Minnie Pearl Cancer Research Network participating sites: Tennessee Oncology, PLLC (Nashville, TN); Consultants in Blood Disorders and Cancer (Louisville, KY); Jackson Oncology Associates (Jackson, MS); Comprehensive Cancer Institute (Huntsville, AL); Northeast Alabama Regional Medical Center (Anniston, AL); Southeast Florida Hematology Oncology Group (Ft. Lauderdale, FL); Oncology Hematology Group of South Florida (Miami, FL); Florida Oncology Associates (Orange Park, FL); Atlanta Cancer Care (Atlanta, GA); Northeast Georgia Medical Center (Gainesville, GA); Northwest Georgia Oncology Centers, P.C. (Marietta, GA); Northwest Oncology and Hematology (Elk Grove, IL); King's Daughters' Medical Center (Ashland, KY); Graves Gilbert Oncology Clinic (Bowling Green, KY); Greenview Regional Hospital (Bowling Green, KY); Louisiana Oncology (Lafayette, LA); Mary Bird Perkins Cancer Center (Baton Rouge, LA); Terrebonne General Medical Center (Houma, LA); Upstate Carolina CCOP (Spartanburg, SC); Cancer Outreach Associates (Abingdon, VA); Oncology and Hematology Associates of SW Virginia, Inc. (Salem, VA).
The objective of this study was to evaluate the feasibility, toxicity, and efficacy of a novel three-drug regimen containing paclitaxel, carboplatin, and topotecan followed by oral etoposide in the first-line treatment of patients with small cell lung carcinoma.
One hundred five patients with previously untreated, limited stage or extensive stage small cell lung carcinoma were treated in this multicenter, community-based, Phase II trial. All patients received paclitaxel 135 mg/m2 by 1-hour intravenous (IV) infusion on Day 1, carboplatin at an area under the serum concentration-time curve of 5.0 IV on Day 1, and topotecan 0.75 mg/ m2 IV on Days 1–3. The treatment regimen was repeated at 21-day intervals for 4 courses. Patients with limited stage disease also received radiation therapy (45 grays [Gy]; in single daily fractions of 1.8 Gy) beginning concurrently with the third course of chemotherapy. Patients who had an objective response or stable disease after 4 courses of combined paclitaxel, carboplatin, and topotecan then received 3 courses of oral etoposide (50 mg alternating with 100 mg for 10 consecutive days) repeated at 21-day intervals.
Treatment with paclitaxel, carboplatin, and topotecan produced response rates of 88% and 93% in patients with extensive stage disease and limited stage disease, respectively. The median survival for patients with extensive stage and limited stage disease was 8.3 months and 17.2 months, respectively. The addition of oral etoposide was feasible, but there was no suggestion that it prolonged remission. This three- drug regimen was associated with acceptable toxicity in patients with a good performance status, although it was tolerated very poorly by patients with an Eastern Cooperative Oncology Group performance status of 2; 5 of 12 patients (42%) had treatment-related deaths.
Small cell lung carcinoma is a major health problem in the United States, accounting for 15–20% of all incidents of lung carcinoma. Although it is highly sensitive to a number of standard chemotherapeutic agents initially, remissions usually are temporary, and a cure for small cell lung carcinoma is achieved by only a small percentage of patients. For the last 15 years, the platinum and etoposide combination (using either cisplatin or carboplatin) has been the most commonly used systemic therapy, and it is considered standard first-line therapy. For patients with extensive stage disease, attempts to improve this regimen by adding drugs, intensifying the regimen, or using alternating combinations have been unsuccessful, and the median survival for these patients remains at 8–10 months. Improved methods of combining chemotherapy and radiation therapy have resulted in survival improvements for patients with limited stage small cell lung carcinoma: recent large trials have documented a median survival of 20–24 months, with 20% of patients disease free at 4–5 years.1
During the last several years, the introduction of several active new agents has led to improvements in therapy for patients with a number of epithelial malignancies. Several of these new drugs, including the taxanes, topotecan, irinotecan, and gemcitabine, are active in the first-line treatment of patients with extensive stage small cell lung carcinoma, with response rates ranging from 20% to 50%.2–5 Activity of these agents also has been documented in previously treated patients with small cell lung carcinoma, but it is limited primarily to patients who develop recurrent disease after a treatment free interval ≥ 3 months.6–8 Because these drugs have novel mechanisms of action, it is possible that their use in a first-line combination regimen will result in improved therapy compared with standard platinum plus etoposide regimens.
