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Topotecan in the First-Line Treatment of Small Cell Lung Cancer

David J. Stewart

The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Correspondence: David J. Stewart, F.R.C.P.C., The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Room FC-9-3062, Houston, Texas 77030, USA. Telephone: 713-792-6363; Fax: 713-796-8655; e-mail: dstewart{at}mdanderson.org


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Topotecan-Based Combination...
 Single-Agent Topotecan in First...
 Summary
 References
 
After completing this course, the reader will be able to:

  1. Discuss the role of topotecan combinations as first-line therapy for SCLC.
  2. Discuss the role of single-agent topotecan as first-line therapy or consolidation therapy for SCLC.
  3. Discuss the toxicity profile of topotecan alone and in combinations.

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
 Topotecan-Based Combination...
 Single-Agent Topotecan in First...
 Summary
 References
 
Small cell lung cancer (SCLC) is generally sensitive to first-line chemotherapy, but limited disease often recurs and extensive disease is rarely curable. The most common first-line therapy regimen is cisplatin (Platinol®; Bristol-Myers Squibb; Princeton, NJ) plus etoposide (Etopophos®; Bristol-Myers Squibb)—PE, which is associated with overall response rates >80% in patients with limited SCLC. Although it is associated with median survival times of approximately 18–20 months for limited disease, PE yields median survival times of only approximately 8–12 months in patients with extensive disease, and symptom palliation becomes the primary therapeutic goal. The toxicities of PE may undermine quality of life and leave patients more susceptible to adverse events during subsequent therapies. Topotecan (HYCAMTIN®; GlaxoSmithKline; Philadelphia, PA), an established treatment for recurrent SCLC, is being investigated in the first-line setting because of its novel mechanism of action; predictable, noncumulative, and manageable toxicities; and potential synergy with other active agents. Several recent phase II trials have generated promising results for topotecan-based combination regimens, including topotecan/paclitaxel (TAXOL®; Bristol-Myers Squibb) (overall response rates 45%–100%), topotecan/etoposide (overall response, 95%), and topotecan, paclitaxel, and platinum agent triplets (overall response rates 51%–93%). The most frequent serious toxicity associated with these regimens was reversible and noncumulative neutropenia, which was generally manageable with supportive care. Additional clinical trials to investigate topotecan-based combination regimens and confirm their role in the first-line treatment of SCLC are under way.

Key Words. First-line • Pulmonary cancer • Small cell lung cancer • Topotecan


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Topotecan-Based Combination...
 Single-Agent Topotecan in First...
 Summary
 References
 
Lung cancer is a global health crisis, accounting for approximately 23% of cancer deaths in men and 11% in women worldwide [1]. Although small cell lung cancer (SCLC) comprises only 20%–25% of cases, it is an extremely aggressive and lethal cancer that is usually not diagnosed until extensive disease is already present [2]. Although SCLC is typically responsive to first-line therapies (chemotherapy and radiation therapy), the cancer ultimately recurs or develops resistance, and most patients diagnosed with SCLC die of their disease within 2 years [3].

Given the poor prognosis of patients with SCLC, first- and second-line therapies for limited disease are typically aggressive, and current therapies for extensive disease are generally considered palliative [4]. Combination regimens containing cisplatin (Platinol®; Bristol-Myers Squibb; Princeton, NJ) and the topoisomerase-II inhibitor etoposide (VEPESID®; Bristol-Myers Squibb) are most often used to treat SCLC [5]. In patients with limited disease, these cisplatin/etoposide (PE) regimens appear more efficacious than other regimens and may also be administered at relapse, depending on the duration of the treatment-free interval. In contrast, compared with other regimens—such as cyclophosphamide/doxorubicin (Adriamycin®; Bedford Laboratories; Bedford, OH)/vincristine (Oncovin®; Eli Lilly and Company; Indianapolis, IN), CAV—PE regimens do not provide a survival advantage in patients with extensive disease or disease that does not respond to PE or relapses shortly after therapy but are generally better tolerated than other first-line therapies [4, 6]. The decision to administer radiotherapy typically depends on the extent of the disease. In patients with limited SCLC, the addition of thoracic radiation to PE has been shown to prolong survival, with a median survival duration of 18–20 months, a 40% 2-year survival rate, and a 15%–25% 5-year survival rate with this aggressive multimodality regimen [6]. In contrast, radiotherapy generally provides relatively little benefit to patients with extensive disease, who are generally treated with only chemotherapy. In extensive disease, chemotherapy results in a median survival time of approximately 8–10 months, a 2-year survival rate ≤10%, and 5-year survival rate approaching 0% [6].

