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Update on the Role of Topotecan in the Treatment of Non-Small Cell Lung Cancer

David J. Stewart

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

Correspondence: David J. Stewart, M.D., F.R.C.P.C., The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 0432, 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 in the Treatment...
 Future Role of Topotecan...
 Summary
 References
 Additional Reading 
 
After completing this course, the reader will be able to:

  1. Explain the toxicity challenges that limit the use of standard platinum-based therapies in patients with NSCLC.
  2. Discuss the role of topotecan as monotherapy and in combination with other agents in the first-line and second-line treatment of patients with NSCLC and its favorable toxicity profile relative to platinum.
  3. Describe the importance of understanding resistance mechanisms to optimize the efficacy of antitumor therapies such as topotecan.

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 the Treatment...
 Future Role of Topotecan...
 Summary
 References
 Additional Reading 
 
Non-small cell lung cancer (NSCLC) is an aggressive disease that is generally resistant to chemotherapy. As a result, the prognosis for patients with NSCLC is poor. Currently, platinum-based regimens are the standard of care for patients with advanced NSCLC. However, these regimens are associated with severe and often cumulative hematologic and nonhematologic toxicities, limiting dose intensity. Therefore, novel chemotherapeutic agents and combination regimens may improve the outcome for these patients. A variety of new agents and combinations have been investigated in the treatment of NSCLC. However, to date, no clearly superior single-agent or combination regimen has emerged. Topotecan (Hycamtin®; GlaxoSmithKline; Philadelphia, PA), a topoisomerase I inhibitor, is currently approved for the treatment of patients with relapsed small cell lung cancer (SCLC) and is associated with manageable, noncumulative, hematologic toxicities. In addition, topotecan demonstrates a favorable nonhematologic tolerability profile compared with agents currently used in the treatment of patients with NSCLC. The success of topotecan in patients with SCLC has made it an attractive option in the NSCLC setting. Topotecan-based combination regimens in the first-line treatment of NSCLC have demonstrated promising antitumor activities with favorable toxicity profiles. Many topotecan combination regimens have induced stable disease, a response that may offer meaningful clinical benefit in the palliative treatment of patients with advanced disease. Topotecan plus gemcitabine (Gemzar®; Eli Lilly and Company; Indianapolis, IN) and single-agent topotecan may be particularly appropriate for patients in the second-line setting, in which palliation of symptoms is an important outcome of chemotherapy. Herein, the future role of topotecan in the first- and second-line treatment of NSCLC and the potential role of resistance mechanisms obtained from in vivo dose-response studies in designing future combination regimens are discussed.

Key Words. Combination chemotherapy • Non-small cell lung carcinoma • Topotecan • Toxicity


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Topotecan in the Treatment...
 Future Role of Topotecan...
 Summary
 References
 Additional Reading 
 
The current American Society of Clinical Oncology guidelines for the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) recommend platinum-based chemotherapy [1, 2]. As single agents, both cisplatin (Platinol®; Bristol-Myers Squibb; Princeton, NJ) and carboplatin (Paraplatin®; Bristol-Myers Squibb) produce response rates of only ~10% [3]. To take advantage of potential synergistic activity, cisplatin and carboplatin have been combined with other chemotherapeutic agents in the hope of increasing tumor response. Cisplatin or carboplatin in combination with agents such as etoposide (Vepesid®; Bristol-Myers Squibb) and paclitaxel (Taxol®; Bristol-Myers Squibb) produce response rates of 12%–63% and median survival times of ~30–40 weeks [4–6]. In a large trial of 1,207 patients with advanced NSCLC treated with platinum-based combination therapy, the median survival time of all patients was 8.0 months, with 33% alive at 1 year [4]. In addition to the disappointing overall patient survival, current standard platinum-based regimens may cause nausea and vomiting, hematologic toxicities, hypersensitivity (for platinum-taxane combinations), and cumulative nephrotoxicity and neuropathy, which is severe and debilitating in some patients. Platinum-based regimens may be particularly poorly tolerated in elderly patients or patients with poorer performance statuses [4].

