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Lung Cancer |
aRoyal Marsden Hospital, Surrey, United Kingdom; bThe Center for Cancer Care and Research, St. Louis, Missouri, USA; cRegional Lung Disease Centre, Oncology Department, Poznan, Poland
Key Words. Lung cancer • Topotecan oral • Chemotherapy
Correspondence: Correspondence: Mary O'Brien, M.D., FRCP, Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM25JS, United Kingdom. Telephone: 00442086613278; Fax: 00442086437371; e-mail: mary.o'brien{at}rmh.nhs.uk
Received May 14, 2007; accepted for publication August 1, 2007.
Disclosure: M.O'B. has acted as a consultant to Schering-Plough, Roche, and GlaxoSmithKline. J.E. has a financial interest in Aventis and GlaxoSmithKline. No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.
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Learning Objectives
Top
Learning Objectives
Abstract
Introduction
i.v. Topotecan for Untreated...
Development of Oral Topotecan
Oral Topotecan in SCLC
Second-Line Oral Topotecan in...
Oral Topotecan in Advanced...
Topotecan as a Candidate...
Conclusions
References
After completing this course, the reader will be able to:
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ABSTRACT |
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TopLearning ObjectivesAbstractIntroductioni.v. Topotecan for Untreated...Development of Oral TopotecanOral Topotecan in SCLCSecond-Line Oral Topotecan in...Oral Topotecan in Advanced...Topotecan as a Candidate...ConclusionsReferences |
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INTRODUCTION |
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Although surgery and radiation play integral roles in lung cancer management, chemotherapy is the mainstay of treatment for SCLC and is increasingly being used in non-small cell lung cancer (NSCLC). Platinum-based regimens are the standard first-line strategy in both settings for either early-stage or advanced disease. The agents used as second-line therapy vary by setting [2, 3].
Topotecan, a semisynthetic derivative of camptothecin, is a topoisomerase I inhibitor with well-established antineoplastic properties. In the mid-1990s, i.v. single-agent topotecan was shown to have activity against relapsed ovarian cancer [4] and SCLC [5]. This activity led to approval by the U.S. Food and Drug Administration (FDA) of single-agent topotecan for the treatment of metastatic ovarian carcinoma after failure of initial or subsequent chemotherapy, and for the treatment of SCLC sensitive disease after failure of first-line chemotherapy. Most recently, topotecan, in combination with cisplatin, was approved for use in stage IV-B recurrent or persistent cervical cancer [6]. The principal dose-limiting toxicity of i.v. topotecan is myelosuppression, which is short lived, noncumulative, and reversible; nonhematologic toxicities are manageable [5]. For SCLC and ovarian cancer, the approved dose of i.v. topotecan is 1.5 mg/m2 given as a 30-minute i.v. infusion, daily for five consecutive days, every 21 days. However, multiple trials have evaluated alternative doses and schedules, including lower starting doses of 1.25 or 1.0 mg/m2 given for 5 days, 3-day schedules, and weekly bolus schedules [7–9]. i.v. topotecan has been used as a single agent and in combination regimens for the treatment of various tumor types. Topotecan is currently recommended by the National Comprehensive Cancer Network as the first choice in treating chemotherapy-sensitive SCLC, specifically for disease that has relapsed within 2–6 months after primary treatment [2].
Since the approval of topotecan for use in relapsed SCLC, various studies have been conducted in the first-line setting. An oral formulation of topotecan has been investigated and provided added convenience for patients. Oral topotecan has been studied in the first- and second-line settings for both SCLC and NSCLC. This paper reviews the role of topotecan in the treatment of lung cancer, focusing on recent data with i.v. topotecan in first-line SCLC and the new oral formulation in both SCLC and NSCLC.
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I.V. TOPOTECAN FOR UNTREATED SCLC |
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Recent studies evaluating topotecan in first-line SCLC have primarily examined its use in combination with either cisplatin or etoposide. Results of a phase II study in 36 patients with limited or extensive disease suggested that sequential administration of i.v. topotecan (0.75 mg/m2 daily for 5 days) and oral etoposide (50 mg twice daily for 7 days) as 21-day cycles is effective for SCLC [14]. The median progression-free survival duration was 7.3 months and the median survival time was 12.0 months. The incidences of grade 3 or 4 neutropenia and thrombocytopenia were 25% and 11%, respectively; two patients died from neutropenic sepsis.
