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Emerging Role of Weekly Topotecan in Recurrent Small Cell Lung Cancer

John R. Eckardt

The Center for Cancer Care and Research, St. Louis, Missouri, USA

Correspondence: John R. Eckardt, M.D., The Center for Cancer Care and Research, 12855 North Forty Drive, Suite 200, St. Louis, Missouri 63141, USA. Telephone: 314-628-1210; Fax: 314-628-1220; e-mail: jeckardt{at}tcccr.com


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Rationale for Alternate...
 Weekly Topotecan Regimens
 Weekly Topotecan in SCLC
 Conclusions
 References
 
After completing this course, the reader will be able to:

  1. Identify the limitations of the established 5-day topotecan administration schedule in treating patients with recurrent SCLC.
  2. Explain the rationale for the use of weekly topotecan regimens in the recurrent SCLC setting.
  3. Discuss the efficacy and safety results from studies of weekly topotecan regimens in SCLC.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Rationale for Alternate...
 Weekly Topotecan Regimens
 Weekly Topotecan in SCLC
 Conclusions
 References
 
Small cell lung cancer (SCLC) is an aggressive tumor that often metastasizes before the primary cancer is diagnosed. Patients with SCLC are typically elderly and often have comorbidities that may predispose them to adverse events during therapy. Although topotecan (Hycamtin®; GlaxoSmithKline; Philadelphia, PA), 1.5 mg/m2/day via a 30-minute i.v. infusion on days 1–5 of a 21-day cycle, is a standard therapy for relapsed SCLC, this regimen can result in significant neutropenia, especially in previously treated patients. This hematologic toxicity is noncumulative and reversible, but its management can be challenging in this poor-prognosis population. Therefore, alternate treatment regimens have been investigated. Weekly topotecan (4.0 mg/m2) is currently investigational and has shown promising activity and favorable tolerability in patients with relapsed ovarian cancer, another aggressive malignancy with a poor prognosis. Preliminary results from a phase II trial of weekly bolus topotecan (4.0 mg/m2) in patients with recurrent SCLC were recently reported, and this regimen was generally well tolerated. Furthermore, weekly topotecan has been successfully included in several combination therapy regimens in patients with a variety of solid tumors. In untreated SCLC patients, a combination regimen of weekly topotecan, paclitaxel (Taxol®; Bristol-Myers Squibb; Princeton, NJ), and cisplatin (Platinol®; Bristol-Myers Squibb) was explored and found to be well tolerated and active in patients with extensive and limited-stage disease. Further clinical trials of weekly topotecan and regimens that include weekly topotecan in the SCLC setting are warranted.

Key Words. Alternate schedule • Recurrent • Small cell lung cancer • Topotecan • Weekly topotecan


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Rationale for Alternate...
 Weekly Topotecan Regimens
 Weekly Topotecan in SCLC
 Conclusions
 References
 
Despite current attempts at prevention and treatment, lung cancer exerts a heavy toll, causing more than 1 million deaths each year worldwide, which is approximately 18% of all cancer deaths worldwide [1]. In the U.S., lung cancer is the second most commonly diagnosed malignancy in both men and women but is the most deadly, accounting for more than one in four cancer-related deaths [2]. Lung cancer is primarily a disease of the elderly, with approximately 66% of lung cancer diagnoses in the U.S. in patients over the age of 65 [3]. Small cell lung cancer (SCLC), an especially aggressive and deadly malignancy, comprises approximately 20% of lung cancer cases. Most patients are diagnosed after extrapulmonary or metastatic disease has already developed [4]. Although the response rates to first-line chemotherapy (e.g., cisplatin [Platinol®; Bristol-Myers Squibb; Princeton, NJ] and etoposide [Etopophos®; Bristol-Myers Squibb], PE; cyclophosphamide, doxorubicin [Adriamycin®; Bedford Laboratories; Bedford, OH], and vincristine [Oncovin®; Eli Lilly and Company; Indianapolis, IN], CAV) are typically very high, especially for patients with limited disease, SCLC usually recurs within a year after treatment. After relapse or failure to respond to chemotherapy, patients generally succumb to their disease within a few months [4]. The median survival time for patients with SCLC ranges from approximately 8 months, in patients with extensive disease, to 12–34 months, in patients with limited disease [5]. Treatment of patients with relapsed SCLC is complicated by the high rate of comorbidities (e.g., impaired pulmonary, hepatic, or renal function) in SCLC patients, the advanced median age of the patient population, and by the dose-limiting cumulative effects of prior treatment regimens on bone marrow reserves. The introduction of newer chemotherapeutic agents with noncumulative hematologic toxicities and more favorable nonhematologic toxicity profiles and the development of alternate dosing regimens may provide better-tolerated and effective treatment options for these poor-prognosis patients.