Because of the marginal response rates and poor tolerability of the standard platinum-based regimens, a number of other agents, including vinorelbine (Navelbine®; GlaxoSmithKline; Philadelphia, PA), docetaxel (Taxotere®; Aventis Pharmaceuticals Inc.; Bridgewater, NJ), gemcitabine (Gemzar®; Eli Lilly and Company; Indianapolis, IN), and irinotecan (Campostar®; Pfizer Pharmaceuticals; New York, NY), have been investigated in the treatment of patients with NSCLC. Single-agent vinorelbine has demonstrated antitumor activity in the first-line treatment of advanced NSCLC, with overall response rates of 8%–37% [7–10]. In addition, vinorelbine in combination with cisplatin is associated with superior response and survival rates compared with cisplatin alone [11]. Vinorelbine in combination with docetaxel has also demonstrated antitumor activity, with response rates of 23%–51% [12, 13]. Gemcitabine in combination with cisplatin has been shown to be effective in the first-line treatment of patients with advanced NSCLC [2]. Finally, single-agent gemcitabine, docetaxel, and irinotecan, although associated with some antitumor activity, do not have established roles in the first-line setting [9, 13]. Unfortunately, despite the generally superior toxicity profiles and promising antitumor activities of these newer agents compared with the standard platinum-based regimens, no clearly superior single-agent or combination regimen has emerged [4, 6].

The continued poor outcome of patients with NSCLC indicates that the current recommended regimens are falling short. In addition, many of the chemotherapy agents used regularly to treat NSCLC are associated with severe nonhematologic toxicities that are often cumulative and nonreversible and impair quality of life in this essentially palliative setting. Therefore, agents with novel mechanisms of action and superior safety profiles need to be investigated in this patient population. Topotecan (Hycamtin®; GlaxoSmithKline), a topoisomerase I inhibitor, is currently approved for the treatment of relapsed small cell lung cancer (SCLC) and has recently shown activity in the NSCLC setting [14–16]. This review summarizes the recent findings on topotecan in the treatment of these patients and explores the potential role of topotecan in the treatment of patients with NSCLC.


   TOPOTECAN IN THE TREATMENT OF NSCLC
Top
 Learning Objectives
 Abstract
 Introduction
 Topotecan in the Treatment...
Future Role of Topotecan...
 Summary
 References
 Additional Reading 
 
Rationale for Topotecan
The recommended dose of topotecan is 1.5 mg/m2 via a 30-minute i.v. infusion on days 1–5 of a 21-day cycle. In SCLC, topotecan is associated with overall response rates of approximately 10%–30% [17–20]. In chemotherapy-sensitive SCLC, topotecan was associated with an overall response rate of 24%, or 6% greater than the rate in patients treated with CAV chemotherapy (cyclophosphamide, doxorubicin [Adriamycin®; Bedford Laboratories; Bedford, OH], and vincristine [Oncovin®; Eli Lilly and Company]) [18]. An overall response rate of 24% has also been reported with topotecan in chemotherapy-resistant SCLC [20], although some other trials have reported lower response rates. Adverse events occurring during topotecan treatment for chemotherapy-resistant SCLC were predictable, manageable, and noncumulative. Myelosuppression was the primary adverse event, consisting of grade 4 neutropenia in 49% of patients, grade 4 anemia in 10% of patients, grade 4 thrombocytopenia in 44% of patients, and grade 4 febrile neutropenia in 15% of patients [20]. Prophylactic treatment with growth factors such as G-CSF may reduce the duration and severity of hematologic toxicities, permitting treatment of patients who otherwise could not receive chemotherapy because of comorbidities and/or a poor performance status. Nonhematologic toxicities associated with topotecan were mild to moderate in severity, noncumulative, and reversible. Given the established antitumor activity and favorable safety profile of topotecan in SCLC, topotecan has been studied in both the first- and second-line settings in patients with NSCLC.

