ARTICLE

Randomized Phase III Trial of Paclitaxel, Etoposide, and Carboplatin Versus Carboplatin, Etoposide, and Vincristine in Patients With Small-Cell Lung Cancer

Martin Reck, Joachim von Pawel, Hans-Nicolas Macha, Eckhard Kaukel, Karl-Matthias Deppermann, Reiner Bonnet, Kurt Ulm, Sybill Hessler, Ulrich Gatzemeier

Affiliations of authors: M. Reck, U. Gatzemeier, Department of Thoracic Oncology, Hospital Grosshansdorf, Hamburg, Germany; J. von Pawel, Asklepios Hospital, Gauting, Germany; H.-N. Macha, Lungenklinik Hemer, Hemer, Germany; E. Kaukel, Allgemeines Krankenhaus Harburg, Hamburg; K.-M. Deppermann, Fachkrankenhaus für Lungenheilkunde und Thoraxchirurgie, Berlin, Germany; R. Bonnet, Zentralklinik Bad Berka, Klinik für Pneumologie, Bad Berka, Germany; K. Ulm, Institut für Medizinische Statistik und Epidemiologie, Technical University Munich, Germany; S. Hessler, Bristol-Myers Squibb GmbH, Munich.

Correspondence to: Ulrich Gatzemeier, MD, Department of Thoracic Oncology, Hospital Grosshansdorf, Woehrendamm 80, 22927 Grosshansdorf, Hamburg, Germany (e-mail: u.gatzemeier{at}t-online.de).


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: Paclitaxel administered in combination with a topoisomerase-II inhibitor (such as etoposide) and carboplatin is an effective and safe first-line treatment for patients with small-cell lung cancer (SCLC). We conducted a randomized phase III multicenter trial to determine whether paclitaxel plus etoposide plus carboplatin improves the outcome of patients with primary SCLC relative to standard chemotherapy (carboplatin, etoposide, and vincristine). Methods: Between January 1998 and December 1999, 614 patients with SCLC stages I–IV were randomly assigned to the standard arm (309 patients) or the experimental arm (305 patients). Treatment courses were repeated every 21 days for a maximum of six courses. All patients were evaluated for response rate, survival, and toxicities every two courses. The primary endpoint was survival. Survival curves were estimated with the Kaplan–Meier method and compared using the log-rank test. All statistical tests were two-sided. Results: A total of 608 patients were evaluable for all endpoints (standard arm 307 patients, experimental arm 301 patients). The hazard ratio [HR] of death for patients receiving the standard treatment was statistically significantly higher than that for patients receiving the experimental treatment (HR = 1.22, 95% confidence interval [CI] = 1.03 to 1.45; P = .024). Progression-free survival was also statistically significantly shorter for patients in the standard arm relative to that of patients in the experimental arm (HR = 1.21, 95% CI = 1.03 to 1.42). There were no differences in the response rates (complete and partial combined) to the treatments (standard arm: 69.4%, 95% CI = 63.9% to 74.5%; experimental arm: 72.1%, 95% CI = 66.7% to 77.1%; difference = 2.7%, 95% CI = 4.5% to 9.9%). Rates of severe grade of anemia, leukocytopenia, neutropenia, and thrombocytopenia were lower in the experimental arm than in the standard arm. Conclusion: Patients with previously untreated SCLC who received paclitaxel, etoposide, and carboplatin showed improved overall and progression-free survival and less frequent hematologic toxicities than those who received the standard therapy.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Lung cancer is the leading cause of cancer-related death. In Western countries, the incidence of lung cancer is between 60 and 80 per 100 000 for women and between 100 and 200 per 100 000 for men (1). The 5-year survival rate for patients diagnosed with lung cancer is 13%. The proportion of all lung cancers diagnosed as small-cell lung cancer (SCLC) varies from 17% to 29% (2). On a cellular level, SCLCs grow faster than other types of lung cancer (3). Moreover, the frequent spread of SCLC to regional lymph nodes and extrathoracic sites by the time of initial diagnosis suggests that SCLC should be considered a systemic disease.

