (%) Grade 4 neutropenia including platinum analogues (carboplatin or cisplatin) and/or alkylating agents (cyclophosphamide or ifosfamide). Prior carboplatin therapy is associated with myelosuppression, particularly thrombocytopenia, during second-line or salvage therapy with topotecan [40-42]. Recognizing this, Cass et al. [40] recommended that the starting topotecan dose be reduced to 1.0 mg/m 2 for heavily pretreated patients with ovarian cancer. Heavily pretreated patients are defined as those patients who have received large-field radiation to bone marrow, six or more courses of chemotherapy containing platinum or an alkylating agent, or at least two courses of nitrosourea or mitomycin [32]. Therefore, the number of prior therapies is an important factor when determining topotecan dose and schedule. Furthermore, it is beneficial to consider the timing of topotecan and carboplatin if both are to be used in the treatment of recurrent disease. In some instances, it may be beneficial to use topotecan before retreatment with carboplatin therapy. Topotecan-induced myelosuppression is not cumulative and is less likely to affect subsequent carboplatin-related myelosuppression, whereas more extensive prior carboplatin therapy clearly influences topotecan-induced myelosuppression n of regimens Febrile neutropenia n of regimens Patients (%) Patients (%) Grade 3/4 platelets n of regimens Platelet transfusions n of regimens

4 36 Topotecan Dosing Guidelines In a phase I study, Rowinsky et al. [43] reported significantly worse neutropenia and thrombocytopenia when cisplatin was administered before topotecan in a combination regimen, rather than topotecan before cisplatin. This greater myelosuppression was thought to be the result, in part, of acute, subclinical, cisplatin-induced nephrotoxicity and its resultant lower topotecan clearance. The chronic, long-term, cisplatin-related nephrotoxicity that persists after cisplatin treatment also affects subsequent tolerance to topotecan, possibly by the same mechanism. Further clinical investigations are clearly necessary to determine the appropriate sequencing of topotecan and platinum-based therapies in a disease in which salvage treatment is rarely curative and emphasis is placed on symptom palliation, long-term treatment tolerance, and quality of life. Age Advanced age is a recognized risk factor for the development of chemotherapy-related myelosuppression, presumably because of the progressive deterioration of renal function with aging and the natural reduction in cellular reserves in the bone marrow [44]. For this reason, age is an important determinant of renal function and may be a surrogate measure for the progressive loss of glomerular function. Therefore, patient age is an important consideration when determining the dose and schedule for topotecan therapy. Renal Function (Creatinine Clearance) Because topotecan is eliminated from the body mostly via renal and hepatic routes, reduced topotecan clearance as a result of renal or hepatic impairment could increase a patient s drug exposure and drug-related toxicities. Therefore, the pharmacokinetics and tolerability of topotecan have been investigated in patients with renal and hepatic impairment [32, 45]. Patients with hepatic impairment were able to tolerate the FDA-recommended dose provided they had normal renal function [45]. However, for patients with elevated bilirubin levels, performance status, age, and comorbidities must be considered when determining the appropriate initial topotecan dose. In a phase I pharmacologic study of topotecan in patients with mild renal impairment, O Reilly et al. [32] noted that dose-limiting events were predominantly experienced by patients who were extensively pretreated or had evidence of extensive bony metastatic disease. Similarly, in patients with moderate renal impairment, the extent of prior chemotherapy correlated with a higher incidence of doselimiting toxicity. The authors of that study noted the importance of using creatinine clearance (estimated by the Jelliffe [46] or Cockcroft and Gault [47] methods) rather than serum creatinine levels [48] to assess renal function. Some patients with mild to moderate renal impairment exhibit normal serum creatinine levels