Single-Agent Topotecan in First-Line Therapy of NSCLC

i.v. Topotecan
Studies of single-agent topotecan in the first-line treatment of NSCLC are summarized in Table 1Go [21–25, 28]. In a study by Lynch et al. [21], patients with metastatic NSCLC received i.v. topotecan at a dose of 2.0 mg/m2 on days 1–5 of a 21-day cycle. Two cycles were administered before response was evaluated. Enrollment was halted after 20 of a planned 30 patients were enrolled because no clinical responses were observed; however, 11 (55%) patients achieved stable disease (SD), and the median survival time of 30 weeks was comparable with that obtained with combinations of agents in similar patient populations [4]. Because therapy for patients with advanced lung cancer is primarily palliative, it has been argued that a high SD rate is a clinically meaningful response [26]. Indeed, the distinction between partial response (PR) and SD may not be useful [26], as the overall survival times are not different for patients with PRs and those with SD (Fig. 1Go) [27]. Grade 3/4 leukopenia, thrombocytopenia, and febrile neutropenia were reported in 19 (95%), three (15%), and three (15%) patients, respectively [21]. The high dose of topotecan (2.0 mg/m2) compared with the currently recommended dose (1.5 mg/m2) was likely a factor in the high incidence of hematologic toxicities. In a later phase II study [28], previously untreated NSCLC patients received i.v. topotecan at a dose of 1.5 mg/m2 on days 1–5 of a 21-day cycle. Of 40 evaluable patients, six (15%) achieved PRs for durations of 8–61 weeks, and 10 (25%) achieved SD. The overall median survival time was 38 weeks, and 30% of patients were still alive at 1 year. Grade 3/4 granulocytopenia was reported during 76% of courses, and grade 3/4 thrombocytopenia was reported during 10% of courses.


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  		Table 1. Clinical trials of single-agent topotecan in first-line NSCLC
 


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  		Figure 1. Kaplan-Meier curves showing similar overall survival rates for NSCLC patients with PRs and those with SD. Abbreviation: PD = progressive disease. Adapted from Johnson [27].

 
Alternative topotecan dosing schedules have also been explored in previously untreated NSCLC patients. In a phase II study, Weitz et al. [22] compared the standard i.v. topotecan dosing regimen with a 1.3-mg/m2/day dose of topotecan administered by continuous i.v. infusion (CIV) over 72 hours, every 4 weeks. An overall response rate of 11% was reported for the standard regimen and a 5% response rate was reported for the CIV regimen. In patients receiving standard topotecan dosing, grade 3/4 leukopenia and thrombocytopenia occurred in 60% and 16%, respectively; in patients receiving CIV dosing, these toxicities occurred in 43% and 38%, respectively. CIV infusion (although at a lower dose) was also studied by Mainwaring et al. [23] and Kindler et al. [24]. Topotecan was administered via a CIV infusion at a dose of 0.5 or 0.6 mg/m2/day for 21 days every 28 days, and response rates of 4%–8% were reported [23, 24]. Kindler et al. [24] also reported SD in an additional 23% of patients, and 23 of 58 (40%) symptoms recorded in the 52 patients at baseline had resolved by the end of best response.

Oral Topotecan
In a phase II study, patients received oral topotecan (2.3 mg/m2/day) on days 1–5 of a 21-day cycle, with dose modification after cycle 1 dependent on tolerability [25]. Oral topotecan may be better tolerated and more convenient for some patients than bolus i.v. injection. Dose escalation to 2.7 mg/m2/day was possible in 83% of patients. Minor responses occurred in 3 of 27 (11%) evaluable patients, and 10 (37%) patients had SD. The median survival time was 41 weeks and was comparable with that of other agents used in NSCLC. Oral topotecan was well tolerated: 14 (52%) patients experienced grade 3/4 neutropenia, four (15%) experienced grade 3/4 anemia, and one (4%) experienced grade 3 thrombocytopenia. Oral topotecan provided clinically significant symptom palliation and a tolerability profile that warrants further study in NSCLC patients who require palliative therapy. Additionally, the convenience of oral topotecan makes it an appropriate option for combination therapy, especially with agents that have nonoverlapping toxicities.

Topotecan-Based Combination First-Line Therapies
Topotecan has also been studied in first-line NSCLC treatment in combination with other agents including platinum agents, vinorelbine, gemcitabine, etoposide, and taxanes. Recent studies of topotecan-based combination therapies are summarized in Table 2Go [14–16, 29–33].


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  		Table 2. Clinical trials of topotecan combinations in first-line NSCLC
 

Topotecan Plus Platinum
Platinum compounds were among the first agents to be studied in combination with topotecan. Raymond et al. [29] conducted a phase I study in which topotecan dose escalation was studied in combination with a fixed dose of cisplatin. Fifteen patents were enrolled; 14 were evaluable for toxicity analyses. Topotecan was administered at an initial dose of 0.75 mg/m2 (30-minute i.v. infusion) on days 1–5 of a 21-day cycle along with a single dose of cisplatin (75 mg/m2) on day 1. All 11 patients treated at this dose level of topotecan experienced at least one episode of grade 4 neutropenia; in six of those patients, the absolute neutrophil count was <50 x 109/l for >5 days, and two of those patients also experienced grade 4 thrombocytopenia. At the next topotecan dose level (1.0 mg/m2), grade 4 neutropenia for > 5 days occurred in all three evaluable patients, and one of those patients died from subsequent neutropenic sepsis. Although four of the 13 (31%) patients who completed the study achieved PRs, the duration of response was short, and the toxicity profile suggested synergistic toxicity at even the lowest dose levels.

