The Oncologist, Vol. 10, No. 9, 728-733, October 2005; doi:10.1634/theoncologist.10-9-728
© 2005 AlphaMed Press
Paclitaxel/Carboplatin/Etoposide Versus Paclitaxel/Topotecan for Extensive-Stage Small Cell Lung Cancer: A Minnie Pearl Cancer Research Network Randomized, Prospective Phase II Trial
F. Anthony Grecoa,
Dana S. Thompsona,
Lisa H. Morrisseya,
Joan B. Erlanda,
Howard A. Burris, IIIa,
David R. Spigela,
Geetha Josephb,
Steven W. Corsoc,
Ellen Spremullid,
John D. Hainswortha
a Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, Tennessee, USA;
b Consultants in Blood Disorders and Cancer, Louisville, Kentucky, USA;
c Upstate Carolina CCOP, Spartanburg, South Carolina, USA;
d Northeast Alabama Regional Medical Center, Anniston, Alabama, USA
Key Words. Small cell lung cancer • Chemotherapy • Randomized study • Nonplatinum doublet
Correspondence:
F. Anthony Greco, M.D., Sarah Cannon Research Institute, 250 25th Avenue North, Suite 110, Nashville, Tennessee 37203, USA. Telephone: 615-329-7274; Fax: 615-986-0029; e-mail fgreco{at}tnonc.com
Received April 28, 2005;
accepted for publication August 1, 2005.
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ABSTRACT
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Purpose. To compare the combination of paclitaxel (Taxol®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) and topotecan (Hycamtin®; Glaxo SmithKline, Philadelphia, http://www.gsk.com) with paclitaxel, carboplatin (Paraplatin®; Bristol-Myers Squibb), and etoposide (Etopophos®, VePesid®; Bristol-Myers Squibb) in patients with previously untreated extensive-stage small cell lung cancer.
Patients and Methods. In this phase II trial, 120 patients were randomly allocated to receive either topotecan (1.5 mg/m2 i.v. days 1, 2, and 3) and paclitaxel (175 mg/m2 i.v. day 1) every 21 days orpaclitaxe l (200mg/m2 i.v. day 1), carboplatin (area under the concentration–time curve 6 i.v. day 1), and etoposide (50 mg/100 mg alternating daily by mouth days 1–10) every 21 days, each regimen for a maximum of eight cycles. The primary end points were objective response rate and time to progression.
Results. The paclitaxel–carboplatin–etoposide combination produced a significantly higher overall response rate (78% versus 48%), longer median time to progression (7.6 months versus 5.5 months), and greater number of patients free from progression at 1 year (14% versus 8%) compared with paclitaxel plus topotecan. There was no difference in overall survival. Toxicities were similar in the two treatment arms.
Conclusions. The paclitaxel–carboplatin–etoposide combination produced a superior overall response rate and time to progression in patients with extensive-stage small cell lung cancer compared with paclitaxel plus topotecan. The platinum compounds continue to be a necessary component of the initial therapy for these patients.
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INTRODUCTION
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For the past few decades, standard chemotherapy for patients with extensive-stage small cell lung cancer has included a platinum (either cisplatin [Platinol®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com] or carboplatin [Paraplatin®; Bristol-Myers Squibb) plusetoposide [Etopophos®, VePesid®; Bristol-Myers Squibb]. Several new cytotoxic agents have been tested during recent years [1–6], including the topoisomerase-I inhibitors topotecan (Hycamtin®; GlaxoSmithKline, Philadelphia, http://www.gsk.com) and irinotecan (Camptosar®; Pfizer Pharmaceuticals, New York, http://www.pfizer.com). Topotecan as second-line therapy is now a standard for patients with chemotherapy-sensitive relapsed disease. Irinotecan plus cisplatin may be superior to etoposide plus cisplatin [1], and a confirmatory Southwest Oncology Group study is in progress. Although these newer agents are certainly active, thus far, there is no definitive evidence showing their superiority when incorporated into first-line therapy over the standard of a platinum and etoposide.