In a previous Phase II trial, we were successful in adding full-dose paclitaxel to a carboplatin and etoposide combination for the first-line treatment of patients with small cell lung carcinoma. This regimen had a high level of activity, with a median survival in patients with extensive stage disease and limited stage disease of 10 months and 25 months, respectively.9 Early experience with a regimen containing paclitaxel and topotecan also yielded impressive results, including a median survival of 12 months in a small group of patients with extensive stage disease.10 In a further attempt to incorporate topotecan into first- line combination therapy for patients with small cell lung carcinoma, we performed a Phase I trial to determine the optimum doses of paclitaxel, carboplatin, and topotecan when used in combination.11 Although the tolerated doses of all three drugs in this combination were below the maximally effective single-agent doses, we observed objective responses in 8 of 14 previously treated patients with small cell lung carcinoma in that Phase I trial. Based on these encouraging results, we performed a Phase II trial of the three-drug combination of paclitaxel, carboplatin, and topotecan in patients with previously untreated, extensive stage small cell lung carcinoma. For patients with limited stage disease, radiation therapy was administered concurrently with the third and fourth courses of this three-drug regimen. After the completion of four courses, patients who continued to respond continued treatment with three courses of oral etoposide. The results of this Phase II trial are detailed in this report.
MATERIALS AND METHODS
This Phase II study was initiated in June 1998 and was performed in the Minnie Pearl Cancer Research Network, a multicenter, community-based, collaborative clinical trials group. All patients were required to have histologically confirmed small cell lung carcinoma that was untreated previously with either chemotherapy or radiation therapy. Patients with limited stage or extensive stage small cell lung carcinoma were eligible. All patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, and all patients had measurable or evaluable disease. Patients with parenchymal brain metastases were eligible, but only if they had minimal neurologic symptoms and met all other entry criteria. Additional eligibility requirements included total leukocytes ≥ 4000/μL, platelets ≥ 100,000/μL, serum bilirubin < 1.5 mg/dL, and serum creatinine < 1.5 mg/dL. All patients were required to give written informed consent before enrollment into this trial. This study was approved by the Institutional Review Board at Centennial Medical Center and by the Institutional Review Boards of the participating sites in the Minnie Pearl Cancer Research Network.
Before treatment, all patients underwent complete staging for small cell lung carcinoma, which included a chest radiograph, chemistry profile, radionuclide bone scan, and computed tomography scans of the head, chest, and abdomen. If no distant metastases were documented with any of these staging procedures, then patients underwent bone marrow aspiration and biopsy. Based on the results of these staging procedures, patients were categorized with either limited stage disease or extensive stage disease using standard definitions.
All patients received chemotherapy with the following regimen: paclitaxel 135 mg/ m2 by 1-hour intravenous (IV) infusion on Day 1, carboplatin at an area under the serum concentration-time curve (AUC) of 5.0 by IV infusion on Day 1, and topotecan 0.75 mg/m2 IV on Days 1–3. This regimen was repeated every 21 days. Routine premedication for paclitaxel included dexamethasone 20 mg IV, diphenhydramine 50 mg, and cimetidine 300 mg, all given 30 minutes prior to receiving paclitaxel. The carboplatin dose was calculated using the Calvert formula (dose = [glomerular filtration rate + 25] × desired AUC).12 The glomerular filtration rate was calculated using the method of Cockcroft and Gault.13 Cytokines were not used routinely with this regimen. Patients with brain metastases at the time of study enrollment were allowed to receive whole brain irradiation concurrently with the initiation of chemotherapy.