Although the response rates to PE chemotherapy regimens are generally high (80%–90%) for limited SCLC, the cumulative toxicities of cisplatin—which include nephrotoxicity and peripheral neuropathy—may limit the tolerability of available treatment options when the disease ultimately returns. Therefore, agents with noncumulative toxicities are of particular interest when developing alternative first-line regimens to maintain current treatment options.

Topotecan (HYCAMTIN®; GlaxoSmithKline; Philadelphia, PA), a topoisomerase-I inhibitor, has a favorable toxicity profile compared with most other agents that are active in SCLC [7]. Topotecan has a well-characterized and predictable hematologic toxicity profile that includes dose-limiting neutropenia, which is manageable, short-lived, and reversible. The nonhematologic effects of topotecan are generally mild and include manageable gastrointestinal toxicities. Topotecan at a dose of 1.5 mg/m2/day for 5 consecutive days of a 21-day cycle is an established single-agent therapy in the relapsed SCLC setting, with response rates in phase II trials of 13%–37% in patients with sensitive disease [8–10] and a 24% response rate in a phase III trial that enrolled mostly patients with relapsed, extensive SCLC [11]. In this "sensitive relapse" setting (defined as relapsed >3 months after completion of front-line therapy), tumors have generally displayed a lack of cross-resistance between topotecan and a number of agents used in the first-line setting (e.g., platinum agents, etoposide, and taxanes). Furthermore, topotecan is active against cerebral metastases in heavily pretreated patients with SCLC, producing responses even in previously irradiated lesions [12, 13].

The clinical profile of topotecan in the second-line treatment of SCLC has prompted investigators to study topotecan as first-line therapy both alone and in combination with other agents. In addition to its different mechanism of action, topotecan has displayed in vitro antitumor synergy with taxanes, platinum agents, and topoisomerase-II inhibitors [14–16]. Several characteristics of topotecan—including potential synergies, lack of cross-resistance with other agents, and clinical evidence that topotecan may possibly affect cerebral metastases—have suggested that topotecan may also provide benefits to patients with previously untreated SCLC [17]. As a result, the optimal application of topotecan in this setting is an area of active investigation. This review provides an update on recent clinical trials of topotecan in novel combinations and as single-agent therapy in previously untreated patients with SCLC.


   TOPOTECAN-BASED COMBINATION REGIMENS IN FIRST-LINE SCLC
Top
 Learning Objectives
 Abstract
 Introduction
 Topotecan-Based Combination...
Single-Agent Topotecan in First...
 Summary
 References
 
Although the introduction of new chemotherapy agents has resulted in limited gains in survival for patients with SCLC, the development of new combination regimens and the optimization of treatment schedules could potentially be an alternate approach to reach this goal. Indeed, preclinical data suggest that certain combinations of chemotherapeutic agents can result in antitumor synergy, and that the likelihood of cross-resistance is lower between agents that have differing mechanisms of action [14, 18]. As a topoisomerase-I inhibitor, topotecan has a mechanism of action different from those of many agents that have demonstrated activity in the SCLC setting and has demonstrated promising antitumor synergy with both paclitaxel (TAXOL®; Bristol-Myers Squibb) and etoposide in SCLC cell lines and with platinum agents in tumor model systems [15, 18].

