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1999 European Cancer Conference Summary of Phase II Trials
1999 European
ECCO
r nb
Meeting
research in brief
Cancer Conference
Summary of Phase II Trials Paclitaxel/Etoposide/Cisplatin versus Etoposide/Cisplatin for Small-Cell Lung Cancer
Rationale
• The combination of etoposide/cisplatin has been the standard first-line therapy for small-cell lung cancer (SCLC). The response rate for this regimen is greater than 80%, and median survival is 15-20 months (when combined with thoracic irradiation) for patients with limited disease and 7-10 months for patients with extensive disease. • Paclitaxel has an encouraging singleagent activity in SCLC and can reverse induced drug resistance in SCLC cell lines in vitro.1,2 • Phase I and II trials of paclitaxel/ etoposide/cisplatin in patients with SCLC have shown relatively high response rates.3,4 However, the incidence of grade 4 neutropenia has been as high as 95%.3,4 Table 1: Major Eligibility Criteria • Histologically or cytologically proven limited or extensive SCLC • Measurable disease • WHO PS 0-2 • No prior chemotherapy • Weight loss ≤ 20% • Life expectancy of ≥ 3 months
Table 2: Patient Characteristics
Number of Patients
Paclitaxel/Etoposide/Cisplatin
Etoposide/Cisplatin
62
71
Age Median
62 years
64 years
Range
36-75 years
37-75 years
Male
94%
90%
WHO PS 2
11%
11%
Extensive Disease
53%
58%
• The Greek Lung Cancer Cooperative Group conducted a phase III trial to compare safety and efficacy of the standard etoposide/cisplatin regimen with a novel three-drug combination of paclitaxel/etoposide/cisplatin for patients with previously untreated SCLC.5 Dr. Mavroudis reported the trial at the 10th European Cancer Conference, which was held in Vienna, Austria, in August 1999.
Patient Eligibility Characteristics To be eligible for the trial, patients were required to have histologically or cytologically proven SCLC (limited or extensive stage), measurable disease, a World Health Organization performFigure 1: Treatment Schema
Trial Design The study design and drug doses are shown in Figure 1. Sixty-two patients were randomized to the paclitaxel/etoposide/cisplatin regimen and 71 were randomized to the etoposide/cisplatin arm. Treatment cycles were repeated every 28 days. Responding patients with limited disease were given thoracic and prophylactic cranial irradiation.
Stratify by: • Disease stage • Age • LDH
R A N D O M I Z E
Paclitaxel (175 mg/m2) 3-hour infusion, day 1 Etoposide (80 mg/m2) I.V., days 2-4 Cisplatin (80 mg/m2) I.V., day 2 plus G-CSF (5 μg/kg) s.c., days 5-15
Etoposide (120 mg/m2) I.V., days 1-3 Cisplatin (80 mg/m2) I.V., day 1 plus G-CSF as needed
February 2000
175
Response and Survival
TEP
EP
P Value
Overall†
50%
46%
0.68
Limited Disease
67%
69%
NS
Extensive Disease
65%
32%
0.03
10.5 months
10 months
NS
41.5%
33.2%
NS
Response Rate
Median Survival One-year Survival †intent-to-treat
analysis Abbreviations: EP = etoposide/cisplatin; TEP = paclitaxel/etoposide/cisplatin; NS = not significant
Figure 2: Toxicity Summary
The response rates were similar for both regimens (46% for etoposide/cisplatin and 50% for paclitaxel/etoposide/ cisplatin [Table 3]). There were three complete responders in each arm. Among patients with limited disease, there was no significant difference in the response rates to either paclitaxel/etoposide/cisplatin or etoposide/cisplatin regimens. However, for patients with extensive disease, the response rate was significantly higher with paclitaxel/etoposide/ cisplatin (65%), as compared to etoposide/cisplatin (32%) (P = 0.03). Although there was no significant difference in median survival for the two regimens (10.5 months for paclitaxel/ etoposide/cisplatin and 10 months for etoposide/cisplatin), one-year survival was higher at 41.5% for patients treated with paclitaxel/etoposide/cisplatin, compared to 33.2% for those treated with etoposide/cisplatin. This difference did not reach statistical significance.
neurotoxicity also were more frequent with the paclitaxel/etoposide/cisplatin regimen. There were eight treatmentrelated deaths on the paclitaxel/etoposide/cisplatin regimen. Because of the unacceptable toxicity, the study was closed early. The dose of paclitaxel used was high (especially combined with irradiation in limited-disease patients), and may have accounted for the high toxic death rate.
