Weekly topotecan in the management of ovarian cancer

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Gynecologic Oncology 90 (2003) S34 –S38

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Weekly topotecan in the management of ovarian cancer Robert T. Morris* Wayne State University School of Medicine, Detroit, MI 48201, USA Received 30 June 2003

Abstract Topotecan is an established treatment for patients with relapsed ovarian cancer, with good antitumor activity in both platinum-sensitive and -resistant disease. However, the perception of dose-limiting myelosuppression may have limited its use. Myelosuppression with topotecan is noncumulative, reversible, and predictable and as such can be successfully managed. Dose reductions and/or delays in patients at elevated risk, for example, patients with preexisting bone marrow damage from earlier treatment and those with diminished creatinine clearance, are usually effective in preventing complications. Most patients recover without incident and the requirement for specific therapy is generally low. The therapeutic index of topotecan may be improved by its use at first relapse, when patients have sustained less bone marrow damage. Alternative dosing schedules also show promise. Preclinical data suggest that repeated exposure to topotecan may be as effective as prolonged exposure, supporting the idea of weekly dosing. Phase I/II studies have confirmed that weekly topotecan dosing, using either a 24-h or a 30-min intravenous infusion, produces substantially less myelosuppression than the standard schedule (1.5 mg/m2 daily for 5 days every 21 days). Early results indicate that antitumor activity is maintained, although further data are required to confirm this. Weekly administration of topotecan is an exciting new therapeutic option in the treatment of relapsed ovarian cancer. © 2003 Elsevier Inc. All rights reserved. Keywords: Myelosuppression; Relapsed ovarian cancer; Topotecan; Weekly dosing

Introduction Epithelial ovarian cancer is the most lethal of the gynecologic malignancies [1] and is the leading gynecologic cause of death in the United States [2]. Most patients have advanced-stage disease at diagnosis [1]. The standard firstline therapy is cytoreductive surgery and combination chemotherapy [3], and the most widely used chemotherapy options are platinum-based regimens and taxanes. Although the majority of patients respond to first-line therapy [3], ovarian cancer recurs in around 50% of patients [2]. Relapsed ovarian cancer is generally incurable [1] and patients who relapse will eventually die of their disease. Nevertheless, second- or third-line chemotherapy can achieve tumor responses and palliate symptoms, and there is some evidence that it may improve survival [1,4]. Several

* Division of Gynecologic Oncology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA. E-mail address: [email protected] (R.T. Morris). 0090-8258/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0090-8258(03)00470-0

agents have shown activity in salvage chemotherapy for relapsed ovarian cancer, including topotecan, etoposide, pegylated liposomal doxorubicin, gemcitabine, and oxaliplatin [3,4]. The sequence in which the available salvage regimens are used is important. Cumulative toxicities, such as megakaryocyte toxicity with the platinum agents, neuropathy with taxanes and platinum agents, and fatigue with some other drugs, can limit future treatment options. If used in a carefully selected sequence, salvage chemotherapy agents may prolong survival and improve quality of life [3,5]. Indeed, recurrent ovarian cancer may be approached as a chronic (albeit lethal) disease, using most or even all of the available salvage agents. As well as proven antitumor efficacy, the choice of salvage therapy depends on numerous factors. The length of the platinum-free interval is particularly important; patients who have progressed on platinum therapy or relapsed within 6 months should not receive platinum agents as salvage therapy [6]. The pattern of cumulative toxicity is also a crucial factor, both for minimizing potential problems with

R.T. Morris / Gynecologic Oncology 90 (2003) S34 –S38

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Table 1 Response rates, overall survival, and myelosuppression in trials of topotecan in recurrent ovarian cancer

No. of patients entered Response rate (% of patients) Platinum-sensitive Platinum-resistant and/or -refractory Overall survival (weeks) Grade 3–4 toxicity (% of patients) Neutropenia Thrombocytopenia Anemia

Creemers et al. [8]

ten Bokkel Huinink et al. [9]

McGuire et al. [10]

Gordon et al. [11]

111

112

48

235

27 24 N/A

29 13 61

33 N/A 80

29 7 57

97 33 32

95 50 41

100 51 28

77 34 28

Note. N/A, not available.

future treatment and for avoiding the aggravation of preexisting toxicities from earlier treatments. Patient convenience and costs may also play a role in the selection of treatment [6], and the effects on patients’ quality of life should also be considered.

and adjusting the topotecan dose as appropriate, should enablethecliniciantominimizecomplicationsfrommyelosuppression in patients receiving topotecan.