and would, therefore, be improperly dosed if renal function was determined solely by serum creatinine levels. Radiation Therapy Although not extensively used in the treatment of patients with ovarian cancer, wide-field radiation therapy, including whole-pelvis irradiation, depletes bone marrow reserves and also predisposes patients to hematologic toxicities. Therefore, as with previous platinum therapy, previous radiation therapy should be factored into the dose determination for topotecan. DOSE DETERMINATION AND MANAGEMENT OF HEMATOLOGIC TOXICITIES Proposed dosing guidelines for topotecan are summarized in Table 2 and Table 3 [48]. Currently, there is no precise algorithm for determining the starting topotecan dose, and clinicians are encouraged to use their own judgment in determining the most appropriate starting dose. Therefore, these guidelines should be considered as a supplement to the information contained in the package insert. Table 2. Topotecan dosing guidelines according to myelosuppression risk factors Risk factor Initial topotecan dose None mg/m 2 on days 1-5 of a 21-day course if patient is not heavily pretreated and has good performance status Extensive prior treatment 1.25 mg/m 2 on days 1-5 of a 21-day course; prophylactic dose reduction to 1.0 mg/m 2 may be necessary for patients who have additional risk factors Prior platinum therapy 1.25 mg/m 2 on days 1-5 of a 21-day course; prophylactic dose reduction to 1.0 mg/m 2 may be necessary for patients who have additional risk factors Advanced age mg/m 2 on days 1-5 of a 21-day course Renal function impairment See Table 3 Radiation therapy mg/m 2 on days 1-5 of a 21-day course

5 Armstrong 37 Table 3. Topotecan dosing recommendations for patients with renal impairment and prior myelosuppressive therapy a Recommended topotecan dose per course (every 21 days) based on extent of prior myelosuppressive therapy (mg/m 2 /day 5 days) Creatinine clearance (ml/minute) Minimal Extensive b <20 NE NE Abbreviation: NE = not established. a Based on actual creatinine clearance instead of serum creatinine as a marker of renal function. b Extensive prior therapy is defined as 6 courses of prior platinum. Adapted with permission from O Reilly et al. [48]. Dose Reductions Prophylactic topotecan dose reductions may be appropriate to prevent hematologic toxicities in some patients. To minimize hematologic toxicity, it is recommended that most patients be initiated on a topotecan dose of 1.25 mg/m 2. Dose escalation (up to 1.5 mg/m 2 ) or reduction, based on hematologic toxicity, should then be performed for subsequent courses to minimize myelosuppression and ensure that each patient is treated with the maximally tolerated dose, as the effects of dose intensity on the antitumor efficacy of topotecan have not been thoroughly investigated [33]. Dosing guidelines according to hematologic toxicity risk factors are outlined in Table 2. For patients with mild to moderate renal function impairment who have been extensively pretreated, further dose reductions may be required. Extensively pretreated patients include those who have received large-field radiation to bone marrow and those who have received six or more courses of chemotherapy containing a platinum or alkylating agent or at least two courses of nitrosourea or mitomycin [32]. The previously published dosing recommendations based on creatinine clearance (ml/minute) and the extent of prior myelosuppressive therapies have been updated (Table 3) [48]. To date, studies have not examined a sufficient number of patients with severe renal impairment to define a recommended dose in that patient population. Because of interpatient variability in topotecan clearance, further dose reductions may be required for subsequent courses. However, the guidelines summarized above should provide sufficient information to individually tailor the starting topotecan dose. Prospective studies have evaluated the potential role of lower-dose topotecan ( mg/m 2 daily on days 1-5 of a 21-day course) in patients with heavily pretreated platinum- and paclitaxel-resistant or refractory ovarian cancer [18, 49-52]. The individual response rates for those studies are summarized in Table 4 [18, 49-52]. Among the 151 evaluable patients