The median survival of patients receiving only supportive care is 12 weeks for those with stages I–IIIA disease and 5 weeks for those with stage IIIB or IV disease (4). SCLC is sensitive to a variety of chemotherapy agents, and patients with good performance status and early-stage SCLC who receive combined-modality therapy with chemotherapy and radiotherapy have a more favorable prognosis and better overall survival than those diagnosed with late-stage disease and those who receive single-agent chemotherapy (5,6). During the 1980s, patients who received cyclophosphamide in combination with doxorubicin and vincristine had a median survival of 7–8 months (7). In subsequent years, etoposide was added or substituted for doxorubicin, and median survival was found to increase (8). Consequently, this combination was tested in two randomized clinical trials (9,10), both of which showed better responses to the etoposide plus cisplatin combination than to other drug combinations. In other clinical trials (1113), carboplatin had adequate efficacy and fewer neuro- and nephrotoxicities than cisplatin. Thus, the substitution of carboplatin for cisplatin has yielded an active regimen with reduced toxicities. Carboplatin is, however, still associated with hematologic toxicities, predominantly thrombocytopenia (1418). In general, active chemotherapeutic regimens are those for which patients with extensive disease (stages IIIB–IV) have a median survival of 7–10 months and patients with limited disease (stages I–IIIA) have a median survival of up to 16 months.

Patients with SCLC who were treated with the combination of carboplatin plus etoposide had remission rates of 79% if they had limited disease and 65% if they had extensive disease (19,20). Moreover, patients with limited disease had survival times of 10–15 months, whereas patients with extensive disease had survival times of 8–12 months (19,20). After the addition of vincristine to this treatment regimen, patients with limited disease had remission rates of 90%, complete responses of 56%, and median survival times of 13 months; patients with extensive disease had remission rates of 83%, complete responses of 35%, and median survival times of 10 months (2123). Consequently, these results provided the basis for the current use in Germany of this three-drug combination to treat patients with SCLC.

Paclitaxel (Taxol, Bristol-Myers Squibb) has subsequently been found to be a safe and effective drug in the first-line treatment of SCLC (24,25). When paclitaxel was administered as a single agent, overall response rates of 34% and 41% and median survival times of 7.1 and 11.2 months were reported in SCLC patients with extensive disease in (24) and (25), respectively. In a subsequent study, paclitaxel infused for 3 hours in combination with other drugs was used because data from patients with ovarian cancer showed that this infusion time resulted in drug efficacy and toxicity comparable with those of a 24-hour infusion (26).

Results from several multicenter trials (2732) have recently shown encouraging response rates from paclitaxel-containing regimens used as first-line treatments for patients with SCLC. In all of these studies, paclitaxel was combined with a platinum derivative, and in three studies (27,30,31), a topoisomerase II inhibitor such as etoposide was also added. Overall, patients treated with the three-drug regimens had better results than those treated with any of the two-drug regimens, regardless of stage of disease. Depending on the stage of disease, patients achieved response rates of 68%–98% and had median survival times of 10–18 months. On the basis of these data, we initiated a multicenter randomized phase III study to compare survival among patients with SCLC who received first-line treatment with a combination therapy containing carboplatin, etoposide, and vincristine with that for patients who received paclitaxel, etoposide, and carboplatin.


    PATIENTS AND METHODS
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 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Patient Eligibility

Patients with histologically and/or cytologically documented SCLC of any stage were eligible for the study. Patients were included if 1) they had no previous treatment, including radiotherapy, chemotherapy (including intrapleural), or surgery; 2) they had measurable (defined as tumor bidimensionally measurable by physical examination or radiologic investigation [i.e., x-ray, computed tomography (CT) scan, ultrasound, or bronchoscopy, with a minimum size of 2 cm x 2 cm]) or evaluable disease (defined as tumor unidimensionally measurable by physical examination or radiologic investigation); 3) were male or female patients aged 18–75 years; 4) had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or lower (33); 5) had a life expectancy of at least 12 weeks; 6) had no brain metastases or asymptomatic brain metastases; 7) had acceptable initial laboratory data, including an absolute neutrophil count of at least 1500/µL, a platelet count of at least 100 000/µL, a total bilirubin concentration of less than 1.25 times the upper normal limit, a serum creatinine concentration of less than 1.25 times the upper normal limit, and liver enzymes (AST and ALT) of less than three times the upper normal limit; and 8) provided written informed consent, according to the local institutional ethics committee requirements.

Patients were excluded from the study if they 1) were pregnant or lactating; 2) had a past or current history of cancer other than SCLC; 3) had a clinically significant history of cardiac disease; 4) had pre-existing severe motor or sensory neuropathy higher than grade 1, according to the National Cancer Institute Common Toxicity Criteria (CTC) Scale (34); 5) had active infections or other serious concomitant medical conditions that would impair the ability of a patient to receive the protocol treatment; 6) had dementia; or 7) had had any other anticancer treatment, including immunotherapy.

