Topotecan: An Oncologist s View

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1 Topotecan: An Oncologist s View JEAN-FRANÇOIS HÉRON Centre François Baclesse, Centre Régional de Lutte Contre le Cancer, Caen, France Key Words. Topotecan Clinical trials Ovarian neoplasms Small cell lung carcinoma Leukemia Review ABSTRACT Topotecan (Hycamtin ) is a topoisomerase I inhibitor which demonstrated a wide spectrum of antitumor activity in preclinical models. During phase I assessment, evidence of activity was most promising when topotecan was administered on an i.v. daily 5 schedule and a dose of 1.5 mg/m 2 /day was selected for phase II/III evaluation. This regimen has been shown to have activity in a wide range of tumor types, including recurrent ovarian cancer, relapsed small cell lung cancer (SCLC), non-small cell lung cancer, colon cancer, and breast cancer, as well as hematological malignancies. In patients with ovarian cancer who had failed standard therapy, topotecan demonstrated response rates of 13% to 25%, with median times to progression of 12 to 19 weeks. Compared with paclitaxel, the response rates were similar, 20.5% and 14.0%, respectively, as were median times to progression (19 weeks INTRODUCTION Topotecan (Hycamtin ) is a semi-synthetic analog of the alkaloid camptothecin, which was isolated in the mid- 1960s. Although camptothecin had impressive antineoplastic activity, phase II evaluation was terminated when severe and unpredictable toxicities, including severe hemorrhagic cystitis, were observed [1]. Poor aqueous solubility also precluded further development [2]. Interest then focused on the development of water-soluble synthetic analogs, such as topotecan, which had an improved toxicity profile and broad-spectrum antitumor activity [3]. Topotecan belongs to the class of drugs known as topoisomerase I inhibitors, which have a unique mode of action. They produce DNA damage in the presence of the nuclear enzyme topoisomerase I, which is involved in the control of DNA topology by relieving the strain in DNA supercoils during replication and translation. Topotecan stabilizes the covalent intermediate between topoisomerase I and DNA, the cleavable complex; it inhibits topoisomerase I and causes for topotecan versus 15 weeks for paclitaxel). Results in recurrent SCLC have also been encouraging. Patients sensitive to previous chemotherapy have shown response rates of 19% and 39%, and even patients resistant or refractory to previous chemotherapy have had responses of 3% and 7%. Survival ranged from 20 weeks in refractory disease to 12 months in both sensitive and resistant/refractory disease combined. The safety profile of topotecan is well established. The principal toxicity is noncumulative myelosuppression, and serious sequelae are uncommon. Nonhematological toxicities are generally mild. The use of topotecan in combination regimens is promising, although clinical results are currently at an early stage. To date, topotecan has demonstrated its activity in recurrent ovarian cancer and offers a valuable addition to treatment options in relapsed SCLC. The Oncologist 1998;3: single-strand DNA breaks which inhibit DNA function and lead ultimately to cell death by generating double-stranded DNA breaks when DNA replication occurs [4]. Preclinical evaluation of topotecan revealed a wide spectrum of antineoplastic activity. In in vitro models of human tumors, topotecan was active against a range of cell types, particularly ovarian and renal cells. Several tumors resistant to other cytotoxic agents, such as doxorubicin, etoposide, cyclophosphamide, and fluorouracil, were sensitive to topotecan [5]. Studies carried out in in vivo preclinical models indicated activity in a number of tumor types, including colon carcinoma, lung carcinoma, and multi-drug-resistant cell lines [6-9]. Pharmacokinetic and phase I studies were then undertaken to investigate the activity revealed in the preclinical work. This review reports the results of these studies and concentrates on the clinical data obtained from later phase II/III trials to determine the efficacy of topotecan in the treatment of a range of solid tumors and leukemias. Correspondence: Jean-François Héron, M.D., Centre François Baclesse, Centre Régional de Lutte Contre le Cancer, Route de Lion sur Mer, Caen, France. Telephone: ; Fax: ; jfheron@baclesse.fr Accepted for publication September 2, AlphaMed Press /98/$5.00/0 The Oncologist 1998;3:

2 Héron 391 PHARMACOKINETIC AND PHASE I STUDIES Preclinical results suggested that topotecan activity was greatest when given intermittently or continuously over a prolonged period of time. Although an i.v. bolus was briefly evaluated [10], this was not developed further, and phase I studies employed regimens involving 5 to 21 days of treatment with 30-min i.v. infusions or continuous i.v. infusions varying in duration from 24 h to 21 days. Similarly, oral topotecan was given for five to 21 days every three or four weeks. A series of studies has been conducted to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) for each regimen (Table 1). Intravenous Daily 5 Regimens After i.v. administration, topotecan undergoes rapid hydrolysis of the lactone to the ring opened dihydroxy carboxylic acid with a ratio of lactone to acid of approximately 1:1 within 15 min of the end of the infusion, with the ratio rising to 1:4 or 1:5 over several hours [11]. Plasma clearance is high, approximately l/h/m 2, and plasma half-life is short at 2 to 3 h [12]. In patients receiving topotecan 0.5 to 2.5 mg/m 2 /day for five days, the relationship between the AUC for topotecan and the mean percentage decrease in absolute neutrophil count (ANC) was well described by a sigmoidal model. This model also described the change in ANC for patients who had dose escalations or reductions, thus Table 1. Dosing schedules with single-agent topotecan Dosing schedule DLTs MTD/Recommended dose Reference Single intravenous infusion i.v. bolus q 3 weeks Neutropenia grade mg/m 2 [10] Intravenous daily 5 30-min infusion daily 5 q 3 weeks Neutropenia grade 3/4 1.5 mg/m 2 /day [11] 30-min infusion daily 5 q 3 weeks Leukocytopenia grade 3/4 1.5 mg/m 2 /day [14] 30-min infusion daily 5 q 4 weeks Granulocytopenia grade mg/m 2 /day (previously untreated); [15] 1.25 mg/m 2 /day (previously treated); MTD not increased with G-CSF 30-min infusion daily 5 q 3 weeks Thrombocytopenia grade 3/ mg/m 