in five studies with platinum/paclitaxelresistant patients, 7%-22% achieved a response lasting from 3-10 months; stable disease (SD) was observed in 18%-60% of evaluable patients. Although a direct comparison with the FDA-recommended dosing regimen is not available, lower-dose topotecan appeared to be active and resulted in lower incidences of grade 4 neutropenia and thrombocytopenia. However, randomized studies are required before conclusions can be made regarding the comparative efficacies and safety profiles of the lower-dose regimens and the full-dose regimen. Dose reductions may also be used to manage myelosuppression that develops after the first and/or subsequent courses. In patients who develop grade 4 neutropenia, thrombocytopenia, or anemia lasting more than 3 days, the dose of topotecan should be reduced in decrements of 0.25 mg/m 2 for each subsequent course until a dose with acceptable hematologic toxicity is established [33]. Treatment delays of up to 7 days may be appropriate for patients who have incomplete hematologic recovery by day 21. Table 4. Response rates and hematologic toxicities after lower-dose topotecan therapy in heavily pretreated patients with platinum/paclitaxel-refractory ovarian cancer Topotecan Patients ORR Neutropenic Grade 4 (%) Study dose (mg/m 2 ) (n evaluable) (%) fever (%) Neutropenia Thrombocytopenia Rodriguez and Rose, 2001 [49] (36) Swisher et al., 1997 [18] (28) Aravantinos et al., 1998 [50] (17) 18 NR 36 a 50 a Nielsen et al., 2000 [51] (27) Gronlund et al., 2002 [52] (43) 12 2 NR NR Abbreviations: ORR = overall response rate; NR = not reported. a Grade not specified.

6 38 Topotecan Dosing Guidelines In addition to dose reductions and delays, alternative dosing schedules may be considered. Alternative dosing regimens are currently under investigation and, when fully evaluated, may be appropriate for preventing dose-limiting myelosuppression in high-risk patients. Hematopoietic Growth Factors Hematologic toxicities are common with the FDAapproved topotecan dose and schedule. Individualized topotecan dosing based on hematologic risk factors may decrease the incidence of hematologic toxicity and concomitantly reduce the need for growth factors and/or transfusion therapy. Growth factors such as G-CSF and GM-CSF can be used to manage neutropenia and prevent neutropenic fevers and infections. In the 452 patients enrolled in the ovarian cancer trials, the incidence of neutropenic fevers or infectious complications was approximately 26% [17, 20, 33, 39, 53]. In the phase III comparison of topotecan with paclitaxel, the incidence of neutropenic fevers was highest after the first topotecan dose because dose reductions and G-CSF were used for the subsequent treatment courses [20]. The incidence of neutropenic fevers by course was not reported in the more recent phase III trial [37]. Growth factors can be used in conjunction with the FDA-recommended dose to prevent the need for dose reductions and, therefore, may help to optimize the efficacy of the topotecan regimen. In high-risk patients, particularly in patients with multiple risk factors, prophylactic G-CSF treatment beginning on day 6 of each course is recommended [33]. As an alternative to dose reduction, G-CSF may be administered beginning on day 6 of subsequent courses. Grade 4 thrombocytopenia has occurred in approximately 26% of patients receiving topotecan at the FDA-recommended dose [17, 20, 33, 39, 53]. Notably, topotecan-induced thrombocytopenia is noncumulative and significantly decreases in severity after the first treatment course without dose reduction (Fig. 2) [54]. In the absence of a reliable platelet growth factor, the initial topotecan dose should be reduced for patients identified to be at high risk for developing severe thrombocytopenia (Table 3) [48]. Although the incidences of grade 4 anemia in phase II and III topotecan trials in ovarian cancer patients were typically lower than those of grade 4 neutropenia or thrombocytopenia, red blood cell transfusions were administered to 56% of patients and after 23% of therapeutic courses [17, 20, 33, 39, 53]. As with any myelosuppressive regimen, prophylactic erythropoietin treatment and/or dose reductions should be considered to prevent severe