1 Vall dHebron 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
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Abstract |
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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 etoposidecisplatin.
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 paclitaxeltopotecan 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
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Introduction |
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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].
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Patients and methods |
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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 310 inclusive after paclitaxel and days 615 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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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 KaplanMeier method. All patients entering the trial were included in the survival determinations.
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Results |
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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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The estimated median overall survival for all patients included was 10.5 months (95% CI 8.312.8), with a 1-year survival rate of 41% (Figure 2). The median progression-free survival was 8.5 months (95% CI 7.39.7) (Figure 3).
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Discussion |
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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 platinetoposide 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 etoposidecisplatin compared with no further treatment significantly improved overall survival [19]. However, in a prospective, randomized ECOG study, four cycles of etoposidecisplatin 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 etoposidecisplatin, response rate to etoposidecisplatin 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 paclitaxelcarboplatin 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 irinotecancisplatin arm were 12.8 months and 19.5%, respectively, compared with 9.4 months and 5.2% for patients randomized to receive etoposidecisplatin. Confirmatory randomized trials are ongoing. The value of adding a third new agent to etoposideplatinum combinations in SCLC has been analyzed. In a phase II study using paclitaxelcarboplatinoral etoposide an overall response rate of 84% was reached [23]. A paclitaxeletoposidecisplatin 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 etoposidecisplatin 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.
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Acknowledgements |
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Footnotes |
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References |
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