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The Oncologist, Vol. 7, No. 6, 509–515, December 2002
© 2002 AlphaMed Press

A Dose-Escalation Study of Weekly Topotecan, Cisplatin, and Gemcitabine Front-Line Therapy in Patients with Inoperable Non-Small Cell Lung Cancer

Michael J. Guarinoa, Charles J. Schneidera, Stephen S. Grubbsa, David D. Biggsa, Andrew L. Himelsteina, Kurt Hogaboomb, Samir Tilakc

a Medical Oncology Hematology Consultants, PA, Christiana Care Health System, Helen F. Graham Cancer Center, Wilmington, Delaware, USA; b GlaxoSmithKline, Philadelphia, Pennsylvania, USA; c Virtua Memorial Hospital, Mt. Holly, New Jersey, USA

Correspondence: Michael J. Guarino, M.D., Medical Oncology Hematology Consultants, PA, Helen F. Graham Cancer Center, 4701 Ogletown-Stanton Road, Suite 2200, Newark, Delaware 19713, USA. Telephone: 302-366-1200; Fax: 302-366-1700; e-mail: mguarino{at}magpage.com


   ABSTRACT
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 Conclusions
 Additional Reading
 References
 
Purpose. To determine the optimal dose of combination topotecan, cisplatin, and gemcitabine in advanced non-small cell lung cancer patients.

Materials and Methods. This single-center, single-practice, phase I trial enrolled chemotherapy-naïve patients with inoperable stage IIIB/IV disease. Initial treatment was 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. Dose-limiting thrombocytopenia at week 3 necessitated less frequent gemcitabine dosing (days 1 and 15 of each cycle). Thereafter, topotecan dose escalation proceeded to the target dose of 2 mg/m2.

Results. Thirty patients were enrolled and evaluable for toxicity assessment. Treatment was extremely well tolerated: only one grade 4 adverse event (leukopenia); no hospitalizations for treatment-related toxicities; no fever/neutropenia. Although no dose-limiting toxicities developed, 1.75 mg/m2 topotecan is considered optimal and recommended for further study because it was well tolerated, active, and did not require dose adjustments or delays in therapy. Eleven of 29 (38%) evaluable patients achieved a partial response. Median survival was 38 weeks (range 4-110 weeks), median progression-free survival was 17 weeks, and the 1-year survival rate was 33%. Two patients remain alive after 108-122 weeks of follow-up.

Conclusion. A 28-day cycle of topotecan (1.75 mg/m2 days 1, 8, 15), cisplatin (20 mg/m2 days 1, 8, 15), and gemcitabine (1,000 mg/m2 days 1, 15) was a safe and well-tolerated outpatient treatment for advanced non-small cell lung cancer. The favorable preliminary efficacy and safety of this regimen suggest that further study in phase II trials, including quality-of-life end points, is warranted.

Key Words. Cisplatin • Dose escalation • Gemcitabine • Maximum-tolerated dose • Non-small cell lung cancer • Topotecan


   INTRODUCTION
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 Conclusions
 Additional Reading
 References
 
Non-small cell lung cancer (NSCLC) is a common, aggressive, and deadly tumor type [1–3]. In the year 2002, it is estimated that approximately 169,400 new cases of lung cancer will be diagnosed, and there will be 154,900 lung-cancer-related deaths [4]. Non-small cell lung cancer accounts for approximately 80% of all lung cancer cases [5]. Approximately 70% of patients diagnosed with NSCLC present with locally advanced (inoperable) or metastatic disease [6]. The 5-year survival rate for patients with unresectable stage III or stage IV NSCLC is less than 10%. Median survival time for patients with metastatic disease is short, ranging in the neighborhood of 3 to 6 months without chemotherapy. A number of phase II and III trials with combination chemotherapy have median survivals significantly under 1 year.