Therapeutic Doublets
By targeting multiple intracellular targets and by inducing synergistic antitumor effects, the combination of two chemotherapeutic agents can increase response rates. However, overlapping toxicities may limit the optimal dosing of some regimens. The safety profile of topotecan makes it an appropriate option for combination therapy. Moreover, recent evidence from a phase III trial suggests that the combination of another topoisomerase-I inhibitor (irinotecan; Camptosar®; Pfizer Pharmaceuticals Inc.; New York, NY) with cisplatin in patients with extensive SCLC has a comparable toxicity profile and produces a significantly longer median survival time than standard PE therapy (12.8 months for irinotecan/cisplatin versus 9.4 months for etoposide/cisplatin; p = 0.002) [19]. In the first-line SCLC setting, topotecan has been investigated in doublet regimens with cisplatin, carboplatin (Paraplatin®; Bristol-Myers Squibb), paclitaxel, and etoposide (Table 1Go) [20–29].


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  		Table 1. Topotecan-based doublets in untreated patients with extensive SCLC (21-day regimens)
 

Topotecan Plus a Platinum Agent
Platinum-based therapy is the current treatment of choice for SCLC, and the combination of topotecan with a platinum agent could provide additional antitumor efficacy. The initial investigations of topotecan/platinum combination therapy in patients with solid tumors combined i.v. topotecan (1.0–1.25 mg/m2) on days 1–5 with cisplatin (25–100 mg/m2) on day 1 of a 21-day cycle [30]. However, despite the use of G-CSF support, this regimen was associated with severe neutropenia, and platinum agents were administered later during the treatment cycle in subsequent clinical trials. For example, Seifart et al. [28, 29] investigated regimens that combined topotecan with either cisplatin or carboplatin, administered on day 5 of the treatment cycle instead of day 1. In the first of these randomized phase II trials [28], cisplatin (75 mg/m2) was administered on day 5 and combined with topotecan, either 1.0 mg/m2 on days 1–5 or 1.5 mg/m2 on days 1–3 of a 21-day cycle. Toxicities and efficacies were generally comparable between treatment arms, but a higher proportion of patients on the 5-day topotecan regimen experienced grade 3 or 4 hematologic toxicities compared with the 3-day regimen. Gervais et al. [20] conducted a randomized phase II trial that included the combination of 5-day topotecan with a lower dose of cisplatin. Patients in that treatment arm received topotecan (1.25 mg/m2/day) on days 1–5 and cisplatin (50 mg/m2) on day 5 of a 21-day cycle. The regimen was well tolerated and resulted in a 57% response rate in patients with previously untreated extensive SCLC [20].

A phase II trial comparing the combination of carboplatin (at an area under the concentration-time curve [AUC] of 5 on day 5) with 3-day and 5-day topotecan regimens (1.25 mg/m2 on days 1–3 or 0.75 mg/m2 on days 1–5, respectively) is currently under way. Preliminary evidence suggests that both treatments are active and well tolerated and produce lower incidences of grade 3 or 4 hematologic toxicities than the cisplatin/topotecan regimens [29]. The comparative efficacies of oral topotecan/cisplatin and cisplatin/etoposide in patients with extensive SCLC are currently under investigation in the HOPE trial (protocol National Cancer Institute [NCI]-G02-2092) [31]. The relative efficacies and tolerabilities of topotecan/etoposide, topotecan/cisplatin, and cisplatin/etoposide doublets are also being investigated in an ongoing study.

Topotecan Plus Paclitaxel
Similar to the platinum agents, paclitaxel is active against a broad range of primary tumors. Furthermore, paclitaxel has shown antitumor synergy with topotecan in SCLC cell lines, suggesting that the paclitaxel/topotecan combination might prove effective [14]. The combination of topotecan (administered for 5 consecutive days of a 21-day cycle) with paclitaxel has yielded promising overall response rates (ORRs) ranging from 45%–100% and median survival times ranging from 8.6–12.6 months in patients with extensive disease [22–26]. However, these regimens have resulted in a high rate of severe hematologic toxicities. Recently, West et al. [21] investigated the safety, preliminary efficacy, and maximum tolerated dose (MTD) of a regimen that combines paclitaxel with 3 days of topotecan treatment per 21-day cycle in patients with extensive SCLC. That trial determined the MTDs as 1.5 mg/m2 on days 1–3 for topotecan and 135 mg/m2 on day 1 of a 21-day cycle for paclitaxel and reported an ORR of 53% (including all dose levels). At the MTD level this regimen had efficacy comparable with that from earlier trials of topotecan plus paclitaxel combination therapy but had a better tolerability profile, with lower incidences of severe neutropenia, anemia, and thrombocytopenia than with topotecan plus a platinum agent. The authors of that study recommended additional prospective trials and possible further dose escalation using G-CSF support [21].

