Key Words. Chemotherapy Topotecan Weekly administration

Transcription

1 The Oncologist Weekly Topotecan: An Alternative to Topotecan s Standard Daily 5 Schedule? ERIC K. ROWINSKY Institute for Drug Development, The Cancer Therapy and Research Center, The University of Texas Health Science Center, San Antonio, Texas, USA Key Words. Chemotherapy Topotecan Weekly administration ABSTRACT INTRODUCTION Topotecan (Hycamtin ), a semisynthetic derivative of the alkaloid, camptothecin, is an anticancer drug with specific topoisomerase-i inhibitory activity. Inhibitors of topoisomerase-i cause cytotoxicity by producing DNA damage through interfering with topoisomerase function during the replication process [1-6]. Topotecan, which has shown response rates ranging from 13%-33% in single-agent studies of salvage treatment for ovarian cancer, received regulatory approval by the Food and Drug Administration (FDA) in 1996, initially for second-line therapy in ovarian cancer [7-11]. Topotecan has also received regulatory approval for second-line therapy in small cell lung cancer and is currently being investigated in other malignancies. With topotecan, the most important determinant of cytotoxicity, based on both preclinical data observed in vitro and in clinical studies of pharmacokinetics, appears to be the Relapsed ovarian cancer and small cell lung cancer are frequently treated with topotecan (Hycamtin ), for which the standard dose and schedule are 1.5 mg/m 2 daily for five consecutive days every 3 weeks. Clinical experience has shown that this dose and schedule may be too toxic for some patients, especially those who have been heavily pretreated with platinum-based therapeutics, and it has been suggested that starting doses of topotecan be reduced to mg/m 2 /d. Recently, multiple clinical trials have begun to evaluate the feasibility and preliminary antitumor activity of an alternative schedule based on weekly administration of topotecan. The potential benefits of weekly administration include not only reduced toxicity without significant compromise of antitumor activity, but also greater patient convenience and quality of life and greater potential for developing new topotecan-containing combination therapies. This report reviews the rationale for a weekly schedule, as well as a growing base of emerging clinical data. These preliminary data suggest that weekly topotecan is active; further evaluations are planned to confirm the activity and therapeutic index and to determine optimal dosing of a weekly schedule. The Oncologist 2002;7: duration of exposure above a biologically relevant threshold concentration [5-8]. Because prolonged exposure appeared superior to intermittent treatment in early studies, the standard dose and schedule developed was 1.5 mg/m 2 by i.v. infusion over 30 minutes, daily for 5 consecutive days every 3 weeks [8-10]. This dose and schedule emerged as one of several plans of administration that subsequently demonstrated activity in phase I clinical trials, leading rather rapidly to phase II and phase III evaluations that confirmed efficacy [9-14]. Other doses and schedules offering continuous exposure of topotecan were not pursued at that time. The dose-limiting toxicity of topotecan is myelosuppression, which is also the most common serious toxicity [6-8]. Indeed, at the standard dose and schedule, topotecan may predispose patients to neutropenia. This toxicity, although brief and reversible, may be severe in patients who have previously received therapy with platinum-based regimens. This Correspondence: Eric K. Rowinsky, M.D. (Z414), Director, Clinical Research, Institute for Drug Development, 4th Floor, Zeller Building, 7979 Wurzbach Road, San Antonio, Texas 78229, USA. Telephone: ; Fax: ; erowinsk@saci.org Received February 21, 2002; accepted for publication May 9, AlphaMed Press /2002/$5.00/0 The Oncologist 2002;7:

2 Rowinsky 325 is due primarily to the effect of impaired renal function on topotecan excretion following treatment with cisplatin, or decreased hematopoietic reserve following treatment with carboplatin [6-10]. However, after several years of experience in the oncology clinic, it now appears that compared with the 1.5 mg/m 2 daily 5 schedule, lower doses of topotecan are associated with less myelosuppression and maintained therapeutic benefit [15]. This is an especially welcome development in patients with prior exposure to platinum, as well as in elderly and frail patients, patients with poor performance status, and in those with other comorbid diseases [15]. SCHEDULE MODIFICATIONS Modifying the schedule of topotecan