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The Oncologist, Vol. 8, No. 1, 76–82, February 2003
© 2003 AlphaMed Press

ORIGINAL PAPER
LUNG CANCER

Phase I Study of Paclitaxel and Topotecan for the First-Line Treatment of Extensive-Stage Small Cell Lung Cancer

William Westa, Robert Bircha, Frederick Schnellb, John Hainsworthc, Jose Tongold, Luis Campose

a Response Oncology, Memphis, Tennessee, USA; b Central Georgia Hematology Oncology Associates, Macon, Georgia, USA; c Tennessee Oncology, Nashville, Tennessee, USA; d Phoebe Cancer Center, Albany, Georgia, USA; e Oncology Consultants, Houston, Texas, USA

Correspondence: Robert Birch, Ph.D., Online Collaborative Oncology Group, 1805 Moriah Woods Boulevard, Memphis, Tennessee 38117, USA. Telephone: 901-684-1900; Fax: 901-684-6168; e-mail: b.birch{at}ocog.net


   ABSTRACT
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Extensive-stage small cell lung cancer (SCLC) is an aggressive disease with a median survival of approximately 8 months. Although current combination chemotherapy regimens provide high initial tumor response rates, they have not translated into large gains in survival. Topotecan and paclitaxel have nonoverlapping mechanisms of action and are active agents in SCLC. Additionally, these two agents demonstrate in vitro synergy in animal and human tumor models. We investigated the maximum tolerated dose of 3-day topotecan in combination with paclitaxel in previously untreated patients with extensive SCLC. Seventeen patients were enrolled in an open-label, phase I, dose-escalation study and were treated with intravenous paclitaxel 135-175 mg/m2 over 1 hour on day 1, followed by intravenous topotecan 1.25-1.5 mg/m2 over 30 minutes on days 1-3 of a 21-day course. Sixty-nine courses of therapy were administered with no delays due to hematologic toxicity. Prophylactic hematologic support was required for 24% of patients. The topotecan/paclitaxel combination was well tolerated, with 24%, 12%, and 6% of patients experiencing grade 3/4 neutropenia, anemia, or thrombocytopenia, respectively. Dose-limiting neutropenia was seen in three of five patients treated with topotecan 1.5 mg/m2 and paclitaxel 175 mg/m2. Therefore, topotecan 1.5 mg/m2 with paclitaxel 135 mg/m2 was determined to be the maximum tolerated dose. Of the 17 evaluable patients, 53% achieved a partial response and 18% achieved stable disease. In summary, we have identified a regimen of topotecan 1.5 mg/m2 and paclitaxel 135 mg/m2 that was well tolerated and active in this patient group. Additional studies of topotecan and paclitaxel at these dose levels are needed to fully elucidate the efficacy of this combination in extensive SCLC.

Key Words. Drug therapy • Paclitaxel • Lung neoplasms • Topotecan


   INTRODUCTION
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Lung cancer is the leading cause of cancer-related death in the U.S., accounting for approximately 28% of all cancer deaths [1]. Small cell lung cancer (SCLC) is among the most aggressive types of cancer and is associated with early regional and distant metastases [2]. The median survival for patients with extensive-stage SCLC is approximately 8 months despite treatment with a host of novel combination chemotherapy regimens [3–5]. Chemotherapy has been associated with high initial objective response rates; however, antitumor activity has not translated into significant increases in survival. Currently recommended and widely used regimens for patients with extensive SCLC include etoposide/cisplatin, cyclophosphamide/doxorubicin/vincristine, cyclophosphamide/ doxorubicin/etoposide, and cyclophosphamide/doxorubicin/ vincristine/etoposide [6]. Overall response rates achieved with these regimens range from 50%-78% [7, 8]. Nonetheless, patient benefits from optimized therapy are generally limited to symptom palliation and modest increases in survival. Therefore, other agents and combination therapies are being investigated.

Several promising agents with novel mechanisms of action have recently emerged as effective agents in extensive SCLC, including paclitaxel, topotecan, irinotecan, and gemcitabine [9]. Paclitaxel (Taxol®; Bristol-Myers Squibb Co.; Princeton, NJ) is a taxane that promotes the assembly and stabilization of microtubules. Inappropriate stabilization of microtubules leads to an accumulation of cells in the mitotic phase, which leads to apoptosis. The efficacy of paclitaxel in patients with previously untreated SCLC was established in two phase II studies by the Eastern Cooperative Oncology Group (ECOG) and the North Central Cancer Treatment Group. These studies reported an objective response rate of 53%-68% and a median survival of 7.3-11 months [10, 11].