For patients with advanced NSCLC, platinum-based chemotherapy has been the standard of care [7, 8]. A number of recent analyses have shown that cisplatin-based chemotherapy prolongs survival over best supportive care and also improves quality of life (QOL) [9–13]. These advantages are generally restricted to patients who have relatively good functional status, and the advantages of treatment have been modest at best. Because no combination regimen has emerged as clearly superior, there is a need to identify programs that may increase median survival and improve QOL with minimal/acceptable toxicity.

Topotecan (Hycamtin®; GlaxoSmithKline; Brentford, Middlesex, UK; http://www.gsk.com) is a topoisomerase I inhibitor that has demonstrated activity in both small cell lung cancer (SCLC) and NSCLC. In phase I and II trials, the primary dose-limiting toxicity (DLT) of topotecan was myelosuppression, with a maximal-tolerated dose (MTD) of 1.5 mg/m2 x 5 days every 21 days [14–17]. Modest single-agent activity in NSCLC has been demonstrated in phase II studies [18–21]. The favorable tolerability profile of topotecan makes it a candidate for combination with other agents, such as cisplatin, which generally have non-overlapping toxicities.

The rationale for combining topotecan with gemcitabine and cisplatin is several-fold. First, all three agents have demonstrated single-agent tumor activity in NSCLC [18, 22–24]. Second, topotecan and gemcitabine are generally considered to be well tolerated. Therefore, only minimal cumulative toxicity is expected when the two agents are combined with cisplatin [23, 24]. Finally, topotecan and cisplatin have novel and potentially synergistic mechanisms of action [25, 26]: topotecan inhibits topoisomerase I, an enzyme required for DNA replication and repair, whereas cisplatin is thought to cross-link and interfere with DNA function and may have downstream effects on RNA. Much of the toxicity of cisplatin is dose related. However, there is no evidence that a dose-response relationship for cisplatin in NSCLC exists. Therefore, the topotecan/cisplatin/gemcitabine combination takes advantage of cisplatin/topotecan synergy and cisplatin/gemcitabine improved responses while limiting toxicity. The development of a well-tolerated weekly treatment regimen may improve QOL compared with existing treatment options for NSCLC patients who have a foreshortened life expectancy.

Several phase I and II trials in both ovarian cancer and SCLC have suggested that weekly topotecan administered as monotherapy, as well as in combination with paclitaxel, cisplatin, carboplatin, and gemcitabine, may be efficacious. In a phase II ovarian cancer clinical trial, topotecan administered weekly via continuous i.v. infusion (1.75 mg/m2/week for 4 weeks) was associated with less toxicity than the 5-day regimen [27]. In a second phase II study in platinum- and paclitaxel-resistant ovarian cancer patients, 8.7% of patients receiving weekly 72-hour continuous i.v. topotecan (2.0 mg/m2) achieved a partial response (PR), and 26.1% achieved stable disease [28]. Treatment-associated toxicities were mild. Weekly bolus doses of topotecan (>=2 mg/m2) have also achieved responses in patients with epithelial ovarian cancer, with manageable toxicity [29]. Finally, in patients with SCLC, weekly topotecan (2.25 mg/m2) in combination with cisplatin (40 mg/m2) and paclitaxel (85 mg/m2) yielded eight (22%) complete responses and 22 (59%) PRs [30]. The authors concluded that the combination therapy was well tolerated and active for the treatment of SCLC.

The present study was undertaken to define the MTD and optimal administration schedule of topotecan in combination with cisplatin and gemcitabine for the treatment of NSCLC. The safety, tolerability, and preliminary efficacy of the weekly regimen were also evaluated.