administration is another approach to resolution of the myelotoxicity issue. A 3-day or 4-day schedule every 3 weeks may offer improved tolerability compared with the standard 5-day schedule. For example, in a study of 29 patients at the Cleveland Clinic Foundation, Belinson and colleagues [16] showed that a 3- day regimen of topotecan resulted in much less grade 4 neutropenia (24%) compared with the 82% grade 4 neutropenia historically associated with the standard 5-day regimen [10]. Also, whereas 30% of patients experience grade 4 thrombocytopenia with the standard 5-day schedule, no patients in this study of 3-day topotecan experienced grade 4 thrombocytopenia [16]. Similar shorter schedules are now being evaluated in a number of clinical trials [17-19]. Other investigators have theorized that, based on preclinical as well as clinical evidence, weekly bolus administration of topotecan may be a viable alternative to the daily 5 schedule. They reason that irinotecan, gemcitabine, paclitaxel, and several other prominent schedule-dependent cytotoxic drugs show significant clinical activity on a weekly schedule, frequently with an amelioration of their toxicity. In other words, intermittent treatment schedules (e.g., weekly dosing) have been associated with clinical efficacy at doses associated with tolerable toxicity profiles with the aforementioned cytotoxics. Despite initial perceptions that optimal topotecan schedules would be those resulting in continuous or frequent drug treatment, it now appears that topotecan is similar to these other drugs, particularly the taxanes, with regard to pharmacokinetics and relatively prolonged tissue binding [20, 21]. Thus, several investigators have proposed that a weekly schedule of topotecan may be at least as well tolerated, and perhaps better tolerated, than the daily 5 schedule with little or no significant compromise in activity. The balance of this appraisal reviews several clinical studies testing this hypothesis, as well as relevant preclinical data, concluding that there is a growing body of evidence to support the administration of topotecan weekly as an alternative to daily 5 every 3 weeks. PRECLINICAL STUDIES OF WEEKLY TOPOTECAN In cellular, microbial, and biochemical assays, topotecan has been shown to be a potent and specific inhibitor of DNA topoisomerase-i. Experiments using purified enzyme or cultured mammalian cells show that topotecan stabilizes a covalent complex between topoisomerase-i and DNA that results in enzyme-linked DNA cleavage. It is the production of enzyme-mediated DNA damage that results in cytotoxicity. A threshold exposure period is required for cytotoxicity, consistent with the S-phase dependence of this class of drugs [1-4, 22-28]. In subsequent studies, topotecan demonstrated a high degree of activity in a broad spectrum of animal tumor models, including solid tumor models such as HT-29 human colon carcinoma [29-31], murine melanoma [32], Lewis lung carcinoma [33], and murine colon carcinomas [34]. It is important to note that, in many of these studies, topotecan was administered to animals on intermittent schedules that are consistent with weekly administration in humans. For example, the twice-weekly schedules of topotecan administration in murine models simulate lessfrequent dosing schedules weekly schedules in humans because of the kinetics. It is also important to note that in most of these experiments, the animals received topotecan at the maximum tolerated dose (MTD). CLINICAL STUDIES OF WEEKLY TOPOTECAN IN OVARIAN CANCER Clinical reports of weekly administration of topotecan in recurrent ovarian cancer began to emerge in One of the first trials was a randomized study of standard versus weekly topotecan therapy performed by Hoskins et al. for the National Cancer Institute of Canada (NCI-C) s Clinical Trials Group [35]. In that trial, patients with recurrent ovarian cancer were randomized to either 1.5 mg/m 2 topotecan i.v. over 30 minutes daily for 5 days, repeated every 3 weeks (Arm A, the standard regimen) or to 1.75 mg/m 2 topotecan administered as a 24-hour infusion once a week for 4 weeks, repeated every 6 weeks (Arm B, the weekly arm). Of 63 patients assessable for response, the response rate in Arm A was 22.6%, which was significantly superior to that in Arm B, 3.1%. Survival data were similar in both arms. The overall results are summarized in Table 1. On the basis of these data, the standard regimen of topotecan administration, 1.5 mg/m 2 daily 5 every 3 weeks, remained the regimen of choice [32]. Upon further review, however, the Canadian data prompted speculation as to whether the 1.75 mg/m 2 dose administered in the weekly arm may have been too low, for the regimens were not equitoxic: 94% of patients on the standard arm experienced grade 3/4 neutropenia compared