anemia and the accompanying fatigue and weakness. Transfusion Therapy Although dose reductions and growth factors should remain the primary management techniques, transfusion therapy should be considered for patients with severe or complicated thrombocytopenia or anemia. Patient symptomatology (i.e., bruising, hematuria, severe fatigue, and hypotension), vascular status, and absolute platelet or red blood cell counts should be considered when determining whether a transfusion is required [33]. In addition, transfusion therapy should be considered for patients who have not recovered from blood loss related to prior surgery. ALTERNATIVE DOSING SCHEDULES When using the FDA-recommended treatment schedule, a prospective determination of the appropriate topotecan dose should be made for each patient based on the criteria noted in Table 2 and Table 3 [48]. As an alternate to dose reduction, alternative treatment schedules may be considered to reduce the incidence of myelosuppression. These regimens are still investigational in nature. Several small clinical trials have evaluated alternative topotecan doses and administration schedules in an effort to identify efficacious treatment regimens that reduce myelosuppression. These alternative dosing schedules may increase the flexibility of combining topotecan with other chemotherapeutic agents to further improve efficacy. Three-Day Topotecan Treatment Schedule Several studies have evaluated topotecan administered on a 3-day schedule. In a phase II study, Markman et al. [23] administered topotecan at doses of 1.5 mg/m 2 /day on days 1-3 of a 21-day course to 29 heavily pretreated Patients (%) Cycle number Figure 2. The percentage of patients experiencing grade 4 thrombocytopenia per topotecan course. Each course consisted of 1.25 mg/m 2 /day topotecan for 5 days every 3 weeks. No dose reductions were performed and no G-CSF was administered. Data from Goldwasser et al. [54]. 5 6

7 Armstrong 39 patients with platinum- and paclitaxel-refractory ovarian cancer. Two (7%) patients exhibited clinical responses to treatment, and six (21%) patients achieved SD for >4 months. Grade 4 neutropenia occurred in 24% of treated patients and neutropenic fever occurred in 10%; no patient experienced grade 4 thrombocytopenia. The 3-day topotecan regimen appeared less toxic than the standard 5-day regimen. However, further study in a less heavily pretreated patient population was recommended before the efficacy could be compared with the 5-day regimen. In an open-label, multicenter phase II trial with platinumsensitive ovarian or primary peritoneal cancer patients, topotecan, 1.0 to 2.0 mg/m 2 /day, was administered on days 1-3 of a 21-day course [27]. Of the 30 patients enrolled, all but one had received prior chemotherapy. Grade 3 and 4 neutropenia were experienced by 30% and 60% of patients, respectively. No patients experienced grade 4 leukopenia, and grade 4 thrombocytopenia was reported in only 3% of the patients. Grade 3 leukopenia was reported in 33% of patients. Of the 29 evaluable patients, 14% experienced an objective response and an additional 55% achieved SD. In a dose-escalating study by Brown et al. [55], the 3-day regimen was also well-tolerated in patients with recurrent epithelial ovary, tubal, or peritoneal carcinoma treated with two or more prior regimens. The maximum tolerated dose was determined to be 3.75 mg/m 2. Seventeen of 20 (85%) patients experienced grade 4 neutropenia after the first course; however, the use of G-CSF (5 µg/kg) prevented the development of dose-limiting neutropenia. Two of seven patients with measurable disease exhibited SD, and three of six patients achieved decreases in their serum cancer antigen 125 (CA-125) levels. In a subsequent study, Brown et al. [26] treated 31 patients who had recurrent ovarian cancer with topotecan at doses of 2 mg/m 2 on days 1-3 of a 21-day course. Grade 3 or 4 neutropenia was reported in 29% and 24% of courses, respectively. However, only 3% of courses required G-CSF support. Grade 4 thrombocytopenia was rare, occurring in only 1% of courses. Of the 28 evaluable patients, 32% experienced objective responses including three complete responses and six partial responses (PRs). The authors of that study