Baseline evaluations had to be performed within 2 weeks before study entry and included a complete history and physical examination; complete blood cell count with differential, platelet count, and serum chemistry analysis, including creatinine clearance (calculated by the Jelliffe formula), total bilirubin, and liver enzymes (AST and ALT); tumor evaluation (by chest x-ray, thoracic CT [TCT], abdominal CT [ACT], bone scintigraphy, CT of the brain, or bronchoscopy); and quality of life.

Treatment Protocol

Patients were stratified before randomization. Stratification parameters were treatment center, stage of disease (I–IIIB versus IV), and ECOG performance status (0–1 versus 2). We used a centralized randomization system based on the Pocock-type minimization procedure for stratified randomization (35). Six hundred fourteen patients were randomly assigned to receive carboplatin, etoposide, and vincristine (CEV; standard arm, 309 patients), or paclitaxel, etoposide, and carboplatin (TEC; experimental arm, 305 patients).

Patients in the standard arm received carboplatin (Carboplat; Bristol-Myers Squibb, Munich, Germany) at an area under the curve (AUC) of 5 [Calvert formula (36)] diluted with a 5% glucose or 0.9% NaCl solution to a concentration of up to 0.5 mg/mL, given as an intravenous 0.5- to 1-hour infusion on day 1; etoposide phosphate (Etopophos; Bristol-Myers Squibb) at 159 mg/m2 (for patients with stage I–IIIB disease) or 125 mg/m2 (for patients with stage IV disease), diluted with a 5% glucose or 0.9% NaCl solution to a concentration of up to 2.0 mg/mL, given as an intravenous 30-minute infusion on days 1–3; and vincristine (Vincristin; Bristol-Myers Squibb) at 2 mg, administered as an intravenous 10-mL infusion concentrate on days 1 and 8.

Patients in the experimental arm received etoposide phosphate at 125 mg/m2 (for patients with stage I–IIIB disease) or 102.2 mg/m2 (for patients with stage IV disease), diluted and administered as for patients in the standard arm; paclitaxel at 175 mg/m2, diluted in a minimum volume of 250 mL to a maximum volume of 1000 mL of a 5% glucose or 0.9% NaCl solution; and carboplatin, which was diluted and administered as in the standard arm, except that it was administered on day 4 rather than on day 1. To avoid acute allergic reactions, all patients in the experimental arm received dexamethasone (20 mg), clemastine (or equivalent, 2 mg), and cimetidine (or equivalent, 300 mg) intravenously 30 minutes before receiving paclitaxel. Paclitaxel was administered as a 3-hour intravenous infusion on day 4 and was immediately followed by an infusion of carboplatin AUC 5 (Calvert formula).

Complete in vivo dephosphorylation of etoposide phosphate after intravenous infusion yields the active drug etoposide. The bioequivalence of etoposide phosphate and etoposide has been demonstrated in two randomized trials (37,38). Because etoposide phosphate is more soluble and requires a smaller infusion volume and a shorter infusion time than etoposide, this study was performed with etoposide phosphate. The doses of etoposide phosphate correspond to the following doses of etoposide: in the standard arm, 140 mg/m2 for patients with stage I–IIIB disease and 110 mg/m2 for patients with stage IV disease; in the experimental arm, 110 mg/m2 for patients with stage I–IIIB disease and 90 mg/m2 for patients with stage IV disease.

All patients were allowed to receive antiemetics, according to the participating institutions’ policies. Chemotherapy for patients in both arms was repeated every 21 days or after recovery from toxicities, as defined in the study protocol, for a maximum of six courses. Doses of paclitaxel, etoposide phosphate, and carboplatin were reduced when white blood cell counts were less than 1.0 x 109/L, when platelet counts were less than 25 x 109/L for more than 1 week, or when febrile neutropenia or severe non-hematologic toxicity occurred. The dose of vincristine was reduced only when severe non-hematologic toxicity occurred.