3 326 Weekly Dosing of Topotecan Table 1. Weekly 24-hour topotecan infusions: results of NCI-C randomized trial [35] Arm A Arm B Standard regimen Weekly regimen 1.5 mg/m 2 daily mg/m 2 /wk 30-minute bolus n = hour infusion n = 32 Partial response 7 (23%) 1 (3%) Stable disease 9 (25%) 14 (44%) Progressive disease 15 (52%) 17 (53%) Median survival 11.0 months 12.4 months Table 2. Weekly 24-hour topotecan infusions: hematologic toxicities of NCI-C randomized trial (worst ever per patient) [35] Arm A Arm B (standard regimen) (weekly regimen) by grade by grade Toxicity Any (%) Any (%) Infection/Febrile neutropenia % 3 9% Granulocytopenia % % Thrombocytopenia % % Anemia % % with 52% of patients on the weekly arm. Indeed, a substantial proportion of patients on weekly topotecan had no relevant toxicity. Topotecan is a dose-dependent drug, and the substantially lower toxicity in the weekly arm of the study, as shown in Table 2, suggests suboptimal dosing. Also, as seen in Table 1, although there were few major responders to the weekly therapy, there was a high incidence of stable disease as the best response. A closer look at the results shows that the proportion of patients benefiting from weekly topotecan, 47% (partial response + stable disease), was virtually the same as those benefiting from the standard schedule, 48% (partial response + stable disease), despite the suboptimal dosing in the weekly arm of the trial [32]. Together, these observations suggest that perhaps another randomized study should be performed, but with a higher (e.g. equitoxic) dose of topotecan in the investigational (weekly) arm and/or with bolus dosing instead of 24-hour infusions. More recently, Homesley and colleagues completed a phase I/II pilot study in which weekly topotecan, in escalating Table 3. Results of dose-escalating study of weekly bolus topotecan [36] Topotecan dose Patients (n) Partial Stable (mg/m 2 ) response disease < > Total doses, was studied in 32 patients with previously treated ovarian cancer [34]. The trial was designed to identify a suitable dose of weekly topotecan for further investigation. No antitumor activity was seen with doses <2 mg/m 2 /wk, but at doses >2 mg/m 2 /wk, 10 of 21 assessable patients achieved either stable disease or partial responses (Table 3). No notable toxicity was observed, with a near absence of dose-limiting hematologic toxicity at doses up to 4 mg/m 2 /wk (Table 4). In this dose-escalation trial, the relative lack of significant myelotoxicity was not appreciated until the last 10 patients were entered in the study; because of initial concern that myelotoxicity could be severe, patients were started at relatively low doses, with doses escalated in a cautious manner. As a consequence, the investigators reported that a number of patients may have been able to tolerate significantly higher dose levels; their recommended dose for further studies was 4 mg/m 2 /wk, with a maximum recommended dose of 6 mg/m 2 /wk. Finally, in this study, no patient required regular G-CSF support. Only one patient with grade 4 neutropenia was given filgrastim, and four patients received epoetin alfa for grade 3 anemia. All severe hematologic toxicities rapidly resolved in patients receiving filgrastim and epoetin alfa, and these patients continued with their respective doses without further complications [36]. Meanwhile, an ongoing phase II study of weekly bolus topotecan is currently being performed by Morris and colleagues in patients with recurrent ovarian and peritoneal cancer. The objective of this multi-institutional trial is to assess the response and toxicity of topotecan in potentially Table 4. Hematologic toxicities in dose-escalating study of weekly bolus topotecan [36] Myelotoxicity Grade 1 Grade 2 Grade 3 Grade 4 Total Anemia Leukopenia Neutropenia Thrombocytopenia