concluded that the 3-day topotecan regimen was effective and well tolerated in this patient population and could be delivered on schedule without routine G-CSF support. In another phase II trial, platinum-sensitive patients with relapsed ovarian cancer were treated with topotecan at doses of 2.0 mg/m 2 /day on days 1-3 of a 21-day course [28]. Grade 3/4 neutropenia and leukopenia were reported in 53% and 20% of the 156 administered courses, respectively. As with the other 3-day studies, severe thrombocytopenia was rare; only 2% of the courses were associated with grade 3 or 4 thrombocytopenia. Of the 26 evaluable patients, 23% achieved responses. SD was achieved in an additional 50% of the evaluable patients. The 3-day treatment regimen may be more convenient than the 5-day regimen and may cause less myelosuppression than the standard regimen. Further clinical investigations of the 3-day topotecan regimen and of a 24-hour continuous infusion regimen in patients with recurrent platinum-sensitive ovarian cancer are under way (e.g., Gynecologic Oncology Group [GOG]-0146K and GOG-0146F, respectively). The results of these ongoing trials will provide important insights into the relative efficacies and tolerabilities of these alternate treatment regimens and the standard 5-day regimen. However, a randomized comparison of these regimens is required. Weekly Topotecan Therapy Because a weekly regimen would further enhance patient convenience and would facilitate combination with therapies that are commonly administered on a weekly schedule, there is heightened interest in developing a weekly topotecan treatment regimen. Several phase I and II trials of weekly topotecan have been performed in ovarian cancer patients [19, 24, 29, 30, 56]. In those trials, topotecan was administered as a weekly continuous i.v. or bolus infusion. A summary of the tolerability and antitumor activity of weekly topotecan clinical trials in ovarian cancer patients is presented in Table 5 [19, 24, 29, 57]. Two clinical trials of continuous i.v. topotecan have been performed in patients with recurrent ovarian cancer. In a randomized, phase II trial (n = 68) comparing weekly 24-hour continuous i.v. topotecan at a dose of 1.75 mg/m 2 /week for 4 weeks with 5-day topotecan (1.5 mg/m 2 ), the weekly dosing arm was associated with less toxicity than the 5-day regimen [19]. The 5-day dosing regimen was associated with a higher response rate (23%) than the weekly regimen (3%, p = 0.026). However, 44% of patients receiving weekly topotecan achieved SD compared with 29% of patients receiving the 5-day topotecan regimen. The authors of that study suggested that responses may have been suboptimal due to an inadequate topotecan dose rather than an ineffective schedule. The second phase II trial investigating continuous i.v. topotecan was also in patients with platinum- and paclitaxel-resistant ovarian cancer [24]. In that study, 2 of 23 (9%) patients treated with topotecan achieved PRs of 2 and 3 months duration, and six (26%) patients achieved SD. Weekly bolus infusion of topotecan was investigated in two phase I clinical trials. In the second- or third-line treatment of patients with epithelial ovarian cancer, topotecan was initiated at a dose of 1.5 mg/m 2 weekly and was escalated by 0.5-mg/m 2 increments every 21 days [29]. The

8 40 Topotecan Dosing Guidelines Table 5. Hematologic toxicities after weekly topotecan therapy for heavily pretreated patients with ovarian cancer Topotecan Evaluable patients Grade 3 or 4 Grade 4 Grade 4 Study dose (mg/m 2 ) (efficacy/safety) neutropenic fever (%) neutropenia (%) thrombocytopenia (%) Hoskins et al., 1998 [19] 1.75 (24-hour 32/ continuous i.v. infusion) Rose et al., 2000 [24] 2.0 (72-hour 23/23 NR 0 0 continuous i.v. infusion) Homesley et al., 2001 [29] /32 NR 3 0 <2.0 (i.v. bolus) >5.0 7 Morris and Munkarah, 2002 [57] 4.0 (i.v. bolus) 17/21 NR 5 0 Abbreviation: NR = not reported. maximum tolerated dose was 6 mg/m 2, and the maximum recommended dose for further study was 4 mg/m 2 /week. At topotecan doses of 2 mg/m 2 /week, 4 of the 32 (13%) evaluable patients achieved PRs and six (19%) achieved SD. In a second trial conducted in patients with a variety of tumor types, weekly topotecan at doses of mg/m 