Patients with limited stage small cell lung carcinoma also received concomitant radiation therapy. To allow for better evaluation of the toxicity and efficacy of this novel chemotherapy regimen, we began radiation therapy concurrently with the third course of chemotherapy (Day 42). Radiation therapy was administered in fractions of 1.8 grays (Gy) per day to a total dose of 45 Gy given over 5 weeks. The size of the radiation therapy field was based on the tumor size after the initial two courses of chemotherapy and included the primary lesion with a minimum of 2 cm and a maximum of 2.5 cm around the mass. The radiation field also included the mediastinum, encompassing ipsilateral and contralateral hilar lymph nodes as well as superior mediastinal, paratracheal, and subcarinal lymph nodes.
Patients were restaged for initial response after completing two courses of chemotherapy. All patients with objective responses or stable disease continued treatment with paclitaxel, carboplatin, and topotecan for a total of four courses, at which time they were restaged. Patients who had objective responses or stable disease then received etoposide 50 mg alternating with 100 mg orally for 10 consecutive days. Three courses of etoposide were repeated at 21-day intervals.
After the completion of all chemotherapy, patients in complete remission received prophylactic whole brain radiation (total dose, 24 Gy in 2-Gy single daily fractions). Patients were then followed without further specific treatment until disease progression occurred. At the time of disease progression, further treatment was at the discretion of the treating physician.
During combination chemotherapy, blood counts were measured weekly. Dose reductions for myelosuppression were based on blood counts measured on the day of scheduled treatment. If patients had a white blood cell (WBC) count ≥ 2500/μL and platelets ≥ 75,000/μL, then they received treatment with full doses of all three agents. If patients had a WBC count < 2500/μL or platelets < 75,000/μL, then treatment was delayed for 1 week or until the WBC count had risen to > 3000/μL and platelets had risen to > 100,000/μL; patients were then retreated using full doses. For patients with limited stage disease who were receiving chemotherapy and radiation therapy, the radiation therapy was continued as long as the WBC count was > 1000/μL and platelets were > 50,000/μL. If counts fell below these levels, then radiation therapy was interrupted for 1 week or until the blood counts had risen to WBC > 1000/μL and platelets > 75,000/μL. The total radiation therapy dose delivered was not changed.
Patients who required hospitalization for neutropenia and fever received 75% doses of all three drugs during subsequent courses. Patients who required platelet transfusions or who had any bleeding episodes associated with thrombocytopenia received 75% doses of carboplatin and topotecan during all subsequent treatment courses. Paclitaxel was omitted if patients had severe (Grade 4) hypersensitivity reactions. For other Grade 3 or 4 nonhematologic toxicity (with the exception of alopecia, nausea, and emesis), further treatment was delayed until the toxicity resolved to Grade ≤ 2; then, treatment was resumed with 75% doses of the responsible agents. Patients who developed irreversible Grade 3 or 4 nonhematologic toxicity were removed from the study.
During the three courses of oral etoposide, dose adjustments were based on blood counts measured on Days 8 and 21 of each course. On Day 8, if patients had a WBC count < 1500/μL or platelets < 75,000/μL, then the remainder of the 10-day course of etoposide was discontinued. On Day 21, if patients had a WBC count < 2500/μL or platelets < 75,000/μL, then treatment was delayed 1 week or until the patient had a WBC count ≥ 2500/μL and platelets ≥ 75,000/μL. At that time, patients were retreated with oral etoposide at the full dose.