Toxicity
Conclusion
The addition of paclitaxel to cisplatin/etoposide signficantly increased toxicity (Figure 2). Thirty-nine percent of patients in the paclitaxel/etoposide/cisplatin arm had grade 4 neutropenia, while 22% of patients experienced grade 4 neutropenia with cisplatin/etoposide (P = 0.04). Severe thrombocytopenia, diarrhea, asthenia, and
176
Table 3: Results at a Glance
February 2000
Paclitaxel/Etoposide/Cisplatin Etoposide/Cisplatin
50 40
Toxicity (%)
research in brief
ance status (WHO PS) of 0-2, and a life expectancy of at least 3 months. Prior chemotherapy was not permitted. See Table 1. The median age of patients in the paclitaxel/etoposide/cisplatin arm was 62 years, as compared to 64 years for patients receiving etoposide/cisplatin (Table 2). Most patients in both arms (89%) had a performance status of 0 or 1. Fifty-eight percent of patients in the etoposide/cisplatin arm and 53% of patients in the paclitaxel/etoposide/ cisplatin arm had extensive disease.
39%
30 20
22% 18%
10
13%
11% 8%
6%
0 Grade 4 Neutropenia
Grade 3/4 Thrombocytopenia
3% Grade 3/4 Asthenia
The addition of paclitaxel to cisplatin/etoposide increases the efficacy of the regimen in patients with extensivestage SCLC but without a significant effect on survival. One has to be careful when combining the new agents with irradiation. Weekly doses of paclitaxel are better tolerated with thoracic irradiation. Another way to test the efficacy of a
1%
Grade 3 Neurotoxicity
0% Death from Toxicity
new agent is to give it sequentially after 3 to 4 cycles of the standard etoposide/cisplatin regimen. Trials designed on this rationale are underway and will provide valuable information for future treatment strategies in this disease.
References
1. Ettinger DS, Finkelstein DM, Sarma RP, et al. Phase II study of paclitaxel in patients with extensive-disease small-cell lung cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 1995; 13:1430-1435. 2. Su GM, Davey MW, Davey RA. Induction of broad drug resistance in small cell lung cancer cells and its reversal by paclitaxel. Int J Cancer 1998; 76:702-708. 3. Kelly K, Pan Z, Wood ME, et al. A phase I study of paclitaxel, etoposide, and cisplatin in extensive stage small cell lung cancer. Clin Cancer Res 1999; 5:3419-3424. 4. Glisson BS, Kurie JM, Perez-Soler R, et al. Cisplatin, etoposide, and paclitaxel in the treatment of patients with extensive small-cell lung carcinoma. J Clin Oncol 1999; 17:2309-2315. 5. Mavroudis D, Papadakis E, Veslemes M, et al. Paclitaxelcisplatin-etoposide (TEP) versus cisplatin-etoposide (EP) as first line treatment in small-cell lung cancer (SCLC): A preliminary analysis of a multicenter randomized phase III trial. Eur J Cancer 1999; 35 (Supp 4):247 (Abstract #980).
ECCO
r nb
Meeting
research in brief
Cancer Conference
Summary of Phase II Trials Paclitaxel/Etoposide/Cisplatin versus Etoposide/Cisplatin for Small-Cell Lung Cancer
Rationale
• The combination of etoposide/cisplatin has been the standard first-line therapy for small-cell lung cancer (SCLC). The response rate for this regimen is greater than 80%, and median survival is 15-20 months (when combined with thoracic irradiation) for patients with limited disease and 7-10 months for patients with extensive disease. • Paclitaxel has an encouraging singleagent activity in SCLC and can reverse induced drug resistance in SCLC cell lines in vitro.1,2 • Phase I and II trials of paclitaxel/ etoposide/cisplatin in patients with SCLC have shown relatively high response rates.3,4 However, the incidence of grade 4 neutropenia has been as high as 95%.3,4 Table 1: Major Eligibility Criteria • Histologically or cytologically proven limited or extensive SCLC • Measurable disease • WHO PS 0-2 • No prior chemotherapy • Weight loss ≤ 20% • Life expectancy of ≥ 3 months
Table 2: Patient Characteristics
Number of Patients
Paclitaxel/Etoposide/Cisplatin
Etoposide/Cisplatin
62
71
Age Median
62 years
64 years
Range
36-75 years
37-75 years
Male
94%
90%
WHO PS 2
11%
11%
Extensive Disease
53%
58%
• The Greek Lung Cancer Cooperative Group conducted a phase III trial to compare safety and efficacy of the standard etoposide/cisplatin regimen with a novel three-drug combination of paclitaxel/etoposide/cisplatin for patients with previously untreated SCLC.5 Dr. Mavroudis reported the trial at the 10th European Cancer Conference, which was held in Vienna, Austria, in August 1999.
Patient Eligibility Characteristics To be eligible for the trial, patients were required to have histologically or cytologically proven SCLC (limited or extensive stage), measurable disease, a World Health Organization performFigure 1: Treatment Schema
Trial Design The study design and drug doses are shown in Figure 1. Sixty-two patients were randomized to the paclitaxel/etoposide/cisplatin regimen and 71 were randomized to the etoposide/cisplatin arm. Treatment cycles were repeated every 28 days. Responding patients with limited disease were given thoracic and prophylactic cranial irradiation.