2 was administered as 30-minute bolus infusions [56]. One patient achieved a minor response, and there were no dose-limiting toxicities. Morris et al. [30] and Morris and Munkarah [57] are investigating weekly topotecan in patients with platinumsensitive relapsed ovarian cancer in their ongoing openlabel, multicenter, phase II study. Patients with measurable disease are being treated with weekly topotecan at doses of 4.0 mg/m 2, with dose reductions by 0.5-mg/m 2 increments to 2.5 mg/m 2 /week if patients experience uncomplicated grade 3 or 4 hematologic or nonhematologic toxicity. In a recent update based on 21 enrolled patients, 7 of 17 (41%) evaluable patients had achieved PRs, with a median time to progression of 20.6 weeks [57]. An additional six (35%) patients had achieved SD. All 21 patients enrolled in the trial were assessable for toxicity. Of the 293 planned treatments, 89% were administered on time. Grade 4 neutropenia was reported in only one patient, and no other grade 4 toxicities were reported. In summary, although further studies are required to fully evaluate the efficacy and safety of the alternative topotecan dosing schedules, results from early studies suggest that lower-dose, 3-day infusion, and weekly infusion schedules warrant further investigation. Future investigations of weekly topotecan regimens should examine the effect of disease stabilization on patient quality of life and duration of survival, which are particularly important in patients with recurrent ovarian cancer because many of them will receive long-term treatment. Furthermore, the study of alternative dosing regimens may identify the optimal doses and schedules for topotecan treatment of patients with small cell lung cancer and ovarian cancer. It is hoped that these alternative dosing regimens will provide equivalent efficacy, facilitate combination with other therapeutic regimens, and provide greater patient and caregiver convenience. DISCUSSION Topotecan is an established, effective therapeutic option for patients with ovarian cancer who have relapsed after platinum therapy. Clinical evidence, however, indicates that the FDA-approved topotecan dose of 1.50 mg/m 2 i.v. for 5 consecutive days results in a higher incidence of grade 3 or 4 myelosuppression in ovarian cancer patients than would be predicted from phase I studies. The differences between the observed and the expected myelosuppression rates may be explained, in part, by the increasing use of carboplatin for the treatment of ovarian cancer over the past decade and the long-term effects of carboplatin on the bone marrow. Recognition of this and other risk factors for topotecan-associated myeloid toxicities may allow dose and/or schedule modifications that can prevent or minimize these toxicities. Five risk factors predictive of topotecan-associated myelosuppression have been identified. Two of these factors, renal function and age, predict decreased topotecan clearance, while the others extent of prior treatment, prior platinum therapy, and prior radiation therapy predict increased sensitivity of bone marrow due to compromised reserve. Although the rates of myelosuppression with the FDA-approved dose of topotecan are high, neutropenia

9 Armstrong 41 and thrombocytopenia are generally transient, noncumulative, and manageable. Furthermore, thrombocytopenia is regressive in nature, as the incidence decreases with subsequent courses. Although precise dosing guidelines are not available, these updated treatment guidelines should provide assistance in prospectively determining the appropriate topotecan dose for each patient by considering the five key risk factors. In general, myelosuppression may be minimized or managed while topotecan activity is maintained with prospective dose reductions or the administration of growth factors. Alternative treatment schedules (i.e., 3-day and weekly regimens) are still under investigation; however, preliminary data show that these regimens may allow high-risk patients to better tolerate topotecan therapy. Further investigation in randomized trials is required to fully evaluate the efficacy of these regimens in comparison with the FDA-recommended dose and schedule. 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