The topotecan–etoposide combination was compared with a topotecan–cisplatin combination, with results suggesting similar efficacy [15]. In that randomized phase II study, 82 patients with previously untreated ED-SCLC received either i.v. topotecan (1.25 mg/m2 per day) on days 1–5 plus cisplatin (50 mg/m2) on day 5 or i.v. topotecan (0.75 mg/m2 per day) on days 1–5 plus i.v. etoposide (60 mg/m2 per day) on days 1–5. Response rates and median survival times were similar in the two groups (63.4% versus 61.0% and 9.6 months versus 10.1 months, respectively). Hematologic toxicities in the topotecan–cisplatin arm versus the topotecan–etoposide arm, respectively, were grade 3 or 4 anemia (46.4% versus 20.0%) and grade 4 neutropenia (56.1% versus 65.0%). The incidence of sepsis was 0% with topotecan plus cisplatin versus 9.8% with topotecan plus etoposide. Secondary to the significant myelosuppression of the topotecan–cisplatin combination, investigators have studied shorter schedules of topotecan in combination with cisplatin [7, 16, 17], including a 3-day administration schedule of topotecan that appears to be comparable with the standard 5-day schedule [7]. A randomized phase II study in 86 patients with ED-SCLC compared a 1.0-mg/m2 dose of topotecan on days 1–5 with a 1.5-mg/m2 dose on days 1–3, each with cisplatin (75 mg/m2) on the last day of topotecan treatment. While the efficacies were similar, the 3-day regimen may offer a more tolerable option. The median survival times in the 5- and 3-day arms were 8.7 months and 7.6 months, respectively. There was no significant difference in overall survival (p = .68), and response rates were 62% and 60%, respectively. Grade 3 or 4 toxicities in the 5- and 3-day arms, respectively, included leukocytopenia (64% versus 48%), anemia (43% versus 21%), and thrombocytopenia (52% versus 40%).
Topotecan has been evaluated in a consolidation approach to untreated SCLC. A randomized phase III trial by the Eastern Cooperative Oncology Group (ECOG) evaluated topotecan following cisplatin plus etoposide in patients with previously untreated ED-SCLC [18]. Four cycles of cisplatin plus etoposide were given to 402 patients; those with response or stable disease were then randomized to either continue chemotherapy with topotecan (1.5 mg/m2) daily for 5 days every 3 weeks for four cycles (n = 112) or proceed to observation alone (n = 111). The progression-free survival interval was significantly longer in the topotecan arm (median, 3.7 months with topotecan versus 2.3 months with observation alone; p < .001). The overall survival duration was not significantly different between the two groups (median, 9.3 months with topotecan versus 8.9 months with observation; p = .43). Administration of topotecan did not worsen quality of life; no significant differences occurred in Trial Outcome Index or Functional Assessment of Cancer Therapy–Lung scores.
Finally, a phase III trial comparing two different schedules of the cisplatin–etoposide–topotecan combination has been completed [19]. The study employed either sequential administration—cisplatin (75 mg/m2) on day 1 and etoposide (100 mg/m2 per day) on days 1–3 for four cycles followed by topotecan (1.5 mg/m2 per day) on days 1–5 for four cycles—or alternating administration of the same doses of i.v. cisplatin and etoposide (cycles 1, 3, 5, and 7) and topotecan (cycles 2, 4, 6, and 8) in 284 chemotherapy-naïve patients with ED-SCLC. The preliminary analysis indicated comparable activity and safety in the two comparison groups, with no significant differences between groups in response, overall survival, time to progression (TTP), or response duration. For the sequential versus alternating groups, the overall response rates were 53% versus 55%; the median survival times were 10.2 versus 9.5 months; the median TTP were 6.0 versus 6.8 months; and the median response durations were 5.5 versus 5.2 months, respectively. Grade 3 or 4 hematologic toxicities were neutropenia (51% and 52%), anemia (12% and 11%), febrile neutropenia (7% and 9%), and thrombocytopenia (19% and 20%). There were seven toxicity-related deaths (four in the sequential arm and three in the alternating arm). Taken together, these studies add useful information about the use of i.v. topotecan in the first-line treatment of SCLC and prepare a basis for further investigation of topotecan as a potential new agent in the treatment of this disease.