Topotecan (Hycamtin®; GlaxoSmithKline; Philadelphia, PA), 1.5 mg/m2 administered via an i.v. injection on days 1–5 of a 21-day cycle, is an established treatment regimen for recurrent SCLC. This regimen is the only single-agent therapy to demonstrate significant palliative benefits over CAV chemotherapy in a randomized trial in patients with recurrent SCLC [6]. Response rates, median times to progression, and median survival times were comparable between the two treatment groups. However, patients in the topotecan group reported significantly (p < 0.05) greater improvements in general symptoms, including anorexia, fatigue, interference with daily activities, and pulmonary symptoms (e.g., dyspnea and hoarseness), compared with patients in the CAV group [6]. Topotecan is active in patients with platinum-sensitive or platinum-refractory disease and good performance status. In several large trials, overall response rates (ORRs) ranged from 11%–38% in patients with platinum-sensitive disease [6–10]. Additionally, approximately 20% of patients achieved stable disease (SD) as a best response [6–10]. Similarly, ORRs of 2%–6% with 4%–21% rates of SD have been reported in patients with platinum-resistant or -refractory disease. Median survival has ranged from 5.8–6.9 months for patients with platinum-sensitive and 3.7–4.7 months for patients with platinum-refractory SCLC [6–10].

Topotecan is generally well tolerated, with a toxicity profile characterized by transient myelosuppression (lasting approximately 7 days) that is noncumulative and manageable and nonhematologic toxicities that are generally mild to moderate in severity. Hematologic toxicities are dose limiting with the standard 5-day administration schedule, with approximately 70% of patients experiencing grade 4 neutropenia and 29% of patients experiencing grade 4 thrombocytopenia [6]. Elderly patients or patients with significant comorbidities may be more susceptible to these events, and dose delays, dose reductions, and hematopoietic growth factor support may be required to manage hematologic toxicities—especially in the recurrent SCLC setting. Furthermore, the 5-day dosing regimen may not be convenient for some patients—especially if dose delay or growth factor support is needed—and scheduling considerations limit the possibilities for combining topotecan with other active agents. Moreover, the optimal dosing schedule has not been established. Based on data from both preclinical experiments and clinical trials in other aggressive cancers, there is good rationale for regimens that administer topotecan on a weekly schedule in patients with SCLC. Results from recent phase II trials suggest that regimens containing weekly topotecan may be better tolerated and active in patients with SCLC. Weekly topotecan may be an appropriate alternative to the 5-day topotecan dosing regimen in select patient populations.


