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Topotecan in the Treatment of Recurrent Small Cell Lung Cancer: An Update

Andrea Ardizzoni

University Hospital, Parma, Italy

Correspondence: Andrea Ardizzoni, M.D., Medical Oncology, University Hospital, Via Gramsci 14, 43100 Parma, Italy. Telephone: 39-0521-702316; Fax: 39-0521-995448; e-mail: aardizzoni{at}ao.pr.it


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Topotecan in Recurrent SCLC
 Oral Topotecan
 Topotecan in Patients With...
 Topotecan-Based Combinations
 Conclusion
 References
 
After completing this course, the reader will be able to:

  1. Discuss the results of clinical trials of topotecan both as a single agent and in combination therapy in patients with recurrent SCLC.
  2. Describe differences in the incidences of hematologic toxicities between recurrent SCLC patients treated with lower-dose topotecan and those treated with the standard dose.
  3. Discuss the efficacy and safety of oral topotecan versus the i.v. formulation in recurrent SCLC patients.

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 in Recurrent SCLC
 Oral Topotecan
 Topotecan in Patients With...
 Topotecan-Based Combinations
 Conclusion
 References
 
Small cell lung cancer (SCLC) is an aggressive malignancy with a high propensity for early regional and distant metastasis. Response rates to first-line chemotherapy are typically high, but short lived. The outlook for patients with recurrent SCLC is poor. A variety of single- and multi-agent chemotherapy regimens have met with limited success in patients with recurrent SCLC, and survival is generally measured in weeks. Until recently, further chemotherapy was not widely considered appropriate for patients with relapsed SCLC. The choice of chemotherapy at relapse is dependent on many factors, including type of and response to first-line therapy, the treatment-free interval, and the patient’s performance status. Intravenous topotecan (Hycamtin®; GlaxoSmithKline; Philadelphia, PA) has provided oncologists and patients in many countries with an effective and tolerable therapeutic option for recurrent SCLC. The clinical profile of topotecan was established in several phase II studies and confirmed in a randomized, phase III trial versus cyclophosphamide, doxorubicin (Adriamycin®; Bedford Laboratories; Bedford, OH), and vincristine (Oncovin®; Eli Lilly and Company; Indianapolis, IN)—CAV. In those studies, topotecan exhibited antitumor activity in both chemosensitive and refractory disease. Further, topotecan therapy is associated with significant symptom palliation in this patient population. Because the toxicity profile of topotecan is predictable, generally manageable, and noncumulative, the agent also has potential utility in patients with a poor prognosis and/or a poor performance status. Alternative dosing regimens (lower dose, weekly) and the introduction of an oral formulation may expand the use of topotecan as a single agent and in combination therapy in the second- and first-line treatment of this disease.

Key Words. Recurrent • Small cell lung cancer • Topoisomerase I • Topotecan


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Topotecan in Recurrent SCLC
 Oral Topotecan
 Topotecan in Patients With...
 Topotecan-Based Combinations
 Conclusion
 References
 
Lung cancer is the most common cancer worldwide with 1.04 million new cases and 921,000 deaths in 1990 [1]. In the European Union (E.U.), there were an estimated 196,800 new lung cancer cases and 183,700 deaths due to lung cancer in 1998 [2]. In the U.S., lung cancer accounts for approximately 30% of cancer deaths in men and 25% in women [3], and small cell lung cancer (SCLC) accounts for approximately 18% of all lung cancers in the U.S. [4]. One of the most aggressive types of cancer, SCLC has a high propensity for early regional and distant metastasis [4]. The interval between emergence of symptoms and diagnosis is generally short, as is the interval from diagnosis to death.