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DEVELOPMENT OF ORAL TOPOTECAN |
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Quality of life is an important issue for patients with lung cancer. In another survey of patients with advanced NSCLC, given the choice between supportive care and chemotherapy, only 22% selected chemotherapy if it provided a survival benefit of 3 months, whereas 68% chose chemotherapy if it substantially reduced symptoms without prolonging survival [22]. Advantages of oral agents include eliminating the need for i.v. lines that cause discomfort and possibly lead to infections, the potential for fewer side effects than the injectable counterparts, and perhaps easier integration into combination regimens.
Phase I studies evaluating the pharmacokinetics and early safety data of single-agent oral topotecan have been completed (Table 1) [23–31]. Single-dose studies determined that the absolute bioavailability of the oral formulation is 30%–44% [23–25] and is not affected by food intake [23]. A multiple-dose study found that approximately 57% of the oral dose is eliminated unchanged in the urine and feces [26]. A population pharmacokinetic analysis revealed that renal creatinine clearance and, to a limited extent, performance status (PS) are factors that significantly affect oral topotecan clearance [27].
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Phase I trials that evaluated oral topotecan given in combination with other chemotherapeutic agents have identified the maximum-tolerated dose of oral topotecan with cisplatin, capecitabine, and carboplatin plus paclitaxel [32–35]. In a randomized, crossover design, 49 patients received oral topotecan at escalating doses daily for 5 days every 21 days with i.v. cisplatin (75 mg/m2) on either day 1 or day 5 of topotecan [32]. Consistent with previously reported data with i.v. topotecan and cisplatin [36], myelotoxicity was significantly more severe when cisplatin preceded topotecan. As such, the recommended maximum-tolerated dose of oral topotecan is lower in the cisplatin–topotecan sequence—topotecan (1.25 mg/m2 per day) for 5 days preceded by cisplatin (75 mg/m2) on day 1 once every 3 weeks versus topotecan (2.0 mg/m2 per day) for 5 days followed by cisplatin (75 mg/m2) on day 5. Evaluation of an all-oral combination of topotecan and capecitabine in 19 patients led to a recommended regimen of topotecan (1.5 mg/m2 per day) for 5 days on days 1–5 of each week for 2 weeks and capecitabine (1,800 mg/m2 twice daily) on days 1–14 of a 21-day cycle in future trials [34]. A study of 13 patients receiving escalating doses of topotecan on days 1–5 in combination with paclitaxel (175 mg/m2) and carboplatin (AUC, 5) on day 1 found significant myelotoxicity at all dose levels of topotecan (0.75, 1.0, and 1.25 mg/m2), and the authors could not recommend any of the doses for further study [33]. However, a subsequent phase I–II study in patients with ovarian cancer administered the triplet in a "reverse schedule," with the same doses of paclitaxel plus carboplatin on day 5 of oral topotecan dosing (rather than day 1) [35]. In the phase I portion, a topotecan dose of 2.0 mg/m2 for 5 days was reached; however, in the phase II portion, a dose reduction to 1.75 mg/m2 was required after the first course as a result of febrile neutropenia. The triplet was well tolerated after the dose reduction.