The duration of treatment was determined on the basis of response evaluations at the beginning of every second cycle. Patients whose disease progressed or did not change while on the protocol received two cycles of second-line treatment consisting of 1000 mg/m2 of intravenous cyclophosphamide on day 1, 60 mg/m2 of intravenous doxorubicin on day 1, and 2 mg of vincristine on days 1 and 8. For patients with a partial or complete response, treatment was continued. Patients with stage I–IIIB disease who responded to first-line therapy received consolidation radiotherapy after completing chemotherapy. A standard radiotherapy regimen—according to the participating hospitals—was used, with a total dose of 50–56 Gy given in standard fractions of 1.8–2 Gy/day over a period of 6 weeks. Patients with limited disease who had reached complete remission received additional cranial radiation with a total dose of 30 Gy given in fractions of 2–2.5 Gy/day over a period of 3 weeks. Patients went off study if their disease progressed, if hematologic recovery was incomplete 2 weeks after scheduled treatment, or if there was evidence of grade 3 neuropathy according to CTC, or if there was any other CTC grade 3 non-hematologic toxicity, except alopecia. Patients were taken off study if conditions requiring therapeutic intervention not permitted by the protocol were needed, if the patient asked to be taken off study, if the patient became pregnant, and/or if any other situation arose for which, in the opinion of the investigator, continued participation in the study would not be in the best interest of the patient.

Treatment Evaluation

The primary objective was to compare survival between the two treatment arms. Secondary objectives were to determine toxicities, response rates, time to progression, and quality of life. A total of 608 patients were evaluable for toxicity from the time of their first dose of either study therapy. All eligible patients who received at least two courses of therapy were considered evaluable for response (n = 608). In addition, patients whose tumors rapidly progressed, who died of progressive disease, who discontinued treatment, or who died of a treatment-related toxicity before response evaluation were also considered evaluable for response. A "complete response" was defined as a disappearance of all clinical evidence of the tumor for a minimum of 4 weeks. A "partial response" was defined as a decrease of at least 50% in the sum of the products of the longest perpendicular diameters of all measurable lesions (or an estimated decrease of more than 50% for non-measurable lesions) lasting at least 4 weeks, without appearance of any new lesions and without disease progression at any site. "No change" was defined as a decrease of less than 25% or an increase of less than 25% in the sum of the products of the longest perpendicular diameters of all measurable lesions (or an estimated decrease of less than 25% or an increase of less than 25% in non-measurable lesions) lasting at least 4 weeks, without appearance of any new lesions. "Progressive disease" was defined as an increase of at least 25% in the sum of the products of the longest perpendicular diameters of the measurable lesions (or an estimated increase of at least 25% for non-measurable lesions) or appearance of any new lesion. Time to response was recorded for all patients with a complete or partial response (n = 430). Time to complete response corresponded to the period between the first day of therapy and the date the complete response was first noted. Time to partial response corresponded to the period between the first day of therapy and the date the measurement criteria for a partial response was reported. Time to progression was calculated from the day of randomization to the date that progressive disease or death was first reported. Patients whose disease did not progress were censored at the last date they were known to be alive. Patients who died of disease and for whom a date of progression was not available were considered to have progressed on the day of their death. Response duration was measured according to World Health Organization criteria (39). The duration of complete response was calculated from the date the complete response was recorded to the date progressive disease was first noted. The duration of all responses was calculated for all patients who responded and was defined as the period between the first day of therapy and the date progressive disease was first noted. Patients whose disease did not progress were censored at the last date they were known to be alive. For all patients, survival was calculated from the day of randomization to the day of death. Patients who had not died were censored at the date they were last known to be alive. A total of 614 randomly assigned patients were included in the analyses of survival and time to progression.

Statistical Considerations

The primary endpoint of this study was survival. The study had 80% power to detect a hazard ratio of 1.3, which would correspond to a difference in the median survival time of 3 months (10 versus 13 months) and a statistical significance level of 5%. Assuming an accrual rate of 25 patients per month, about 600 patients had to be enrolled over 2 years, with an additional follow-up period of 14 months. The data have been analyzed on an intent-to-treat basis.

Secondary endpoints were progression-free survival, tumor response, symptoms, laboratory measurements, and other events, such as the frequency of hospitalization, number of blood transfusions needed, and use of second-line therapy. Continuous data, expressed as median with interquartile ranges, were analyzed by using the Mann–Whitney U test. Qualitative data, expressed as numbers and percentages, were analyzed by using the {chi}2 test. The survival curves were estimated by the Kaplan–Meier method (40) and compared by using the log-rank test (41). For the survival curves, the median survival times with 95% confidence intervals (CIs) were calculated (42). Multivariable analyses were performed using the Cox proportional hazards model (43). Proportional hazards assumptions were checked (44) and confirmed to hold. Using this model, the influence of various factors such as performance status, age, sex, stage and tumor–node–metastasis (TNM) classification were investigated, and the results are reported as relative risks (RRs) with 95% CIs. All statistical tests were two-sided. Differences were considered to be statistically significant when P<.05 (SPSS, Release 11.5; SPSS Inc., Chicago, IL).