Given the poor prognosis of patients with SCLC, first-line therapies are typically aggressive [5]. Currently recommended combinations for previously untreated SCLC patients include cisplatin (Platinol®; Bristol-Myers Squibb; Princeton, NJ) and etoposide (Etopophos®; Bristol-Myers Squibb)—PE; carboplatin (Paraplatin®; Bristol-Myers Squibb) and etoposide—CE; cyclophosphamide, doxorubicin (Adriamycin®; Bedford Laboratories; Bedford, OH), and vincristine (Oncovin®; Eli Lilly and Company; Indianapolis, IN)—CAV; cyclophosphamide, doxorubicin, and etoposide—CAE; and cyclophosphamide, doxorubicin, vincristine, and etoposide—CAVE. These regimens have been associated with high initial objective response rates (ORRs) of 50%–80% [6]. Patients with limited SCLC achieve initial response rates as high as 80%–90% with standard first-line chemotherapy. A complete clinical response can be achieved in 50%–60% of these patients, and 2-year survival rates for patients with limited SCLC treated with the combination of chemotherapy, thoracic irradiation, and prophylactic cranial irradiation are reportedly as high as 40% [7, 8]. In general, however, 5-year survival rates remain discouraging, ranging from 5%–10% [6].

In patients with extensive SCLC, treatment is typically palliative. Despite high tumor response rates to initial chemotherapy, the duration of response is short and overall survival is dismal. Median survival times range from 34–43 weeks, with a 2-year survival rate of generally ≤10% [6, 7, 9]. Virtually no patients are alive at the 5-year mark [7]. Clearly, high tumor response rates in previously untreated patients have not translated into a substantial increase in long-term survival rates, and there remains an urgent need for new regimens in treating extensive SCLC.

The vast majority of patients with SCLC who respond to first-line therapy experience tumor recurrence and die of their disease. In these patients, symptom palliation and quality of life are primary considerations. Chemotherapy in the second-line setting may provide symptom relief; however, many patients with relapsed SCLC have comorbidities, poor performance status (PS) scores, and often are elderly and, as a result, they may be unable to tolerate aggressive combination chemotherapy [10, 11]. In addition, many first-line chemotherapy regimens are associated with cumulative toxicities, including nephrotoxicity, neuropathy, and bone marrow suppression, and may limit the patient’s ability to tolerate therapy on disease recurrence [12, 13]. Therefore, the cumulative toxicity profile of first-line treatments must also be considered when selecting treatments for managing recurrent disease.

Until recently, there has been no well-established treatment available for patients with recurrent SCLC. In the U.S., CAV and single-agent etoposide have been widely used in clinical practice; however, the use of these treatment options has been based mostly on retrospective data or on data from a few small, nonrandomized studies. The use of a three-drug combination regimen, such as CAV or CAE, in the second-line setting can be limited by toxicities. Indeed, it has been suggested that triplet combination regimens should not be used in patients with recurrent SCLC [14, 15]. Single-agent etoposide can be more convenient than CAV given the availability of an oral formulation; however, the benefits from oral etoposide appear to be limited to patients with chemosensitive disease [16]. Further, second-line chemotherapy often yields poor results because of the emergence of acquired drug resistance.

Within the E.U., there are currently no registered standards of care for the treatment of relapsed SCLC. In the absence of approved regimens, clinical practice has driven the strategies used for the treatment of these patients. Both reinduction and crossover therapy strategies are used, with platinum- and taxane-based regimens being the most common. Treatment of patients with relapsed SCLC who have adequate PS scores is based on the treatment-free interval and recovery from treatment-specific toxicities experienced in the first-line setting [17]. For patients with a treatment-free interval >6 months, most oncologists use a reinduction strategy of platinum plus etoposide. The choice of treatment strategy in patients with treatment-free intervals <6 months is variable. Nonetheless, the gap between clinical practice and registered standards of care remains in the E.U.

Because of the poor prognosis and the importance of symptom palliation in patients with recurrent SCLC, there is a clear need for active agents with better toxicity profiles. Single-agent chemotherapy has been a focus in this setting due to the greater toxicities of combination regimens. Several agents—including paclitaxel (Taxol®; Bristol-Myers Squibb), docetaxel, vinorelbine (Navelbine®; GlaxoSmithKline; Philadelphia, PA), gemcitabine (Gemzar®; Eli Lilly and Company), irinotecan (Camptosar®; Pfizer Pharmaceuticals; New York, NY), and topotecan (Hycamtin®; GlaxoSmith-Kline)—have been investigated. Of these, topotecan has the best-characterized clinical profile in this patient population.

