Sequential dose-dense paclitaxel followed by topotecan in untreated extensive-stage small-cell lung cancer: a Spanish Lung Cancer Group phase II study

E. Felip1,+, R. Rosell2, M. Domine3, L. Santomé1, P. Garrido4, A. Font2, A. Carrato5, J. Terrasa6, C. Vadell7, J. M. Mañe8 and J. Baselga1

1 Vall d’Hebron University Hospital, Barcelona; 2 Hospital Germans Trias i Pujol, Badalona, Barcelona; 3 Fundación Jiménez Díaz, Madrid; 4 Hospital Ramón y Cajal, Madrid; 5 Hospital General de Elche, Alicante; 6 Hospital Son Dureta, Palma de Mallorca; 7 Hospital del Mar, Barcelona; 8 Hospital de Cruces, Baracaldo, Spain

Received 5 March 2003; revised 30 April 2003; accepted 4 June 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

Poor survival rates in extensive-stage small-cell lung cancer (SCLC) patients prompted us to evaluate a sequential dose-dense schedule of paclitaxel followed by topotecan.

Patients and methods:

Forty-three patients with previously untreated, extensive-stage SCLC received three cycles of paclitaxel 250 mg/m2 over 3 h every 14 days followed by three cycles of topotecan 2.5 mg/m2 for 5 days every 21 days. Granulocyte colony-stimulating factor was given after every cycle. Patients progressing at any time and those not achieving complete response (CR) subsequently received four cycles of standard-dose etoposide–cisplatin.

Results:

A total of 118 cycles of paclitaxel were administered with minimal hematological toxicity. Grade 2/3 peripheral neuropathy was observed in 21% of patients. Response rate to paclitaxel was 48.8%, and 25.6% had stable disease (SD). Thirty-two patients achieving SD or response to paclitaxel subsequently received a total of 90 topotecan cycles. Topotecan-related toxicities included febrile neutropenia in 15.6% of patients with one toxic death, grade 3/4 anemia in 25% of patients and grade 3/4 thrombocytopenia in 31.3%. Non-hematological toxicities were mild. At completion of sequential paclitaxel–topotecan treatment the overall response rate was 55.8% (22 partial response, two CRs). Median survival for all patients was 10.5 months and median progression-free survival was 8.5 months.

Conclusions:

Sequential treatment with dose-dense paclitaxel followed by topotecan is feasible despite significant hematological toxicity during topotecan treatment. This schedule is an active regimen in extensive-stage SCLC and merits further investigation.

Key words: dose-dense, paclitaxel, sequential treatment, small-cell lung cancer, topotecan


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Although small-cell lung cancer (SCLC) is a highly chemosensitive disease, outcome is generally poor and >90% of patients die of the disease. Several strategies could be analyzed with a view to improving prognosis, ranging from the introduction of new agents to more active administration schedules. Alternating chemotherapy based on the Goldie and Coldman mathematical model has been evaluated in randomized trials [1]. The alternating use of two regimens with a proven degree of non-cross-resistance results in no improvement in survival in extensive disease [2, 3]. Another, less studied, approach is sequential treatment prompted by the Gompertzian kinetic model proposed by Norton and Simon [4]. Those authors hypothesized that the administration of rapidly recycled chemotherapy cycles in as short an interval as feasible may be beneficial to chemosensitive tumors. Using this strategy, the efficacy of chemotherapy is maintained, the incidence and severity of toxicity is minimized and the probability of eradicating drug-sensitive populations is increased. Experience in the use of dose-dense sequential therapy in SCLC is limited. In order to test this model, we designed a phase II multicenter study in which chemotherapy-naïve patients with extensive-stage SCLC were treated with a dose-intensive program consisting of rapid recycling of paclitaxel followed sequentially by high-dose topotecan with granulocyte colony-stimulating factor (G-CSF) support. Our rationale for studying this schedule was based on the following observations: paclitaxel and topotecan are two of the most active agents in chemotherapy-naïve patients with extensive-stage SCLC and the overlapping toxicities of these agents point to the advantages of sequential rather than concurrent administration [5-8]. Furthermore, recent studies support the fact that paclitaxel and topotecan can be given in a dose-dense fashion. In the adjuvant treatment of breast cancer patients, paclitaxel 250 mg/m2 in a 24-h infusion every 14 days can be easily administered with G-CSF support [9]. In a phase I study, dose-limiting neutropenia and thrombocytopenia occurred when topotecan was given at 4.2 mg/m2 daily for 5 days with G-CSF starting on day 6 [10].

