Clinical Guidelines for Managing Topotecan-Related Hematologic Toxicity

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1 Clinical Guidelines for Managing Topotecan-Related Hematologic Toxicity DEBORAH ARMSTRONG, SEAMUS O REILLY Johns Hopkins Oncology Center, Baltimore, Maryland, USA Key Words. Topotecan Topoisomerase I inhibitor Chemotherapy Ovarian cancer ABSTRACT Purpose: Topotecan, a semisynthetic water-soluble camptothecin analog, was recently approved as a second-line treatment for women with ovarian cancer. In clinical trials, hematologic toxicity has been the predominant toxicity associated with its use. The purpose of this article is to provide guidelines on the clinical management of these toxicities. Methods: The guidelines on the management of hematologic toxicities associated with topotecan therapy for advanced ovarian cancer patients were established through a review and analysis of phase I, II, and III clinical trials. Results: In phase I studies, noncumulative neutropenia was the predominant toxicity associated with topotecan therapy. In subsequently conducted phase II trials, thrombocytopenia related to prior carboplatin and alkylating agent therapies has become a prominent toxicity, and neutropenia has been more severe INTRODUCTION Topotecan (Hycamtin; SmithKline Beecham, King of Prussia, PA), a synthetic hydrophilic camptothecin analog that inhibits topoisomerase I, has demonstrated antitumor activity in phase I and II trials in several types of solid tumor and hematologic malignancies [1-5]. Based on its antitumor activity in relapsed ovarian cancer, topotecan was approved for this indication in In phase I trials, a variety of schedules have been evaluated, including 3-min infusions every three weeks to infusions of three weeks duration every four weeks [6]. Based on the schedule-dependent nature of topotecan s mechanism of action, its relatively short plasma half-life, and the antitumor activity observed in phase I testing, a 3- min infusion schedule administered intravenously for five consecutive days every three weeks has been most extensively evaluated and is the approved schedule for clinical than anticipated from phase I studies. The risk for both toxicities relates to the extent of prior myelosuppressive chemotherapy and to renal impairment. These toxicities can be managed through the identification of high-risk patients and implementation of appropriate prophylactic measures. Such measures include dose reductions or the use of hematopoietic growth factors. For patients with persistently low blood cell parameters, transfusion therapy remains a viable option. Conclusion: Hematologic toxicities associated with topotecan therapy are noncumulative. Consequently, once a dosing regimen is established, toxicity patterns are predictable. Pretreatment assessment of the nature and toxicities of prior therapy and renal function should assist the clinician in preventing complications caused by the myelosuppressive effects of topotecan therapy. The Oncologist 1998;3:4-1 use. However, in all schedules evaluated to date, neutropenia has been the predominant toxicity observed. In phase I studies evaluating a daily-times-five schedule, neutropenia was characteristically brief, noncumulative, and uncomplicated, and rarely resulted in treatment delays [1-3]. Reduced tolerance for hematologic toxicity was observed in patients who had received extensive prior myelosuppressive therapy in one of these phase I trials [3]. Additional toxicities observed in these studies included thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, stomatitis, fatigue, and alopecia, but these were generally mild and clinically manageable. Since the approval of topotecan for the treatment of ovarian cancer, it has been our impression that hematologic toxicity has been a major concern to clinicians using this agent. The purpose of this paper is to discuss the clinical aspects of these toxicities and strategies to prevent or ameliorate these toxicities. Correspondence: Seamus O Reilly, M.D., Ph.D., Johns Hopkins Oncology Center, North Wolfe Street, Room 137, Baltimore, Maryland , USA. Telephone: ; Fax: ; oreilse@welchlink.welch.jhu.edu Accepted for publication January 2, AlphaMed Press /98/$5./ The Oncologist 1998;3:4-1

2 Armstrong, O Reilly 5 Table 1. Phase I studies of topotecan administered as a 3-min infusion daily 5 days: hematologic toxicity Reference Dose (mg/m 2 /d) Patients Courses Neutropenia Platelet Gr 3 Gr 4 >5 d Fever Gr 3 Gr 4 Verweij et al. [2] rare n/a 1 Rowinsky et al. [3] rare Saltz et al. [1]* rare * Reported leukopenia rather than neutropenia. INCIDENCE OF HEMATOLOGIC TOXICITY WITH TOPOTECAN A summary of the hematologic toxicity observed at the recommended phase II doses in the three phase I studies that evaluated a daily-times-five-day schedule of topotecan is presented in Table 1. In these studies, both minimally and extensively pretreated patients were evaluated. Patients were considered to have been extensively pretreated with therapies that result in long-term hematopoietic dysfunction if they had received one or more of the following: A) radiation to >25% of marrow-bearing bones, or B) greater