Topotecan Plus Etoposide
The combination of topotecan and etoposide targets both topoisomerase enzymes that are responsible for maintaining DNA topology, and this combination has demonstrated significant antitumor synergy in preclinical models [14]. i.v. topotecan (0.5 or 0.75 mg/m2) and i.v. etoposide (60 mg/m2/day) administered sequentially on days 1–5 of a 21-day schedule produced a 95% response rate and an overall survival duration of 10 months in a phase I trial in patients with previously untreated SCLC [27]. The regimen was well tolerated, and hematologic toxicities were dose limiting. The role of this combination in SCLC is unclear because the trial included patients with both limited and extensive disease, which may have resulted in a response rate higher than would have been seen with extensive disease alone.

In a phase II, randomized trial, topotecan/etoposide was compared with a topotecan/cisplatin doublet in previously untreated patients with extensive SCLC [20]. Both regimens produced an ORR of 57%, and the nonhematologic toxicity profile of the topotecan/etoposide regimen appeared more favorable than that of the topotecan/cisplatin doublet. Further investigations using topotecan at a dose of 0.75 mg/m2 and etoposide at a dose of 60 mg/m2 were recommended.

Triplet Regimens
Although combination chemotherapies that target multiple cellular targets may overcome resistance to chemotherapy and can result in antitumor synergy, triplet combination trials in SCLC have been limited because many of the antitumor agents have overlapping toxicities that may adversely affect quality of life, and no combinations that contain more than three drugs have been conclusively demonstrated to be superior to regimens containing just 2 drugs. However, because of topotecan’s efficacy and favorable toxicity profile, there has been interest in exploring its addition to older two-drug regimens.

Topotecan has been added to carboplatin plus etoposide in the first-line SCLC setting. Gillenwater et al. [32] established the feasibility of pharmacokinetic-guided dosing of topotecan on days 1–3, followed by carboplatin on day 3 and etoposide on days 4–6, in patients with extensive SCLC (Table 2Go) [32–37]. Zarogoulidis et al. [33] investigated a regimen of topotecan (0.8 mg/m2) on days 1–3, carboplatin (at an AUC of 5) on day 3, and etoposide (100 mg) on days 15–17 of a 32-day cycle in patients with limited (37% of patients) or extensive (63% of patients) SCLC. Although this regimen was well tolerated, the 63% ORR and 8.9-month median overall survival duration were disappointing and may have been related to the low dose intensity of this regimen.


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  		Table 2. Topotecan-based triplets in first-line SCLC
 
Regimens combining topotecan with paclitaxel and carboplatin have resulted in response rates at least comparable with those of PE regimens, but the unfavorable toxicity profiles may limit the potential use of carboplatin/paclitaxel/topotecan combinations. Hainsworth et al. [34] investigated four cycles of the combination of paclitaxel (135 mg/m2) on day 1, carboplatin (AUC of 5) on day 1, and topotecan (0.75 mg/m2) on days 1–3 of a 21-day cycle. ORRs of 93% and 88% were reported for patients with limited and extensive SCLC, respectively. The overall survival time was 17.2 months for patients with limited disease and 8.3 months for patients with extensive disease. However, the toxicity profile compared poorly with those of other regimens with comparable efficacies and was especially poorly tolerated in patients with poor performance status (PS) scores (PS = 2). A different regimen (paclitaxel [175 mg/m2] and carboplatin [AUC of 5] on day 4 and topotecan [1.0 mg/m2/day] on days 1–4 of a 21-day cycle) in patients with extensive SCLC resulted in a more favorable median survival time of 12 months and a 1-year survival rate of 50% [35]. However, five (7%) of the safety-evaluable patients (each with a PS score = 2) died of treatment-related complications.