2 /day (with post-topotecan G-CSF) [16] 30-min infusion daily 5 q 3 weeks Thrombocytopenia & neutropenia 3.5 mg/m 2 /day (with post-topotecan G-CSF) [17] Continuous intravenous (civ) infusion 24-h civ infusion q 3 weeks Leukopenia grade 3/4 & 8.4 mg/m 2 [21] thrombocytopenia grade 4 24-h civ infusion q 3 weeks Neutropenia, thrombocytopenia 4 mg/m 2 (heavily pretreated) [23] grade 3/4 24-h civ infusion q 3 weeks Neutropenia & thrombocytopenia 4 mg/m 2 (heavily pretreated); 10 mg/m 2 [24] (minimally pretreated) 24-h civ infusion q 7 days Granulocytopenia grade 3/4 1.5 mg/m 2 [25] 120-h civ infusion q 3 weeks Granulocytopenia grade 3/ mg/m 2 [22] 72-h civ infusion q 3 weeks Thrombocytopenia grade 3/4 1.6 mg/m 2 [22] 72-h civ infusion q 7 or 14 days Myelotoxicity 2.0 mg/m 2 /72 h q 7 days [26] 7- to 21-day civ infusion q 4 weeks Leukopenia grade 3/4 & 0.53 mg/m 2 /day for 21 days (heavily pretreated) [27] thrombocytopenia grade 4 21-day civ infusion q 4 weeks Hematological (not specified) 0.6 mg/m 2 /day (minimally pretreated); [28] 0.8 mg/m 2 (no pretreatment) Oral administration 5 days po od q 3 weeks Granulocytopenia grade 3/4 2.3 mg/m 2 /day [30] 10 days po od q 3 weeks Granulocytopenia grade mg/m 2 /day [30] & diarrhea grade 3 10 days po bid q 3 weeks Granulocytopenia grade mg/m 2 /bid [30] & diarrhea grade 3/4 21 days po bid q 4 weeks Diarrhea grade mg/m 2 /bid [30]

3 392 Review of Clinical Trials with Topotecan confirming the lack of cumulative myelotoxicity. In phase II studies where myelosuppression was assessed, no evidence of cumulative toxicity was found [13]. A later pharmacokinetic study found similar values for AUC but a better correlation between dose and AUC, although the topotecan dose range in the study was smaller (0.5 to 1.5 mg/m 2 /day for five days) [14]. In these two studies [12, 14], patients with a variety of solid tumors received topotecan as a 30-min i.v. infusion. Myelosuppression was the DLT, with an MTD for topotecan of 1.5 mg/m 2 /day for five days every 21 days [11, 14]. A third phase I study confirmed this MTD, but recommended a more conservative starting dose of 1.25 mg/m 2 /day for five days every 21 days for previously treated patients [15]. Responses were observed in patients with platinum-refractory ovarian cancer, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Results from studies in which granulocyte-colony stimulating factor (G-CSF) was administered to investigate its effects on topotecan myelosuppression were not always in agreement. Investigators in one study found that the MTD was not increased [15], whereas others showed that doses of or 3.5 mg/m 2 /day for five days could be given [16, 17]. However, these last two studies demonstrated that the timing of G-CSF administration was critical. When G-CSF was given concurrently with the topotecan infusions, myelosuppression was severe. Post-topotecan treatment administration of G-CSF enabled a 2.3-fold dose escalation of topotecan above the normal MTD in patients with solid tumors. The effects of renal or hepatic impairment on topotecan tolerability have also been studied. In renal impairment, plasma clearance of topotecan was reduced as the degree of impairment increased, although there was considerable interpatient variability even when difference in renal function was taken into account [18]. It was also found that previous receipt of extensive myelosuppressive therapy was associated with greater toxicity within patients grouped according to their renal function. In patients with mild renal impairment (creatinine clearance ml/min), a clearance of 67% of that in patients with normal renal function was observed and the MTD was not reduced, but in moderate impairment (creatinine clearance ml/min), clearance was reduced substantially to 34% of that in normal patients, with a concurrent increase in plasma half-life to approximately 5 h. The authors concluded that both renal function and extent of prior therapy should be considered when selecting topotecan dose (Table 2). In a study comparing patients with hepatic impairment and those with normal hepatic function, topotecan clearance varied only to the extent of the difference in liver function between the groups [19]. Patients with moderate hepatic impairment (bilirubin <10mg/dl) had plasma clearance reduced to 67% of the normal value, and plasma halflife increased slightly to approximately two and one-half h. The MTD was unchanged, although the lack of hematological toxicity could have reflected the minimal prior therapy received by these patients. A drug interaction affecting topotecan disposition has been reported [20]. A pediatric patient with high-risk medulloblastoma receiving two cycles of topotecan at a dose adjusted to achieve a target topotecan lactone plasma AUC was also administered phenytoin as seizure prophylaxis. This resulted in a significant increase in the clearance of both topotecan lactone and total topotecan and of the plasma AUC of the N-desmethyl metabolite. The resulting decrease in exposure to topotecan lactone during co-administration of phenytoin suggested that an increase in topotecan dose might be required to maintain the pharmacological effect. Continuous-Infusion Regimens The ring opened dihydroxy carboxylic acid appears more slowly in plasma following continuous i.v. infusions. After a 24-h infusion of topotecan, 50% conversion to the carboxylic acid occurred after approximately 4 h [21], and the elimination half-life was 4.4 h for both the lactone and the carboxylic acid. Patients received doses in the range of 2.5 to 10.5 mg/m 2 every 21 days, and topotecan AUC was not linear with respect to dose at the higher doses. Total AUC and percentage decrease in ANC fit a sigmoidal model as before. Following a 72-h continuous infusion of topotecan at doses of mg/m 2 /day every 21 days, approximately 60% of topotecan was unchanged at steady state [22]. The MTD determined with the 24-h continuous infusion regimen every three weeks was 8.4 mg/m 2 [21], but tolerated Table 2. Dosing recommendations for i.v. daily 5 regimen in patients with renal impairment Degree of renal impairment Creatinine clearance Minimally pretreated patients Extensively pretreated patients None >60 ml/min 1.5 mg/m 2 /day 1.5 mg/m 2 /day Mild ml/min 1.5 mg/m 2 /day 1.0 mg/m 2 /day Moderate ml/min 0.75 mg/m 2 /day 0.5 mg/m 2 /day Severe <20 ml/min insufficient data insufficient data Data from [18].