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ORAL TOPOTECAN IN SCLC |
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Phase III Trial
In a subsequent randomized, phase III trial, the combination of oral topotecan and cisplatin was compared with the standard etoposide–cisplatin regimen in previously untreated patients with ED-SCLC [10]. Treatment consisted of oral topotecan (1.7 mg/m2 per day) for 5 days with i.v. cisplatin (60 mg/m2) on day 5 (TC, n = 389) or i.v. etoposide (100 mg/m2 per day) for 3 days with i.v. cisplatin (80 mg/m2) on day 1 (PE, n = 395) every 21 days. The primary endpoint of the study, overall survival, was not significantly different between arms (p = .48). The hazard ratio adjusted for interim analyses was 1.05 (95% confidence interval [CI], 0.90–1.24). The median survival times were 39.3 weeks with TC versus 40.3 weeks with PE. The 1-year survival rates were similar between TC and PE (31% in both groups). The 95% CI for the coprimary endpoint of difference in the 1-year survival rate between TC and PE was –6.5 to 6.5, indicating that TC was not inferior to PE in 1-year survival rate based on a 10% noninferiority margin. The median TTP for TC and PE were 24.1 weeks and 25.1 weeks, respectively. Response rates were 63% with TC and 69% with PE. Of grade 3 or 4 hematologic toxicities, neutropenia occurred more frequently with PE (84% versus 59%), while anemia and thrombocytopenia occurred more frequently with TC (38% versus 21% and 38% versus 23%, respectively). Fever and infection occurring within 2 days of grade 4 neutropenia was observed in 10% of patients on PE versus 4% on TC. Differences between arms were observed for nonhematologic toxicities. Patients on TC had a higher incidence of diarrhea (33% for TC versus 18% for PE), but a lower incidence of serum creatinine elevations (12% for PE versus 5% for TC) and alopecia (40% for PE versus 24% for TC). Overall, this phase III study demonstrated similar efficacy and tolerability between oral topotecan plus cisplatin and the standard etoposide–cisplatin combination as first-line treatment for patients with ED-SCLC.
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SECOND-LINE ORAL TOPOTECAN IN SCLC |
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60 days after the end of chemotherapy) [41]. The primary endpoint of difference in response rate between topotecan and CAV was 6.0% in favor of topotecan, with a 95% CI of –5.9 to 18, indicating that, at the lower limit of the CI, topotecan may be inferior to CAV by at most 5.9%. No significant differences between i.v. topotecan and CAV were observed in the response rate (24.3% versus 18.3%), TTP (median, 13.3 versus 12.3 weeks; p = .552), or overall survival time (median, 25.0 versus 24.7 weeks; p = .795). However, several disease-related symptoms (dyspnea, fatigue, anorexia, hoarseness, and interference with daily activity) improved to a significantly greater extent with topotecan than with CAV. Some safety advantages were observed with topotecan as well. While grade 3 or 4 thrombocytopenia and anemia occurred more frequently with topotecan, grade 4 neutropenia occurred less frequently than with CAV. Additionally, fewer dose reductions for nonhematologic toxicities occurred in the topotecan arm. A subsequent study demonstrated activity with topotecan in patients previously treated for SCLC who relapsed with symptomatic brain metastases [42]. Of the 30 patients in the single-arm phase II study, eight had prior whole-brain irradiation (WBI). Responses in cerebral metastases were observed in 33% of patients, including four of the eight patients who had undergone WBI. These data support the current role of i.v. topotecan in relapsed SCLC and the investigation of the oral formulation in this setting. To evaluate whether oral topotecan could alternatively be used in chemotherapy-sensitive SCLC, i.v. and oral topotecan were compared in a phase II trial [37] and further explored in a phase III trial [10] (Table 2) [10, 37–40]. In these randomized studies, patients with relapsed, sensitive SCLC (defined as relapse >90 days after the end of chemotherapy) received second-line therapy with either oral topotecan (2.3 mg/m2 per day) or i.v. topotecan (1.5 mg/m2 per day) for 5 days every 21 days. Efficacy parameters indicated similar activity between the two treatments and possibly a lower incidence of severe neutropenia with the oral formulation. From the phase III trial, response rates and median survival times for oral versus i.v. topotecan were 18.3% versus 21.9% and 33 weeks versus 35 weeks, respectively [38]. The incidences of grade 4 neutropenia were 47% versus 64% for the oral and i.v. formulations, respectively. In the phase II trial, the incidences of grade 4 neutropenia were 35% versus 67% for the oral and i.v. formulations, respectively [37]. These data suggest that oral topotecan has similar efficacy to the i.v. formulation and is a suitable alternative to the i.v. route in patients with relapsed SCLC, with the added advantage of convenient administration.