The triplet regimen used by Hainsworth et al. [34] has also been combined with radiation therapy in patients with limited-stage SCLC [36], where it produced a complete response (CR) rate of 51% and an actuarial median survival time of 20 months. However, severe hematologic toxicities occurred in most patients, hospitalization for febrile or severe neutropenia was required in 11 (14%) patients, and there were three (4%) treatment-related deaths.

The limited data currently available indicate that cisplatin may be more tolerable than carboplatin when combined with topotecan and paclitaxel. Frasci et al. [37] investigated the safety and efficacy of a 12-week regimen that combined weekly treatment with cisplatin (40 mg/m2), paclitaxel (85 mg/m2), and topotecan (2.25 mg/m2) with G-CSF support. That regimen produced a 22% CR and a 59% partial response (PR) rate in patients with extensive SCLC. The 1- and 2-year projected survival rates were 55% and 21%, respectively. The regimen was generally well tolerated, with grade 3 or 4 diarrhea (16%), paresthesias (5%), and fatigue (27%) composing the predominant nonhematologic toxicities. Although 16% of patients experienced grade 4 neutropenia, only one case of sepsis occurred, and there were no treatment-related deaths. Given the comparable efficacy and relatively favorable toxicity profile of this regimen compared with other active therapies in the first-line SCLC setting, further trials of this weekly regimen are warranted.

A phase II clinical trial is being developed to compare the safety and efficacy of the topotecan/cisplatin/etoposide combination with that of irinotecan/cisplatin/etoposide in previously untreated patients with extensive SCLC (Eastern Cooperative Oncology Group-5501). The safety and efficacy of a sequential triplet regimen of topotecan (days 1–5), carboplatin (day 6), and etoposide (days 6–10) are being evaluated in an ongoing phase II clinical trial (NCI-5333).

Alternating Regimens
Innovative treatment strategies have been investigated in an attempt to increase therapeutic intensity and to maximize the breadth of antitumor effects by administering agents either in alternating or sequential regimens. Alternating chemotherapy cycles can provide breaks from each chemotherapy agent to allow recovery from toxicity while still maintaining active therapy throughout the treatment regimen. Such regimens could theoretically allow for the use of multiple agents whose toxicity profiles would prevent their concomitant administration. This therapeutic approach could also theoretically minimize the emergence of resistant disease.

In a phase II clinical trial, Jett et al. [38] investigated the safety and efficacy of six alternating 21-day cycles of etoposide/cisplatin and topotecan/paclitaxel in previously untreated patients with extensive SCLC. The administration schedule for the first of the two alternating cycles was etoposide (100 mg/m2) on days 1–3 and cisplatin (30 mg/m2) on days 1–3. The second cycle was topotecan (1 mg/m2) on days 1–5 and paclitaxel (200 mg/m2) on day 5 with G-CSF support. The CR rate was 9%, and the PR rate was 68% (Table 3Go). The median time to progression was 6.9 months, and the median survival time was 10.5 months. The 1-year survival rate was 37%, and the 2-year survival rate was 12%. However, hematologic toxicities were considerable, with 95% of patients experiencing grade 3 or 4 neutropenia, 42% experiencing grade 3 or 4 thrombocytopenia, and 7% developing grade 3 or 4 infections. Additionally, grade 3 or 4 nonhematologic toxicities were frequent, with 23% fatigue, 18% nausea, and 11% emesis. Nonetheless, these toxicities were manageable, and there were no treatment-related deaths.


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  		Table 3. Alternating chemotherapy regimensa in first-line SCLC
 
Similarly, Mavroudis et al. [39] investigated an eight-cycle regimen of alternating 21-day cycles of cisplatin (75 mg/m2 on day 1) plus etoposide (100 mg/m2 on days 1–3) and topotecan (1.5 mg/m2 on days 1–5). This regimen produced an ORR of 64% and 1-year survival rate of 49% in patients with extensive SCLC. However, treatment delays and dose reductions were necessary to manage hematologic toxicities.

Despite the theoretical advantages, alternating treatment regimens have, to date, failed to generate any efficacy benefits above those of therapeutic doublets in the SCLC setting [38, 39] and have resulted in considerable toxicity. Further investigations are necessary to determine what role, if any, such regimens will play in the future treatment of patients with SCLC.