4 Héron 393 doses were found to be lower (4 mg/m 2 ) in heavily pretreated patients [23, 24]. DLTs were hematological neutropenia and thrombocytopenia. In the 72-h continuous-infusion study, MTD was 1.6 mg/m 2 /day repeated every 21 days, with hematological toxicities dose-limiting [22]. When cycles were repeated more frequently, MTDs were lower: 1.5 mg/m 2 /24 h every seven days [25], and 2.0 mg/m 2 /72 h every seven days, or 2.6 mg/m 2 /72 h every 14 days [26]. Continuous infusions of longer duration have also been investigated resulting in MTDs of 0.68 mg/m 2 /day for fiveday infusions repeated every 21 days [22], and 0.8 mg/m 2 /day for 21-day infusions repeated every 28 days [27, 28]. In the last two studies, the MTD was reduced in patients who had received extensive prior myelosuppressive therapy. The DLTs were all hematologic. Oral Regimens Oral bioavailability following a single dose of 1.5 mg/m 2 po was calculated as 30% with a moderate degree of interpatient variation (in the order of 20%-40%), and maximum plasma concentrations occurred 0.8 h post-dose [29]. A range of schedules has been subject to evaluation: five- or 10-day once-daily dosing every three weeks; 10-day twice-daily dosing every three weeks, and 21-day twice-daily dosing every four weeks [30]. The DLT varied according to dosing regimen, with neutropenia for the five-day schedule, a combination of hematological toxicity and diarrhea for both 10-day schedules, and diarrhea alone for the 21-day schedule. The diarrhea was always self-limiting, although it was sometimes uncontrollable with loperamide, particularly on the 21-day schedule [31]. The exact mechanism is not known, but local intestinal exposure to topotecan could be an inducing factor. The MTDs were 2.3 mg/m 2 /day and 1.4 mg/m 2 /day for five-day and 10-day once-daily dosing, respectively; 0.7 mg/m 2 /day bid for 10-day twice-daily dosing, and 0.5 mg/m 2 /day bid for 21-day twice-daily dosing. Combination Regimens In the future, interest is likely to focus on the use of topotecan in combination regimens, although clinical results are currently at a preliminary stage. Phase I studies have investigated the MTD of topotecan in combination with a variety of established agents, including paclitaxel. Preclinical work with a combination of topotecan and cisplatin in animal models demonstrated evidence of therapeutic synergism [32, 33]. Evaluation of the combination in patients with solid tumors refractory to conventional chemotherapy demonstrated a greater degree of myelotoxicity with the combination than for either agent alone [34]. The authors recommended a dose of topotecan 1.0 mg/m 2 /day 5 in combination with cisplatin on day 1 at a dose of 50 mg/m 2, or 75 mg/m 2 with G-CSF support. In a phase I/II study in advanced NSCLC, 15 patients receiving cisplatin 75 mg/m 2 on day 1 and topotecan 0.75 mg/m 2 /day 5 showed a partial response rate of 13% [35]. Subsequent use of this cisplatin/topotecan combination in a phase II trial in patients with extensive SCLC, however, has resulted in some cases of fatal treatment-related sepsis. The authors recommended that the criteria for DLT used to determine the MTD in phase I studies be considered carefully against the acceptable level of risk for specific patient populations [36]. Later work demonstrated that the extent of myelotoxicity was dependent on the order of administration of the two agents [37]. The sequence of cisplatin followed by topotecan produced significantly worse neutropenia than the alternative sequence, and the MTD determined by the authors for the former combination was slightly lower than in the earlier work, cisplatin 50 mg/m 2 on day 1 and topotecan 0.75 mg/m 2 /day on days 1-5. Currently, however, there are no data available on the comparative efficacy of the two schedules, and since toxicity with cytotoxic agents is generally equated with efficacy, the sequence selected for most clinical trials to date has been cisplatin followed by topotecan. Other schedules have also been investigated. Both agents were administered together on a daily 5 basis at the following doses: cisplatin 16 mg/m 2 /day and topotecan 0.75 mg/m 2 /day every 28 days with G-CSF support [38]. The unusually late occurrence of myelosuppression (day 21) compared with the situation for topotecan alone, was suggestive of topotecan-enhanced cisplatin toxicity. In addition, a phase I study using a continuous i.v. topotecan infusion is under way in the absence of growth factor support. Currently, patients are able to tolerate cisplatin 37.5 mg/m 2 on day 1 and topotecan 0.4 mg/m 2 /day as a continuous 14-day infusion [39]. In combination with paclitaxel, the MTDs identified in patients with solid tumors have been topotecan 1.0 mg/m 2 /day for five days every 21 or 28 days with paclitaxel 80 mg/m 2 given as a 3-h infusion on day 1 [40], or an increased paclitaxel dose of 230 mg/m 2 as a 3-h infusion on day 1 with G-CSF support [41]. Responses were seen in patients with NSCLC, head and neck cancer, and colon carcinoma. In a phase II trial, however, this combination of paclitaxel 230 mg/m 2 as a 3-h infusion on day 1 and topotecan 1.0 mg/m 2 /day for five days resulted in three cases of fatal treatment-related sepsis [36]. The MTD for a continuous 14-day infusion of topotecan in combination with paclitaxel has been reported as paclitaxel 135 mg/m 2 as a 3-h infusion on day 1 and topotecan 0.3 mg/m 2 /day for 14 days, with the study continuing to confirm this MTD [42]. In contrast to the combination of topotecan/cisplatin, the toxicities associated with administration of topotecan and paclitaxel did not appear to be sequence-dependent [43]. The