Topotecan is a water-soluble, semisynthetic derivative of camptothecin that has a nonoverlapping toxicity profile with other agents used in the treatment of SCLC. Topotecan has demonstrated antitumor activity in both chemosensitive and chemoresistant SCLC [18–22]. Likewise, data from the same trials have demonstrated the tolerability profile of topotecan, which is characterized by manageable, noncumulative myelosuppression and a generally favorable nonhematologic safety profile [18–22]. Additionally, topotecan has demonstrated significant symptom palliation in this patient population [22–25]. Topotecan is currently approved in approximately 40 countries worldwide (including the U.S. and Switzerland) for the treatment of patients with SCLC who have failed or relapsed after first-line chemotherapy. In the U.S., topotecan is now recognized as a standard treatment for patients with relapsed SCLC. Topotecan is also currently approved in the U.S. and E.U. for patients with metastatic carcinoma of the ovary after failure of first-line or subsequent therapy. Unfortunately, topotecan has not been approved for the treatment of relapsed SCLC within the E.U., despite the significant unmet medical need. The regulatory approval of topotecan for the treatment of recurrent SCLC in some countries has provided an important treatment option for these patients. This review summarizes the evidence supporting the use of single-agent topotecan in patients with recurrent SCLC and explores the potentials of single-agent oral topotecan and novel topotecan-based combinations in these patients.


   TOPOTECAN IN RECURRENT SCLC
Top
 Learning Objectives
 Abstract
 Introduction
 Topotecan in Recurrent SCLC
Oral Topotecan
 Topotecan in Patients With...
 Topotecan-Based Combinations
 Conclusion
 References
 
i.v. Topotecan

Phase II Trials
The efficacy and safety of topotecan in patients with recurrent SCLC have been demonstrated in several phase II studies (Table 1Go). These multicenter trials administered i.v. topotecan at a dose of 1.5 mg/m2 on days 1–5 of a 21-day cycle (standard regimen). Enrolled patients had PS scores ≤2 and a mean age of 58 years at baseline. Topotecan was efficacious in both chemosensitive (i.e., relapsed >90 days after first-line chemotherapy) and chemorefractory (i.e., relapsed <90 days after first-line chemotherapy or did not respond) patients. Among chemosensitive patients, the ORR ranged from 14%–38%, with stable disease (SD) occurring in 16%–31% of patients. Median survival times among all patients in these studies ranged from 25–36 weeks. Among chemorefractory patients, the ORR was 2%–7%, with 5%–40% of patients achieving SD as a best response. The median overall survival time for patients with refractory disease was 16–21 weeks [18–21].


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  		Table 1. Phase II/III studies of topotecan in relapsed SCLC
 
In one of the largest phase II trials conducted with single-agent topotecan in patients with recurrent SCLC, Ardizzoni et al. [18] treated 101 patients with a total of 403 courses of topotecan administered using the standard regimen. Ninety-two patients were evaluable for response, with an overall ORR of 22% and an overall median duration of response of 32.7 weeks. Among 45 patients with chemosensitive SCLC, the ORR was 38%, including six complete responses (CRs) and 11 partial responses (PRs). SD was reported in 31% of patients. The median survival time of chemosensitive patients was 29.7 weeks; the median survival time of all responding patients was 53.8 weeks. Among 47 patients with refractory SCLC, the ORR was 6%, including one CR and two PRs. Forty percent of patients achieved SD as a best response. The median survival time among all chemorefractory patients was 20.2 weeks. Hematologic toxicities were predictable, manageable, and noncumulative. Grade 3/4 neutropenia occurred in 75% of courses but was of short duration, reversible, and generally manageable with ongoing dose adjustments of topotecan (administering topotecan at a reduced dose in subsequent cycles if severe neutropenia occurred) and treatment with G-CSF to expedite recovery from severe neutropenia. Nonhematologic toxicities were generally mild to moderate in severity. Fatigue/malaise was reported in 39% of cycles, and nausea/vomiting, stomatitis, and diarrhea were rare.