   RATIONALE FOR ALTERNATE TOPOTECAN REGIMENS
Top
 Learning Objectives
 Abstract
 Introduction
 Rationale for Alternate...
Weekly Topotecan Regimens
 Weekly Topotecan in SCLC
 Conclusions
 References
 
Topotecan binds to and inhibits topoisomerase I, which is necessary for the maintenance of chromosomal DNA topology during cell division [11]. Inhibition of topoisomerase I leads to double-strand breaks when the DNA is replicated and eventually results in cell death. Consistent with its mechanism of action, topotecan has S-phase-specific cytotoxicity against human cancer cell lines [12]. In preclinical testing in non-small cell lung cancer (NSCLC) cell lines, the cytotoxicity of topotecan was concentration dependent and exposure time dependent for the first 8–24 hours of exposure, after which time the cells became less sensitive [13]. This resistance correlated with a decrease in cellular topoisomerase I levels. However, 7 days after topotecan was removed from the culture medium, topoisomerase I levels had returned to baseline levels [13]. The transient and reversible change in topoisomerase I, the cellular target of topotecan, provides a rationale for using an intermittent weekly schedule, as opposed to the standard 5-day regimen.

Regimens with pharmacokinetics similar to those of weekly topotecan therapy in humans have resulted in potent antitumor activity in animal model systems. In a mouse model of Lewis lung carcinoma, s.c. treatment with weekly topotecan cured the majority of mice treated with the maximum tolerated dose (MTD). Lewis lung tumors in mice treated with topotecan on days 1, 5, and 9 (which has similar pharmacokinetics to weekly topotecan administration in humans) [14] regressed to 10% of their original volume by day 13 [15]. Similar schedules of treatment were also active in mouse model systems of lymphocytic leukemia [15], melanoma, and colon cancer, and in murine xenograft models of human colon cancer [14].

Several other S-phase-specific drugs, including taxanes and gemcitabine (Gemzar®; Eli Lilly and Company) [16–19], have shown significant antitumor activity using weekly dosing schedules. Topotecan has pharmacokinetics similar to those of taxanes [14]. Therefore, based on preclinical evidence and results from clinical trials of other S-phasespecific agents, weekly topotecan regimens are being investigated in a broad range of malignancies.


   WEEKLY TOPOTECAN REGIMENS
Top
 Learning Objectives
 Abstract
 Introduction
 Rationale for Alternate...
 Weekly Topotecan Regimens
Weekly Topotecan in SCLC
 Conclusions
 References
 
Weekly topotecan regimens have been investigated in patients with a variety of solid tumors. In early trials, relatively long infusion times (e.g., 24 or 72 hours) and relatively low doses of topotecan (e.g., 1–2 mg) were associated with low response rates [20–22]. More recent trials have used shorter and more convenient 30-minute i.v. bolus injections and attempted to increase dose intensity up to 10 mg/m2 in one trial in patients with advanced malignancies [23–26]. These regimens have been well tolerated and have demonstrated activity against sarcomas, prostate cancer, and ovarian cancer in phase I trials [24, 26].

Similar to SCLC, ovarian cancer is an aggressive and often symptomatic cancer. Ovarian cancer is commonly treated with platinum-based therapy in the first-line setting and is prone to recurrence. The aggressiveness of ovarian cancer is similar to that of SCLC such that SD, in addition to partial and complete responses, is considered a therapeutic benefit [27]. The same 5-day topotecan regimen that is approved for use in recurrent SCLC is also an established treatment for relapsed ovarian cancer, and it is associated with a 17% ORR and a 40% rate of SD [28]. However, similar to patients with SCLC, many patients with ovarian cancer have comorbidities, and patients with recurrent disease typically have cumulative toxicities from prior chemotherapy exposure. These factors may predispose these patients to hematologic toxicities. Therefore, the standard 5-day topotecan dosing regimen may not be optimal in terms of tolerability, and alternate treatment regimens have been investigated in this setting [14, 29]. One very promising alternative dosing regimen is weekly topotecan (Table 1Go) [21–23, 29, 30]. Hoskins et al. [21] compared weekly topotecan (1.75 mg/m2/week via a 24-hour i.v. infusion on weeks 1–4 of a 6-week cycle) with the standard regimen of topotecan (1.5 mg/m2/day via a 30-minute i.v. injection on days 1–5 of a 21-day cycle) in patients who had been previously treated for ovarian cancer. The response rate to weekly topotecan was lower than the response rate to the standard regimen (3% versus 23%, respectively), but both the median survival times (12.4 months for weekly compared with 11.0 months for the 5-day regimen) and the proportions of patients who showed clinical benefit from therapy (response or SD; 47% for weekly compared with 52% for the 5-day regimen) were comparable. Further studies in patients with ovarian cancer suggest that higher-dose weekly bolus topotecan regimens appear to be more active than this relatively low-dose regimen. Despite the increases in dose intensity, these regimens maintain a low incidence of grade 3 or 4 hematologic toxicities, and ORRs have ranged from 9%–32%, with SD rates from 19%–45% [22, 23, 29, 30].