Carboplatin displays a more manageable toxicity profile than cisplatin [4], with substantially less nephrotoxicity, neurotoxicity, and ototoxicity. Thus, topotecan has also been investigated in combination with carboplatin. In a phase II study, Pujol et al. [16] enrolled 47 patients with unresectable stage III or IV NSCLC. Patients received i.v. topotecan (0.5 mg/m2) on days 1–5 of a 21-day cycle plus carboplatin on day 1 of each cycle at an estimated area under the concentration-time curve (AUC) of 5 mg/ml/minute. Carboplatin was administered 3 hours after the end of the topotecan infusion. Preliminary response data included a 13% overall response rate, and an additional 36% of patients had prolonged SD. The median survival time was >33 weeks, and 32% of patients were alive at 1 year. Grade 3/4 neutropenia and thrombocytopenia occurred in 53% and 58% of patients, respectively, and were not cumulative. Sepsis was documented in only one course. Toxicities were manageable; G-CSF, platelet transfusions, and RBC transfusions were administered in 4%, 4%, and 13% of courses, respectively. Nonhematologic toxicities were generally mild to moderate in severity. Overall, the manageable and noncumulative toxicities of the regimen and the encouraging preliminary response and SD rates suggest that further study is warranted.

Topotecan Plus Vinorelbine
Topotecan has also been investigated in combination with nonplatinum agents in the first-line treatment of NSCLC. Stupp et al. [15] reported interim results of an ongoing phase I/II trial with topotecan and vinorelbine that investigated whether nonplatinum combinations could produce efficacy comparable with that of platinum-containing regimens. The trial enrolled both patients with previously untreated metastatic and recurrent NSCLC. Patients received i.v. topotecan (0.5 to 1.0 mg/m2) on days 1–5 of a 21-day cycle plus vinorelbine (20–30 mg/m2) on days 1 and 5. Of the 29 patients enrolled at the time of the interim report, the overall response rate was 42%, and at 15 months of follow-up, the median survival time was 13 months. At doses of 0.75–1.0 mg/m2, the dose-limiting toxicity (DLT) without G-CSF support was myelosuppression with neutropenic fever; however, when G-CSF was administered prophylactically, the DLT was not reached. This combination was well tolerated, compared with standard platinum-based regimens, and active in advanced NSCLC. Although the study population was small, the median survival time of 13 months associated with this combination was favorable and warrants further investigation. Thus, topotecan plus vinorelbine could be an excellent palliative treatment option for these patients.

Topotecan Plus Gemcitabine
A phase II study of topotecan in combination with gemcitabine was conducted in patients with previously untreated advanced NSCLC. Joppert et al. [31] administered topotecan (1.0 mg/m2) on days 1–5 of a 28-day cycle plus gemcitabine (1,000 mg/m2) on days 1 and 15, both drugs by a 30-minute i.v. infusion, with treatment continuing until progression or unacceptable toxicity. Of 47 evaluable patients, eight (17%) achieved PRs and 11 (23%) achieved SD; the 1-year survival rate was 39% and the median survival time was 30 weeks (range <4–78 weeks). Grade 3/4 hematologic toxicities included neutropenia (53%), anemia (18%), thrombocytopenia (12%), and febrile neutropenia (6%). Topotecan plus gemcitabine appeared to be better tolerated than topotecan in combination with platinum; however, this combination also exhibited lower antitumor activity than the platinum-based topotecan regimen.