4 Rowinsky 327 platinum-sensitive patients, while reducing the incidence of myelotoxicity by using a weekly schedule. To date, 12 patients have been enrolled, receiving topotecan as a weekly 30-minute bolus with a starting dose of 4.0 mg/m 2. At the time of data review, with 10 patients evaluable for response, five (50%) had achieved a partial response and two (20%) had achieved stable disease (Table 5). Among the responders, the median progression-free interval was 24.6 weeks (range, 17-32). Myelotoxicity had been infrequent, with two episodes of grade 3/4 neutropenia and three episodes of grade 3 anemia. Two patients had grade 3 fatigue [37]. CLINICAL STUDIES OF WEEKLY TOPOTECAN IN OTHER MALIGNANCIES Weekly administration of single-agent topotecan has also been studied in lung cancer. For example, Nogami and colleagues (submitted manuscript) studied this regimen in advanced non-small cell lung cancer, giving doses up to 4 mg/m 2 on days 1, 8, and 15 every 4 weeks to previously treated patients. No dose-limiting toxicities were observed. In previously untreated patients, topotecan was well tolerated at doses up to 6 mg/m 2. In both untreated and previously treated patients, regressions of the primary tumors and/or lymph node metastases were observed, but no patient achieved a partial or complete response. It should be mentioned, however, that in this phase I trial, the majority of patients received low (<2 mg/m 2 ) doses of the drug. Follow-up studies are planned by Nogami and colleagues (submitted manuscript) to determine the true activity of the weekly schedule at higher doses. Clark and colleagues reported a study of weekly topotecan in 14 patients with a variety of malignancies; bolus infusions, with doses escalating from 1.5 mg/m 2 to 2.25 mg/m 2, were administered. At the time of this preliminary report, there were no dose-limiting hematologic or nonhematologic toxicities, and the investigators were continuing their studies with the objective of reaching a weekly dose of 3.0 mg/m 2 [38]. COMBINATION REGIMENS THAT INCLUDE WEEKLY TOPOTECAN There have also been reports of trials of combination regimens that include weekly treatment with topotecan. For example, Homesley and colleagues recently reported a phase I study of weekly topotecan combined with weekly paclitaxel in second-line or third-line treatment of ovarian cancer. Escalating doses of both drugs were administered. Due to intrapatient escalation, the median MTD was estimated to be 4 mg/m 2 topotecan and 100 mg/m 2 paclitaxel. Of 21 evaluable patients, 18 required epoetin alfa, transfusion, or colony-stimulating growth factor; otherwise, the Table 5. Interim results of ongoing trial with weekly bolus topotecan [37] Number of evaluable patients 10 Partial response 5 (50%) Stable disease 2 (20%) Episodes of grade 3-4 neutropenia 2 Episodes of grade 3 anemia 3 treatment was well tolerated. At the time of this report, there were six complete responses (29%), with five of these based on CA125 and one based on measurable disease, and one partial response, for an overall response rate of 33%. Further evaluations of this regimen are planned [39]. Guarino and colleagues recently reported a dose-escalation study of weekly topotecan, cisplatin, and gemcitabine as first-line therapy in advanced non-small cell lung cancer. Thirty patients received cisplatin, 20 mg/m 2, gemcitabine 1,000 mg/m 2, and escalating doses of topotecan on days 1, 8, and 15 of a 28-day cycle. Topotecan dosing began at 0.5 mg/m 2 in cohort 1 and was escalated by 0.25 mg/m 2 in each cohort to a maximum dose of 2.0 mg/m 2 in cohort 7. During the trial, the gemcitabine regimen was changed to days 1 and 15 due to treatment-limiting thrombocytopenia. A total of 301 cycles were administered. There were 11 partial responses in 29 evaluable patients (38%). The median progression-free interval was >17 weeks, and the median survival was 38 weeks. At the time of this report, seven patients remained alive, with a survival in excess of 45 weeks. There were no febrile neutropenic events and no treatment-related hospitalizations. Nonhematologic toxicities were mild. The investigators concluded that, because of the activity and tolerability of this three-drug regimen, the recommended doses and schedules for phase III trials should be cisplatin, 20 mg/m 2, and topotecan, 1.75 mg/m 2, on days 1, 8, and 15, and gemcitabine, 1,000 mg/m 2, on days 1 and 15, repeated every 28 days [40]. Frasci and colleagues evaluated a weekly first-line regimen of cisplatin, paclitaxel, and topotecan with G-CSF support for patients with extensive small cell lung cancer. Dosages were cisplatin, 40 mg/m 2, paclitaxel 85 mg/m 2, and topotecan, 2.25 mg/m 2. All agents were administered weekly, with G-CSF (5 µg/mg days 3-5) support, for a maximum of 12 weeks. In this phase II study, 37 patients were treated, with eight complete responses and 22 partial responses for an overall response rate of 81%. At the time of this report, with a median follow-up of 13 months, median progression-free and overall survival were 8 months and 12.5 months, respectively, with 1-year and 2- year projected survivals of 55% and 21%, respectively.