Phase III Trials
Results from the phase II studies were confirmed in a randomized, multicenter, phase III trial of topotecan versus CAV conducted in patients with progressive or recurrent, limited or extensive SCLC [22]. Patient demographics and baseline disease characteristics were comparable at the time of randomization. Of the 107 patients treated with topotecan (1.5 mg/m2/day on days 1–5 of a 21-day cycle), 83% had extensive SCLC and 77% had PS scores ≤1. Of the 104 patients receiving CAV, 85% had extensive SCLC and 81% had PS scores ≤1. Patients treated with topotecan achieved an ORR of 24% (26 PRs), compared with an ORR of 18% (1 CR, 18 PRs) in the CAV group. An additional 20% of patients treated with topotecan and 12% of patients treated with CAV had SD as a best response. Other efficacy end points were comparable among the two treatment groups. The median time to progression, duration of response, and overall survival time for patients treated with topotecan were 13 weeks, 14 weeks, and 25 weeks, respectively. Similarly, the median time to progression, duration of response, and overall survival time for patients treated with CAV were 12 weeks, 15 weeks, and 25 weeks, respectively. The 1-year survival rate was 14% in both groups. Despite the greater number of survivors in the topotecan arm, there was no significant difference in the median duration of response or survival between patients treated with topotecan and those treated with CAV [22].

Hematologic toxicities were the predominant toxicity for both treatment arms, with similar proportions of patients experiencing grade 4 neutropenia (70% topotecan versus 72% CAV) and anemia (3% topotecan versus 2% CAV). Grade 4 thrombocytopenia occurred more frequently in patients treated with topotecan (29%) than in those treated with CAV (5%). Hematologic toxicities in patients in both arms were of short duration, and clinically important sequelae of neutropenia did not increase with subsequent courses of therapy in either group. Analyses of neutrophil and platelet nadirs for each course of therapy showed no evidence of cumulative toxicity for patients in the topotecan group. Nonhematologic toxicities were generally mild and were comparable between the two groups. Of note, greater improvements were seen in patients treated with topotecan for symptoms of dyspnea, anorexia, hoarseness, fatigue, and interference with daily living (p < 0.05), and time to worsening of dyspnea and anorexia were longer in topotecan patients (p < 0.05) [22].

In summary, single-agent i.v. topotecan has demonstrated efficacy in patients with relapsed SCLC in large phase II and phase III studies. Single-agent topotecan is at least as effective as CAV, while providing superior symptom palliation in this patient population [22, 26].

Lower-Dose Topotecan
Although the recommended starting dose of topotecan is 1.5 mg/m2 on days 1–5 of a 21-day cycle, advanced age, extensive pretreatment, prior platinum therapy, prior radiotherapy, and renal impairment are potential risk factors for increased myelosuppression during topotecan therapy [27]. These risk factors can reduce the patient’s ability to tolerate the standard dose level. Therefore, topotecan therapy in these patients may require dose reduction or treatment delays. Lower-dose topotecan regimens have been evaluated in an attempt to minimize hematologic toxicities and to maintain the efficacy of topotecan in patients at higher risk (Table 2Go) [18–20, 22, 28–32]. In a phase II single-arm, multicenter study of 171 patients treated with topotecan (1.25 mg/m2/day) on days 1–5 of a 21-day cycle [30, 31], the ORR was 15%, including one CR and 24 PRs. An additional 28% of patients had SD. The median survival time was 22.4 weeks. Grade 3/4 neutropenia, thrombocytopenia, and anemia were reported in 10%, 5%, and 1% of cycles, respectively. No relevant nonhematologic toxicities were observed. Similarly, Perez-Soler et al. [32] reported on 32 patients with SCLC refractory to etoposide and cisplatin who were treated with topotecan at a dose of 1.25 mg/m2/day for 5 days. Of the 28 evaluable patients, 11% achieved PRs; 7% achieved a minor response, and 17% had SD. The median overall survival time was 20 weeks. Grade 3/4 neutropenia and thrombocytopenia were reported in 70% and 31% of cycles, respectively. There were no grade 3/4 nonhematologic toxicities. Additionally, pretreatment with platinum did not appear to affect response rates or survival following topotecan treatment. Although these studies were noncomparative, topotecan, at a dose of 1.25 mg/m2/day for 5 days, appears to be associated with a lower incidence of severe hematologic toxicities compared with those seen in historical data for the standard regimen.