than six courses of a chemotherapeutic agent containing an alkylating agent, or C) greater than two courses of a nitrosourea or mitomycin C. Recommended doses for phase II studies were comparable between trials; however, in one study, a lower dosing recommendation was made for extensively pretreated patients. The latter study also demonstrated that further dose escalation of topotecan with the use of granulocyte-stimulating factor was not feasible due to the development of thrombocytopenia [1]. Based on the antitumor activity observed in these studies, phase II and III evaluations were initiated in patients with ovarian cancer. A summary of four of these trials, including 452 patients with advanced ovarian cancer, demonstrates that 81% of patients experienced grade 4 neutropenia (<5 /µl); 26% experienced grade 4 thrombocytopenia (<25,/µl); and % experienced grade 4 anemia (<8 g/dl) (Table 2). Twenty-six percent of patients experienced fever and/or infection or sepsis with grade 4 neutropenia [7-1]. The largest of these studies compared topotecan with paclitaxel in patients with progressive or recurrent ovarian cancer after receiving platinum-containing regimens [1]. For topotecan, grade 4 neutropenia and thrombocytopenia, and grade 3/4 anemia were observed in %, 25%, and 41% of 112 patients, respectively, and 37%, 1%, and 16% of 555 courses, respectively (Table 3). Neutropenic fevers occurred in 23% of topotecan-treated patients and 5% of courses. Sepsis was reported in 5% of topotecan-treated patients and 1% of courses [1]. Table 2. Summary of hematologic adverse events in patients receiving topotecan Patients Courses Hematologic n = 452 n = 2,375 adverse events % incidence % incidence Neutropenia Grade Grade 4 81 Leukopenia Grade Grade Thrombocytopenia Grade Grade Anemia <1 g/dl <8 g/dl 16 Neutropenic fever/sepsis 26 7 Platelet transfusions 13 4 Blood transfusions Table 3. Hematologic toxicity profile for ovarian cancer patients receiving topotecan Topotecan Adverse event Patients Courses n = 112 n = 555 Hematologic grade 3/4 % % Grade 4 neutropenia Grade 3 anemia Grade 4 thrombocytopenia Febrile neutropenia Documented sepsis Death related to sepsis 1.8.4

3 6 Managing the Hematologic Toxicities of Topotecan When data from these phase II trials are further analyzed, differences between the frequencies of hematologic toxicity are apparent. Table 4 displays the incidence of hematologic toxicity between the studies of Kudelka et al. [7] and Creemers et al. [8]. For comparative purposes, hematologic toxicity observed in previously untreated pancreatic cancer patients enrolled in a phase II study are also included [11]. While the criteria for dose reductions and the use of granulocyte colony-stimulating factor (G-CSF) varied between these studies, differences in the prevalence of neutropenia and thrombocytopenia are evident (Fig. 1). Despite the use of G- CSF in the study of Creemers et al., a consistent trend is apparent between studies with respect to hematologic toxicity. These data illustrate the important role of prior therapy on topotecan-associated myelosuppression, with the highest incidence in the study by Kudelka et al., in which a more extensively pretreated patient population was evaluated. RISK FACTORS FOR HEMATOLOGIC TOXICITY Prior Therapy It is apparent from the above discussion that pretreatment with myelosuppressive chemotherapy agents and/or radiation therapy is the most important risk factor for severe topotecan-induced myelosuppression. The majority of patients with relapsed ovarian cancer will have typically received platinum analogs (cisplatin, carboplatin) and/or alkylating agents (cyclophosphamide, ifosfamide). Of these Table 4. Hematologic toxicity in phase II studies Grade 4 neutropenia 1 2 Febrile neutropenia 1 2 Grade 3/4 platelets agents, pretreatment with carboplatin, which has cumulative myelotoxic effects, is associated with the most significant risks for patients undergoing second-line or salvage therapy with topotecan, particularly thrombocytopenia. In a phase II 1 2 Platelet transfusions 1 2 Figure 1. The influence of the extent of prior therapy on: the percentage of patients experiencing (A) grade 4 neutropenia; (B) grade 3 or 4 thrombocytopenia; (C) neutropenic fever, or (D) the percentage of patients requiring platelet transfusions. Data for this figure were obtained from studies listed in Table 4. O Reilly et al. [11] Creemers et al. [8] Kudelka et al. [7] Number of patients Courses administered Not stated Number of prior regimens 1 2 (1-4) Granulocyte-colony stimulating No Yes No factor (G-CSF) used Dose reduction criteria Grade 4 neutropenia Infection Grade 4 neutropenia >1 wk Grade 3/4 thrombocytopenia Treatment delay >2 wks Infection Complicated grade 3/4 Treatment delay > 2 wks thrombocytopenia Grade 4 neutropenia >2 wks (with G-CSF) Toxicities (% of patients) Grade 4 neutropenia 52% 78% 9% Grade 3/4 thrombocytopenia 4% 18% 77% Febrile neutropenia 11% 9.9% 13% Platelet transfusions % 7% 23% Treatment delays 19% 25% 57% Dose reductions 22% 7% 7%