    RESULTS
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Patient Characteristics

Between January 1998 and December 1999, 614 patients were enrolled on the study from 19 participating centers (Fig. 1Go). Median time of follow-up for the analyses performed in April 2002 was 11.8 months (range = 0.1–43.8 months). Patient characteristics are listed in Table 1Go. There were no statistically significant differences between patients in the two study arms with respect to performance status (>90% of the patients in each arm had an ECOG performance status of 0–1), stage of disease (approximately 50% of patients had stage I–IIIB disease), age, sex, or site(s) of metastases.



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Fig. 1. Consolidated Standards of Reporting Trials (CONSORT) flow diagram. All 307 patients in the standard (carboplatin, etoposide, vincristine [CEV]) arm and 301 patients in the experimental arm (paclitaxel, etoposide, carboplatin [TEC]) arm were available for all analyses.

 

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Table 1. Characteristics of patients with small-cell lung cancer enrolled on a randomized trial of carboplatin plus etoposide plus vincristine (CEV) versus paclitaxel plus etoposide plus carboplatin (TEC)
 
Second-line therapy was defined per protocol to avoid an influence on median survival time. In both treatment groups, the percentage of patients who received second-line therapy was similar (52.7% in the standard arm and 52.1% in the experimental arm). The regimen used for second-line treatment was epirubicin or adriamycin in combination with cyclophosphamide and vincristine (61.3% in the standard arm and 60.4% in the experimental arm).

Of the 614 patients, 608 were evaluable for toxicity and survival. Four patients withdrew informed consent and two were diagnosed with cancers other than SCLC, making all six patients ineligible for toxicity and survival analyses.

Dosing

The 608 patients received a total of 3250 courses of chemotherapy, of which 1655 courses of CEV were administered to 307 patients in the standard arm and 1595 courses of TEC therapy were administered to 301 patients in the experimental arm. Patients in the standard arm received a median of 4.4 courses, and those in the experimental arm received a median of 4.3 courses.

Tumor Response

All 307 patients in the standard arm and 301 patients in the experimental arm who were available for analyses were evaluable for response, as determined by the availability of two observations no less than 4 weeks apart (confirmed response). There were no statistically significant differences in the response rates between patients in the two treatment arms (Table 2Go). The percentage of patients in the standard arm who had a complete response was 15.3, and in the experimental arm, 17.6 (difference = 2.3%, 95% CI on the difference = -3.6% to 8.2%). Approximately 70% of patients in each arm had either a complete or partial response (standard arm: 69.4%, 95% CI = 63.9% to 74.5%; experimental arm: 72.1%, 95% CI = 66.7% to 77.1%; difference = 2.7%, 95% CI = 4.5% to 9.9%). There was no statistically significant difference between the treatment responses among patients with stage I–IIIB disease and those with stage IV disease, although in the latter group, there was a slight difference between the rates with complete response (13.7% versus 7.8%; difference = 5.9%, 95% CI = -1.0% to 12.8%).


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Table 2. Confirmed response rates for patients with small-cell lung cancer enrolled on a randomized trial of carboplatin plus etoposide plus vincristine (CEV) versus paclitaxel plus etoposide plus carboplatin (TEC)
 
Median Survival, Time to Progression, and Long-Term Survival

A total of 515 patients (271 of 307 patients in the standard arm and 244 of 301 patients in the experimental arm) died during the follow-up period. The hazard ratio [HR] of death for patients receiving the standard treatment was statistically significantly higher (HR = 1.22, 95% CI = 1.03 to 1.45; P = .024) than that for patients receiving the experimental treatment (Fig. 2Go). The median survival time was 12.7 months (95% CI = 11.2 to 14.1 months) for patients in the experimental arm and 11.7 months (95% CI = 10.9 to 12.6 months) for patients in the standard arm. Mean 1-year, 2-year, and 3-year survival rates were 48% (95% CI = 42% to 53%), 16% (95% CI = 11% to 20%), and 9% (95% CI = 6% to 13%) for patients in the standard arm and 51% (95% CI = 46% to 57%), 20% (95% CI = 16% to 25%), and 17% (95% CI = 12% to 21%) for patients in the experimental arm.