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  		Table 1. Efficacy and safety of weekly i.v. topotecan in ovarian cancer
 
The MTD of weekly bolus topotecan without growth factor support was investigated by Homesley et al. [23] in heavily pretreated patients with ovarian cancer. Topotecan was well tolerated and had antitumor activity at dose levels above 2 mg/m2/week. The MTD was 4 mg/m2/week (without break), above which anemia, chronic fatigue, and gastrointestinal toxicities became dose limiting. Because of the similar cumulative toxicity profiles of first-line therapies for SCLC and ovarian cancer and the common comorbidities among these patients, the 4-mg/m2/week topotecan dose level may also be well tolerated and efficacious in the relapsed SCLC setting. Furthermore, the weekly regimen and lower need for growth factor support could provide added convenience over the standard 5-day topotecan regimen for these patients.

The favorable toxicity profile and the schedule of weekly topotecan have enabled topotecan doses comparable with those used in monotherapy to be successfully combined with other chemotherapy agents in patients with ovarian cancer, NSCLC, and a range of other solid tumor types (Table 2Go) [31–36]. In a dose-escalation trial in patients with previously treated ovarian cancer, Homesley et al. [31] found that the combination of weekly topotecan and paclitaxel (Taxol®; Bristol-Myers Squibb) was well tolerated and active, with a 33% ORR and 19% SD rate. The recommended doses for further study were 3 mg/m2/week for topotecan and 80 mg/m2/week for paclitaxel, although the use of hematopoietic growth factor support did allow for further dose escalation; however, doses with growth factors were not recommended. Frasci et al. [34] added weekly topotecan to cisplatin plus paclitaxel, a therapeutic doublet that requires G-CSF support in patients with ovarian cancer or SCLC. The regimen was well tolerated and active, both in pretreated and chemotherapy-naïve patients. Similarly, combination regimens—including weekly topotecan with gemcitabine or weekly topotecan with gemcitabine and cisplatin—have been well tolerated and active in patients with NSCLC. Dabrow et al. [32] investigated a combination regimen of gemcitabine (1,250 mg/m2/week) and topotecan (1.0–2.0 mg/m2/week) for three consecutive weeks of a 4-week cycle in patients with advanced-stage NSCLC. Neutropenia was dose limiting, and nonhematologic toxicities were infrequent. There were five (21%) partial responses, and the median survival time was 22 weeks, with two patients surviving for >2 years. Similarly, Guarino et al. [33] found that a combination regimen of weekly topotecan plus gemcitabine and cisplatin was well tolerated and active in patients with recurrent NSCLC, with no febrile neutropenia or treatment-related hospitalizations. In 29 evaluable patients, the ORR was 38% and the median survival time was 38 weeks. Topotecan (1.75 mg/m2) on days 1, 8, and 15, cisplatin (20 mg/m2) on days 1, 8, and 15, plus gemcitabine (1,000 mg/m2) on days 1 and 15 of a 28-day cycle was recommended for further study.