4 Armstrong, O Reilly 7 clinical trial of topotecan for advanced ovarian cancer patients conducted at the Johns Hopkins Oncology Center [12], patients who received extensive prior treatment with carboplatin were at increased risk to develop transfusiondependent thrombocytopenia during topotecan therapy. Three patients, all with a prior history of treatment with carboplatin, experienced prolonged grade 4 thrombocytopenia requiring multiple platelet transfusions and had topotecan therapy discontinued after the first course of treatment due to severe thrombocytopenia. Bone marrow transplantation is also a risk factor for severe hematologic toxicity during topotecan therapy. Although relatively uncommon, wide-field radiation therapy, including whole-pelvis irradiation, also causes the loss of bone marrow reserve that predisposes patients to hematologic toxicity. In some cases, previous wide-field radiation may be a relative contraindication for treatment with topotecan or other myelosuppressive agents. Renal Impairment Topotecan is eliminated via both hepatic and renal routes. As a result of prior cisplatin therapy, metastatic disease, or other disease-related factors, cancer patients frequently have evidence of hepatic or renal dysfunction. Phase I studies have been performed in such patient populations to provide dosing recommendations for topotecan therapy [13, 14]. Patients with hepatic impairment were found to tolerate topotecan dosages up to 1.5 mg/m 2, the previously established maximum tolerated dose [13]. The nature and severity of treatment-induced toxic effects were similar in patients with and without hepatic injury. As a result, topotecan dose modifications do not appear to be required for most patients with hepatic dysfunction and normal renal function. However, clinicians should be aware that elevated bilirubin, when combined with poor performance status, age, and comorbidities, may be considered in determining whether dose modification is appropriate. Patients with significant renal impairment, in contrast to those with hepatic impairment, are at risk for severe hematologic toxicities when given the current maximum tolerated dose of topotecan [14]. In patients with mild renal dysfunction (creatinine clearance [CrCl] = to 59 ml/min), dose-limiting hematologic toxicity was observed in three of eight patients receiving topotecan 1. mg/m 2 /d and in two of five patients receiving 1.5 mg/m 2 /d. In patients with moderate renal dysfunction (CrCL = to 39 ml/min), dose-limiting hematologic toxicity was observed in three of eight patients receiving.5 mg/m 2 /d and in two of four patients receiving 1. mg/m 2 /d. Dose-limiting events were more frequently observed in extensively pretreated patients. It is noteworthy that a significant proportion of patients with renal impairment had normal serum creatinine levels. Pharmacokinetic analyses indicated that reduced doses in patients with renal impairment produce topotecan exposure and toxicity similar to those observed at higher doses in patients with normal creatinine clearance. As a result, dose modifications among these patients are not to be expected to yield significant alterations in topotecan efficacy. Antitumor activity was observed in patients with ovarian cancer who were treated at these lower doses. MANAGEMENT STRATEGIES Dose Reductions The primary approach to managing the hematologic toxicities of topotecan is preventive, and the optimal preventive strategy is dose reduction. Patients at risk due to extensive pretreatment with carboplatin or other myelosuppressive agents may commence with the standard regimen of 1.5 mg/m 2 /d 5 every 21 days. The appearance of complicated or prolonged (>3 days) grade 4 thrombocytopenia, neutropenia, or anemia during a course of topotecan can be followed immediately by stepwise dose reductions in decrements of.25 mg/m 2 /d. Patients deemed to be at extremely high risk due to a combination of factors including, for example, extensive prior treatment with carboplatin, multiple platelet transfusions, and poor performance status, are not necessarily disqualified from topotecan treatment. Dose reduction at the onset of therapy may be considered as a prophylactic option. Reductions to 1.25 mg/m 2 or 1. mg/m 2 are feasible. For patients who have had bone marrow transplants, anecdotal reports suggest that a topotecan dose of 1. mg/m 2 /d 5 every 28 days can be a viable regimen. Renal function is an important determinant of topotecan clearance and, consequently, of susceptibility to hematologic toxicity at a given dose. Topotecan dosing guidelines have been established for ovarian cancer patients with varying degrees of renal impairment. (Serum creatinine has not been determined to be a sufficiently reliable marker for renal dysfunction; creatinine clearance should be the exclusive basis for topotecan dose adjustments.) Dosing recommendations for patients with renal impairment are shown in Table 5 [15]. No recommendation is available for severe renal impairment, as only two patients meeting these criteria were evaluated. The recommendations in Table 5 do not represent a precise dosing algorithm based on creatinine clearance. In phase I studies, interpatient variability in topotecan exposure at given dose levels ranged from a fourfold to tenfold difference [3].