In a single-center, dose-escalation phase II trial, Guarino et al. [30] administered a triplet regimen of i.v. topotecan (0.5–2.0 mg/m2), cisplatin (20 mg/m2), and gemcitabine (1,000 mg/m2) on days 1, 8, and 15 of a 28-day cycle to patients with stage IIIB/IV NSCLC. Because of dose-limiting thrombocytopenia at week 3, gemcitabine was administered only on days 1 and 15 in subsequent cycles. Eleven of 29 (38%) evaluable patients had PRs; the median survival time was 38 weeks (range 4–110 weeks), and the 1-year survival rate was 33%, with two patients still alive at 108+ to 110+ weeks of follow-up. The triplet was generally well tolerated; there were no reports of grade 4 neutropenia or febrile neutropenia and only one case of grade 4 leukopenia. Although topotecan dose escalation proceeded to the 2.0-mg/m2 target, the authors recommended the 1.75-mg/m2 dose for further evaluation. The low toxicity and comparable or better response with topotecan/cisplatin/gemcitabine relative to many other NSCLC treatment regimens suggest that this triplet regimen should be investigated further. Guarino et al. [30] recommended including quality-of-life end points in phase II studies of this triplet regimen to determine whether the prolonged survival observed was also associated with symptom palliation.

Topotecan Plus Etoposide
Inhibition of topoisomerase I often leads to increases in topoisomerase II levels and may increase the susceptibility of tumor cells to topoisomerase II inhibitors such as etoposide. In vitro and preclinical studies have shown schedule-dependent synergy between topotecan and etoposide [34]. A phase II study examined the efficacy and safety of this combination in patients with advanced NSCLC [32]. Topotecan was administered at a dose of 0.85 mg/m2/day as a 72-hour CIV infusion on days 1–3, and oral etoposide, 100 mg twice daily (BID), was administered on days 7–9 of a 21-day cycle. One (5%) patient had a PR and two (11%) experienced SD. The 1-year survival rate was 33%. Hematologic toxicities included grade 4 neutropenia in 7% of courses. The authors noted that the lack of efficacy in their study may have been related to the short-lived (<24 hours) effect of topoisomerase II elevation after topoisomerase I inhibition; thus, it may be necessary to administer etoposide much earlier in a combined regimen with topotecan [32].

Topotecan Plus Paclitaxel
Oral topotecan has also been investigated in combination with paclitaxel in the first-line setting. In a phase I/II trial, oral topotecan plus i.v. paclitaxel was administered to chemotherapy-naïve patients with stage III/IV NSCLC [33]. To establish the maximum tolerated dose (MTD) for topotecan in combination with paclitaxel, 18 patients were enrolled in the phase I portion of the trial. Oral topotecan was administered at a starting dose of 1.0 mg/m2 on days 1–5 of a 21-day cycle and escalated by 0.25 mg/m2 in subsequent cohorts if tolerability permitted. Paclitaxel (175 mg/m2) was administered on day 1 of each cycle. Hematologic toxicities included grade 3/4 neutropenia in 61% of patients, grade 3 anemia in 6% of patients, and no grade 3/4 thrombocytopenia. One (6%) patient experienced a DLT of febrile neutropenia in cohort 1, and two patients experienced DLTs in cohort 3 (one febrile neutropenia, one fatal neutropenic sepsis). The MTD of 1.25 mg/m2 was recommended for the ongoing phase II portion of the study. Combined response data for all cohorts included one (6%) complete response, three (17%) PRs, and one (6%) unconfirmed PR.

Similar results were also reported in another phase I/II trial of oral topotecan plus i.v. paclitaxel [14]. Eighteen patients were enrolled in the phase I portion of that study. Although one episode of febrile neutropenia was reported with the 1.0-mg/m2 topotecan dose, no DLTs were reported with the 1.25-mg/m2 topotecan dose; one episode of febrile neutropenia and one death from neutropenic sepsis were reported with the 1.5-mg/m2 topotecan dose. Similar to the previous trial [33], the MTD of topotecan was defined as 1.25 mg/m2. A total of 41 patients (six in phase I, 35 in phase II) received 147 cycles at the MTD. Pooled phase I and II incidences of grade 3/4 neutropenia and anemia were 68% and 18%, respectively. Nonhematologic toxicities were mild to moderate and self-limiting. Preliminary responses from both portions of the study include 12% of patients with PRs and 27% with SD.

Topotecan Second-Line Therapies
For the second-line therapy of NSCLC, the emphasis is on palliation of symptoms and maintenance of quality of life. With its favorable nonhematologic toxicity profile, topotecan may be an appropriate agent in the palliative setting. Recent studies of topotecan in combination with other agents in this patient population are summarized in Table 3Go [35–37].