The Minnie Pearl Cancer Research Network developed the triplet of paclitaxel (Taxol®; Bristol-Myers Squibb), carboplatin, and oral etoposide [2, 5]. The overall responses and survival in both limited and extensive-stage small cell lung cancer patients appeared promising. Therefore, the triplet was considered a reasonable standard at the time, likely to be at least as efficacious as, if not more so than, etoposide and cisplatin.
Platinum appears to be an important component of combination chemotherapy. A meta-analysis of 19 randomized trials showed higher response rates and a significantly lower risk for death at 6 and 12 months with platinum-containing chemotherapy when compared with nonplatinum-containing regimens [7]. The addition of paclitaxel to a platinum and etoposide is at least as efficacious, although more toxic, than a platinum plus etoposide [8–12]. Paclitaxel doublet combinations have been developed, including paclitaxel plustopotecan, and have been associated with relatively high response rates [2–4, 13–15]. The combination of paclitaxel and topotecan may offer advantages over platinum-based chemotherapy. We initiated a randomized phase II trial in patients with extensive-stage small cell lung cancer in which topotecan was combined with paclitaxel (PT) and compared with paclitaxel, carboplatin, and etoposide (PCE).
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PATIENTS AND METHODS
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Eligibility
Patients with histologically confirmed extensive-stage small cell lung cancer were eligible. Patients with mixed histology were excluded. Other eligibility requirements included: age >18 years; measurable tumor; Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1; ANC >1,500/µl; platelet count >100,000/µl; serum bilirubin 
1.5 mg/dl, for those without known hepatic metastases, and <2.5 mg/dl for those with known hepatic metastases; serum creatinine 1.5 mg/dl; no previous treatment for small cell lung cancer; no history of prior malignancy within 5 years, with the exception of nonmelanoma skin cancer or cervical carcinoma in situ; and no history of congestive heart failure or myocardial infarction within 3 months. Written informed consent was required. This study was approved by the Institutional Review Board of all participating investigators of the Minnie Pearl Cancer Research Network and was conducted in accordance with the U.S. Food and Drug Administration Clinical Practice Requirements.
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STUDY DESIGN AND TREATMENT
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Eligible patients were randomly assigned to receive either PCE or PT. Patients received up to eight cycles of either chemotherapy regimen. With PCE, patients received paclitaxel at a dose of 200 mg/m2 i.v. over 1 hour on day 1. Carboplatin dosing was based on the Calvert formula with a target area under the concentration–time curve of 6 given i.v. over 1 hour on day 1 and etoposide given orally with a total dose of 50 mg, alternating with 100 mg, on a daily basis on days 1–10. Courses were repeated every 21 days. For PT, paclitaxel was administered at a dose of 175 mg/m2 i.v. over 1 hour on day 1, and topotecan was given at a dose of 1.5 mg/m2 i.v. over 1 hour on days 1, 2, and 3. Courses were repeated every 21 days. Patients with brain metastasis were treated with whole-brain radiotherapy concurrently with the beginning of chemotherapy.
CBCs were obtained weekly for all patients during therapy. Dose reductions were made on the basis of hematologic as well as nonhematologic toxicities. With the exception of oral etoposide, dose modifications were not based on nadir blood counts. If the ANC was <1,500/µl or platelet count was <75,000/µl on day 8, oral etoposide was not administered for the remaining 2 days of the 10-day course. Dose modifications on day 1 of treatment were as follows: if ANC <1,500/µl or platelet count <75,000/µl, delay treatment for 1 week or until ANC >1,500/µl and platelet count >75,000/µl, then retreat with 75% doses of all drugs. If the ANC was >1,500/µl and platelet count was >75,000/µl, full doses of all agents were administered. Any patient hospitalized for neutropenia and fever required a 25% dose reduction for all drugs during subsequent courses. Any patient who required a platelet transfusion or experienced a bleeding episode associated with thrombocytopenia received 75% doses of all drugs during subsequent courses. Any patient who developed a severe, acute hypersensitivity reaction did not receive further doses of the offending agent. Patients developing other grade 3 or 4 nonhematologic toxicities, with the exception of alopecia, nausea, or vomiting, had further treatment held until the toxicity resolved to grade 2 or less and then received treatment with 75% doses of the drugs for the remainder of their therapy. Cytokines were used at the discretion of each investigator; however, they were not used during the first course of therapy. All patients received standard supportive care, including blood and platelet transfusions, antiemetics, and antibiotics.