Another agent with a novel mechanism of action for the treatment of SCLC is topotecan. Topotecan (Hycamtin®; GlaxoSmithKline; Brentford, UK) is a topoisomerase I inhibitor that prevents the re-ligation of single-stranded DNA breaks, leading to irreparable double-stranded DNA damage during replication. The efficacy of topotecan in the treatment of SCLC was demonstrated in three phase II studies and one phase III study in patients who had failed first-line chemotherapy [12–15]Topotecan is currently approved for second-line therapy in SCLC at a starting dose of 1.5 mg/m2 by a daily 30-minute i.v. infusion for 5 consecutive days of a 21-day course. The primary dose-limiting toxicity associated with the 5-day regimen is myelosuppression. In some patients, myelosuppression can lead to treatment interruptions or dose reductions that could potentially limit tumor response. Therefore, the optimal dosing strategy has not yet been defined. As a consequence, alternative doses and schedules of topotecan are currently under investigation.

It is widely accepted that combinations of cytotoxic drugs produce higher response rates and survival rates in patients with SCLC compared with single-agent therapy. Combinations of agents with unique, nonoverlapping mechanisms of action may offer synergy with respect to antitumor activity. In vitro studies have indicated that the combination of topotecan/ paclitaxel results in synergistic activity in both cell lines and primary cultures of human tumor cells [16, 17]. Therefore, a combination of topotecan and paclitaxel may provide antitumor activity in the clinical setting. In addition, the combination of these two agents with nonoverlapping mechanisms of action may provide improved antitumor activity compared with cisplatin/etoposide, the current standard of care in previously untreated patients with SCLC.

As a single agent, topotecan has demonstrated antitumor activity in previously untreated patients with extensive SCLC, with an objective response rate of 40% and a median survival of 10 months [18]. Recently, 5-day topotecan in combination with paclitaxel was investigated by several groups for the treatment of SCLC patients with extensive disease [19–23]. Although topotecan/paclitaxel was felt to be active, there was a high incidence of serious hematologic toxicity, which was not prevented with the use of G-CSF or filgrastim support, especially when combined with higher paclitaxel doses (>=175 mg/m2). Because of the high incidence of myelosuppression associated with the standard 5-day topotecan regimen, several alternative dosing regimens have been investigated. The feasibility of a 3-day topotecan regimen has been reported in patients with ovarian cancer [24, 25]. The 3-day topotecan regimen was less toxic than the 5-day topotecan regimen and showed promising antitumor activity. A 3-day topotecan regimen is likely to provide a similar safety profile advantage in patients with SCLC, particularly if topotecan is combined with another agent that is associated with significant hematologic toxicity.

In a Cancer and Leukemia Group B (CALGB) phase I study, the maximum tolerated doses (MTDs) for topotecan in combination with paclitaxel, when using the standard 5-day dosing regimen for topotecan, were paclitaxel 80 mg/m2 on day 1 and topotecan 1.0 mg/m2 on days 1-5 of a 21-day course [26]. With G-CSF support, paclitaxel could be escalated to as high as 230 mg/m2 following topotecan 1.0 mg/m2. We hypothesized that administration of topotecan over 3 days would allow dose escalation of both topotecan and paclitaxel without routine use of G-CSF support. Therefore, the objective of this study was to determine the MTD of 3-day topotecan that could be administered with paclitaxel. Because of associated hypersensitivity reactions with paclitaxel, we chose to first escalate topotecan, followed by an escalation of paclitaxel if toxicity permitted. A preliminary report of this study was previously published [27].


   MATERIALS AND METHODS
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Eligibility
Patients >=18 years of age with histologically confirmed extensive SCLC with measurable or evaluable disease were eligible. Patients were required to have an ECOG performance score of <=2, normal liver function (bilirubin <=1.5 mg/dl), and normal renal function (creatinine <=1.5 mg/dl). Patients were required to have WBC counts >=4,000 cells/µl and platelet counts >=100,000/µl. Patients with brain metastases were eligible and could receive whole-brain irradiation concurrently with the chemotherapy, but only if they had minimal neurologic symptoms and met all other eligibility criteria. Patients with a history of prior malignancy within 5 years, with the exception of skin cancer and cervical carcinoma in situ, were ineligible, as were patients who had received prior treatment for SCLC. Patients with severe coexisting medical illnesses that would prevent them from receiving combination regimens, and patients with a history of allergic reactions to drugs mixed with a polyoxyethylated castor oil (Cremophor®; BASF AG; Stuttgart, Germany) stabilizer were also ineligible. Women who were pregnant or lactating were ineligible, and women on the study who were capable of childbearing were required to take appropriate precautions to prevent pregnancy during treatment. All patients were required to give written informed consent.