Phase III Trial: Superior Survival in Relapsed Advanced SCLC Compared with Best Supportive Care
The phase III trial, designed to assess whether active chemotherapy has a role in second-line SCLC, evaluated oral topotecan versus best supportive care (BSC) in patients with relapsed SCLC [40]. In this open-label study, 141 patients were randomized to receive oral topotecan (2.3 mg/m2 per day) for 5 days every 3 weeks plus BSC or BSC alone. A clinically and statistically significant improvement in the primary endpoint of overall survival was observed in the oral topotecan arm (p = .01). The unadjusted hazard ratio for oral topotecan relative to BSC was 0.64 (95% CI, 0.45–0.90), indicating a 36% lower risk for death in the oral topotecan group. The median survival time was 86% longer in the topotecan arm than in the BSC arm (25.9 weeks versus 13.9 weeks). The 6-month survival rates were 49% in the topotecan arm and 26% in the BSC arm. On entry, patients were stratified according to the TTP since first-line therapy (
or >60 days). Importantly, the survival advantage for topotecan was maintained in both strata: namely, patients with resistant disease (TTP 60 days) and patients with sensitive disease (TTP >60 days). The overall response rate to topotecan was 7%. Importantly, an additional 44% experienced stable disease. As shown in Table 2, this clinical benefit rate of 51% (representing the sum of the percentages of patients experiencing an objective response and stable disease) is consistent with the range of 36%–45% observed with oral or i.v. topotecan in other phase II and III clinical trials in second-line SCLC [37, 38]. The median TTP in the topotecan arm was 16.3 weeks. Response and progression data were not collected for the BSC arm. Quality of life (measured with the EuroQoL-5 Dimensions [EQ-5D] questionnaire) deteriorated significantly faster in patients receiving BSC alone. The rate of deterioration per 3-month interval in EQ-5D scores was –0.20 (95% CI, –0.27 to –0.12) on BSC compared with –0.05 (95% CI, –0.11 to 0.02) on topotecan. The difference in rate of change was significant (+0.15; 95% CI, 0.05–0.25). Oral topotecan also significantly improved the symptom of dyspnea, clinically important in this patient population. This finding is consistent with the study of i.v. topotecan versus CAV, in which dyspnea was improved to a significantly greater extent with topotecan than with CAV [41]. The most common toxicities related to oral topotecan were hematological (grade 3 or 4 neutropenia, 61%; grade 3 or 4 thrombocytopenia, 38%; grade 3 or 4 anemia, 25%). All-cause mortality within 30 days of starting the study was not higher in the topotecan group (7% for topotecan versus 13% for BSC). The most commonly occurring nonhematologic toxicity was diarrhea in the topotecan group (6%) and dyspnea in the BSC group (9%). These data suggest that treatment with oral topotecan should be considered for all patients with relapsed SCLC, including those with resistant disease. Until this study, the role of chemotherapy in resistant disease was not well defined, and some evidence previously suggested that chemotherapy may not be beneficial in such patients [43]. This study made an important contribution by being the first to show that active chemotherapy can in fact prolong survival in patients with resistant SCLC and improve quality of life in patients with relapsed SCLC.
SCLC is an aggressive and fatal disease. Novel active therapies are urgently needed in all subsets of patients with this disease. Taken together, the studies with oral topotecan support a role for this new agent in the treatment of SCLC.
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ORAL TOPOTECAN IN ADVANCED NSCLC |
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Two phase II trials of oral topotecan have been conducted in untreated patients with NSCLC. Monotherapy was evaluated in 30 patients with inoperable stage III or IV NSCLC and an ECOG PS score of 0 (7%), 1 (70%), or 2 (23%) [48]. The dose of oral topotecan was escalated starting with 2.3 mg/m2 per day up to 3.1 mg/m2 per day and administered for five consecutive days every 3 weeks for up to six cycles. No responses were observed; however, 43% of patients achieved stable disease. The median survival time was 39.9 weeks, the 1-year survival rate was 33%, and the median TTP was 12.3 weeks. Grade 3 or 4 hematologic toxicities were neutropenia (40%), anemia (17%), and thrombocytopenia (7%). Disease-related symptom improvement was observed in some patients for all parameters, including dyspnea (17%), cough (31%), chest pain (20%), and hemoptysis (33%).