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STUDY PARAMETERS
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Baseline evaluation included a history and physical examination, assessment of ECOG performance status, standard hematology, chemistry, electrocardiogram, and chest radiograph. Baseline tumor assessments with identification of lesions to be followed over the course of the study also included computed tomography (CT) scans of the chest and abdomen, CT or magnetic resonance imaging of the brain, and a bone scan. Bone marrow aspiration and biopsy were required in those patients who otherwise could not be staged as extensive by all other testing. Tumor status was assessed after two courses of chemotherapy (6 weeks), and thereafter every two courses until the completion of treatment (four to eight courses). After the completion of four courses of chemotherapy, patients responding well to treatment and tolerating treatment with no grade 4 toxicity could continue on treatment for a maximum of eight courses at the discretion of the treating physician.
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STATISTICAL CONSIDERATIONS
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The primary efficacy end points were tumor response rate and time to progression (TTP). The secondary end point was overall survival. These analyses were based on intent to treat. The TTP and survival analysis used the Kaplan-Meier method. The log-rank test was used to assess the difference between the treatment arms. The Cox proportional hazards model was used to estimate the hazard ratio. A two-sided 
2 test was used to compare tumor responses. The study was designed to have approximately 80% power to detect a difference in the response rate of 20% (from 65%–85% in the PT treatment arm). The study had an 80% power to detect a 100% improvement in the median TTP, comparing PCE with PT.
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RESULTS
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Patient Characteristics
This study was done at 29 affiliate Minnie Pearl Cancer Research Network participating sites (Table 1
). The patient characteristics are illustrated in Table 2. The patients were well balanced with respect to most known prognostic features. There were 10 more women (31 versus 21) and four more patients with initial brain metastasis in the PT arm of the study.
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TREATMENT RECEIVED
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The median number of treatments in each arm was 4.5 courses, ranging from one to eight courses in both groups. The mean dose intensities, that is, the actual dose received during the treatment period compared with the assigned dose, were similar in the two arms, 80% and 75%, respectively, for PT and PCE.
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EFFICACY
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The overall response rate showed a significant (p = .01) advantage for PCE (78%) over PT (48%). Complete responses, although not significantly different, were seen in eight patients in the PCE arm (13%) and four patients in the PT arm (7%). The median TTP for the PCE regimen was 7.6 months (95% confidence interval, 6.8–8.3 months), versus 5.5 months (95% confidence interval, 3.6–6.5 months) for the PT regimen (Fig. 1), representing a significant difference by log-rank analysis (p = .01). Using the Cox proportional hazard model, this represents a 39% reduction in the hazard of progressing on the PCE regimen versus the PT regimen. The progression-free survival rate at 1 year was 14% with the PCE regimen versus 8% with the PT regimen. Overall survival comparing the two arms showed no significant difference, with median survival durations of 10.6 months (95% confidence interval, 9.5–12) for the PCE regimen and 9.1 months (95% confidence interval, 7.7–10.4) for the PT regimen (Fig. 2). The 1-year survival rates were 39% and 35%, respectively (p = .79), by log-rank analysis. However, 32 of the 60 patients treated with the PT regimen subsequently received some variety of platinum-based chemotherapy. There was no additional evaluation regarding the effect of secondary therapy following progression.
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Figure 1. Kaplan-Meier curve showing time to progression for the pacitaxel–carboplatin–etoposide and paclitaxel–topotecan treatment arms. Abbreviations: PCE, paclitaxel, carboplatin, and etoposide; PT, paclitaxel and topotecan.