Sequential Regimens
There are also theoretical potential benefits to sequential regimens over concomitant therapy, including less toxicity and potentially greater efficacy by tumor sensitization (antitumor synergy) or by extending the duration of exposure to active therapy. Sequential topotecan regimens have generally included one aggressive combination therapy and single-agent topotecan as either induction or consolidation treatment, although two trials have investigated topotecan in sequence with other single-agent therapies. The efficacy of these regimens appears comparable with those of more standard approaches (Table 4Go) [40–44].


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  		Table 4. Sequential regimens in first-line SCLC
 

Topotecan as Consolidation Therapy
Sequential regimens of PE followed by topotecan were investigated in two phase II trials [43, 44]. In the first of these trials, Schiller et al. [44] found that the addition of topotecan consolidation therapy extended progression-free survival by 5.6 weeks for patients who either responded or had stable disease during treatment with four 3-week cycles of cisplatin (60 mg/m2) on day 1 and i.v. etoposide (120 mg/m2) on days 1–3 (p < 0.001 for comparison between topotecan consolidation therapy and observation only). However, topotecan consolidation therapy did not result in a survival advantage, perhaps because patients who relapsed received second-line therapies that may have prolonged their survival.

Mavroudis et al. [43] investigated a different sequential PE and topotecan regimen in patients with extensive SCLC. Patients were treated with four 21-day cycles of cisplatin (75 mg/m2) on day 1 and i.v. etoposide (100 mg/m2) on days 1–3 followed by four 21-day cycles of topotecan (1.5 mg/m2) on days 1–5. After the PE treatment, 3% of patients had CRs and 44% had PRs. After treatment with topotecan, 24% of the patients who had PRs to PE had CRs, but no responses were noted in patients who had not responded to the initial PE therapy. Survival of the overall patient population was consistent with that seen for PE therapy alone. The addition of topotecan consolidation therapy after treatment with four cycles of carboplatin (300 mg/m2) on day 1 and etoposide (100 mg/m2/day) on days 1–3 of a 21-day cycle was investigated in a phase I trial [45]. The results from that trial are preliminary, but—in contrast to the results from the PE trials—topotecan treatment resulted in PRs in some patients who had not responded to the initial PE therapy [45]. Data from these three trials suggest that topotecan consolidation therapy after PE regimens might either improve responses or prolong time to progression, but further clinical trials are necessary before it can be concluded that this approach is beneficial, especially in patients who have not responded to PE therapy.

Another promising consolidation therapy regimen involves dose-dense paclitaxel and topotecan [41]. In a phase II trial in patients with previously untreated extensive SCLC, treatment with three cycles of paclitaxel (250 mg/m2) every 14 days, followed by three cycles of topotecan (2.5 mg/m2) on days 1–5 of a 21-day cycle with G-CSF support produced comparable activity and safety to that of platinum-based regimens. The ORR was 73%, including a 10% CR rate, and the median survival duration was 10.5 months. Therapy was generally well tolerated, although 19% of patients developed febrile neutropenia, and there was one treatment-related death.

Topotecan as Induction Therapy
The use of dose-dense topotecan induction therapy before carboplatin/etoposide was recently investigated in a phase II trial in patients with extensive SCLC. Garst et al. [42] treated patients with three 2-week cycles of topotecan (2.25 mg/m2/day) on days 1–3 (with G-CSF support), followed by four 3-week cycles of carboplatin (AUC of 6) on day 1 and i.v. etoposide (100 mg/m2/day) for 3 days. Notably, 30% of patients responded to topotecan induction therapy, although the ORR for the entire regimen and the median survival time were not higher than those reported with PE therapy. Treatment was well tolerated in patients with good PS scores, and data from the trial suggest that topotecan induction therapy could play a role in the first-line therapy of SCLC.

Safety data are available for an aggressive sequential regimen that combined topotecan/paclitaxel induction therapy with chemoradiation therapy in patients with limited SCLC [46]. Two 21-day cycles of topotecan (1 mg/m2/day) on days 1–5 and paclitaxel (175 mg/m2) on day 1 with G-CSF support were administered before treatment with three 21-day cycles of carboplatin (AUC of 5) on day 1 and etoposide (100 mg/m2/day) on days 1–3 with concurrent thoracic irradiation. The addition of the topotecan/paclitaxel induction therapy did not appear to increase the overall toxicity of the chemoradiotherapy, although further investigations are necessary to determine the potential efficacy benefits of this treatment.