Defining the optimum schedule for topotecan Topotecan in relapsed ovarian cancer Topotecan is a topoisomerase I inhibitor with proven antitumor efficacy in a number of malignancies, including ovarian cancer [7]. It has become an established treatment for relapsed ovarian cancer and has demonstrated good response rates in both platinum-sensitive and -resistant tumors (Table 1) [8 –11]. Around 30% of patients with platinum-sensitive tumors respond to salvage therapy with topotecan, and even in patients with platinum-resistant tumors the response rate was up to 24%. Median overall survival was 60 – 80 weeks (Table 1). Myelosuppression is generally considered the doselimiting toxicity with topotecan, although it is noncumulative, reversible, and predictable, and strategies for its successful management are well established [7]. The standard dosing regimen is 1.5 mg/m2 daily for 5 days every 21 days and dose reductions and/or dose delays are usually sufficient to manage myelosuppression, with the requirement for hematologic support generally low. The currently recommended strategy in patients who develop complicated or prolonged myelosuppression is a stepwise dose reduction in increments of 0.25 mg/m2/day [7]. Patients who have been extensively pretreated may have cumulative bone marrow damage from prior therapy and are at higher risk of experiencing myelosuppression [7] (Fig. 1). Using topotecan early in relapsed disease could therefore reduce the risk of myelosuppression, improving the therapeutic index. For patients who receive topotecan after extensive pretreatment, dose reductions from the start of therapy may be considered [7]. Dose reductions are also recommended in patients with diminished creatinine clearance [7]. Assessing renal function and the likelihood of cumulative toxicities from prior therapies in each patient,

Various strategies have been suggested for reducing the myelosuppression associated with topotecan, including use at first relapse, dose reductions, and a curtailed treatment period (3 days rather than 5), as well as alternative dosing schedules. Alternative dosing schedules are currently the focus of considerable research interest. Topotecan is S-phase-specific, and this feature provides support for repeated expo-

Fig. 1. The influence of the extent of prior therapy on the toxicity observed with topotecan. Reproduced from Armstrong and O’Reilly [7] with permission. www.Theoncologist.com.

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R.T. Morris / Gynecologic Oncology 90 (2003) S34 –S38

Table 2 Response rate and myelosuppression with topotecan administered weekly or by the standard regimen

No. of patients Overall response rate (% of patients) Median overall survival (months) Disease stabilization (% of patients) Grade 3–4 toxicity (% of patients) Neutropenia Thrombocytopenia Anemia

Standard regimen (1.5 mg/m2 as 30-min infusion daily for 5 days, every 21 days)

Weekly regimen (1.75 mg/m2 as 24-h infusion weekly for 4 weeks, every 6 weeks)

34 23 11.0 44

34 3* 12.4 52

94 21 39

52* 6* 21

Note. Adapted from Hoskins et al. [14] with permission from the American Society of Clinical Oncology. * P ⬍ 0.05.

sure. In vitro data in non-small-cell lung cancer cell lines show that the cytotoxic effect of topotecan reaches a plateau with prolonged exposure, which correlates with a downregulation of the topoisomerase I target enzyme. This downregulation appears to be reversible, as topoisomerase I levels returned to baseline 7 days after the removal of topotecan [12]. These preclinical data suggest that repeated exposure to topotecan, perhaps on a 7-day cycle, could have similar antitumor effectiveness to prolonged exposure. This supports the concept of weekly dosing for topotecan, and this schedule is being explored in several clinical studies.

Clinical data on weekly topotecan Twenty-four-hour infusion Preliminary data on the use of topotecan as a weekly 24-h infusion came from a phase I trial in 32 patients with solid tumors (mainly gastrointestinal malignancies) [13]. This study investigated doses of 1.0 –2.0 mg/m2 topotecan administered by 24-h continuous intravenous infusion and repeated weekly. The results showed that dose-limiting neutropenia occurred at doses at or above 1.75 mg/m2. A weekly 24-h infusion of topotecan was studied in patients with ovarian cancer in a phase II study, comparing the weekly schedule with the standard dosing regimen [14]. A total of 66 patients previously treated for recurrent epithelial ovarian cancer received either the standard topotecan schedule or topotecan 1.75 mg/m2 as a 24-h infusion weekly for 4 weeks followed by a 2-week break. The overall response rate was significantly lower in the weekly treatment arm but overall survival was similar in both arms and myelosuppression was significantly reduced with weekly treatment (Table 2) [14]. The proportion of patients with stable disease was higher in the weekly treatment arm (Table 2), which may underlie the finding of equivalent survival benefit. This is an interesting result, as it suggests that disease stabilization may be of benefit for survival. The lower rate of myelosuppression in the weekly

dosing arm may also suggest that dose escalation could be explored. Thirty-minute bolus infusion A phase I dose-escalation study is ongoing in patients with advanced malignancies using topotecan administered as a 30-min bolus infusion weekly [15]. Topotecan was administered to cohorts of three patients as a 30-min bolus infusion weekly for 3 weeks, with a 1-week break between cycles, at doses of 1.5– 8.5 mg/m2. Transient grade 3– 4 neutropenia was observed at doses above 3.5 mg/m2, but it was not dose-limiting. The maximum tolerated dose has not yet been reached, with the most recent cohort of patients receiving 10 mg/m2. The weekly 30-min infusion regimen was studied in 32 previously treated patients with relapsed ovarian cancer by Homesley and colleagues [16]. In this phase I/II doseescalation study, topotecan was administered as a 30-min iv bolus weekly, starting at 1.5 mg/m2 and escalating in 0.5 mg/m2 increments every 21 days as tolerability allowed. No notable toxicity occurred at doses below 4 mg/m2. Hematologic toxicity was low (Table 3) and not doselimiting. No patient required regular support with granulocyte colony-stimulating factor. The dose-limiting toxicity was grade 2–3 anemia combined with gastrointestinal toxicity. Four patients (13%) achieved partial responses, all of whom were receiving doses of 2 mg/m2 or higher. The recommended dose was 4 mg/m2, with the option of inTable 3 Hematologic toxicity with weekly topotecan administered as a 30-min intravenous bolus Event