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  		Table 3. Clinical trials of topotecan and gemcitabine in second-line NSCLC
 
Gemcitabine also has a superior nonhematologic toxicity profile compared with platinum-based regimens. Therefore, the combination of topotecan plus gemcitabine may be feasible for patients with previously treated NSCLC. Rinaldi et al. [35, 36] have reported results from phase I and phase II trials investigating topotecan plus gemcitabine. The first phase I/II trial established the MTD for topotecan as 0.75 mg/m2 and for gemcitabine as 400 mg/m2 when topotecan was administered on days 1–5 and gemcitabine was administered on days 1 and 5 of a 21-day cycle [35]. Of 19 patients treated, 3 of 17 (18%) with measurable disease achieved PRs and 6 of 19 (32%) achieved SD. A second trial using the MTD doses and schedule for this combination regimen reported PRs in 4 of 35 (11%) patients and SD in eight (23%) patients [36]. Particularly interesting was that 3 of 17 (18%) patients with refractory disease (progression during first-line treatment) had responses, with 18% having SD for four or more courses. Grade 4 neutropenia and thrombocytopenia were observed in 14% and 9% of patients, respectively. Grade 3 fatigue was reported in one (3%) patient and grade 2 nonhematologic toxicities were reported in eight (23%) patients. Although the nonhematologic toxicities were generally mild to moderate in severity, such adverse effects may be of greater concern in the second-line setting because of the emphasis on quality of life.

A third study of topotecan in combination with gemcitabine enrolled both SCLC and NSCLC patients [37]. Patients naïve to topotecan and gemcitabine and refractory to at least one chemotherapy regimen were treated with i.v. topotecan (2.0–2.75 mg/m2) followed by i.v. gemcitabine (800–2,000 mg/m2) on days 1 and 15 of a 28-day cycle. Grade 3/4 neutropenia was reported in 11 of 35 (31%) patients, and grade 3 thrombocytopenia was reported in one (3%) patient. There was a low incidence of severe nonhematologic toxicities: grade 3 nausea and vomiting in one (3%) patient and grade 3 oral mucositis in one (3%) patient. One of 24 (4%) patients had a PR (NSCLC patient) and four (17%) patients had SD. The MTD has not been reached and further dose escalation is in progress.

A number of ongoing studies are evaluating various dosing and administration schedules and novel combinations of topotecan with other agents for second-line therapy of NSCLC. These studies include: a randomized, phase III study of oral topotecan versus docetaxel; a phase I study of weekly topotecan in combination with weekly docetaxel [38], which has led to a phase III study of weekly topotecan plus weekly docetaxel; a phase I study of weekly topotecan with docetaxel every 3 weeks; and a phase III study of docetaxel with or without topotecan. The results of these trials are pending.


   FUTURE ROLE OF TOPOTECAN IN NSCLC
Top
 Learning Objectives
 Abstract
 Introduction
 Topotecan in the Treatment...
 Future Role of Topotecan...
Summary
 References
 Additional Reading 
 
Topotecan has displayed encouraging utility in the treatment of NSCLC, a disease well known for its resistance to chemotherapy. Incremental increases in responses, survival, and quality of life are considered advances in the treatment of this difficult disease. Although overall response rates with single-agent topotecan have been relatively low in some studies, SD rates, when reported, are frequently high. Because NSCLC is a disease for which—given the current treatment state of the art—cure is not possible for patients with advanced disease, delays in disease progression are desirable, especially if nonhematologic toxicities are mild and hematologic toxicities are manageable and noncumulative. In patients with advanced disease, SD may be a meaningful clinical response; therefore, single-agent topotecan may be particularly appropriate in the second-line setting.

Topotecan in combination with a number of established and novel antitumor agents has demonstrated superior antitumor activity compared with single-agent topotecan and allows for the reduction of the dose intensity of other agents, and thereby the potential for the nonhematologic toxicities associated with these agents. Some of the more encouraging responses have been obtained when topotecan was combined with vinorelbine or gemcitabine, with manageable toxicities. In contrast, when topotecan was combined with etoposide, a high degree of schedule dependency was indicated and antitumor activity was less promising at the doses and schedules studied. In addition, toxicities were problematic when topotecan was combined with platinum or taxanes. The ideal regimen combining topotecan and other agents has yet to be defined.