5 8 Managing the Hematologic Toxicities of Topotecan Similar interpatient variability was also reported among patients with renal impairment receiving topotecan [14]. In addition, the role of hepatic excretion, the possibility of renal tubular secretion, and variations in previous treatments preclude the development of a precise algorithm (as has been developed for carboplatin [16]), which might assist in preventing myelotoxicity. However, these recommendations accurately reflect the results of our clinical trial, as well as clinical experience, and they account for the important variable of extensive pretreatment with myelosuppressive chemotherapy. Establishing a dose and schedule that are tolerable and potentially efficacious among high-risk patients also involves clinical judgments that cannot be quantified with absolute precision. Performance status, extent and rapidity of disease progression, age, comorbidities, and related factors should all be considered in establishing dose adjustments. The use of curtailed treatment (e.g., three days versus five days) as a therapeutic strategy for minimizing myelosuppression while maintaining antineoplastic effect has not yet been adequately evaluated. Hematopoietic Growth Factors Grade 4 neutropenia is the most frequent hematologic toxicity associated with topotecan therapy. In four clinical trials with 452 patients, grade 4 neutropenia occurred in 81% of patients and % of chemotherapy courses (Table 2). Neutropenic fevers or infections occurred in 26% of patients and 7% of courses. G-CSF was routinely used as prophylaxis in all but one of these studies [7]. In the phase III clinical trial of topotecan versus paclitaxel, the incidence of grade 4 neutropenia was highest during the first course of topotecan therapy and decreased during subsequent courses, presumably due to prophylactic growth factor support or dose reduction [1]. The median onset of grade 4 neutropenia occurred on day 9, with a median duration of six days. Grade 4 neutropenia of over 7 days duration was observed in 12% of topotecan treatment courses. G-CSF or other cytokines are not considered first-line approaches for managing hematologic toxicities in patients with renal impairment. However, any patient with multiple risk factors, including extensive pretreatment that has caused loss of bone marrow reserves, may be a candidate for G-CSF prophylaxis. G-CSF may enable patients with renal dysfunction to tolerate the modified dose recommended on the basis of creatinine clearance. Some high-risk patients may be deemed candidates for G-CSF support from the onset of topotecan therapy. However, the current recommendation is to restrict G-CSF to prophylactic use after the patient has experienced febrile neutropenia, infection, or persistent neutropenia [17, 18]. A standard dose of G-CSF can be administered to the patient during subsequent courses of topotecan, thus accelerating neutrophil recovery and reducing the incidence of febrile neutropenia or infections. Prophylactic G-CSF may also curtail the requirement for dose reductions. In general, uncomplicated grade 4 neutropenia during a course of topotecan does not necessitate growth factor support unless poor performance status or a combination of other risk factors suggest to the clinician that the patient is highly susceptible to febrile neutropenia or infections. In the phase III trial of topotecan versus paclitaxel, G-CSF was used prophylactically to maintain topotecan dose intensity in 23% of courses, and it was used to ameliorate complicated neutropenia in 7% of courses [1]. In the clinical trial at the Johns Hopkins Oncology Center, prophylactic G-CSF was used for patients with complicated neutropenia in 9% of courses [12]. Patients receiving topotecan are as likely to experience grade 4 thrombocytopenia (26%) as they are to experience neutropenic fevers or infections (26%) (Table 2). However, thrombocytopenia can be a more vexing concern for clinicians. Thrombopoietic growth factors are expected to be available for this purpose in the near future. In the interim, extensively pretreated patients at risk for severe thrombocytopenia are candidates for dose reduction and/or transfusion therapy. It should be pointed out, however, that topotecan-related thrombocytopenia, like neutropenia, is Nadir platelet count Table 5. Dosing recommendations for patients with renal impairment Creatinine clearance Minimal prior therapy Extensive prior therapy > ml/min 1.5 mg/m 2 /d 1.5 mg/m 2 /d -59 ml/min 1.5 mg/m 2 /d 1. mg/m 2 /d -39 ml/min.75 mg/m 2 /d.5 mg/m 2 /d < ml/min Not established Not established Adapted from [15]; used with permission. See text for definitions of minimal and extensive prior therapy Course Figure 2. Sequential platelet nadirs observed in a patient with ovarian cancer receiving topotecan 1.5 mg/m 2 /day for five days every three weeks, demonstrating the noncumulative nature of topotecan-related hematologic toxicity.