5 394 Review of Clinical Trials with Topotecan recommended doses were paclitaxel 135 mg/m 2 on day 1 and topotecan 0.75 mg/m 2 /day for five days with G-CSF support, with possible topotecan dose escalation to 1.25 mg/m 2 /day if the initial dose was well tolerated. In four of 11 patients with recurrent or refractory ovarian cancer and measurable disease, there was a complete or partial response. A number of other topotecan combinations are under investigation. In combination with cyclophosphamide 600 mg/m 2 on day 1, the MTD of topotecan was 0.75 mg/m 2 /day for five days or 1.0 mg/m 2 /day for five days with growth factor support [44]. Preclinical data have suggested that the combination of topotecan and etoposide, a topoisomerase II inhibitor, is synergistic when given sequentially. Studies have either involved administration of topotecan, 1.25 mg/m 2 /day 5 with etoposide 40 mg bd on days 6-12 every four weeks, or 1.0 mg/m 2 /day 5 with etoposide 20 mg bid on days 6-15 every three weeks [45], or continuous i.v. infusions of topotecan for 72 h at doses of up to 1.1 mg/m 2 /day or for 120 h at a dose of 1.5 mg/m 2 /day followed by etoposide 100 mg/m 2 /day for three or five days [46-48]. There are indications of activity in acute leukemia when topotecan is used in combination with cytarabine. Patients Table 3. Clinical studies in ovarian cancer and SCLC received cytarabine 1 g/m 2 /day for five days with topotecan mg/m 2 /day 5, 12 h after each cytarabine dose [49]. The recommended dose of topotecan was 4.75 mg/m 2 /day 5 for patients who had had more than one prior chemotherapy regimen and 7.0 mg/m 2 /day 5 for patients with no more than one prior regimen. Mucositis was dose-limiting. Responses were seen with both combinations in acute myelogenous leukemia, acute lymphoblastic leukemia, and chronic myelogenous leukemia in blast phase. PHASE II/III STUDIES The therapeutic efficacy of topotecan has been investigated in a range of tumors. Currently, it has been shown to be active as second-line therapy in ovarian cancer and is marketed as such in the U.S. and most European countries. Topotecan also has activity in SCLC. Work in other tumor types is at an earlier stage of development, but results in NSCLC, colon cancer, breast cancer, and hematological malignancies look promising. The most extensive experience has been with a daily 5 i.v. schedule. A summary of the trials carried out in ovarian cancer and SCLC is shown in Table 3. n evaluable Topotecan regimen Response rate Median time to progression/ Patients patients (mg/m 2 /day) (complete; partial) median survival Reference Ovarian Cancer Relapsed ovarian cancer q 21 days 14.3% (0%; 14.3%) Time to progression: 10.8 months (responders) [50] Treatment-refractory ovarian cancer q 21 days 25% [51] Failed first-line therapy with q 21 days 16.3% (1.1%; 15.2%) Time to progression: 11.9 weeks [52] cisplatin/carboplatin Failed first-line therapy with paclitaxel q 21 days 12.9% Time to progression: 17 weeks [53] + cisplatin/carboplatin Failed second-line therapy with paclitaxel q 21 days 16.9% Time to progression: 11 weeks [53] + cisplatin/carboplatin Failed first-line therapy with q 21 days 20.6% (4.5%; 16.1%) Time to progression: 18.9 weeks [57] platinum-based regimen Small Cell Lung Cancer (SCLC) Progressive SCLC: sensitive q 21 days 37% (13%; 24%) Survival: 6.9 months [58] Progressive SCLC: refractory q 21 days 6% (2%; 4%) Survival: 4.7 months [58] Progressive SCLC: sensitive q 21 days 14% (2%; 12%) Survival: 25.7 weeks [59, 60] Progressive SCLC: refractory q 21 days 2% (0%; 2%) Survival: 16.3 weeks [59, 60] Progressive SCLC: sensitive q 21 days 19% (8%; 11%) Survival: 26.6 weeks [61] Progressive SCLC: refractory q 21 days 3% (0%; 3%) Survival: 20.4 weeks [61] Relapsed SCLC q 21 days 24.3% Survival: 24.7 weeks [64] SCLC refractory to etoposide q 21 days 11% (0%; 11%) Survival: 20 weeks [66] Extensive SCLC, naive to chemotherapy q 21 days 39% (0%; 39%) Survival: 10 months [67] Extensive SCLC, naive to chemotherapy paclitaxel 92% (17%; 75%) [68] 135 mg/m 2 on day 5

6 Héron 395 Ovarian Cancer In an initial phase II trial, 28 evaluable patients with relapsed ovarian cancer who had all previously received platinum-containing regimens were treated with i.v. topotecan at a starting dose of 1.5 mg/m 2 /day for five days every 21 days [50]. The results were encouraging and showed an overall response rate of 14% in this heavily pretreated population. In addition, preliminary results of a study conducted by the U.S. National Cancer Institute confirmed this activity [51]. Patients with treatment-refractory ovarian cancer who progressed following first-line therapy received i.v. topotecan 1.5 mg/m 2 /day 5 every 21 days with a response rate of 25% in the 16 patients evaluable at the time of the report. Three larger phase II/III trials were then undertaken for further evaluation of these early results. Two of the studies were uncontrolled, one in patients who had received one previous platinumcontaining regimen [52], and one in patients who had failed platinum and paclitaxel, given either together as a first-line regimen or separately during first- and second-line therapy [53]. The third trial was a comparative study versus paclitaxel [54], and all were carried out with the 1.5 mg/m 2 /day 5 q 21 days i.v. topotecan regimen. In the European trial of 92 evaluable patients with measurable disease who had failed one previous regimen [52], a response rate of 16.3% was obtained, with a median duration of response of 21.7 weeks. In all evaluable patients, the median time to progression was 11.9 weeks. Patients were categorized according to their response to first-line therapy and, although response rates were higher at 26.7% and 17.8%, respectively, in those with platinum-sensitive and platinum-resistant disease (patients who had initially responded and subsequently relapsed either more than or less than six months after the end of initial chemotherapy), even patients with platinum-refractory disease (those with progressive or stable disease during initial chemotherapy) had a response rate of 5.9%. All responses were confirmed by a rigorous independent radiological review process which led to rejection of eight of the 24 claimed responses, reducing the response rate by 33% [55]. Although the response in platinum-refractory disease was low, a further 26.5% of patients had disease stabilization. While not usually considered as a response to treatment, periods of