   PATIENTS AND METHODS
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 Conclusions
 Additional Reading
 References
 
Patients
Patients >=18 years of age with histologically or cytologically confirmed inoperable NSCLC (stage IIIB or IV) or recurrent or progressive disease after surgery or radiotherapy were eligible for the study. Patients with IIIB disease must have been deemed ineligible to receive radiotherapy. No prior chemotherapy for metastatic disease was permitted. Patients who had received prior radiation therapy were included if treatment had ended >=4 weeks prior to the study. Patients were required to have adequate bone marrow function (platelets >100 x 109/l, absolute neutrophil count >1.5 x 109 cells/l), liver function (total bilirubin <=34 µmol/l), and creatinine clearance (creatinine <=150 µmol/l, blood urea nitrogen <=10.7 mmol/l of urea). Eastern Cooperative Oncology Group (ECOG) performance status was required to be <=2, and life expectancy was required to be >=8 weeks. Patients with a history of human immunodeficiency virus infection or with any uncontrolled infection were excluded, as were patients with concomitant malignancy, previous malignancies within 5 years of study, an uncontrolled psychiatric disorder, prior treatment with topotecan or gemcitabine, or an allergic reaction to related compounds. Patients who were pregnant, lactating, or refused to use contraception as appropriate were also excluded. Patients with treated brain metastases were permitted entry provided their neurologic status was stable and the brain metastases were considered "controlled." All patients signed an informed consent form. The study was performed on approval by the Christiana Care institutional review board.

Study Design and Treatment Plan
The study was designed as an uncontrolled, prospective, single-center, nonrandomized, dose-escalation study. Patients received the combination chemotherapy on a 28-day cycle. Cisplatin (20 mg/m2), gemcitabine (1,000 mg/m2), and topotecan (0.5 to 2.0 mg/m2) were administered via i.v. infusion on days 1, 8, and 15. The protocol was modified in the second cohort because grade 3 thrombocytopenia limited treatment on day 15. For the remainder of the study, gemcitabine (1,000 mg/m2) was administered via i.v. infusion on days 1 and 15. Treatment was delayed in patients who did not meet the baseline entry criteria for platelets and granulocytes until baseline levels were achieved. Patients were monitored for toxicity prior to each treatment. Treatment was delayed for all patients with grade 3 or 4 toxicity until the patient recovered to grade 1 status. If more than one treatment delay was necessary, the dose was reduced by one dose level.

Dose Escalation
Dose escalation of topotecan was performed in cohorts of three patients. If none of the three patients experienced a DLT, the dose was escalated by 0.25 mg/m2. If one of the three patients experienced a DLT, then three additional patients were accrued at that dose level. If none of the additional three patients experienced a DLT, then the dose was further escalated. If two of the three patients experienced a DLT, then the MTD had been reached, and three additional patients were treated at the previous dose level. If no DLT developed during dose escalation, additional patients were accrued at the maximum dose until a total of 30 patients was enrolled. All toxicities were graded and reported according to dose level, and toxicities were assessed after the first cycle of therapy.

DLTs were defined according to Common Toxicity Criteria. A DLT was any grade 4 hematologic toxicity lasting >7 days, any grade 3 or 4 nonhematologic toxicity (except nausea, vomiting, or alopecia), or any grade 3 or 4 diarrhea or mucositis lasting more than 3 days.

Assessments
Adverse events, vital signs, and laboratory measurements (complete blood count, blood urea nitrogen and creatinine, bilirubin, serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase, alkaline phosphatase, and routine chemistries) were monitored to evaluate the safety and tolerability of the regimen. Performance status was recorded every 4 weeks. Chest radiographs and computed tomography scans or chest magnetic resonance imaging scans were performed every 8 weeks to determine tumor response to the treatment regimen. All radiologic measurements were reviewed by an independent radiologist. A complete response was defined as the complete disappearance of all clinically detectable malignant disease for >=4 weeks with no appearance of new disease. A patient who had radiographic evidence of bony metastases prior to therapy had to have normalization of radiographs or complete sclerotic healing of lytic metastases in association with a normal bone scan. A patient who had an abnormal bone scan and normal radiographs prior to therapy had to have normalization of the bone scan. A PR was defined as >=50% decrease from baseline in the product of the areas of all measurable lesions for >=4 weeks with no appearance of new disease. Stable disease was defined as no significant change in measurable or evaluable disease for >=4 weeks and no significant change in bony metastases for 12 weeks. A <50% decrease or a <25% increase in metastases at any site and no deterioration in ECOG performance status of greater than or equal to one level was also defined as stable disease. Progression of disease was defined as a >=25% increase in any lesion, reappearance of measurable disease, clear worsening of evaluable disease, appearance of any new lesions (including brain metastases even if there was response outside of the brain), or significant worsening condition presumed to be related to malignancy (i.e., decline in performance status).