6 Armstrong, O Reilly 9 not cumulative. An example of this is presented in Figure 2, documenting nadir platelet counts for a patient who received standard-dose topotecan at 1.5 mg/m 2 /d 5, every 21 days. The nadir platelet count after the first course of therapy was 33,/µl, the lowest documented platelet count over 12 consecutive treatment courses. Transfusion-dependent anemia is not uncommon among patients receiving topotecan, although the incidence has varied in clinical trials. The summary data on 452 patients demonstrated that red blood cell transfusions were required for 56% of patients and 23% of courses. In the clinical trial at Johns Hopkins Oncology Center, grade 4 anemia was observed in only 1.2% of courses [12]. Hemolytic anemia has not been documented in patients with solid tumor malignancies receiving topotecan, but has been suggested as a cause for precipitous anemia after therapy in patients with leukemia [4]. For patients with symptomatic grade 4 anemia, dose reductions comparable to those implemented for symptomatic grade 4 neutropenia or thrombocytopenia may be considered. Patients with grade 4 anemia who experience severe symptoms of fatigue and weakness may be candidates for prophylactic treatment with erythropoietin. Although it is not expected that many patients receiving topotecan will require erythropoietin, it is an option available to clinicians for improving patients well being while possibly reducing the requirement for dose reductions and red blood cell transfusions. Transfusion Therapy Transfusion therapy is the final option for patients with severe or complicated thrombocytopenia or anemia. The threshold for platelet transfusions in thrombocytopenic patients is somewhat variable. Some physicians prefer to transfuse when platelet counts are less than 25,/µl, while others use values as low as,/µl, or even 1,/µl. Individual factors, including symptomatology (bruising, blood in urine or stool, etc.) and the patient s vascular status should be considered. Red blood cell transfusions are most commonly indicated when hemoglobin levels are less than 7 g/dl. But laboratory data should be combined with observations of clinical symptomatology to determine the necessity for red blood cell transfusions. Severe fatigue, headache, tachycardia, hypotension, or other symptoms of cardiac ischemia should be primary considerations in the decision to transfuse anemic patients. CONCLUSIONS At the present time, the majority of patients with relapsed or persistent ovarian cancer will have received extensive prior No dose reduction required Relapsed ovarian cancer Platinum sensitive or resistant? Candidate for topotecan therapy Nature of prior therapy Prior hematologic toxicity Renal function assessment using Cockcroft Gault or Jeliffe calculations Performance status, comorbidities Dose reduction required Hematopoietic growth factors required Figure 3. Algorithm for the identification and management of topotecan-related hematologic toxicity. myelosuppressive therapy and are therefore at increased risk for topotecan toxicity. G-CSF therapy or dose reductions have been used in the majority of patients experiencing significant toxicity. While the strategy of dose reduction is more attractive clinically and financially, the importance of dose intensity on the antitumor activity of topotecan has not yet been evaluated. Formal pharmacokinetic-pharmacodynamic evaluations, similar to those that have been conducted with carboplatin [19], are required to address this issue. In this regard, a pooled analysis of patient demographics (e.g., prior therapy, performance status), antitumor response, and toxicity from phase II and III studies is warranted to further analyze factors affecting efficacy and toxicity. Precise dosing guidelines for high-risk patients receiving topotecan are not yet available. Even in studies in which renal function alone was assessed, significant interpatient variability was observed, which may make the development of formalized guidelines difficult. However, once a tolerable treatment regimen is established, the non-cumulative, reversible, and predictable nature of topotecan-induced myelosuppression (Fig. 2) facilitates subsequent dosing. An algorithm for use in the evaluation of patients being considered for topotecan therapy is presented in Figure 3 and emphasizes the interaction of prior therapy and renal dysfunction in this population. Due to the high prevalence of renal dysfunction in patients with ovarian cancer, we strongly recommend that patients receiving topotecan routinely have an estimation of creatinine clearance performed [15,, 21]. Once at-risk patients are identified, appropriate measures (dose reduction or the use of growth factors) can be used to prevent severe toxicity.

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