5 328 Weekly Dosing of Topotecan Only one case of neutropenic sepsis was recorded, in a patient following nine cycles of chemotherapy, and hemorrhagic thrombocytopenia was never observed. However, anemia was common in patients receiving six or more cycles of chemotherapy [41]. In an earlier related dose-finding trial, Frasci and the same team of investigators evaluated cisplatin, paclitaxel, and topotecan with G-CSF support in 44 patients, either chemonaive or previously treated, with either small cell or ovarian cancer [42]. In this dose-finding study, severe myelotoxicity was unusual in almost all cohorts, even when heavily pretreated patients were considered. There were eight episodes of grade 4 neutropenia, six in previously treated patients. Although evaluation of the antitumor activity was not a primary aim of the trial, an overall response rate of 80% was observed in chemonaive patients who showed, in general, poor prognostic features. Furthermore, evidence of significant antitumor activity was noted, even in heavily pretreated patients, with a 25% overall response rate in both tumor types. These results were obtained despite a relatively short duration of treatment. It was in this trial that the dose of weekly topotecan, 2.25 mg/m 2, was established for the phase II study described above [41]. Sun and colleagues evaluated weekly topotecan and gemcitabine in a phase I study of 38 patients with a variety of advanced, refractory solid tumors [43]. Granulocytopenia and thrombocytopenia were the major dose-limiting toxicities, with gemcitabine, 1,000 mg/m 2, and topotecan, 2.5 mg/m 2, identified as the MTDs for this combination; those doses are similar to the doses used in monotherapy with either drug. Although evaluation of antitumor activity was not a primary end point of the trial, two patients were observed to achieve a partial response and five patients had stable disease. Five of nine patients treated for pancreatic carcinoma achieved either a partial response or disease stability. Further studies of this regimen are planned. A similar trial of weekly combination topotecan and gemcitabine was reported in 1999 by Dabrow and colleagues in patients with advanced non-small cell lung cancer [44]. In this dose-escalation study, the dose of gemcitabine was held at 1,250 mg/m 2, while the dose of topotecan was escalated in 0.25 mg/m 2 increments in four cohort groups from 1.00 mg/m 2 to 2.00 mg/m 2. Of 13 evaluable patients at the time of this preliminary report, one experienced grade 3/4 neutropenia, and there were no episodes of febrile neutropenia. Anemia was limited to grade 1 or grade 2 in eight patients, and thrombocytopenia was also limited to grades 1 and 2 in seven patients. Four (30%) of the 13 evaluable patients had a partial response, one at each dose level tested. The MTD of topotecan had not yet been achieved, and accrual continues. DISCUSSION AND CONCLUSION The concept of weekly administration of topotecan, both as a single-agent and in combination regimens, is of growing interest as an alternative to the daily 5 schedule because of its greater convenience and reduced toxicity. These advantages are particularly important in disease settings where topotecan is administered on a long-term basis as palliative therapy. Experience to date appears to indicate that responses may be attained that are in a similar range as the daily 5 schedule. Even in patients who do not achieve a major response (e.g., 50% reduction in tumor size), topotecan may contribute to disease palliation and maintenance of quality of life over a protracted period by decreasing the overall tumor growth rate and/or stabilizing the disease process without debilitating adverse effects. Indeed, stable disease with symptom control may represent a desirable end point of topotecan chemotherapy. Studies have shown that, in selected populations of cancer patients, long-term stable disease and partial response are considered similar in terms of survival benefit [45, 46]. Also, in the first-line setting, where the goal of therapy is often to increase overall survival time, it may be more feasible to combine topotecan given on a weekly schedule (than the daily 5 schedule) with other agents to form potentially superior multidrug therapies. As a follow-up to several of the studies described above, weekly regimens of first-line topotecan-containing combination therapies are being developed. The fact that weekly topotecan is less myelosuppressive than the daily 5 regimen further facilitates the development of new topotecan-containing combination chemotherapies. Some important issues remain to be resolved. For example: What is the optimal dose of single-agent topotecan when administered on a weekly schedule? Should weekly dosing be continuous or would it be more feasible to provide intermittent treatment breaks with weekly treatment (i.e., weekly 3 every 28 days)? What influence on response and survival outcomes might be expected with a weekly schedule? What weekly combinations of topotecan-containing multidrug therapies should be pursued in ovarian cancer, small cell lung cancer, and other tumor types? Studies to resolve these and other important questions are currently under way, and alternate dosing schedules for topotecan outside the clinical trial setting should be supported by larger randomized studies to confirm efficacy and reduced toxicity. Meanwhile, based on available evidence, weekly topotecan appears to be a potentially attractive alternative to the currently approved daily 5 schedule in terms of improved patient convenience and reduction in myelotoxicity. ACKNOWLEDGMENT E.K.R. is a consultant and investigator for Glaxo SmithKline.

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