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  		Table 2. Efficacy and safety of weekly i.v. topotecan regimens in various solid tumors
 
In patients with a variety of solid tumors, weekly topotecan has been successfully combined with taxanes, 5-fluorouracil/leucovorin, temozolomide (Temodar®; Schering-Plough Corporation; Kenilworth, NJ), and platinum agents. Kuzur et al. [35] investigated the feasibility of combining topotecan (2–4 mg/m2/week) with docetaxel (Taxotere®; Aventis Pharmaceuticals Inc.; Bridgewater, NJ) (25–30 mg/m2/week) for three consecutive weeks of a 4-week cycle. This regimen was well tolerated, with no severe nonhematologic toxicities. Phase II trials of this regimen in NSCLC, prostate cancer, and ovarian cancer are being developed. Axelrod et al. [36] recently reported the preliminary analysis of a phase I trial of topotecan (1.5–3.0 mg/m2/week) with 5-fluorouracil (400 mg/m2) and leucovorin (20 mg/m2) for three consecutive weeks of a 6-week cycle. That regimen was well tolerated and produced prolonged SD in some patients with advanced malignancies. Ongoing clinical trials are investigating the combination of weekly topotecan with docetaxel or temozolomide in patients with solid tumors. Preliminary results have revealed no dose-limiting toxicities with topotecan doses up to 3.0 mg/m2 on days 1, 8, and 15 of a 28-day cycle in combination with docetaxel at doses of 20–30 mg/m2 (Burris, personal communication). Similarly, preliminary results suggest that weekly topotecan (2.5 mg/m2) on days 1, 8, and 15 and temozolomide (50 mg/m2) on days 1–21 of a 28-day cycle are well tolerated. Phase I trials investigating combination therapy with topotecan on days 1, 8, and 15 of a 28-day cycle with either cisplatin (30 mg/m2), carboplatin (Paraplatin®; Bristol-Myers Squibb) (area under the concentration versus time curve of 2), or oxaliplatin (Eloxatin®; Sanofi-Synthelabo Inc.; New York, NY) (40 mg/m2) are ongoing, and these regimens have already demonstrated activity, including a complete response in a patient with ovarian cancer (topotecan/carboplatin) and a partial response in a patient with colon cancer (topotecan/oxaliplatin). Further studies are necessary to determine the optimal doses for these regimens and to determine the relative benefits of each combination therapy.


   WEEKLY TOPOTECAN IN SCLC
Top
 Learning Objectives
 Abstract
 Introduction
 Rationale for Alternate...
 Weekly Topotecan Regimens
 Weekly Topotecan in SCLC
Conclusions
 References
 
The safety and tolerability of single-agent weekly topotecan has been investigated in patients with relapsed SCLC (Table 3Go) [18, 34, 37]. Recently, Greco et al. [18] presented preliminary results from a phase II study. Patients were treated with topotecan at a dose of 4.0 mg/m2/week for 12 weeks. Consistent with the general demographics of SCLC patients, the median age of the study population was 68 (range: 54–87 years). Therapy was well tolerated, and the most common grade 3 or 4 toxicity was thrombocytopenia, in 17% of patients. All nonhematologic toxicities were < grade 3. Fatigue was manageable in that trial and in other settings with treatment breaks and the introduction of hematopoietic growth factor support. In a preliminary report, 17 patients completed therapy and were evaluable for response [18]. Of 11 evaluable patients with platinum-sensitive disease, one (9%) patient had a partial response and two (18%) patients had SD. Of the six evaluable patients with refractory SCLC, one (17%) had SD. Therefore, single-agent therapy with weekly topotecan is well tolerated in patients with relapsed SCLC and has shown activity, especially in patients with platinum-sensitive disease. That trial is ongoing and is currently enrolling patients. Another phase II study of this regimen in elderly and poor performance status patients with extensive SCLC is ongoing. Because of its more convenient regular schedule and its generally mild toxicity profile, the weekly regimen may provide an especially attractive alternative to the 5-day regimen for this patient population and their caregivers.