stable disease might be interpreted as a beneficial outcome, particularly in aggressive tumors such as these [56]. Topotecan has emerged as a promising new antineoplastic agent in the treatment of a range of solid tumors and hematological malignancies. A preliminary report of the results of the second uncontrolled study in 139 patients shows close agreement [53]. Patients who had failed prior therapy with paclitaxel in combination with cisplatin or carboplatin had a response rate of 12.9% (n = 62), and those who were second-line failures had a response rate of 16.9% (n = 77). Median time to progression was longer for the first-line failures at 17 weeks, compared with 11 weeks for the second-line failures, demonstrating valuable activity in this patient population. Of particular interest are the results of the large, randomized, comparative study versus paclitaxel carried out in North America and Europe in patients with measurable disease who had progressed following first-line therapy with a platinumcontaining regimen. Paclitaxel was administered at the recommended dose of 175 mg/m 2 over 3 h every 21 days and all responses were reviewed by an independent radiologist. In an interim published report [54], the response rate for topotecan was 20.5% (95%, CI = 13%-28.3%; n = 112), compared with 13.2% for paclitaxel (95%, CI = 7.0%-19.4%; n = 114), but the activity of the two treatments was not significantly different (p = 0.138). Median time to progression was significantly longer with topotecan than with paclitaxel, 23 weeks versus 14 weeks (p = 0.002), and median survival was also longer, 61 weeks versus 43 weeks, although not significantly so (p = 0.515). Subsequently, after a final analysis, results were revised to give a response rate for topotecan of 20.5% compared with 14.0% for paclitaxel (p = 0.196) [57]. There was no longer any significant difference between the groups in median time to progression (18.9 weeks for topotecan versus 14.7 weeks for paclitaxel [p = 0.072]), and median survival data were also revised (63 weeks for topotecan versus 53 weeks for paclitaxel [p = 0.872]). Following relapse in this study, patients were permitted to cross over to the alternate arm, with resulting response rates of 13.1% and 10.2%, respectively, for patients who received topotecan and paclitaxel as salvage therapy (p = 0.638). In all these studies, the major side effect of topotecan treatment was myelosuppression. Grades 3 and 4 neutropenia generally occurred in 60%-70% of courses but was not cumulative, and febrile neutropenia of grade 2 or above was infrequent. There were only two deaths attributed to topotecan-induced sepsis. Approximately 90% of topotecan courses were given at the scheduled dose. Nonhematological toxicities were generally mild, and, apart from alopecia,

7 396 Review of Clinical Trials with Topotecan consisted mainly of nausea, vomiting, and fatigue. In comparison with paclitaxel, grade 4 neutropenia was more frequent with topotecan (36% versus 9% of courses) as was grade 4 neutropenia associated with fever or infection, although the overall incidence was low (6% versus 1%). Grade 4 thrombocytopenia also occurred more frequently with topotecan than with paclitaxel (10% versus <1%). Nonhematological toxicity was generally mild for both groups, although alopecia, peripheral neurotoxicity, arthralgia, myalgia, and abdominal pain were reported more frequently by patients receiving paclitaxel. Paclitaxel patients had less nausea and vomiting, but this could have resulted from their premedication with dexamethasone, required to prevent hypersensitivity reactions. SCLC Activity in progressive SCLC has been demonstrated. A study was carried out by the European Organisation for Research and Treatment of Cancer (EORTC) in 50 patients sensitive to previous therapy (patients who initially responded but progressed after a treatment-free interval of at least three months) and 51 patients refractory to previous therapy (patients who failed first-line treatment or who initially responded but progressed within three months of the end of treatment) [58]. Patients received topotecan at an initial dose of 1.5 mg/m 2 /day i.v. for 5 days every 21 days and median survival in 92 evaluable patients was 5.4 months. Response rates were 37.8% in sensitive disease and 6.4% in refractory disease and median survival was 6.9 months and 4.7 months, respectively. As in ovarian cancer, the principal side effect was myelosuppression with grade 3 or 4 neutropenia occurring in 75% of treatment courses. Nonhematological toxicities were generally mild. In a similar study, patients with relapsed SCLC also received topotecan at a dose of 1.5 mg/m 2 /day i.v. for five days every 21 days [59, 60]. Fifty-seven patients sensitive to previous therapy and 41 patients refractory to previous therapy were evaluable for response. The response rates were lower than in the EORTC study: 14.0% in sensitive disease and 2.4% in refractory disease, although median survival was similar: 25.7 weeks and 16.3 weeks, respectively. It was noted, however, that 9 of the 11 patients with stable disease were removed from the study after only two or three cycles of topotecan treatment and offered alternative therapy. In a further multicenter study conducted in the U.S. using the same dosing regimen, response rates of 19% and 3%, respectively, were observed in patients sensitive (n = 36) and refractory (n = 38) to previous chemotherapy [61]. In addition, 36% and 45% of patients in the respective groups had stable disease. Median survival was slightly longer in the sensitive (26.6 weeks) than in the refractory (20.4 weeks) group. The predominant toxicity was hematological; grade 4 neutropenia occurred in 52% of courses, and nonhematological toxicities were generally of mild/moderate intensity. Pooled results for 168 patients from this and the two previous studies described showed an overall response rate of 18% and a median survival of 30 weeks. The one-year survival rate was 21% [62, 63]. Results from a randomized, comparative phase III trial