Based on the results of these two studies, we decided to administer paclitaxel 250 mg/m2 as a 3-h infusion every 14 days followed sequentially by topotecan 2.5 mg/m2 daily for 5 days every 21 days with G-CSF support. Since topotecan is active in ovarian cancer patients with paclitaxel-resistant disease, and has favorable second-line activity in SCLC patients, we were prompted to use the sequence of paclitaxel first followed by topotecan [1114].


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Eligibility
Criteria for study entry were as follows: (i) histologically or cytologically confirmed SCLC; (ii) extensive-stage disease, defined as disease extending beyond one hemithorax or involving contralateral hilar lymph nodes and/or pleural effusion with positive cytology; (iii) age >=18 years; (iv) Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2; (v) measurable disease; (vi) adequate bone marrow (absolute neutrophil count >=1500/ml, platelet count >=100 000/ml), hepatic (total bilirubin level <=1.5 mg/dl), and renal (creatinine concentration <=1.5 mg/dl) function; (vii) absence of active infection; (viii) no prior chemotherapy or radiotherapy; (ix) no history of myocardial infarction in the last 6 months, congestive heart failure or significant arrhythmia; (x) no prior second primary cancer, except skin cancer; and (xi) no brain metastases. Written informed consent was obtained from all patients and the protocol was approved by the institutional ethics committees of the participating centers.

Pretreatment evaluation
Before protocol enrollment, all patients underwent a complete history and physical examination. Laboratory evaluation included a complete blood cell count, electrolytes, glucose, calcium, albumin, transaminases, alkaline phosphatases, total bilirubin, urea and creatinine levels. ECG, chest X-ray, a computed tomographic (CT) scan of the chest and abdomen, a CT scan of the brain and bone scintigraphy were carried out on all patients within the month preceding entry into the study. A bronchoscopy was not necessary initially if pathological diagnosis of SCLC was established by another procedure. Additional imaging studies were carried out if clinically indicated or to measure areas of known disease.

Treatment plan
The treatment schedule consisted of three cycles of paclitaxel 250 mg/m2 i.v. given as a 3-h infusion at 14-day intervals followed by three cycles of topotecan 2.5 mg/m2 i.v. given as a 30-min infusion daily for 5 days every 21 days (Figure 1). During treatment with paclitaxel, patients were given prophylactic premedication with dexamethasone, diphenhydramine and cimetidine. All six cycles of chemotherapy were supported by G-CSF at a dose of 5 µg/kg subcutaneously on days 3–10 inclusive after paclitaxel and days 6–15 inclusive after topotecan. Complete blood cell counts and serum chemistry were carried out immediately before each chemotherapy cycle, at which time patients were evaluated for toxicity according to standard World Health Organization (WHO) criteria.



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Figure 1. Treatment plan for sequential dose-dense therapy. G-CSF, granulocyte colony-stimulating factor.

 
Paclitaxel administration was delayed if the granulocyte count was <1500/ml or the platelet count was <100 000/ml on the scheduled day of administration. Paclitaxel treatment resumed when these levels were achieved. Paclitaxel dose was reduced 20% for neutropenic fever, for grade >=3 neurotoxicity, or for any other grade 3 non-hematological toxicity attributable to a prior paclitaxel dose.

Topotecan treatment was delayed if on the scheduled day of administration, the granulocyte count was <1500/ml or the platelet count was <100 000/ml. It was resumed when these minimal levels were achieved. Topotecan was withheld for grade 2/3 mucositis, dysphagia and/or diarrhea, but it was resumed at full dose when these toxicities resolved. Dose reductions of 25% were required for patients who developed neutropenic fever or a documented bacteriemia.