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Fig. 2. Overall survival curves for the 608 evaluable patients with small-cell lung cancer enrolled on a randomized trial of carboplatin, etoposide, and vincristine (CEV) versus paclitaxel, etoposide, carboplatin (TEC). The numbers below the graph are the patients at risk and 95% confidence intervals for overall survival at the various time points.

 
We stratified survival by stage of disease and found that patients with early-stage disease in the experimental arm lived longer than those in the standard arm (stage I–IIIA, 18.7 versus 16.9 months; stage IIIB, 15.7 versus 13.2 months; and stage I–IIIB, 17.6 versus 16.6 months, respectively). There was no difference in median survival between the standard and experimental arms for patients with stage IV disease (9.8 months versus 10.0 months, respectively).

In the multivariable Cox model, the HR associated with therapy was adjusted for known prognostic factors, including ECOG performance status, stage of disease, sex, and lymph node status (Table 3Go). The HR for death was 28% higher for patients in the standard arm relative to that for patients in the experimental arm (HR = 1.28, 95% CI = 1.08 to 1.53). Stage of disease was the most important prognostic factor for the HR for overall survival. Patients with stage IV disease had an approximately twofold higher mortality rate than patients with stage I–IIIB disease (HR = 1.98, 95% CI = 1.66 to 2.37). There was no interaction between the treatment and the prognostic factors.


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Table 3. Results of the Cox model (univariate and multivariable analyses) to adjust the risk associated with therapy for various prognostic factors
 
Progression-free survival was statistically significantly higher for patients in the experimental arm (HR = 1.21, 95% CI = 1.03 to 1.42; P = .033; Fig. 3Go) than for patients in the standard arm. Patients in the experimental arm had a median progression-free survival time of 8.1 months (95% CI = 7.4 to 8.8 months), whereas patients in the standard arm had a median of progression-free survival time of 7.5 months (95% CI = 6.7 to 8.3 months).



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Fig. 3. Progression-free survival for the 608 evaluable patients with small-cell lung cancer enrolled on a randomized trial of carboplatin, etoposide, vincristine (CEV) versus paclitaxel, etoposide, carboplatin (TEC). The numbers below the graph are the patients at risk and 95% confidence intervals for progression-free survival at the various time points.

 
Toxicity

All 307 evaluable patients in the standard arm and 301 evaluable patients in the experimental arm received at least one dose of therapy and were evaluable for toxicity. There was no statistically significant difference in the number of treatment-related deaths between patients in the two arms (nine patients in the standard arm and 11 patients in the experimental arm died of treatment-related causes). All treatment-related deaths were associated with hematologic toxicity.

All hematologic and non-hematologic toxicities were related to the number of courses of therapy. A delay in the administration of chemotherapy of more than 4 days resulting from toxicity occurred in 25% of the patients in the standard arm and 16% of the patients in the experimental arm.

Hematologic toxicities are summarized in Table 4Go. The frequency and severity of anemia and thrombocytopenia (CTC grades III and IV) were statistically significantly less for patients in the experimental arm than for those in the standard arm (P<.01). Consequently, patients in the experimental arm had a lower incidence of platelet and red blood cell transfusions than patients in the standard arm (after 11.6% of the treatment courses for patients in the standard arm versus after 5.3% of the treatment courses for patients in the experimental arm). Rates of leukocytopenia, neutropenia, and febrile neutropenia were similar among patients in both arms.


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Table 4. Frequency of hematologic toxicities per percentage of completed chemotherapy courses observed in patients with small-cell lung cancer enrolled on a randomized trial*
 
Among all patients, the incidence of non-hematologic toxicities was low (Table 5Go). Non-hematologic toxicities of CTC grade IV were observed in less than 1% of administered courses per treatment arm. No grade IV peripheral neuropathy or myalgia/arthralgia was observed in any patient.


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Table 5. Frequency of non-hematologic toxicities per percentage of completed chemotherapy courses observed in patients with small-cell lung cancer enrolled on a randomized trial*
 

    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
In this study, we compared response rates and survival of patients with previously untreated SCLC of all stages randomly assigned to receive either standard therapy (CEV) or experimental therapy (TEC). Although we found no statistically significant difference between response rates in both arms regardless of disease stage, we found a statistically significant increase in survival for patients in the experimental arm relative to that for patients in the standard arm.