The future of NSCLC treatment—indeed, the future of treatment for many malignancies—may well be defined by a more rational approach that accounts for tumor biology and resistance mechanisms. A better understanding of tumor resistance mechanisms may assist in optimizing the dose and schedule of chemotherapy agents used in lung cancer therapy. We hypothesized that the shape of dose-response curve (log percent cell survival versus dose) might reflect the major mechanisms of resistance that limit efficacy of a chemotherapy agent in a particular tumor type (Fig. 2Go) [39]. We proposed that resistance that was due to excess of a factor (e.g., P-glycoprotein or glutathione) would arise from gene amplification or overexpression and would be reflected as a shoulder on the dose-response curve (Fig. 2EGo). This would be analogous to competitive inhibition of drug effect and might be amenable to therapy with high-dose chemotherapy or with resistance-modulating agents to increase therapeutic efficacy. "Nonsaturable passive resistance" would arise from gene mutation or factor alteration and would be reflected as a less steep slope on the dose-response curve (Fig. 2CGo), analogous to what one would see with decreased affinity of a drug for a receptor or target. "Saturable passive resistance" would arise from gene downregulation or deletions and would be due to a deficiency or saturation of a factor. It would be analogous to noncompetitive inhibition of drug effect and, graphically, this would appear as a flat dose-response curve or one with a steep initial curve followed by a plateau (Fig. 2DGo). Therefore, it may be predicted that high-dose chemotherapy or therapy with resistance-modulating agents would not be effective against saturable passive resistance. In the future, in vivo studies could be designed in an attempt to define these dose-response relationships and identify resistance mechanisms in patients with NSCLC and other malignancies. The data derived from such studies could yield important information on resistance mechanisms present in various tumor types and could be used to select agents, doses, and schedules to maximize the therapeutic index.



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  		Figure 2. Dose-response curves (log percent cell survival versus dose) suggestive of resistance mechanisms. A) Highly sensitive; B) extremely passive or active and passive; C and D) passive; E) active. Adapted with permission from Stewart et al. [39].

 

   SUMMARY
Top
 Learning Objectives
 Abstract
 Introduction
 Topotecan in the Treatment...
 Future Role of Topotecan...
 Summary
References
 Additional Reading 
 
Combination regimens with topotecan for the first-line treatment of NSCLC may be appropriate for patients who cannot tolerate standard platinum-based first-line treatments because of the associated nonhematologic and hematologic toxicities. In combination with a number of other agents, topotecan has demonstrated response rates equivalent to those of standard therapy, with manageable, noncumulative, hematologic toxicities and a favorable nonhematologic toxicity profile. Many trials of topotecan have also demonstrated high SD rates, which may be seen as a meaningful clinical benefit in patients with advanced NSCLC. Additionally, nonhematologic toxicities, which often have a disproportionate effect on patient quality of life and willingness to continue treatment, are usually mild and manageable with topotecan therapy. Topotecan has also demonstrated activity comparable with that of other agents in the second-line treatment of patients with NSCLC.

Topotecan in combination with investigational agents that have different mechanisms of action and nonoverlapping toxicities may have synergistic antitumor activities and may be therapeutic options for the future in this patient population. Dose-response characteristics and knowledge of resistance mechanisms may help to define the optimum dose and schedule of topotecan in combination with other agents.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Topotecan in the Treatment...
 Future Role of Topotecan...
 Summary
 References
 Additional Reading 
 
Supported by GlaxoSmithKline, Philadelphia, PA. Presented in part at the satellite symposium "New Horizons in the Management of Small Cell Lung Cancer," held during the World Conference on Lung Cancer, Vancouver, Canada, August 2003.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Topotecan in the Treatment...
 Future Role of Topotecan...
 Summary
 References
Additional Reading 
 

  1. Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer. Adopted on May 16, 1997 by the American Society of Clinical Oncology. J Clin Oncol 1997;15:2996–3018.[Abstract]
  2. Manegold C. Chemotherapy for advanced non-small cell lung cancer. Semin Oncol 2001;28(suppl 7):1–6.[Medline]
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   ADDITIONAL READING 
Top
 Learning Objectives
 Abstract
 Introduction
 Topotecan in the Treatment...
 Future Role of Topotecan...
 Summary
 References
 Additional Reading 
 
  1. Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92–98.
  2. von Pawel J, Schiller JH, Shepherd FA et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999;17:658–667.
  3. Perez-Soler R, Fossella FV, Glisson BS et al. Phase II study of topotecan in patients with advanced non-small-cell lung cancer previously untreated with chemotherapy. J Clin Oncol 1996;14:503–513.
Received September 8, 2004; accepted for publication October 9, 2004.




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