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  		Table 3. Efficacy and safety of weekly i.v. topotecan regimens in SCLC
 
Weekly topotecan has also been integrated into a combination regimen for the first-line treatment of patients with extensive SCLC. In a phase I study, Frasci et al. [34] investigated the combination of cisplatin (40 mg/m2), paclitaxel (85 mg/m2), and topotecan (0.75–2.5 mg/m2), all administered on day 1 of a weekly cycle in patients with ovarian cancer or SCLC. Patients received G-CSF support on days 3–5 of each cycle. Therapy was generally well tolerated. Hematologic toxicities—including grade 3 or 4 neutropenia, thrombocytopenia, and anemia—were observed in 34%, 16%, and 9% of patients, respectively. Consistent with the adverse-event profile of cisplatin [38], severe vomiting occurred in 16% of patients and severe diarrhea occurred in 9%. Peripheral neuropathy, which is also relatively common during therapy with platinum and paclitaxel doublets [38], developed in 25% of patients, although no severe cases were reported. The overall response rates were 44% in patients with SCLC (n = 25) and 58% in patients with ovarian cancer (n = 19). In the nine patients with SCLC who had not received chemotherapy before study entry, seven (78%) responded, and in patients with relapsed SCLC, four (25%) responded. Based on the MTD determined in the phase I trial, Frasci et al. [37] investigated weekly therapy with cisplatin (40 mg/m2), paclitaxel (85 mg/m2), and topotecan (2.25 mg/m2), and G-CSF support, in previously untreated patients with extensive SCLC. Grade 4 neutropenia occurred in six (16%) patients, and grade 4 thrombocytopenia occurred in three (8%). Grade 3 or 4 nonhematologic toxicities included diarrhea in six (17%) patients, fatigue in 10 (27%) patients, and paresthesia in two (5%) patients. The ORR was 81%, with eight (22%) complete responses and 22 (59%) partial responses. The median progression-free and overall survival times were 8 months and 12.5 months, respectively.


   CONCLUSIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Rationale for Alternate...
 Weekly Topotecan Regimens
 Weekly Topotecan in SCLC
 Conclusions
References
 
Although platinum-containing regimens produce high response rates in the first-line treatment of SCLC, and the standard 5-day regimen of topotecan produces significant benefits for patients in the relapsed setting, these regimens may be suboptimal for some patients. Indeed, patients with SCLC are typically elderly and usually have comorbidities that render them more susceptible to treatment-related toxicities [3, 39]. Regimens that are more convenient and better tolerated yet maintain or improve on the present expectation for antitumor activity are clearly needed for this poor-prognosis patient population.

Regimens that administer topotecan on a weekly schedule have shown promise in patients with ovarian cancer, NSCLC, and a variety of other solid tumors [14, 32, 33, 35, 36]. Early results from a phase II trial suggest that single-agent therapy with weekly topotecan is well tolerated and active in the SCLC setting [18]. The hematologic toxicity profile of weekly topotecan is favorable compared with the 5-day regimen, and nonhematologic toxicities are generally mild and manageable. Furthermore, weekly topotecan has been successfully included in combination chemotherapy trials, including a combination regimen of topotecan, paclitaxel, and cisplatin that has shown promising safety and activity in the SCLC setting [34, 37].

Ongoing trials of weekly topotecan therapy will provide further insight into the safety and efficacy of weekly topotecan in patients with lung cancer. The final results from the ongoing phase II trial of weekly topotecan monotherapy in patients with SCLC will provide further insight into the safety and efficacy of this new treatment option [18]. In the NSCLC setting, two trials are investigating the combination of weekly topotecan with either vinorelbine or docetaxel. The results of those trials will provide further support and direction for the use of topotecan-based combination regimens in patients with lung cancer. Additional trials to fully characterize the efficacy and tolerability of weekly topotecan in treating subpopulations of patients with SCLC (e.g., elderly, poor-performance status) are warranted.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Rationale for Alternate...
 Weekly Topotecan Regimens
 Weekly Topotecan in SCLC
 Conclusions
 References
 

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Received September 8, 2004; accepted for publication October 9, 2004.




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