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Figure 2. Kaplan-Meier curve showing survival for the paclitaxel–carboplatin–etoposide and paclitaxel–topotecan treatment arms. Abbreviations: PCE, paclitaxel, carboplatin, and etoposide; PT, paclitaxel and topotecan.
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TOXICITY
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Four patients, two in each treatment arm, experienced treatment-related death from sepsis related to neutropenia. Hematologic toxicities are outlined in Table 3. There were no significant differences in associated leukopenia, neutropenia, thrombocytopenia, or anemia. However, the PCE regimen was associated numerically with more cytopenia. There were also no significant differences in the nonhematologic toxicity incidences (Table 4). Practical effects of the toxicities from the two treatment arms are of interest (Table 5). Significantly more RBC transfusions were given with the PCE regimen (p = .001), and more patients received cytokines for neutropenia (p = .01).
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DISCUSSION
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This randomized phase II trial was designed to evaluate the efficacy and toxicity of the combination of paclitaxel and topotecan versus the platinum-based combination of paclitaxel, carboplatin, and etoposide in patients with extensive-stage small cell lung cancer. The overall response rate and progression-free survival rate were superior for paclitaxel, carboplatin, and etoposide compared with paclitaxel and topotecan. The overall response rate for the platinum-based triplet was 78%, versus 49% for the doublet regimen (p = .01), and the median survival durations and 1-year progression-free survival rates were 7.6 months versus 5.5 months and 14% versus 8%, respectively (p = .01). The PCE combination produced more cytopenia necessitating more RBC transfusions and cytokine use. The overall survival was not different when comparing the nonplatinum doublet with the platinum-based triplet. However, it is possible that patients receiving the nonplatinum doublet survived longer following secondary therapy with platinum-based chemotherapy, therefore accounting for the lack of any survival difference compared with the triplet regimen.
There are no reported phase III randomized comparisons of paclitaxel plus topotecan versus standard platinum-based chemotherapy as initial therapy for extensive-stage small cell lung cancer. However, Lena at al. [16] reported on a randomized phase II comparison of paclitaxel plus topotecan in 76 patients versus the standard of cisplatin plus etoposide in 75 patients. The overall response rate favored the cisplatin–etoposide regimen (52% versus 41%) but was not significantly different between the two treatments; however, the TTP was significantly longer (p = .005) for cisplatin plus etoposide (25 weeks versus 18 weeks). These results are similar to the results reported here.
Recently, two randomized phase III studies in patients with extensive-stage small cell lung cancer were reported in abstract form at the 2005 American Society of Clinical Oncology Annual Meetings [17, 18]. Oral topotecan plus cisplatin was compared with standard i.v. etoposide plus cisplatin and showed comparable activity and tolerability [17]. Irinotecan and cisplatin, given on a split-dose (days 1 and 8) schedule every 21 days (unlike the Japanese Study previously reported [1]) was compared with etoposide and cisplatin and showed no difference in survival for either regimen. As expected, the irinotecan combination was associated with less myelosuppression but more diarrhea. The results of the Southwest Oncology Group study with exact duplication of the doses and schedules of the positive Japanese study [1] is awaited.
The nonplatinum doublet of paclitaxel and topotecan as administered in the randomized prospective phase II trial reported here appears inferior to the platinum-based triplet combination. The platinums continue to represent an important and necessary component of the initial therapy for patients with extensive-stage small cell lung cancer.
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
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Dr. Greco has acted as a consultant and received support from Bristol Myers-Squibb and GlaxoSmithKline. Dr. Burris has acted as a consultant for GlaxoSmithKline and received support from Bristol Myers-Squibb and GlaxoSmithKline. Dr. Spigel has received support from GlaxoSmithKline and Bristol Myers-Squibb.
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ACKNOWLEDGMENT
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This research was supported in part by grants from Bristol-Myers Squibb, GlaxoSmithKline, and The Minnie Pearl Cancer Foundation.
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Abstract
Introduction