After completion of four courses of combination chemotherapy (with or without radiation therapy), patients were assigned a response category using standard definitions. Patients with a complete response had total disappearance of all clinically and radiologically detectable disease for at least 4 weeks. Patients with a partial response had a reduction ≥ 50% in the size of all measurable lesions, as measured by the products of the greatest length and greatest width, with no new lesions appearing. Patients with stable disease (or minor response) had a reduction < 50% in the size of measurable lesions, as measured by the product of the greatest length and greatest width, or an increase < 25% in the size of measurable lesions, with no new lesions appearing. Patients with progressive disease had an increase > 25% in the size of measurable lesions or the appearance of new lesions. Treatment-related toxicity was graded according to the World Health Organization toxicity criteria.
After the completion of all treatment, patients were followed at intervals of 2–3 months until tumor progression occurred. Duration of remission was measured from the first day of documented response to the date of tumor progression. The time to progression was measured from the day of first treatment until the date of documented tumor progression. Survival was calculated from the date of first treatment until the date of death. Actuarial survival curves were constructed using the method of Kaplan and Meier.14
The primary objectives of this Phase II study were to evaluate the feasibility and toxicity of this three-drug regimen in the treatment of patients with small cell lung carcinoma. In addition, the feasibility and toxicity of delivering this combination chemotherapy regimen concurrently with radiation therapy were assessed. This Phase II trial also was designed to provide preliminary efficacy information regarding this regimen. Patients with limited stage and extensive stage small cell lung carcinoma were considered separately. Although this trial was not designed to provide definitive information regarding the efficacy of this regimen compared with other regimens, we established certain criteria to aid in decisions regarding the future development of this regimen. Median survivals ≥ 12 months for patients with extensive stage disease and ≥ 24 months for patients with limited stage disease were considered minimum indications for further development of the regimen. By accruing 100 patients, we estimated that at least 40 patients in each subset would be available for analysis. Response rate and rates of specific toxicities were estimated to within ± 10% with 95% confidence intervals.
Between June 1998 and September 1999, 105 patients entered this Phase II trial. The clinical characteristics of the patients are summarized in Table 1. Overall, 54 patients (51%) in the trial were men, and the large majority of patients (89%) had good performance status (ECOG 0 or 1). Fifty-nine patients (56%) had extensive stage disease. Thirty-nine patients (37%) were treated at The Sarah Cannon Cancer Center in Nashville, Tennessee, and the remaining 63% of patients were treated at affiliated network sites.
Ninety-seven of 105 patients (92%) completed 2 courses of combination chemotherapy and were evaluated for response. The remaining eight patients did not complete two courses for the following reasons: treatment-related death (sepsis) in six patients, death from intercurrent illness (emphysema and respiratory failure) in one patient, and requested discontinuation of treatment in one patient. Ninety-two patients (88%) completed all 4 scheduled courses of paclitaxel, carboplatin, and topotecan (plus radiation therapy in patients with limited stage disease). In addition to the eight patients who did not complete the first two courses, septic deaths occurred in two additional patients after the fourth course of treatment, and three patients were removed from the study due to disease progression. Eighty-six patients were eligible to continue therapy with oral etoposide (i.e., they had objective responses or stable disease after completing 4 courses of chemotherapy). Eighty-two of these eligible patients received oral etoposide, and 70 patients (67% of the patients who entered the trial) completed all 3 of the prescribed courses. Reasons for failure to complete oral etoposide were disease progression in seven patients, intercurrent illness in three patients, treatment-related death (sepsis) in one patient, and one patient declined further treatment.
The efficacy of this treatment program in the subgroups of patients with limited stage disease and extensive stage disease is summarized in Table 2. This treatment regimen was highly active, producing overall response rates of 93% and 88% in patients with limited stage disease and extensive stage disease, respectively. Thirty-seven percent of patients with limited stage disease had complete responses, and 8% of patients with extensive stage disease had complete responses.