of topotecan versus CAV (cyclophosphamide, doxorubicin, and vincristine) as second-line therapy in patients sensitive to previous therapy have been reported [64]. Patients received either topotecan 1.5 mg/m 2 /day i.v. for five days every three weeks or cyclophosphamide 1,000 mg/m 2, doxorubicin 45 mg/m 2, and vincristine 2 mg i.v. on day 1 every three weeks. Response rates were topotecan 24.3% (n = 107) and CAV 17.3% (n = 104), and median survival was 24.7 weeks and 22.0 weeks, respectively, with no significant differences between treatments. There was some evidence for a superior effect on symptoms with topotecan: dyspnea, fatigue, hoarseness, and interference with daily activities showed a statistically significant improvement with topotecan. Grade 4 neutropenia occurred to a similar extent with both agents (38% of topotecan courses and 51% of CAV courses), and nonhematological toxicity was generally mild for both groups. Some evidence of antitumor activity in brain metastases has also been noted in these studies of SCLC in patients who had failed first-line therapy [65]. Sixteen patients with asymptomatic brain metastases received topotecan at doses of either 1.5 mg/m 2 /day i.v. for five days every 21 days or 0.4 mg/m 2 /day as a continuous 21-day infusion every 28 days. Ten patients (63%) showed a CNS response, four with a complete response. In addition, patients refractory to etoposide and cisplatin have shown responses to second-line therapy with topotecan [66]. Twenty-eight evaluable patients received topotecan at a dose of 1.25 mg/m 2 /day i.v. for five days every 21 days, and three patients (11%) responded to treatment. Grades 3 and 4 neutropenia occurred in 70% of courses, but there were no episodes of neutropenic fever and no toxic deaths. A study of topotecan in first-line therapy has been conducted by the Eastern Cooperative Oncology Group (ECOG) [67]. Forty-eight patients with extensive-stage SCLC received a slightly higher topotecan dose of 2.0 mg/m 2 /day i.v. for five days every 21 days for a maximum of four cycles before receiving salvage therapy with cisplatin plus etoposide. In order to control neutropenic toxicity, G-CSF was given from day 6 of a treatment cycle. The response rate on topotecan alone was 39%, with a median duration of response of 4.8 months and a median survival of 10.0 months following all cycles of treatment. Similarly, a recent report of a combination of topotecan and paclitaxel shows high activity against untreated SCLC [68]. Patients with extensive disease received topotecan

8 Héron mg/m 2 /day, later reduced to 1.0 mg/m 2 /day, for five days with paclitaxel 135 mg/m 2 on day 5 with G-CSF support. Patients who failed to respond after two cycles were treated with standard chemotherapy. Of 12 evaluable patients, there were 11 responders (92%), two with a complete response. The two-year survival rate was 25%. Hematological Malignancies Recent work in myelodysplastic syndrome (MDS), including refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMML) has shown promise [69]. Forty-seven patients who received i.v. topotecan 2.0 mg/m 2 /day as a continuous five-day infusion had a response rate of 28% (all complete responses) and six patients (13%) had hematologic improvement. The response rates in RAEB (25%), RAEB-T (30%), and CMML (28%) were similar. Apart from myelosuppression, 19% of patients experienced grade 3/4 mucositis and 13% grade 3/4 diarrhea. Phase I work had previously demonstrated that severe mucositis was the DLT in leukemias, in contrast to solid tumors where myelosuppression is dose-limiting [70, 71]. Responses in other hematological malignancies have also been encouraging. Eighteen patients with relapsing lymphoma received topotecan 2 mg/m 2 /day 5 every four weeks with G-CSF support [72]. The response rate was 50%, and hematological toxicity was mainly thrombocytopenia. In patients with resistant and relapsing multiple myeloma, a response rate of 25% has been achieved in 24 patients who received topotecan 1.25 mg/m 2 /day 5 every three weeks with G-CSF support [73]. Median survival was impressive at 21 months. Myelosuppression, principally neutropenia, was the major toxicity. A study in 12 patients with chronic lymphocytic leukemia who had previously received fludarabine, however, showed no responses following a topotecan regimen of 2.0 mg/m 2 /day i.v. for five days every month [74]. Other Tumor Types Response to topotecan treatment has also been observed in NSCLC and central nervous system (CNS) tumors. Two studies in NSCLC in which i.v. topotecan was administered at a dose of 1.5 mg/m 2 /day i.v. for five days every 21 days have shown response rates of 15% [75] and 18.4% [76] and median survival of 38 weeks and eight months, respectively. The former study demonstrated a higher response rate (36%) in those patients with squamous carcinomas, although this was revised to 24% when updated results became available. Median survival, however, was not reduced at 40 weeks [77]. A third study, in contrast, found no responses among 20 patients with advanced, metastatic NSCLC treated at a higher topotecan dose of 2.0 mg/m 2 /day i.v. 5 every 21 days, although 55% of patients had stable disease and median survival was 7.6 months for all treated patients [78]. Responses were poorer, 8% [76] and 4% [79] with continuous i.v. infusions of topotecan at doses of 1.3 mg/m 2 /day for three days every 28 days and 0.5 or 0.6 mg/m 2 /day for 21 days every 28 days, although survival was not similarly reduced, since median values were six and nine months, respectively. Tumors of the CNS have also been treated with topotecan. Patients with malignant gliomas have received both the daily 5 regimen [80] and a continuous i.v. infusion [81]. In the first study, 31 patients with newly diagnosed or recurrent gliomas received topotecan 1.5 mg/m 2 /day i.v. for five days every 21 days with a 6% response rate. In the second study, 10 evaluable patients received 0.4 mg/m 2 /day for 21 days, with two patients having objective responses. A study carried out in 14 evaluable