The sequential administration of a topoisomerase-I and topoisomerase-II inhibitor can result in synergistic antitumor activity. In preclinical studies, exposure of tumor cell lines to topotecan resulted in potentiation of the cytotoxicity of subsequent treatment with etoposide across a broad range of drug concentrations [47]. The feasibility and MTD of sequential topotecan and etoposide therapy were established in a phase I study by Buchholz et al. [48], who also detected promising preliminary activity in patients with untreated extensive SCLC. In a phase I/II study Mok et al. [40] investigated sequential topotecan (0.75 mg/m2) on days 1–5 and oral etoposide (50 mg twice daily) on days 6–12 of a 21-day cycle in previously untreated patients with limited- or extensive-stage SCLC. CRs occurred in 10% of patients with limited disease and in no patients with extensive disease, and PRs occurred in 67% of patients with limited disease and 40% of patients with extensive disease. The median survival times were 12.8 months and 7.0 months for patients with limited or extensive disease, respectively. This regimen was reasonably well tolerated, with grade 3 or 4 neutropenia or thrombocytopenia reported in 25% and 11% of patients, respectively. Although the regimen was not more active than other regimens used in this setting, it does raise the possibility that if oral topotecan could be substituted for i.v. topotecan, an all-oral treatment regimen would be feasible.

Platinum-free sequential regimens—such as topotecan plus etoposide and paclitaxel plus topotecan—may provide benefits to patients by limiting their exposure to the cumulative effects of platinum therapy. Further investigations of platinum-free sequential regimens in the first-line SCLC setting are warranted.


   SINGLE-AGENT TOPOTECAN IN FIRST-LINE SCLC
Top
 Learning Objectives
 Abstract
 Introduction
 Topotecan-Based Combination...
 Single-Agent Topotecan in First...
Summary
 References
 
Although aggressive multiagent regimens form the backbone of first-line therapy for SCLC, patients ≥75 years of age are less than half as likely to receive such therapy as patients <65 years of age [49], and treatment options are limited in patients with poor PS scores or comorbidities [50]. Therefore, less aggressive single-agent therapy may provide an alternative treatment plan for these patient populations. A recent analysis of second-line SCLC trial data found that single-agent topotecan was generally well tolerated in patients with poor PS scores [51]. Based on its efficacy and tolerability in patients with relapsed SCLC [7, 51], topotecan is now being investigated in the first-line SCLC setting.

In a phase II trial, Schiller et al. [52] treated 48 patients with previously untreated extensive SCLC with up to four cycles of topotecan (2.0 mg/m2/day) on days 1–5 of a 21-day cycle [52]. This early trial was designed when topotecan was still in phase I testing, and the optimal phase II dose (1.5 mg/m2/day) had not been established. After a high incidence of severe neutropenia occurred in the first 13 patients treated (92% grade 3 or 4), the protocol was amended to include prophylactic treatment with G-CSF. With G-CSF support, only 29% of patients experienced grade 3 or 4 neutropenia. However, two deaths were attributed, at least partially, to episodes of febrile neutropenia. Nonhematologic toxicities were generally mild to moderate. One reason for the high incidence of myelosuppression in this trial, compared with that observed in the recurrent SCLC setting, could be the high dose of topotecan used in the trial (2.0 mg/m2/day versus an approved dose of 1.5 mg/m2/day in the recurrent SCLC setting). PRs occurred in 39% of patients, and the median response duration was 4.8 months. Notably, eight (24%) of 34 patients who received subsequent chemotherapy regimens during the follow-up period responded to those therapies, suggesting that topotecan treatment did not induce cross-resistance. The overall median survival time was 10.0 months, which is comparable with the survival data for first-line PE regimens in patients with extensive SCLC [6].