Table 2. Treatment Efficacy
Limited stage disease (%)
Extensive stage disease (%)
Response to combined paclitaxel, carboplatin, and topotecan
Best response to treatment (including oral etoposide)
Survival (105 patients included)
Median survival (months)
None of the 40 patients with extensive disease who received oral etoposide had evidence of improved response after etoposide therapy. During the 9 weeks of oral etoposide therapy, six patients with extensive stage disease developed progressive small cell lung carcinoma. Four of 42 patients (10%) with limited stage disease had improved responses while receiving oral etoposide. One patient changed from stable disease to a partial response, and three patients improved from a partial response to a complete response. One patient with limited stage disease developed progressive small cell lung carcinoma while taking etoposide.
Actuarial survival curves for the patients with limited stage and extensive stage small cell lung carcinoma are shown in Figure 1. The median survival of patients with extensive stage disease was 8.3 months, and the median survival of patients with limited stage disease was 17.2 months. With a minimum follow-up of 20 months, the actuarial 2-year survival rate for patients with extensive stage disease was 8%, and the actuarial 2-year survival rate for patients with limited stage disease was 37%.
The acute toxicity produced by the first two courses of chemotherapy with the paclitaxel, carboplatin, and topotecan combination is detailed in Table 3. Myelosuppression was the most frequent toxicity, with Grade 3 or 4 leukopenia occurring in 45% of patients (27% of courses). Fourteen patients (13%) had episodes of neutropenia and fever requiring hospitalization; in 6 patients (6%), sepsis led to treatment- related death. Severe nonhematologic toxicity was uncommon during the first two courses of chemotherapy.
Table 3. Treatment-Related Toxicity During the First 2 Courses of Combined Paclitaxel, Carboplatin, and Topotecan (105 patients; 205 courses)
No. of patients (%)
No. of courses (%)
RBC: red blood cell; G-CSF: granulocyte-cdony stimulating factor.
Anemia (Grade 3)
Grade 3–4 toxicity that occurred during concurrent chemoradiotherapy in patients with limited stage disease is summarized in Table 4. Myelosuppression and its complications, as observed during the first two courses of chemotherapy, were the most common treatment-related toxicities. Nine of 46 patients (20%) required hospitalization for the treatment of neutropenia and fever, and 1 of these patients died as a result of sepsis. The incidence of severe local radiation-related toxicities (i.e., mucositis, esophagitis, and pneumonitis) was low. There were no chronic sequelae of the esophagitis, although one patient required hospitalization for management.
Table 4. Grade 3–4 Toxicity in Patients with Limited Stage Disease during Concurrent Chemotherapy/Radiation Therapy (46 patients)
No. of patients (%)
RBC: red blood cell.
Oral etoposide was generally well tolerated. There were 19 episodes of Grade 3–4 leukopenia, but only 2 patients required hospitalization. One patient had sepsis and treatment-related death during treatment with oral etoposide.
A total of eight patients (8%) died of sepsis while receiving this treatment. Of these eight deaths, six occurred during the first 6 weeks of treatment, seven occurred in patients with extensive stage disease, and five occurred in patients with a poor performance status (ECOG 2). Overall, 5 of 12 patients (42%) with a poor performance status who entered the study had treatment-related deaths due to sepsis. Treatment-related deaths occurred in only 3 of 93 patients (3%) with a good performance status and in only 1 patient (1%) with limited stage disease.
In this large, multicenter, Phase II study, we document the feasibility of administering the novel combination of paclitaxel, carboplatin, and topotecan to patients with small cell lung carcinoma in a community-based setting. Concurrent administration of radiation therapy was not associated with any unexpected toxicity and was feasible in patients with limited stage disease. Follow-up treatment with oral etoposide also was well tolerated. This regimen was efficacious in the treatment of patients with small cell lung carcinoma, producing median survival in patient subgroups with extensive stage and limited stage disease similar to the median survival obtained with other active combination regimens.