patients with metastatic breast cancer who received topotecan i.v. at a dose of 1.5 mg/m 2 /day i.v. for five days every 21 days showed a response rate of 36% [82]. In a second study of 20 patients who had received extensive prior therapy, all with chemotherapy and most also with surgery and radiotherapy, topotecan was administered using the same 1.5 mg/m 2 /day i.v. 5 every 21 days regimen. The response rate was 10%, with an additional 40% of patients having disease stabilization [83]. Other administration schedules were evaluated in patients with metastatic breast cancer, most of whom had metastases in the liver and thorax and had received prior radiotherapy, hormonal therapy, and surgery [84]. A response rate of 6% was seen in 18 patients receiving topotecan 22.5 mg/m 2 as a 30-min i.v. infusion every three weeks, but no responses were seen in 16 patients who received topotecan 1.5 mg/m 2 as a 24-h continuous i.v. infusion every seven days. In combination with paclitaxel (230 mg/m 2 on day 1 prior to topotecan 1.0 mg/m 2 /day i.v. 5 every 21 days), a response rate of 6% lasting approximately one year was observed in 17 patients with advanced, recurrent, or metastatic breast cancer who had received up to two prior chemotherapeutic regimens [85]. In some studies, however, patients with stable disease were withdrawn before four cycles of topotecan were administered. This may have been premature in light of findings with other tumor types [59]. In colorectal cancer, response rates of 7% and 10% have been observed with topotecan regimens of, respectively, 1.5 mg/m 2 /day i.v. for five days every 21 days [86] and a continuous i.v. infusion of topotecan 0.6 mg/m 2 /day for 21 days every 28 days [87]. The proportions of patients with stable disease were high at 56% and 34%, respectively. Work in other cancers is at an early stage of development. Results from a phase II trial in 22 evaluable patients with cervical cancer given a slightly lower topotecan dose of 1.2 mg/m 2 /day i.v. 5 every 21 days have shown an overall

9 398 Review of Clinical Trials with Topotecan response rate of 18% [88]. Responses were seen both in patients with no prior chemotherapy (25%) and in patients with prior treatment regimens (17%), all the responses being in patients diagnosed with squamous cell carcinoma. Some evidence of activity has also been demonstrated in advanced or metastatic adenocarcinoma of the pancreas treated with topotecan 1.5 mg/m 2 /day i.v. for five days every 21 days [89]. Although the response rate in 30 evaluable patients was 10%, 36% of patients had stable disease for more than eight weeks and the median survival was 19 weeks. Two other studies in advanced pancreatic cancer, however, showed no significant activity [90, 91]. Topotecan at a dose of 1.5 mg/m 2 /day i.v. 5 every 21 days has been shown to have only limited activity in phase II studies in metastatic melanoma (response rate of 6%) [92], prostate cancer (8%) [93], and softtissue sarcoma (10%) [94]. No activity, however, has been demonstrated to date in the treatment of germ cell tumors [95], pleural mesothelioma [96], or renal cell carcinoma [97]. DISCUSSION Topotecan has emerged as a promising new antineoplastic agent in the treatment of a range of solid tumors and hematological malignancies. Its novel mode of action via topoisomerase I inhibition and low cross-reactivity with existing agents offers a clear therapeutic option to patients with recurrent or refractory disease. Most of the phase I studies have explored an i.v. daily 5 schedule with topotecan administered at a dose of 1.5 mg/m 2 /day, repeated every three weeks, and phase II/III trials in ovarian cancer and SCLC using this regimen have shown both clinical benefit and a manageable toxicity profile. An oral formulation has, however, been developed which could offer substantial benefit in terms of convenience of administration and patient compliance. Data from an ongoing study in which i.v. and oral administration are being compared in patients with ovarian cancer have shown almost identical response rates (21.5% i.v. versus 21.4% po; yet to be subjected to independent review) [98], which were consistent with previously published data [52, 57]. i.v. administration resulted in a higher incidence of grade 4 neutropenia, whereas oral administration resulted in more diarrhea, although the incidence of grade 3/4 diarrhea was still low (3.1%). Administration of topotecan at a dose of 1.5 mg/m 2 /day 5 q 3 weeks to patients with ovarian cancer who had failed Topotecan s novel mode of action via topoisomerase I inhibition and low cross-reactivity with existing agents offers a clear therapeutic option to patients with recurrent or refractory disease. first-line therapy resulted in response rates of 13% to 25%, with median times to progression of 12 to 19 weeks. In a direct comparison with paclitaxel, the response rate was similar for topotecan, 20.5% versus 14.0% for paclitaxel, and median time to progression was slightly longer with topotecan (19 versus 15 weeks), although not significantly so. Although this response rate for paclitaxel seems low, it may be due to the use of independent radiological review of responses and is in line with the rate of 15% reported in a large European- Canadian study where independent review was also employed [99]. Both agents are now approved in this indication, but as paclitaxel is becoming the standard as first-line therapy, topotecan will be a useful agent following relapse. Activity has also been established in recurrent SCLC. This is a disease for which there is currently no standard therapy, and, historically, survival without treatment is known to be only 7-12 weeks [100, 101]. Patients sensitive to previous chemotherapy have demonstrated response rates of between 14% and 39%, and even patients refractory to previous chemotherapy have shown responses of 2% to 6%. In addition, some studies have reported rates of stable disease as high as 36% in patients sensitive to previous therapy and 45% in patients refractory to previous therapy, with a