Study Design
This was an open-label, phase I, dose-escalation study planned for topotecan on days 1-3 and paclitaxel on day 1 of a 21-day course. All patients received premedication for paclitaxel, including oral dexamethasone 20 mg, 12 and 6 hours prior to treatment; i.v. diphenhydramine 50 mg; i.v. ranitidine 50 mg; and i.v. dexamethasone 20 mg, 30 minutes prior to treatment. The first cohort of patients received i.v. paclitaxel 135 mg/m2 administered over 1 hour on day 1, followed by i.v. topotecan 1.25 mg/m2 over 30 minutes on days 1-3. Patients in the second cohort received i.v. paclitaxel 135 mg/m2 administered over 1 hour on day 1, followed by i.v. topotecan 1.5 mg/m2 over 30 minutes on days 1-3. The third cohort of patients received i.v. paclitaxel 175 mg/m2 administered over 1 hour on day 1, followed by i.v. topotecan 1.5 mg/m2 over 30 minutes on days 1-3. These regimens were repeated at 21- to 28-day intervals for a total of four courses. Complete restaging was performed after the completion of four courses, with partial responders receiving up to two additional courses at the discretion of the physician. Complete responders were to receive no further treatment.

Safety and Tolerability Assessments
Dose-limiting toxicity was defined as at least one of three patients per cohort experiencing grade 4 toxicity, or at least two of three patients per cohort experiencing grade 3 toxicity. In such a case, three additional patients were enrolled at that dose level. If at least two of six patients experienced grade 4 toxicity, or if at least four of six patients experienced grade 3 toxicity in a given cohort, that dose was then considered to be a toxic dose and the dose at the previous cohort was considered the MTD.

Because myelosuppression was expected to be the major toxicity for this regimen, blood counts were obtained on a weekly basis with predetermined dose-reduction criteria. If WBC counts were <2,500 cells/µl or platelet counts were <75,000/µl at day 21, treatment was delayed 1 week or until WBC counts were >=2,500 cells/µl and platelet counts were >=75,000/µl. Patients were treated at full doses on hematologic recovery. Patients who developed grade 4 neutropenia and fever (>38.5°C) or who experienced reversible nonhematologic grade 3/4 toxicity received 75% of the total dose of both drugs during subsequent courses. Patients who developed severe acute hypersensitivity to paclitaxel did not receive further doses of paclitaxel but continued receiving topotecan. Patients were discontinued from the study if they could no longer tolerate their assigned dose level or if they demonstrated disease progression. Patients failing to respond to dose reduction or failing to achieve hematologic recovery were also discontinued from the study at the discretion of the investigator. Prophylactic hematologic support with G-CSF was not routinely used in this study.

Response Criteria
Tumor response was assessed using World Health Organization criteria [28]. Measurable disease was defined as any mass that was reproducibly measurable in two perpendicular diameters by either physical examination, x-ray, computed tomography, or magnetic resonance imaging. Tumor markers, visceromegaly, bone lesions detectable only by bone scan, ill-defined chest radiographic lesions involving infiltrates, serous effusions, and diffuse skin lesions were not considered measurable disease. Evaluable disease was defined as lesions apparent on x-ray, computed tomography, or magnetic resonance imaging scans, but that were accurately measurable in only one dimension, or ill-defined masses that could not be accurately measured in more than one dimension. Other examples of evaluable disease included positive cytology, tumor markers, and lesions seen on bone scan. Fluid collections including pericardial, pleural, and peritoneal were not considered measurable or evaluable. Because of the availability of tumor markers and scans, and factors that influence their size, visceromegaly such as hepatomegaly or splenomegaly was not considered either measurable or evaluable disease. However, lesions within these tissues, such as hepatic or splenic metastases, were considered measurable or evaluable if they passed all other criteria.

For measurable and evaluable disease, a complete response was defined as the disappearance of all known disease for >=4 weeks with no new lesions appearing. A partial response was defined as a >=50% reduction in the diameter product (product of two perpendicular diameters) of all measurable lesions with a response of >=4 weeks in duration with no new lesions appearing, or as an estimated decrease of >=50% for >4 weeks for evaluable disease. Stable disease was defined as a <50% reduction or <25% increase in the diameter product of all measurable lesions without the appearance of new lesions, or an estimated reduction <50% or an estimated increase <25% for evaluable disease. Progressive disease was defined as an increase >=25% in the diameter product of all measurable disease or the appearance of new lesions, or an estimated increase of >=25% for evaluable disease.