A second phase I–II trial in untreated advanced NSCLC evaluated combination therapy with oral topotecan and i.v. paclitaxel [49]. Results from the phase I portion determined that the maximum-tolerated dose of oral topotecan was 1.25 mg/m2 per day for 5 days every 3 weeks when given in combination with paclitaxel (175 mg/m2) on day 1. A total of 41 patients (six from phase I and 35 from phase II) received topotecan at the maximum-tolerated dose. Grade 3 or 4 neutropenia and anemia occurred in 68% and 18% of patients, respectively. Preliminary response data for 33 patients were reported: a 12% partial response rate and a 27% stable disease rate.
Second-Line Oral Topotecan for Advanced NSCLC
Recent data from a large randomized phase III trial show that oral topotecan is not inferior to i.v. docetaxel in the treatment of patients with relapsed or refractory NSCLC [50]. Patients were randomized to oral topotecan (2.3 mg/m2 per day) for 5 days (n = 414) or a standard regimen of i.v. docetaxel (75 mg/m2) on day 1 (n = 415) every 3 weeks. The 1-year survival rates for oral topotecan versus docetaxel were 25.1% versus 28.7%; the 95% CI for the primary endpoint of difference in 1-year survival rate between oral topotecan and docetaxel was –9.6 to 2.5, indicating that oral topotecan was not inferior to docetaxel in 1-year survival rate based on a prespecified 10% noninferiority margin. Overall survival was in favor of docetaxel (log-rank p = .06). The unadjusted hazard ratio was 1.16 (95% CI, 0.99–1.36), indicating a 16% higher risk for death in the topotecan arm. For oral topotecan versus docetaxel, respectively, the median survival times were 27.9 weeks versus 30.7 weeks, 1-year survival rates were 25.1% versus 28.7%, and median TTP were 11.3 weeks versus 13.1 weeks. The response rate was 5% in both arms. Based on the 1-year survival rate, oral topotecan met the criteria for noninferiority to docetaxel in this trial. The quality of life profile favored docetaxel relative to topotecan; however, the magnitude of the difference was small and may not be clinically significant. Grade 3 or 4 toxicities differed between treatments; neutropenia occurred more frequently with docetaxel (60% versus 50%), while anemia and thrombocytopenia occurred more frequently with oral topotecan (26% versus 10% and 26% versus 7%, respectively). This study demonstrated that topotecan may provide an oral alternative for patients with relapsed, advanced NSCLC.
Together, these studies in advanced NSCLC show that oral topotecan represents a feasible treatment option in this setting and offers the advantage of convenient administration.
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TOPOTECAN AS A CANDIDATE FOR COMBINATION WITH NOVEL AGENTS |
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CONCLUSIONS |
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An oral topotecan formulation has been developed. The dose-limiting toxicity of single-agent oral topotecan is grade 4 neutropenia, which appears somewhat less frequently than with i.v. topotecan. Oral topotecan (alone or in combination) may be a viable option for patients with lung cancer who prefer oral treatment to i.v. therapy. Three recent phase III trials have demonstrated the activity of oral topotecan. In chemotherapy-naïve patients with ED-SCLC, oral topotecan plus cisplatin provided efficacy and safety that were similar to those of etoposide plus cisplatin. In patients with relapsed SCLC, treatment with oral topotecan showed a statistically significant and clinically meaningful longer overall survival duration than with BSC alone, a benefit maintained in subgroups of patients with either chemotherapy-resistant or chemotherapy-sensitive disease. In that same study, oral topotecan also improved quality of life over that seen with BSC alone in the study population. In previously treated patients with NSCLC, single-agent oral topotecan was shown to be noninferior in 1-year survival relative to the current standard of i.v. docetaxel based on a 10% noninferiority margin.
In future studies, oral topotecan represents a good candidate for combination therapy with other i.v. or oral chemotherapy agents, monoclonal antibodies, proteosome inhibitors, and small molecule tyrosine kinase inhibitors.
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REFERENCES |
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