Anemia Leukopenia Neutropenia Thrombocytopenia

No. of events Grade 1

Grade 2

Grade 3

Grade 4

Total

19 10 10 7

25 18 12 5

4 0 6 3

0 0 1 0

48 28 29 15

Note. Reproduced from Homesley et al. [17].

R.T. Morris / Gynecologic Oncology 90 (2003) S34 –S38 Table 4 Grade 3 and 4 hematologic and nonhematologic adverse events with weekly topotecan administered as a 30-min intravenous bolus [19] Adverse event Hematologic Neutropenia Thrombocytopenia Anemia Nonhematologic Gastrointestinal toxicity Fatigue

No. of patients

No. of treatments (%)*

6 2 3

6 (1.4) 7 (1.6) 2 (⬍1.0)

2 4

2 (⬍1.0) 7 (1.6)

* Of 430 total treatments.

creasing to 6 mg/m2 in more tolerant patients [16]. The low level of hematologic toxicity may indicate the potential for higher antitumor activity at higher dose levels. The activity of higher doses is presently being investigated in an ongoing multicenter prospective study [17,18]. This trial administers weekly topotecan as a 30-min iv bolus with a starting dose of 4 mg/m2. Unlike the study by Tan and colleagues [15], there are no treatment breaks. Eligible patients are those with potentially platinum-sensitive ovarian or peritoneal cancer, who have received only one previous platinum-based regimen, with a treatment-free interval of at least 6 months, and who have adequate performance and bone marrow status. To date, 28 patients have been enrolled and 25 are evaluable for response. Of these 25 patients, 7 had partial responses (response rate 28%), and a further 13 have stable disease. The median progression-free interval in all patients is 23 weeks and 32 weeks in responders. Overall toxicity in the 28 patients is low (Table 4). Consistent with the results of Homesley and colleagues [16], fatigue was the reason for withdrawal in 2 patients. Most of the patients with grade 3– 4 hematologic toxicity also had reduced creatinine clearance; grade 3– 4 hematologic toxicity was rare in patients with creatinine clearance of 70 ml/min or above. These encouraging findings indicate that weekly topotecan at doses of 4 mg/m2 or above has antitumor activity and modest toxicity in patients with ovarian cancer who are not heavily pretreated and who have good performance status, especially in patients who do not have impaired renal function. Additional studies in lung cancer have also demonstrated response rates similar to those obtained with the 5-day regimen [19]. Further data on a larger number of patients, and mature survival data, are required to define the role of weekly topotecan in ovarian cancer, and several studies are ongoing.

Conclusions Topotecan is an established treatment for patients with relapsed ovarian cancer, with response rates of around 30% in platinum-sensitive tumors and 7–11% in platinum-resis-

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tant tumors. However, despite this demonstrated effectiveness, the perception of topotecan as a myelosuppressive agent may have limited its use in patients with ovarian cancer. Although myelosuppression is dose-limiting, it is noncumulative, reversible, and predictable and as such can be successfully managed by dose reductions and/or treatment delays. Overall, topotecan is generally well tolerated. Patients with preexisting bone marrow damage as a consequence of earlier treatment are at increased risk of myelosuppression. The use of topotecan at first relapse, when patients still have adequate bone marrow function, may significantly reduce myelosuppression. Alternative dosing schedules may also be a means of improving the therapeutic index of topotecan. Weekly dosing, in particular, appears to be associated with substantially less myelosuppression than the standard schedule and, indeed, the dose-limiting toxicities appear to be fatigue, anemia, and gastrointestinal effects rather than neutropenia. Early data from recent trials have indicated that antitumor activity is maintained, although further studies and mature survival data are required to confirm these findings. The mechanism for this improvement in the therapeutic index is unknown, but it may be related to increased dose density. The S-phase specificity of topotecan may also play a part, as preclinical data have indicated that repeated exposure to topotecan may have a greater cytotoxic effect than prolonged exposure. In addition to its improved tolerability, weekly dosing also provides the added benefit of increased convenience for the patient, who has to attend the hospital only once a week. This reduces the burden of traveling to the hospital and is less disruptive for the patient and her carer(s). Further research is required to fully assess the role of weekly topotecan in ovarian cancer, and the optimum dosing regimen, but early data are encouraging.

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