In our study, the percentage of patients with limited disease (stage I–IIIB) who had a complete response (15.3% for those in the standard arm and 17.6% for those in the experimental arm) was lower than that for similar patients in other studies (45,46), which was as high as 60%. This difference in response rates may be related to several factors. First, our study was a multicenter trial. As such, it may have been more representative of the general population and thus may have included patients with a worse prognosis than those in a single-institution study (i.e., patients in a typical phase II study) (47). Second, our guidelines for evaluating responses were stringent, considering only confirmed responses (two observations of response no less than 4 weeks apart). Third, to stratify the patients, the majority of our investigators adopted the simple two-stage system of the Veterans Administration Lung Group (48), with limited-stage disease defined as "tumor confined to one hemithorax and the regional lymph nodes," and extensive-stage disease defined as "disease beyond these boundaries." By contrast, other studies have used the staging system described by Wolf and Havemann (46). Patients with extensive disease are divided in two subgroups: those without and those with distant hematologic metastases, with the latter group having the worst prognosis. Because the difference between limited and extensive disease is not precisely defined and because hematologic metastases are the worst prognostic tumor factor for patients with SCLC, we considered patients with limited disease or with extensive disease without metastases (stage I–IIIB) as one category and patients with extensive disease and hematologic metastases (stage IV) as another. When this stratification was used by Stahel et al. (48), they reported complete response rates for patients with stage I–IIIB and stage IV disease similar to those we present in this study.

We found that patients in the experimental arm lived longer than those in the standard arm (median survival was 12.7 months versus 11.7 months, respectively). The increase in median survival for patients in the experimental arm was statistically significant, despite the fact that the median survival for patients in the standard arm was approximately 2 months longer than that in a previous study (17). When we stratified patients by stage of disease, we found that early-stage patients in the experimental arm had improved survival compared with early-stage patients in the standard arm, which is in line with the results of a recent phase II trial for patients with SCLC by Reck et al. (27). However, there was no difference in median survival between the standard and experimental arms for patients with stage IV disease.

Patients in the experimental arm showed improved long-term survival compared with patients in the standard arm. Although the 1-year survival rate was comparable in both regimens, the 3-year survival rate of patients in the experimental arm was nearly twice that of patients in the standard arm (experimental arm = 17%, standard arm = 9%). Reck et al. (27) reported a 1-year survival rate of 66.3%, which is similar to our survival rate for patients with stage I–IIIB disease (66%). Deppermann et al. (28) and Thomas et al. (29) reported 1-year survival rates for patients with stage IV disease of 42.2% and 22.5%, respectively. In our study, patients with stage IV disease who received the experimental regimen had a 1-year survival rate of 51%. However, direct comparisons between studies cannot be made because we used a three-drug combination regimen. Although Mavroudis et al. (49) compared TEC with carboplatin plus etoposide in patients with SCLC, comparisons between their survival data and ours cannot be made because their follow-up time was much shorter.

Our results show that patients in the experimental arm who received paclitaxel had fewer toxicity-related events than patients in the standard arm. The mortality rate associated with chemotherapy-related toxicity (neutropenic sepsis in all patients) was similar in both groups. However, the frequency of hematologic toxicity (i.e., severe anemia and thrombocytopenia) was statistically significantly lower for patients in the experimental arm than for patients in the standard arm and, consequently, patients in the experimental arm had fewer platelet and red blood cell transfusions. The toxicity data are in accordance with toxicity data of other paclitaxel plus carboplatin-based three-drug combination studies (27,30,45).

The combination of chemotherapy and radiotherapy has been proven to improve survival and local recurrence rate for patients with SCLC (50,51) and was associated with more acute and chronic toxicity. There has been considerable controversy over the value and timing of thoracic irradiation in conjunction with chemotherapy for patients with limited-disease SCLC. Phase III studies of sequential chemotherapy and subsequent radiotherapy versus concurrent chemoradiotherapy have not always shown benefits for the concurrent regimens (52,53). Although some trials have shown an advantage for combined regimens with early thoracic irradiation, the actual differences in survival were often small, and combined modality therapy was associated with more acute and chronic toxicity (50). An intergroup trial directly compared once-daily with twice-daily fractions given at the beginning of concurrent chemoradiation therapy with cisplatin and etoposide (54). Initial analysis showed that median survival was statistically significantly better for patients in the twice-daily radiation group than for those in the once-daily group (23 versus 19 months) (54). Although these results are encouraging, side effects such as myelotoxicity (grade IV: 64% of patients in the hyper-fractionated twice-daily group and 62% of patients in the once-daily radiotherapy group) and esophagitis (5% of patients in both groups) were extremely high compared with the toxicities seen in our study (myelotoxicity, 18%). In this context, attention needs to be drawn to the importance of tolerability of the regimen used in our study.