Response was evaluated following paclitaxel treatment and then again after topotecan administration or, more frequently, when the patient appeared to have disease progression. Restaging was carried out by repetition of initial radiological examinations. Patients were evaluated for response according to WHO criteria. Patients with progressive disease (PD) at any time were withdrawn from the study. In the present trial an adaptation of the design of the ECOG trials for testing new drugs in untreated extensive-stage SCLC patients was used: patients progressing during paclitaxel or topotecan treatment and those not achieving complete response (CR) at completion of the full sequence subsequently received four cycles of i.v. cisplatin 60 mg/m2 on day 1 and etoposide 120 mg/m2 on days 1, 2 and 3 of a 21-day cycle [15].

Statistical analyses
The primary end points for the study were overall response rate and toxicity. In this patient setting, it was assumed that a true response rate of <=50% invalidated the schedule. Sample size was determined by a two-stage design that required an initial accrual of 15 patients followed by an additional 28 patients if at least nine responses [CR or partial response (PR)] were observed in the first cohort. This sample size calculation was based on a 0.05 type I error and 80% power.

Patients who received at least one dose of paclitaxel were assessable for toxicity. Overall response rate was calculated from all patients entered with no attempt to exclude patients whose response was not evaluated or who progressed early. Progression-free survival and overall survival rate were calculated from the first day of treatment until the date of progression or death. Actuarial survival rate curves were constructed using the Kaplan–Meier method. All patients entering the trial were included in the survival determinations.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
From September 1998 to May 2001, a total of 43 patients from eight participating institutions were included in the trial. The characteristics of the patients are shown in Table 1. Median age was 60 years (range 41–76) and the majority of patients were male (91%).


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Table 1. Patient demographics
 
Toxicity
A total of 118 cycles of paclitaxel were administered to 43 patients. Paclitaxel treatment was withdrawn early from three patients: one patient died 10 days after starting the first cycle as a result of pulmonary embolism, the second had early disease progression, and the third developed a hypersensitivity reaction to paclitaxel during the first chemotherapy cycle and could not receive additional cycles. In addition to these three patients, eight did not proceed to topotecan treatment because of PD after the three cycles of paclitaxel. Therefore, 32 patients received topotecan treatment.

Overall, paclitaxel therapy was well-tolerated and no unexpected toxicities were observed (Table 2). No grade 4, anemia nor thrombocytopenia was reported. Febrile neutropenia occurred in one patient in only one cycle. Grade 2/3 peripheral neuropathy was the most significant non-hematological toxicity noted in this study population (grade 2, 18.6%; grade 3, 2.3%). Myalgia/arthralgia grade 2/3 was reported in 18.6% of patients, and nausea and vomiting were uncommon. Paclitaxel dose reduction was required in only two patients (4.7%).


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Table 2. Worst toxicity per patient during paclitaxel chemotherapy (43 patients)
 
A total of 90 cycles of topotecan were administered to 32 patients. Topotecan-related toxicities are summarized in Table 3. Two deaths were considered as possibly related to topotecan. One patient died of neutropenic sepsis after the first topotecan cycle and another patient developed an acute myocardial infarction on day 7 of cycle 2. A third patient decided not to continue treatment. Overall, major topotecan-associated toxicity was hematological. Grade 3/4 granulocytopenia was observed in 28.1% of patients. Neutropenic fever requiring hospitalization occurred in five patients (15.6%). Grade 3/4 anemia was seen in eight patients (25%) and grade 3/4 thrombocytopenia occurred in 10 patients (31.3%). Other non-hematological toxicities, including nausea and vomiting, mucositis and diarrhea were infrequent. Topotecan dose reduction was required in five patients (15.6%).