Stratify by: • Disease stage • Age • LDH
R A N D O M I Z E
Paclitaxel (175 mg/m2) 3-hour infusion, day 1 Etoposide (80 mg/m2) I.V., days 2-4 Cisplatin (80 mg/m2) I.V., day 2 plus G-CSF (5 μg/kg) s.c., days 5-15
Etoposide (120 mg/m2) I.V., days 1-3 Cisplatin (80 mg/m2) I.V., day 1 plus G-CSF as needed
February 2000
175
Response and Survival
TEP
EP
P Value
Overall†
50%
46%
0.68
Limited Disease
67%
69%
NS
Extensive Disease
65%
32%
0.03
10.5 months
10 months
NS
41.5%
33.2%
NS
Response Rate
Median Survival One-year Survival †intent-to-treat
analysis Abbreviations: EP = etoposide/cisplatin; TEP = paclitaxel/etoposide/cisplatin; NS = not significant
Figure 2: Toxicity Summary
The response rates were similar for both regimens (46% for etoposide/cisplatin and 50% for paclitaxel/etoposide/ cisplatin [Table 3]). There were three complete responders in each arm. Among patients with limited disease, there was no significant difference in the response rates to either paclitaxel/etoposide/cisplatin or etoposide/cisplatin regimens. However, for patients with extensive disease, the response rate was significantly higher with paclitaxel/etoposide/ cisplatin (65%), as compared to etoposide/cisplatin (32%) (P = 0.03). Although there was no significant difference in median survival for the two regimens (10.5 months for paclitaxel/ etoposide/cisplatin and 10 months for etoposide/cisplatin), one-year survival was higher at 41.5% for patients treated with paclitaxel/etoposide/cisplatin, compared to 33.2% for those treated with etoposide/cisplatin. This difference did not reach statistical significance.
neurotoxicity also were more frequent with the paclitaxel/etoposide/cisplatin regimen. There were eight treatmentrelated deaths on the paclitaxel/etoposide/cisplatin regimen. Because of the unacceptable toxicity, the study was closed early. The dose of paclitaxel used was high (especially combined with irradiation in limited-disease patients), and may have accounted for the high toxic death rate.
Toxicity
Conclusion
The addition of paclitaxel to cisplatin/etoposide signficantly increased toxicity (Figure 2). Thirty-nine percent of patients in the paclitaxel/etoposide/cisplatin arm had grade 4 neutropenia, while 22% of patients experienced grade 4 neutropenia with cisplatin/etoposide (P = 0.04). Severe thrombocytopenia, diarrhea, asthenia, and
176
Table 3: Results at a Glance
February 2000
Paclitaxel/Etoposide/Cisplatin Etoposide/Cisplatin
50 40
Toxicity (%)
research in brief
ance status (WHO PS) of 0-2, and a life expectancy of at least 3 months. Prior chemotherapy was not permitted. See Table 1. The median age of patients in the paclitaxel/etoposide/cisplatin arm was 62 years, as compared to 64 years for patients receiving etoposide/cisplatin (Table 2). Most patients in both arms (89%) had a performance status of 0 or 1. Fifty-eight percent of patients in the etoposide/cisplatin arm and 53% of patients in the paclitaxel/etoposide/ cisplatin arm had extensive disease.
39%
30 20
22% 18%
10
13%
11% 8%
6%
0 Grade 4 Neutropenia
Grade 3/4 Thrombocytopenia
3% Grade 3/4 Asthenia
The addition of paclitaxel to cisplatin/etoposide increases the efficacy of the regimen in patients with extensivestage SCLC but without a significant effect on survival. One has to be careful when combining the new agents with irradiation. Weekly doses of paclitaxel are better tolerated with thoracic irradiation. Another way to test the efficacy of a
1%
Grade 3 Neurotoxicity
0% Death from Toxicity
new agent is to give it sequentially after 3 to 4 cycles of the standard etoposide/cisplatin regimen. Trials designed on this rationale are underway and will provide valuable information for future treatment strategies in this disease.
References
1. Ettinger DS, Finkelstein DM, Sarma RP, et al. Phase II study of paclitaxel in patients with extensive-disease small-cell lung cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 1995; 13:1430-1435. 2. Su GM, Davey MW, Davey RA. Induction of broad drug resistance in small cell lung cancer cells and its reversal by paclitaxel. Int J Cancer 1998; 76:702-708. 3. Kelly K, Pan Z, Wood ME, et al. A phase I study of paclitaxel, etoposide, and cisplatin in extensive stage small cell lung cancer. Clin Cancer Res 1999; 5:3419-3424. 4. Glisson BS, Kurie JM, Perez-Soler R, et al. Cisplatin, etoposide, and paclitaxel in the treatment of patients with extensive small-cell lung carcinoma. J Clin Oncol 1999; 17:2309-2315. 5. Mavroudis D, Papadakis E, Veslemes M, et al. Paclitaxelcisplatin-etoposide (TEP) versus cisplatin-etoposide (EP) as first line treatment in small-cell lung cancer (SCLC): A preliminary analysis of a multicenter randomized phase III trial. Eur J Cancer 1999; 35 (Supp 4):247 (Abstract #980).