Although this was an active regimen, the results of this trial are somewhat disappointing, because there was no suggestion that the addition of a third drug added to the efficacy of a standard platinum and etoposide regimen.1, 15–19 To administer this three-drug combination safely, doses of all three drugs were reduced compared with the doses feasible in various two-drug combinations. Even with the routine use of granulocyte-colony stimulating factor (G-CSF), our previous Phase I trial demonstrated that dose-limiting thrombocytopenia prevented meaningful dose escalation.11 It is possible that these dose reductions, which were particularly notable with topotecan and paclitaxel, compromised the efficacy of this three-drug regimen. Initial experience with the two-drug combination of paclitaxel and topotecan indicated that larger doses of each agent could be administered safely, and a median survival of 12 months was achieved in a group of patients with extensive stage disease.10 However, these early results with paclitaxel plus topotecan were not duplicated in a recent Cancer and Leukemia Group B trial, in which the median survival was only 8 months.20 Therefore, the role of these new agents in the first-line treatment of patients with small cell lung carcinoma remains undefined.
The level of myelotoxicity observed with this three-drug regimen also was somewhat greater than expected, particularly with reference to the 8% septic death rate. The number of fatal septic episodes was somewhat surprising, because the incidence of Grade 4 leukopenia with this three-drug regimen was not substantially higher than we previously reported with the paclitaxel, carboplatin, and etoposide regimen.9 In contrast to the current regimen, we observed a treatment- related fatality rate of only 3% in a group of 79 patients with the paclitaxel, carboplatin, and etoposide regimen. In the current trial, most of the treatment- related deaths were observed in patients with a poor performance status (ECOG 2); 5 of 12 patients with a poor performance status who were enrolled in this trial had fatal toxicity. In the remaining 93 patients with an ECOG performance status of 0 or 1, the incidence of treatment-related deaths (3%) was similar to that produced by other combination regimens. Although our previous experience with the paclitaxel, carboplatin, and etoposide regimen showed a treatment-related death rate of only 3%, others have observed troublesome toxicity with three-drug regimens containing newer agents. In a Phase II trial conducted by the Southwest Oncology Group, Bunn et al. reported a 10% death rate with paclitaxel, cisplatin, and etoposide, even when it was administered with concurrent G-CSF.21 It is not surprising that the addition of a third drug adds myelosuppression in the treatment of patients with small cell lung carcinoma; these regimens should not be considered routine until superior efficacy is demonstrated in randomized trials.
In the current study, follow-up treatment with single-agent etoposide rarely improved the response to treatment and did not appear to prolong response duration. These results are consistent with the results of a large, Phase III trial recently completed by the ECOG in which patients were randomized to receive single-agent topotecan or no further therapy after receiving four courses of cisplatin and etoposide.22 No benefits of follow-up treatment with topotecan were noted, with only 7% of patients improving their response rate and with no prolongation of survival. However, maintenance oral etoposide after treatment with combined etoposide, ifosfamide, and cisplatin was shown to prolong median progression free survival (8.23 months vs. 6.5 months) and had a trend toward prolonging 2-year survival (16.2% vs. 6.7%; P = 0.07) in a Hoosier Oncology Group trial.23 Therefore, although the issue of maintenance therapy in patients with small cell lung carcinoma is not resolved completely, its overall impact can be expected to be minor at best.
The development of effective therapy for patients with small cell lung carcinoma remains frustrating. To date, there is no clear evidence that the incorporation of one or more new drugs into first-line therapy has improved treatment results compared with standard platinum and etoposide therapy. The paclitaxel, carboplatin, and etoposide triplet regimen currently seems the most promising regimen, because full doses of all three drugs can be administered. Results from a large, randomized trial in Germany comparing this regimen with combined carboplatin, etoposide, and vincristine will be available in the near future.24 In addition, similar randomized trials have been initiated in cooperative groups in the United States. The sequential use of noncross-resistant, two-drug combinations is an alternate strategy that may avoid the toxicity of three-drug regimens and allow the administration of optimum doses of all drugs. The paclitaxel and topotecan combination probably is noncross resistant with platinum and etoposide, and sequential or alternating use of these combinations deserves further investigation. However, major improvements in the treatment of patients with small cell lung carcinoma probably will await the development of other novel treatment approaches.