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Table 3. Worst toxicity per patient during topotecan chemotherapy (32 patients)
 
Response and survival
Overall response data are summarized in Table 4. After paclitaxel treatment, among the 43 patients included, there was one CR and 20 PRs, for an overall response rate to paclitaxel of 48.8% [95% confidence interval (CI) 33.3% to 64.5%]. Eleven patients had stable disease (SD) and nine progressed. Thirty-two of these patients subsequently received topotecan. The following occurred during topotecan treatment in the 21 patients with paclitaxel response: one patient maintained CR, one patient with previous PR achieved CR, 13 patients still had PR, three patients progressed and three patients did not finish topotecan administration (one toxic death, one patient with myocardial infarction, and one patient who chose to leave the study). Nine of 11 patients with SD after paclitaxel, had PR after topotecan. Therefore, at the completion of paclitaxel–topotecan treatment 24 of the 43 patients included (55.8%; 95% CI 39.9% to 70.9%) had objective response: two patients (4.6%) had CRs and 22 (51.2%) had PRs. Thirty of the 43 patients included (69.7%) had responses in at least one of the two radiological evaluations during this sequential treatment.


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Table 4. Response rate
 
Twenty-nine patients later received standard etoposide–cisplatin therapy. No additional responses were observed. Sixteen patients remained stable and 13 progressed.

The estimated median overall survival for all patients included was 10.5 months (95% CI 8.3–12.8), with a 1-year survival rate of 41% (Figure 2). The median progression-free survival was 8.5 months (95% CI 7.3–9.7) (Figure 3).



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Figure 2. Overall survival.

 


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Figure 3. Time to progression.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study sought to determine the feasibility and antitumor activity of sequential dose-dense paclitaxel followed by topotecan in extensive-stage SCLC. Two considerations led us to explore this schedule: both agents are active in SCLC and both can be given at dose-dense schedules without overlapping toxicity. In the first-line treatment of SCLC, single-agent activity of paclitaxel and topotecan compares favorably with activity reported with the most active agents available and is similar to that achieved with standard polychemotherapy. In an ECOG phase II study in previously untreated extensive-stage SCLC patients, paclitaxel achieved an overall response rate of 34% and a 43-week median survival [5]. A North Central Cancer Treatment Group study also confirmed paclitaxel activity in extensive-stage SCLC, reporting a 40.5% response rate in the first-line setting [6]. In an ECOG phase II study, topotecan achieved a 39% response rate with a 10-month median survival in previously untreated extensive SCLC patients [7]. Topotecan is also considered an active agent in second-line therapy in SCLC [1214]. In a randomized study of topotecan versus cyclophosphamide–doxorubicin–vincristine (CAV) in patients who had relapsed at least 60 days after completion of first-line therapy, the overall response rate on the topotecan arm was 24% with a median survival of 25 weeks [14]. In our trial, the response rate was calculated after paclitaxel and then after topotecan administration. A 49% response rate was observed after three cycles of paclitaxel. However, no 4-week follow-up measurements were made after paclitaxel since SD and responding patients subsequently received topotecan because of study design. Topotecan was also active in our patients; 24 of 32 who received this agent had a response. In agreement with ovarian cancer studies, topotecan was found to be non-cross-resistant with paclitaxel: nine of 11 patients with SD after paclitaxel responded to topotecan. In our study, sequential administration of dose-dense paclitaxel followed by topotecan was found to be an active first-line therapy regimen for extensive-stage SCLC, achieving a 55.8% response rate at the completion of the whole sequential treatment in an intention-to-treat analysis. A randomized phase II SCLC trial found oral topotecan to be similar in efficacy to i.v. topotecan with less hematological toxicity [16]. Keeping in mind the greater convenience of oral administration, sequential treatment with paclitaxel followed by oral topotecan seems an attractive option that is worth exploring.