   RESULTS
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 Conclusions
 Additional Reading
 References
 
Patients
Thirty chemotherapy-naïve patients with advanced NSCLC were enrolled in the study. The patient demographics and baseline disease characteristics are detailed in Table 1Go. A total of 301 weekly treatments was administered during the study period.


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  		Table 1. Patient demographics and baseline disease characteristics (n = 30)
 
Safety
All patients were evaluable for toxicity. The hematologic toxicity according to topotecan dose level is summarized in Table 2Go. There was only one grade 4 hematologic adverse event (leukopenia), which developed in one of the three patients in the initial cohort. All three patients in that cohort also developed grade 3 thrombocytopenia. Thereafter, the treatment plan was modified so that gemcitabine was administered on days 1 and 15 rather than on days 1, 8, and 15 as originally planned. There were no grade 4 adverse events in the remaining patient cohorts, and grade 3 hematologic toxicity was infrequent. With the exception of alopecia, there were no notable nonhematologic toxicities.


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  		Table 2. Hematologic toxicity
 
There were no treatment-related hospitalizations and no febrile neutropenic events. No platelet transfusions or white cell or platelet growth factors were required. Four patients received red blood cell transfusions (14 units total), and seven patients received recombinant erythropoietin. The majority (87%) of weekly treatments were administered as scheduled. Although no grade 4 toxicities were encountered, dose delays were frequent for patients in the 2.0-mg/m2 topotecan dose cohort. Because the study was designed to accrue 30 patients, additional patients were enrolled at the maximum dose. Seven of eight (88%) patients in this cohort (2.0 mg/m2 topotecan) had dose delays and/or dose reductions due to decreased blood counts. Therefore, although the toxicity was not dose limiting, the 1.75-mg/m2 topotecan dose level is recommended for further study because this dose was well tolerated and did not result in frequent dose delays or dose reductions.

Efficacy
One patient was not evaluable for response due to early, non-treatment-related death. Among 29 evaluable patients, there were 11 (38%) PRs. No appreciable differences in patient responses according to performance status or gender were noted; however, the response rate in patients with stage IIIB disease (60%) was higher than the response rate in patients with stage IV disease (26%).

After >2 years of follow-up, the median overall survival was 38 weeks (range 4 to 110 weeks, Fig. 1Go). The median progression-free survival was 17 weeks (Fig. 2Go). Two patients remained alive at 108 to 122 weeks of follow-up. The 1-year survival rate was 33%, and the 2-year survival rate was 10%. A total of 17 patients had received second-line chemotherapy—including docetaxel (12 patients), vinorelbine (three patients), carboplatin with paclitaxel (two patients), gemcitabine (two patients), thalidomide (two patients), cisplatin with gemcitabine (one patient), and ZD 1839 (Iressa®; AstraZeneca; Wilmington, DE; http://www.astrazeneca.com) (one patient)—due to relapsed disease. Eleven patients received subsequent radiation therapy.



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  		Figure 1. Overall survival. Survival curve estimation of overall survival. The median overall survival was 38 weeks.

 


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  		Figure 2. Progression-free survival. Survival curve estimation of progression-free survival. The median progression-free survival was >17 weeks.