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  		Table 2. Hematologic toxicity comparison for standard versus lower-dose topotecan
 
Topotecan at a daily dose of 1.0 mg/m2 for 5 days has also been studied. Ogawara et al. [29] conducted a phase II, open-label study of 105 patients, approximately 60% of whom had stage IV disease. Topotecan was started at a dose of 1.0 mg/m2 on days 1–5 of a 21-day cycle. The 96 evaluable patients received a mean of three courses of therapy. The ORR was 26% (1 CR, 24 PRs), with a median survival of 35.1 weeks and a 1-year survival rate of 32%. No grade 4 nonhematologic toxicities were observed. Likewise, Takeda et al. [28] conducted a multicenter study of topotecan (1.0 mg/m2/day) in 53 patients with recurrent SCLC. In the 50 evaluable patients, the ORR was 26% (13 PRs), and additional patients benefited by achieving SD. The median survival time was 37.4 weeks. Grade 3/4 neutropenia, leukopenia, anemia, and thrombocytopenia were observed in 84%, 66%, 46%, and 42% of patients, respectively. The most frequently reported nonhematologic adverse events were anorexia, nausea, vomiting, fatigue, and alopecia. Taken together, results from these studies suggest that topotecan at the 1.0- and 1.25-mg/m2 doses may be appropriate for patients with advanced age, extensive pretreatment, renal impairment, or other risk factors.


   ORAL TOPOTECAN
Top
 Learning Objectives
 Abstract
 Introduction
 Topotecan in Recurrent SCLC
 Oral Topotecan
Topotecan in Patients With...
 Topotecan-Based Combinations
 Conclusion
 References
 
i.v. topotecan has proven efficacy in patients with recurrent SCLC with predictable and manageable hematologic toxicities. However, the 5-day i.v. regimen requires frequent health care visits and may be inconvenient for some patients. There has been an increasing clinical interest in developing oral formulations of many cytotoxic agents. Oral topotecan has a 30%–40% bioavailability and no known food or drug interactions [33–35]. (For more details, see Gralla [36].) In addition, oral topotecan has a lower peak blood concentration than i.v. topotecan, which may result in a lower risk for severe hematologic toxicities. Further, oral topotecan has a longer terminal half-life and mean residence time, which may translate into superior efficacy. These findings provided the rationale for evaluating the clinical profile of oral topotecan.

In an early phase II trial, 106 patients with chemosensitive SCLC were treated with oral topotecan (2.3 mg/m2 on days 1–5 of a 21-day cycle) or i.v. topotecan (standard dosing regimen). The ORR for patients treated with the oral formulation was 23%, compared with 15% in patients treated with i.v. topotecan. The median survival time for patients treated with oral topotecan was 32.3 weeks, compared with 25.1 weeks for patients treated with i.v. topotecan [23]. Topotecan was generally well tolerated in that study. The incidences of grade 3/4 neutropenia (57% for oral versus 94% for i.v.) and leukopenia (45% versus 74%) were lower in patients who received the oral formulation. The incidences of grade 3/4 thrombocytopenia and anemia were comparable between the two patient groups. Nonhematologic toxicities were also generally comparable. Results of this randomized, phase II study suggest that oral topotecan has a similar efficacy to that of i.v. topotecan in the treatment of relapsed SCLC and may have a superior hematologic toxicity profile to i.v. topotecan. The recently reported preliminary results from phase III testing of oral versus i.v. topotecan were consistent with the results of the phase II trials of oral topotecan in patients with relapsed SCLC [19, 36]. The apparently superior hematologic toxicity profile suggests that oral topotecan may be a favorable therapeutic modality for patients with poor PS scores and may offer greater ease of use and convenience to patients [26].