Our study demonstrates the feasibility of administering dose-dense paclitaxel with G-CSF support in newly diagnosed SCLC patients. Dose-dense paclitaxel-related toxicities were infrequent; non-hematological toxicities were uncommon and only one patient developed febrile neutropenia. However, we found clinically meaningful hematological toxicities to be common during topotecan treatment and somewhat higher than that reported using standard platin–etoposide combinations. Two patients died from what was considered to be topotecan-related toxicity, one with neutropenic sepsis. Furthermore, nine of 32 patients treated with topotecan required blood product transfusions. Overall, five of the 29 patients who finished the scheduled three cycles of topotecan required topotecan dose reduction. Due to hematological toxicity during topotecan treatment, we suggest reducing topotecan dose to 2.0 mg/m2 for 5 days every 21 days for further sequential studies. Prompted by one phase II study which found that G-CSF support reduces grade 3/4 neutropenia when topotecan is given at 2.0 mg/m2 for 5 days, we suggest using G-CSF support even at that dose [7]. Although in our study, when topotecan is used at a dose of 2.5 mg/m2, 16% of patients required topotecan dose reduction, we cannot state conclusively that topotecan at a dose of 2.0 mg/m2 will achieve identical results. Probably, a better approach to topotecan administration may well be by adjusting the dose according to individual toxicities in previous cycles [17].

Sequential treatment has proven clinically superior to alternating schedule in breast cancer patients [18]. The present trial is one of the few studies evaluating planned sequential therapy in SCLC patients. A randomized study showed that after CAV therapy, sequential administration of etoposide–cisplatin compared with no further treatment significantly improved overall survival [19]. However, in a prospective, randomized ECOG study, four cycles of etoposide–cisplatin followed by four cycles of topotecan improved progression-free survival but failed to improve either overall survival or quality of life in extensive-stage SCLC [20]. To the best of our knowledge, the present study is the first trial to evaluate the feasibility and activity of a pure dose-dense schedule using monotherapies in SCLC.

The use of new agents in the treatment of chemotherapy-naïve SCLC patients is under consideration. In the ECOG randomized study of topotecan versus observation after etoposide–cisplatin, response rate to etoposide–cisplatin was only 35% (CR, 3%; PR, 32%) [20]. Although response rate does not always predict longer survival, more active combinations should be sought. In a phase II study using paclitaxel–carboplatin in extensive SCLC, the overall response rate was 65% with a 38-week median survival [21]. A phase III trial reported enhanced survival when irinotecan was combined with cisplatin as first-line therapy [22]. The median survival and 2-year survival rate on the irinotecan–cisplatin arm were 12.8 months and 19.5%, respectively, compared with 9.4 months and 5.2% for patients randomized to receive etoposide–cisplatin. Confirmatory randomized trials are ongoing. The value of adding a third new agent to etoposide–platinum combinations in SCLC has been analyzed. In a phase II study using paclitaxel–carboplatin–oral etoposide an overall response rate of 84% was reached [23]. A paclitaxel–etoposide–cisplatin combination with G-CSF support achieved a 57% response rate with a median survival of 11 months and a 1-year survival rate of 43% [24]. However, a recent randomized trial indicates that the addition of paclitaxel to the etoposide–cisplatin combination causes higher toxicity and confers no survival advantage [25]. Although no conclusions should be drawn, the 55.8% response rate obtained in the present study evaluated at the end of sequential dose-dense treatment seems comparable with those reported in the above trials using new agents in platinum combinations.

In summary, our study shows the activity of this dose-dense sequential therapy using paclitaxel followed by topotecan with G-CSF support. This schedule is feasible, although due to clinically significant hematological toxicities during topotecan treatment, a reduction in topotecan dose in future studies seems advisable. Since recent randomized trials have associated the addition of a third chemotherapy agent with higher toxicity and offered no survival advantage, sequential therapy may well be a more promising line of investigation to follow.


    Acknowledgements
 
Supported by a grant from Amgen, Spain; paclitaxel and topotecan were provided free of charge by Bristol-Myers Squibb, Spain and SmithKline Beecham, Spain.


    Footnotes
 
+ Correspondence to: Dr E. Felip, Medical Oncology Service, Vall d’Hebron University Hospital, P. Vall d’Hebron 119-129, 08035 Barcelona, Spain. Tel: +34-93-2746077; Fax: +34-93-2746059; E-mail: efelip{at}vhebron.net Back


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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