suggestion that patients may need to receive at least four cycles of treatment in order to achieve their optimum response. Median survival has ranged from 26 to 30 weeks for patients sensitive to previous therapy and from 16 to 20 weeks for patients refractory to previous therapy despite their low response rate. Comparison with CAV was also encouraging. A response rate of 25% was seen with topotecan compared with 16% for CAV, although median survival was similar for both treatments (22 weeks for topotecan versus 23 weeks for CAV). In addition, the use of topotecan as first-line therapy in SCLC, where a response rate of 39% was observed, has indicated valuable therapeutic efficacy. The safety profile of topotecan has been well established in both phase I trials and in extensive clinical use. In patients with solid tumors, the principal toxicity is myelosuppression. Since regulatory approval of topotecan, there has been some apprehension among clinicians concerning the extent and management of myelosuppression. Reviews of this issue using data from phase I to III studies have shown that, although neutropenia occurs in a majority of treatment courses in monotherapy, it is predictable, noncumulative,

10 Héron 399 and manageable [13, 102]. Serious events, such as neutropenic fever and sepsis, are not common. The optimal preventive strategy is dose reduction, and even patients who have received extensive pretreatment with myelosuppressive agents may start treatment with the standard regimen. The use of G-CSF should be restricted to prophylaxis after the patient has experienced febrile neutropenia, neutropenic infection or persistent neutropenia. Nonhematological toxicities are generally of mild intensity and largely consist of nausea and vomiting. In patients with leukemias, the principal toxicities are mucositis and diarrhea. To date, topotecan has demonstrated its activity in recurrent ovarian cancer and relapsed SCLC and offers a valuable addition to treatment options in hematological malignancies, with high response rates as a single agent in MDS. Future introduction of an oral formulation would offer exciting possibilities in terms of improved convenience of treatment while maintaining therapeutic response. The clinical role of topotecan, however, is still developing. Currently, interest is focused on its use in combination regimens and moving its use to first-line treatment. Preliminary reports of a number of early-phase studies in REFERENCES 1 Eckardt J, Eckhardt G, Villalona-Calero M et al. New anticancer agents in clinical development. Oncology 1995;9: Xie Z-F, Ootsu K, Akimoto H. Convergent approach to water soluble camptothecin derivatives. Bioorg Med Chem Lett 1995;5: Kingsbury WD, Boehm JC, Jakas DR et al. Synthesis of water-soluble (aminoalkyl) camptothecin analogs: inhibition of topoisomerase I and antitumor activity. J Med Chem 1991;34: Hsiang Y-H, Lihou MG, Liu LF. Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res 1989;49: Burris HA III, Hanauske A-R, Johnson RK et al. Activity of topotecan, a new topoisomerase I inhibitor, against human tumor colony-forming units in vitro. J Natl Cancer Inst 1992;84: Johnson RK, McCabe FL, Gallagher G et al. Comparative efficacy of topotecan, irinotecan, camptothecin and G-amino-camptothecin in preclinical tumour models. Proc 7th NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam 1992:85. 7 Houghton PJ, Cheshire PJ, Myers L et al. Evaluation of 9-dimethyl-aminomethyl-10-hydroxycamptothecin against xenografts derived from adult and childhood solid tumors. Cancer Chemother Pharmacol 1992;31: ovarian cancer have shown activity for topotecan in combination with cisplatin and paclitaxel where responses of 50% [103], 62% [104], and 78% (regimen comprised only topotecan and cisplatin) [105] were observed in patients with no prior therapy, and of 42% in a group of both pretreated and chemotherapy-naive patients [106]. In patients with SCLC, a number of combination regimens are under investigation. As for ovarian cancer, the combination with cisplatin and paclitaxel has shown activity with a response rate of 47% in pretreated and chemotherapy-naive patients [106], and in combination with carboplatin and paclitaxel a response rate of 70% was observed in patients with prior treatment 70% [107]. In addition, a regimen of topotecan and ifosfamide resulted in a 45% response rate in a group of patients with SCLC, some with prior chemotherapy [108], and a lower rate of 29% in patients either with sensitive relapse or who were previously untreated who received topotecan in combination with cyclophosphamide [109]. Although the optimum combination doses and sequences of administration are still being defined and these published results are in many cases preliminary, topotecan appears to offer promise in diseases where there is currently no hope. 8 Mattern MR, Hofmann GA, Polsky RM et al. In vitro and in vivo effects of clinically important camptothecin analogs on multidrug-resistant cells. Oncol Res 1993;5: Hendricks CB, Rowinsky EK, Grochow LB et al. Effect of P-glycoprotein expression on the accumulation and cytotoxicity of topotecan (SK&F ), a new camptothecin analog. Cancer Res 1992;52: Wall JG, Burris HA III, Von Hoff DD et al. A phase I clinical and pharmacokinetic study of the topoisomerase I inhibitor topotecan (SK&F ) given as an intravenous bolus every 21 days. Anticancer Drugs 1992;3: Rowinsky EK, Grochow LB, Hendricks CB et al. Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor. J Clin Oncol 1992;10: Herben VMM, ten Bokkel Huinink WW, Beijnen JH. Clinical pharmacokinetics of topotecan. Clin Pharmacokinet 1996;31: Armstrong D, O Reilly S. Clinical guidelines for managing topotecan-related hematologic toxicity. The Oncologist 1998;3: Verweij J, Lund B, Beijnen J et al. Phase I and pharmacokinetic study of topotecan, a new topoisomerase I inhibitor. Ann Oncol 1993;4: Saltz L, Sirott M, Young C et al. Phase I clinical and pharmacology study of topotecan given daily for 5 consecutive days to patients with advanced solid tumours, with attempt