Statistical Methods
All patients who received at least one cycle of chemotherapy were evaluable for response and tolerability. Descriptive summary statistics were used to evaluate demographics and adverse events. Toxicity was graded according to Common Toxicity Criteria. Serious adverse events included grade 3/4 hematologic and nonhematologic toxicities. Response was summarized and tabulated by cohort.


   RESULTS
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Patients
All 17 patients enrolled in the study were evaluable. The patient baseline characteristics and treatment for each cohort are summarized in Table 1Go. All patients were previously untreated and had extensive SCLC. Six patients had liver metastases, five had bone metastases, and four had brain metastases. All patients were >50 years of age and had completed at least two cycles of treatment. The group of 17 patients received 69 courses of therapy, with a median of four courses (range, 2-6 courses).


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  		Table 1. Patient characteristics
 
Safety and Tolerability
Combination topotecan and paclitaxel therapy was generally well tolerated. There were seven episodes of grade 3/4 hematologic toxicities in 5 of the 17 patients (30%; Table 2Go). The predominant toxicity was neutropenia, with three of five patients in cohort 3 and one of six patients in cohort 2 experiencing grade 3/4 neutropenia. Only one of six patients experienced grade 3/4 thrombocytopenia (cohort 1). Grade 3/4 anemia was experienced by one patient in cohort 1 and one patient in cohort 3. Although prophylactic hematologic support was not routinely used, three patients (18%; one in cohort 2 and two in cohort 3) received G-CSF support and one patient (6%) in cohort 1 received red blood cell support.


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  		Table 2. Grade 3/4 hematologic toxicity
 
Topotecan with paclitaxel treatment was also associated with a favorable nonhematologic safety profile (Table 3Go). Grade 3/4 nonhematologic toxicity was experienced by nine patients. Grade 3/4 nonhematologic toxicities occurred in 50% of patients in both cohort 1 and cohort 2 and occurred in 60% of patients in cohort 3.


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  		Table 3. Grade 3/4 nonhematologic adverse events
 
Maximum Tolerated Dose
Because hematologic or nonhematologic grade 3/4 toxicity occurred in all five patients in cohort 3, the dose level administered to patients in cohort 2 (topotecan 1.5 mg/m2 and paclitaxel 135 mg/m2) was considered the MTD. Two patients in cohort 1, one patient in cohort 2, and four patients in cohort 3 required hospitalization. Two patients in cohort 2 withdrew from the study because of pneumonia (n = 1) or disease progression (n = 1). One patient in cohort 3 withdrew because of concurrent disease (cardiac arrest). There were three early deaths in the study: two attributed to progressive disease and one to cardiac arrest following sepsis and neutropenic fever. Treatment with paclitaxel was a limiting factor for patients in cohort 2; i.v. topotecan at a dose of 1.5 mg/m2 was well tolerated as a single agent in patients from cohort 2 who discontinued paclitaxel treatment. As a consequence of these toxicities, up to 20 additional patients will be accrued at the MTD of i.v. topotecan 1.5 mg/m2 and i.v. paclitaxel 135 mg/m2 to further delineate the efficacy of this regimen.

Antitumor Activity
Preliminary antitumor response data in this phase I trial were encouraging. Of the 17 patients, nine (53%) achieved a partial response, with five, one, and three patients achieving a partial response in cohorts 1, 2, and 3, respectively. Of the 17 patients, three (18%) achieved stable disease, and five (29%) experienced progressive disease. Restaging occurred after four cycles of treatment, and patients with a complete or partial response could receive two additional cycles of therapy. One patient in cohort 1, one patient in cohort 2, and two patients in cohort 3 completed six cycles.


   DISCUSSION
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
Platinum-based regimens are the backbone of treatment in patients with extensive-disease SCLC. Although SCLC is highly chemosensitive to these agents, patients quickly relapse, and the initial antitumor response does not translate into significant improvements in survival. Therefore, platinum-based regimens have been combined with other cytotoxic agents with unique mechanisms of action in an attempt to improve antitumor activity and prolong survival. Recently, paclitaxel was combined with the cisplatin and etoposide regimen. Glisson et al. [29] reported an overall response rate of 90% in patients with extensive SCLC treated with cisplatin/etoposide/paclitaxel in the first-line setting. However, in a larger randomized trial comparing cisplatin/etoposide/paclitaxel treatment with cisplatin/ etoposide alone, Mavroudis et al. [30] reported significant hematologic toxicity that led to early termination of the study. Further, in another phase II trial, Kelly et al. [31] reported a significant number of toxic deaths with cisplatin/etoposide/paclitaxel treatment. Clearly, if high-dose paclitaxel is to be used in a combination regimen for the treatment of this patient group, it should be combined with a nonplatinum regimen and with agents with nonadditive hematologic toxicity profiles.