Two randomized trials (49,55) of SCLC patients have compared TEC with cisplatin plus etoposide. The trials were similar to ours with regard to drug concentrations and administration schedules but were different in that one (49) included granulocyte colony-stimulating factor support and patients with limited and extensive disease, whereas the other (55) included only patients with extensive disease. The results of both trials showed no survival advantage but an increase in chemotherapy-associated toxicities for patients in the paclitaxel-containing arm. These results suggest that a cisplatin-based three-drug combination is toxic in the treatment of SCLC.

In our study, we used carboplatin instead of cisplatin within the three-drug combination to increase the tolerability and limit the toxicity of the regimen. Carboplatin is one of the most active single agents used for the treatment of SCLC, with overall response rates of up to 34% in phase I and II trials (5658). The combination of carboplatin plus etoposide had previously been evaluated in SCLC patients with extensive disease. In phase II trials (12,20,57), the overall response rate was 61%; 13% of patients achieved a complete response, and the median survival time ranged from 8 to 12 months. In patients with limited-disease SCLC, the overall response rate was 87%, with 49% of the patients achieving complete response and median survival time ranging from 8.8 to 19 months. Carboplatin and cisplatin have similar efficacies, but patients treated with carboplatin have fewer drug-associated toxicities than patients treated with cisplatin (59,60,61). Using cisplatin-based three-drug combinations as in the Cancer and Leukemia Group B (CALGB) 9732 protocol (55), cisplatin could be associated with a low dose density resulting from frequent dose reductions because of high toxicity, which may be one reason that we detected no difference in survival between the two treatment regimens.

In summary, our results are the first from a randomized trial to demonstrate a statistically significant increase in median and long-term survival, progression-free survival, and a decrease in drug-related toxicities for patients with SCLC on a paclitaxel-containing regimen compared with standard chemotherapy. The three-drug combination of paclitaxel, etoposide, and carboplatin was effective, safe, and well-tolerated, and therefore we conclude that its use is a reasonable treatment choice for at least some patients with SCLC.

Appendix

The participating investigators and institutions (all in Germany) are as follows: Dr. Gatzemeier, Grosshansdorf Hospital, Grosshansdorf; Dr. von Pawel, Zentralkrankenhaus Gauting, Gauting; Dr. Macha, Lungenklinik Hemer, Hemer; Prof. Dr. E. Kaukel, Allgemeines Krankenhaus Harburg, Hamburg; Dr. Deppermann, Fachkrankenhaus für Lungenheilkunde und Thoraxchirurgie, Berlin; Dr. Bonnet, Clinical Professor of Medicine, Zentralklinik Bad Berka, Bad Berka; Dr. Keppler, Hospital Neustadt, Neustadt/Harz; Prof. Dr. Loddenkemper, Hospital Heckeshorn, Berlin; Dr. Gosse, Hospital Robert Koch, Leipzig; Dr. Vallee, Hospital Hildesheim, Diekholzen; Dr. von Bültzingslöwen, Fachklinik für Erkrankungen der Atmungsorgane, Donaustauf; Prof. Dr. Schweisfurth, Carl-Thiem-Klinikum, Cottbus; Dr. Steppert, Bezirksklinikum Kutzenfeld, Ebensfeld: Dr. Chemaissani, Hospital Cologne, Cologne; Dr. Lorsbach, Lungenklinik Ballenstedt, Ballenstedt; Dr. Eberhard, Klinik für Lungen- und Atemwegserkrankungen, Bremen; Dr. Thiele, MNR-Klinik, Düsseldorf; Prof. Dr. Criee, Evangelisches Krankenhaus Göttingen-Weende, Göttingen.


    NOTES
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Supported by grants from Bristol-Myers Squibb.


    REFERENCES
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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Manuscript received September 6, 2002; revised May 13, 2003; accepted June 6, 2003.


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