 

   DISCUSSION
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
Conclusions
 Additional Reading
 References
 
In the present study, outpatient therapy with cisplatin, gemcitabine, and topotecan was well tolerated and active in patients with inoperable, advanced NSCLC. Although no dose-limiting adverse events were experienced by the patients receiving the highest topotecan dose (2.0 mg/m2), because modest neutropenia and thrombocytopenia occurred in this cohort resulting in dose reductions and/or dose delays, topotecan (1.75 mg/m2) with cisplatin (20 mg/m2) and gemcitabine (1,000 mg/m2) is recommended for further study. Furthermore, at the recommended dose there were no grade 3 or 4 hematologic toxicities. The regimen resulted in improvements in median overall and progression-free survival rates compared with those documented for each of the agents alone. Therefore, further investigation of the efficacy and safety of this regimen as well as its impact on patient QOL compared with standard regimens is warranted.

Although combination chemotherapy for NSCLC has resulted in modest improvements in survival and QOL relative to best supportive care, the optimal regimen has yet to be established. In May 2000, at the 36th annual meeting of the American Society of Clinical Oncology in New Orleans, Louisiana, data from ECOG-1594 were presented [12]. This trial randomized 1,163 patients with advanced NSCLC to the following four treatment regimens: cisplatin (75 mg/m2) plus paclitaxel (135 mg/m2); cisplatin (100 mg/m2) plus gemcitabine (1,000 mg/m2); cisplatin (75 mg/m2) plus docetaxel (75 mg/m2); and carboplatin (area under the curve of 6) plus paclitaxel (225 mg/m2). Although not the primary end points of the study, the objective response rates in this trial ranged from 15%-21%, the median overall survival was 7.8 months, and the time to progression ranged from 3.3 to 4.5 months. One-year survival ranged from 31%-36%. It is important to note that patients in this trial had good ECOG performance status (0 or 1). Toxicity in this trial was frequent. The incidence of grade 4 neutropenia ranged from 37%-55%. In the present study, the response rate, median survival, and 1-year survival rate are similar to the data from the ECOG trial. The toxicity data, however, compare favorably because no patients were hospitalized for toxicity and there were no episodes of fever or neutropenia.


   CONCLUSIONS
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Conclusions
Additional Reading
 References
 
Additional study is required to further evaluate the safety and to fully evaluate the efficacy of weekly topotecan, gemcitabine, and cisplatin for the treatment of NSCLC. The present study suggests that the combination is safe and well tolerated and will not require frequent dose reductions or treatment delays. The recommended phase II doses and administration schedule for this 28-day regimen are topotecan (1.75 mg/m2) and cisplatin (20 mg/m2) administered on days 1, 8, and 15, and gemcitabine (1,000 mg/m2) administered on days 1 and 15. No grade 3 or 4 hematologic adverse events developed at the recommended dose; therefore, investigation of the efficacy of this triplet regimen and its impact on patient QOL in NSCLC is warranted. Furthermore, the responses documented in these patients with inoperable, advanced NSCLC suggest that the combination regimen may also be active in patients with less advanced disease or in conjunction with surgery in patients with operable NSCLC.


   ADDITIONAL READING
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Conclusions
 Additional Reading
References
 
Practitioners seeking more background information may wish to review selected works by White et al. [21] and by Schiller [31, 32].


   ACKNOWLEDGMENT
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Conclusions
 Additional Reading
 References
 
We wish to thank Andrew J. and Jeffery M. Guarino for assistance in data collection. We also wish to extend our gratitude to our office nurses, staff, and protocol nurses who provided care and support for the patients. We humbly thank the patients and their families for their participation and their trust in us.

This work was supported by GlaxoSmithKline.


   REFERENCES
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Conclusions
 Additional Reading
 References
 

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Received June 6, 2002; accepted for publication September 30, 2002.




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Update on the Role of Topotecan in the Treatment of Non-Small Cell Lung Cancer
Oncologist, December 1, 2004; 9(suppl_6): 43 - 52.
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