Topotecan has demonstrated antitumor activity in the treatment of extensive SCLC in the second-line setting, with overall response rates of 11%-25% [12, 13, 15, 32]. Further, topotecan has been investigated in the first-line setting. In a preliminary feasibility study, Schiller et al. [18] reported a 40% overall response rate and a median survival of 10 months with single-agent topotecan (5-day) treatment in previously untreated patients with extensive SCLC. Topotecan is also being investigated in the first-line setting in combination with other cytotoxic agents, with improved antitumor activity and overall response rates ranging from 42%-95% [33–36].

Because paclitaxel and topotecan have unique and nonoverlapping mechanisms of action and have non-cross-reactive antitumor activity, several groups have investigated the combination of these two agents for the first-line treatment of patients with extensive SCLC. When patients received paclitaxel 135 mg/m2 on day 5 with topotecan 1.0-1.25 mg/m2 on days 1-5, 60%-92% of patients achieved an overall response [21–23]. The CALGB reported a 61%-68% overall response rate with a regimen of paclitaxel 175-230 mg/m2 on day 1 plus topotecan 1 mg/m2 on days 1-5 of a 21-day course [19, 20]. However, despite G-CSF support, 54%-69% of those patients experienced grade 3/4 neutropenia.

All of the previously reported topotecan and paclitaxel regimens used the currently recommended 5-day topotecan regimen. A shorter dosing regimen for topotecan may ameliorate myelosuppression associated with topotecan treatment. Indeed, the feasibility of a 3-day topotecan regimen in ovarian cancer patients was recently reported by Brown et al. [24] and Markman et al. [25]. This regimen is more convenient for patients and appears to provide a more favorable hematologic toxicity profile. We therefore investigated the feasibility of a 3-day regimen of topotecan combined with paclitaxel therapy in patients with extensive SCLC.

In the current study, the MTD for 3-day topotecan in combination with paclitaxel was investigated. In contrast with previous reports, routine G-CSF support was not used in the current study. Nevertheless, only 24% of patients experienced grade 3/4 neutropenia. Further, three of the four patients who experienced grade 3/4 neutropenia were in cohort 3 and received paclitaxel 175 mg/m2 and topotecan 1.5 mg/m2. Based on the safety profile observed in these patients, the MTD for 3-day topotecan with paclitaxel was determined to be topotecan 1.5 mg/m2 and paclitaxel 135 mg/m2. Given that three of the four patients with grade 3/4 neutropenia received topotecan at a higher dose level than the MTD, the combination of 3-day topotecan plus paclitaxel is likely to be better tolerated than 5-day topotecan plus paclitaxel.

Preliminary efficacy of the 3-day topotecan and paclitaxel combination showed promise. Our overall response of 53% was similar to response rates observed using the 5-day topotecan regimen in combination with other agents, including etoposide and carboplatin [33–36], yet with a better hematologic toxicity profile. Further, one-third of the patients in this study were treated at doses below the MTD, which may have resulted in an underestimation of the true overall response rate. The overall response in this study is higher than the overall response reported with first-line single-agent topotecan in patients with extensive SCLC (40%) [18]. It is important to again point out that prophylactic hematologic support was not routinely used in the current study. It is possible that the antitumor activity of 3-day topotecan with paclitaxel may be increased if hematologic support is used routinely to allow for an increase in the dose levels of topotecan and paclitaxel. However, the value of dose intensification requires further investigation.


   CONCLUSION
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
A combination of 3-day topotecan plus paclitaxel was safe and well tolerated without the use of growth-factor support. The 3-day topotecan regimen provides greater convenience and may increase patient compliance. Additionally, the favorable safety profile of 3-day topotecan and paclitaxel may permit the incorporation of a third cytotoxic agent in the treatment of extensive SCLC. Preliminary results suggest that the combination of topotecan 1.5 mg/m2 with paclitaxel 135 mg/m2 is active in extensive SCLC. Additional patients will be enrolled to further characterize the efficacy of this novel regimen.


   ACKNOWLEDGMENT
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
The authors would like to thank the study nurses, study coordinators, patients, and administrative assistants for their assistance and participation. Supported by GlaxoSmithKline, Brentford, Middlesex, UK.


   REFERENCES
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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Received August 16, 2002; accepted for publication November 25, 2002.




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