   TOPOTECAN IN PATIENTS WITH POOR PS SCORES
Top
 Learning Objectives
 Abstract
 Introduction
 Topotecan in Recurrent SCLC
 Oral Topotecan
 Topotecan in Patients With...
Topotecan-Based Combinations
 Conclusion
 References
 
Many patients with recurrent SCLC are elderly and have multiple comorbidities (e.g., chronic obstructive pulmonary disease, coronary heart disease, arterial hypertension, diabetes) that may render them unable to tolerate intensive chemotherapy. Moreover, impaired end-organ function can significantly alter the pharmacokinetic and tolerability profiles of cytotoxic agents, and many oncologists have been reluctant to retreat these patients. There is a clear need for treatments that provide symptom palliation and improved quality of life in these patients. The reversible and noncumulative toxicity profile of topotecan, with mild to moderate nonhematologic toxicities, makes it an appropriate option for SCLC patients with poor PS scores. Treat at al. [37, 38] investigated the feasibility of using topotecan in patients with poorer PS scores in a retrospective pooled analysis of data from five phase II/III clinical trials. ORRs were similar in patients with poor PS scores (2) and in those with superior PS scores (14% for PS score ≤1 versus 17% for PS score = 2). The incidences of grade 3/4 neutropenia, leukopenia, and thrombocytopenia were comparable between the two patient groups, whereas anemia was more common in the PS score = 2 group (44% versus 30% in the PS score ≤1 group; p = 0.009). Symptom palliation was generally comparable between the two groups, and improvements in dyspnea, cough, chest pain, anorexia, insomnia, hoarseness, fatigue, interference with daily living, and hemoptysis were consistent with the findings of other studies of topotecan in recurrent SCLC [22]. These data suggest that topotecan is an effective treatment in patients with poor PS scores and can be considered in this patient population who might otherwise not receive chemotherapy. Further studies of topotecan in this patient population are warranted.


   TOPOTECAN-BASED COMBINATIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Topotecan in Recurrent SCLC
 Oral Topotecan
 Topotecan in Patients With...
 Topotecan-Based Combinations
Conclusion
 References
 
Rationale for Combination Therapy
Combination regimens that comprise agents with different mechanisms of action can result in synergistic antitumor activity and may overcome resistance to chemotherapy. In SCLC, combination chemotherapy generally yields higher overall response rates than single-agent therapy, but the duration of response is still short [7, 39]. Additionally, care must be taken in the selection of agents to avoid overlapping toxicities that may adversely affect quality of life, especially in patients with extensive SCLC. Many of the more active agents employed in the second-line setting (e.g., topotecan, irinotecan, docetaxel, and vinorelbine) are noncross-resistant to first-line therapies and exhibit novel mechanisms of action relative to agents used in previously untreated patients [12]. Additionally, many of these agents have shown synergy with other agents in tumor model studies, thereby providing the rationale for their investigation in combination therapy.

Topotecan-Based Combinations
As shown in Table 3Go [40–43], topotecan is undergoing clinical testing in doublet and triplet combination regimens. In a patient population with a poor prognosis and potential comorbidities, there is a clear need for noncross-resistant therapeutic options. It’s reversible, nonoverlapping nonhematologic toxicities and in vitro antitumor synergy with platinum agents, taxanes, and topoisomerase II inhibitors may make topotecan an ideal candidate for use in combination with other chemotherapy agents [44–46].