The feasibility of topotecan therapy for SCLC in patients who were not eligible for standard therapies was investigated by Eckardt [53]. In that phase II trial, oral topotecan was administered on days 1–5 of a 21-day cycle. Although topotecan at a dose of 2.0 mg/m2/day resulted in severe neutropenia, the 1.7-mg/m2/day topotecan dose was well tolerated in this patient population composed mainly of elderly patients (mean age 70 years) with multiple comorbidities [53, 54]. Nonhematologic toxicities were generally mild, and the observed activity was comparable with that reported for the standard dose of i.v. topotecan single-agent therapy [53].

These trials demonstrated that topotecan was active in the first-line SCLC setting, supporting the further investigation of alternative topotecan single-agent or combination regimens. Moreover, the activity and tolerability of topotecan in elderly patients with multiple comorbidities suggest that single-agent topotecan could provide an alternative treatment option for SCLC in this patient population for whom there are few treatment options.


   SUMMARY
Top
 Learning Objectives
 Abstract
 Introduction
 Topotecan-Based Combination...
 Single-Agent Topotecan in First...
 Summary
References
 
Despite advances in anticancer therapies, therapy for patients with previously untreated SCLC remains challenging. Although aggressive cisplatin and etoposide regimens in patients with limited disease may result in survival advantages, treatment for patients with extensive disease is generally considered palliative, with patients often succumbing to relapsed or resistant disease within a year of diagnosis. Given the limited survival benefits of therapy in this setting, there is a greater emphasis on quality of life and a demand for regimens with milder toxicity profiles and greater convenience without compromising efficacy. Newer chemotherapy agents with more favorable nonhematologic toxicity profiles than those of platinum agents have been investigated, and the introduction of these agents into the first-line SCLC setting may allow for a more acceptable balance between treatment efficacy and tolerability.

Topotecan is an approved therapy for relapsed SCLC and is currently under investigation in the first-line setting. In the second-line SCLC setting, single-agent topotecan produced numerically higher response rates and overall survival times that were comparable with those produced by CAV, and its activity compared favorably with that reported for other single-agent therapies [7, 11]. Furthermore, second-line single-agent topotecan has been shown to provide improvements in disease-related symptoms, including dyspnea, hoarseness, fatigue, and anorexia, and a decrease in interference with daily activities [11]. The efficacy of topotecan in the second-line SCLC setting makes topotecan an attractive agent for investigation as first-line therapy in patients with extensive disease. Furthermore, the toxicity profile of topotecan—which includes noncumulative and reversible neutropenia and generally mild to moderate nonhematologic toxicities—is well suited for the first-line treatment of patients who have a high likelihood of disease relapse.

Several clinical trials have investigated how to best integrate topotecan into first-line therapy for SCLC. Topotecan has shown activity in previously untreated disease when combined with established first-line regimens or with other agents that have also shown activity in SCLC. Topotecan-based combination regimens with newer nonplatinum agents may be appropriate for patients who cannot tolerate standard platinum-based regimens. As single-agent first-line therapy in patients with extensive SCLC, topotecan has an ORR somewhat lower than the response rates reported for PE regimens, but comparable median survival times (probably attributable in part to subsequent therapy with other agents or regimens) and a superior safety profile [52]. Indeed, Treat and Huang [51] recently presented evidence that topotecan is generally well tolerated in patients with poor PS scores with relapsed SCLC, and this would also be worth investigation in the first-line setting.

Topotecan in combination with paclitaxel, etoposide, and other investigational agents that have different mechanisms of action and no overlapping toxicities or single-agent topotecan in patients who cannot tolerate conventional regimens may provide safe and effective new therapeutic options for patients with SCLC. Further investigations of the optimal combinations, doses, and schedules of topotecan combination therapies in patients with previously untreated SCLC are warranted.


   ACKNOWLEDGMENT
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 Learning Objectives
 Abstract
 Introduction
 Topotecan-Based Combination...
 Single-Agent Topotecan in First...
 Summary
 References
 
Presented in part in the symposium entitled "New Horizons in the Management of SCLC" at the 10th World Conference on Lung Cancer, Vancouver, Canada, August 12, 2003.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Topotecan-Based Combination...
 Single-Agent Topotecan in First...
 Summary
 References
 

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




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