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  		Table 3. Topotecan combination therapy in relapsed SCLC
 

Topotecan and Cisplatin
Cisplatin has shown additive activity with topotecan in preclinical models [47, 48], and the combination was subsequently evaluated in clinical studies. Samantas et al. [41] investigated cisplatin (20 mg/m2) administered i.v. on days 1–3 and topotecan (0.9 mg/m2) administered i.v. on days 1–3 of a 21-day cycle for six cycles. Of the 27 patients with recurrent SCLC previously treated with carboplatin or cisplatin and etoposide, the ORR was 22% (2 CRs, 4 PRs) and the median duration of survival was 30.1 weeks. An additional 41% of patients had SD. The combination was generally well tolerated, with grade 3/4 neutropenia, leukopenia, thrombocytopenia, and anemia reported in 42%, 32%, 14%, and 18% of patients, respectively. Nonhematologic toxicities were uncommon; grade 3 mucositis was reported in 6% of patients, and grade 3 diarrhea was reported in 4% of patients.

More recently, in a phase II European Organization for Research and Treatment of Cancer (EORTC) trial, the activity and toxicity of topotecan in combination with cisplatin as second-line therapy were investigated in patients with refractory or sensitive SCLC [40]. Cisplatin (60 mg/m2) was i.v. administered on day 1 and topotecan (0.75 mg/m2/day) was i.v. administered on days 1–5 of a 21-day cycle. Approximately 40% of patients had received prior platinum-based chemotherapy. Of the 116 patients enrolled, 68 patients with chemosensitive and 42 patients with refractory disease were evaluable for tumor response. The ORR for chemosensitive patients was 29% (1 CR, 19 PRs), with 37% of patients achieving SD as a best response. Similarly, the combination was active in chemorefractory patients, who achieved an ORR of 24% (10 PRs). The median overall survival times were 27.5 and 26.2 weeks for patients with chemosensitive and chemorefractory disease, respectively. Grade 3/4 hematologic toxicities included leukopenia in 79% of patients, neutropenia in 76%, thrombocytopenia in 70%, and anemia in 39%. Together, these studies suggest that the combination of topotecan and cisplatin is feasible and active. Further investigation of this combination may demonstrate greater efficacy than single-agent topotecan in the second-line setting. Furthermore, topotecan plus cisplatin may also be an option in the first-line treatment of patients with SCLC [49]. In the first-line setting, for topotecan and cisplatin combination regimens, administration of cisplatin on the final day of topotecan therapy for each cycle, instead of on day 1, appeared to decrease the need for dose reductions to manage neutropenia [50, 51], and toxicity may also be sequence dependent in the second-line setting.

Other Topotecan-Based Combinations
Platinum-free regimens—such as topotecan plus paclitaxel, vincristine, or etoposide—may provide benefits to patients by limiting their exposure to potentially cumulative effects of platinum therapy. Jett et al. [42] recently reported the results of a phase II trial of the North Central Cancer Treatment Group in which patients were administered i.v. topotecan (1.25 mg/m2) on days 1–3 and i.v. paclitaxel (200 mg/m2) on day 1 of a 28-day cycle. Of the 78 patients enrolled (median age 62 years; PS score ≤2), 55 were chemosensitive and 23 were chemorefractory. The ORR and median survival duration of chemosensitive patients were 26% and 28 weeks, respectively, compared with 9% and 24.5 weeks in chemorefractory patients. Grade 3/4 hematologic toxicities included neutropenia (84%) and thrombocytopenia (39%); grade 3/4 nonhematologic toxicities occurred in 51% of patients.

Topotecan has also been investigated in combination with vincristine. Jordan et al. [43] enrolled 18 patients (range 48–78 years; PS score ≤2) who had recurrent disease following first-line treatment with carboplatin and etoposide. Patients were administered i.v. topotecan (1.5 mg/m2) on days 1–3 and i.v. vincristine (1 mg) on either days 1 and 3 or days 1 and 4 of a 21-day cycle for a median of 3.5 courses per patient. The ORR in 16 evaluable patients was 19% (3 PRs); 44% of patients had SD. The median survival time was 21.5 weeks, with 25% of patients alive at 1 year. Grade 3/4 hematologic toxicities included neutropenia (31%), thrombocytopenia (50%), and anemia (38%).

The sequential administration of topotecan (a topoisomerase I inhibitor) and etoposide (a topoisomerase II inhibitor) can result in synergistic antitumor activity. Preclinical studies in cell lines have indicated a potential collateral sensitivity, with increased tumor growth inhibition to topoisomerase-I inhibitors, such as topotecan, when cells have been previously exposed to topoisomerase-II inhibitors, such as etoposide [52]. Further, 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 [53]. In a phase I study, Aisner et al. [54] suggested that topotecan followed by etoposide plus cisplatin is feasible with G-CSF support. For future phase II studies, a course of topotecan (0.75 mg/m2/day) on days 1–3 followed by etoposide (70 mg/m2/day) and cisplatin (20 mg/m2/day) on days 8–10 with G-CSF (5 µg/kg) support was recommended. The activity of this regimen requires further evaluation in phase II studies.

Topotecan-Based Triplets
The use of triplet regimens such as CAV or CAE may be limited by toxicity, particularly myelosuppression [14]. Indeed, triplet regimens are generally not recommended for patients with extensive SCLC, as a number of studies have demonstrated no additional benefit and greater toxicities compared with doublet regimens [14, 15]. The tolerability of topotecan in triplet regimens has been limited to the first-line setting in combination with paclitaxel and carboplatin [55], with paclitaxel and cisplatin [56], and with carboplatin and etoposide [57]. These triplet regimens have resulted in overall response rates of approximately 80% in preliminary trials with patient populations of previously untreated patients. (For more discussion on the role of topotecan in the first-line treatment of SCLC, see Stewart et al. [49].) As may be expected, myelosuppression was the dose-limiting toxicity in these regimens. More recently, a phase I trial was conducted to investigate the utility of sequential topotecan, paclitaxel, and etoposide in previously treated patients with solid tumors [58]. It is hoped that sequential administration, different mechanisms of action, and lack of cross-resistance of tumor cells to these agents will lead to greater antitumor efficacy and better tolerability than those observed with three-drug combinations.


   CONCLUSION
Top
 Learning Objectives
 Abstract
 Introduction
 Topotecan in Recurrent SCLC
 Oral Topotecan
 Topotecan in Patients With...
 Topotecan-Based Combinations
 Conclusion
References
 
The choice of chemotherapy in relapsed patients is often influenced by comorbidities, toxicities from previous treatment, and the general well-being of the patients; therefore, there exists a medical need for more active and better-tolerated therapies for relapsed SCLC that demonstrate clinical benefit and symptom palliation. Topotecan is an important addition to the physician’s armamentarium for the treatment of relapsed SCLC and is the only single-agent therapy approved by the U.S. Food and Drug Administration for chemosensitive SCLC after failure of first-line chemotherapy; it has highly consistent and reproducible activity, with manageable, nonoverlapping, and noncumulative toxicities. In addition, topotecan provides symptom improvements and may improve quality of life for patients in this population. Therefore, topotecan should be considered a first choice of therapy for patients with recurrent SCLC. Recent evidence suggests that the oral formulation of topotecan provides equivalent efficacy and tolerability to the i.v. formulation with an advantage, for some patients, of fewer visits to the clinic for drug administration. Weekly regimens may lead to further improvements in the toxicity profile and are undergoing testing to determine their activity in patients with extensive SCLC. The role of topotecan in combination therapies for relapsed SCLC remains to be clarified. Finally, numerous trials are under way in patients with previously untreated SCLC and in patients with non-small cell lung cancer. Future studies will more fully characterize the role of topotecan in other clinical settings.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Topotecan in Recurrent SCLC
 Oral Topotecan
 Topotecan in Patients With...
 Topotecan-Based Combinations
 Conclusion
 References
 
Supported by GlaxoSmithKline, Philadelphia, PA.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Topotecan in Recurrent SCLC
 Oral Topotecan
 Topotecan in Patients With...
 Topotecan-Based Combinations
 Conclusion
 References
 

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