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(Chest. 2000;117:156S-162S.)
© 2000 American College of Chest Physicians

New Chemotherapy Agents for Small Cell Lung Cancer*

Karen Kelly, MD

* From the University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: Karen Kelly, MD, Associate Professor of Medicine, Division of Medical Oncology B171, 4200 East Ninth Ave, Denver, CO 80262; e-mail: karen.kelly{at}uchsc.edu


   Abstract
TOP
 Abstract
Introduction
 Current Status of Chemotherapy
 The Search for New...
 Conclusion
 References
 
Background: Approximately 45,000 new cases of small cell lung cancer (SCLC) will be diagnosed in the United States this year. Combination chemotherapy is the cornerstone of treatment for all stages of this disease and results in high response rates (65 to 85%), leading to a meaningful survival advantage for these patients. Patients with limited-stage disease enjoy a median survival of 10 to 15 months with chemotherapy, as compared to 3 months without drug therapy. With addition of chest radiotherapy, survival is further prolonged to 12 to 20 months. Patients with extensive-stage disease experience an average survival of 1.5 months without chemotherapy and 7 to 11 months with chemotherapy. However, no further improvement in survival has been demonstrated since combination chemotherapy regimens were introduced in the late 1970s and early 1980s, despite evaluating numerous strategies; the 5-year survival for all patients remains dismal at 5%. Clearly, new chemotherapy agents with novel mechanisms of action are needed.

Focus: This article will review the experience to date with six new agents that are active against SCLC. It includes two taxanes (paclitaxel and docetaxel), vinorelbine, two camptothecin derivatives (topotecan and irinotecan), and gemcitabine. Single-agent activity as well as combination regimens with other agents and radiotherapy will be discussed. The role of maintenance therapy with oral matrix metalloproteinase inhibitors also is evaluated.

Key Words: carboplatin • cisplatin • gemcitabine • small cell lung cancer • survival • taxanes • topotecan • vinorelbine


   Introduction
TOP
 Abstract
 Introduction
Current Status of Chemotherapy
 The Search for New...
 Conclusion
 References
 
Small cell lung cancer (SCLC) is one of the most aggressive and lethal cancers in man. Approximately 45,000 new cases of SCLC will be diagnosed in the United States this year.1 One third of patients will present with limited-stage disease confined to the chest, and the remaining two thirds of patients will have disseminated disease. Combination chemotherapy is the cornerstone of treatment for these patients, yielding high initial response rates of 65 to 85%, including 10 to 50% complete responses (CRs) depending on stage.2 3 Despite high response rates, relapse and progression occur in the majority of SCLC patients, and median survival is < 1 year for patients with extensive-stage disease. Patients with limited-stage disease receiving chemoradiotherapy sometimes are cured, but the median survival is limited to 15 to 20 months in the majority of patients, and the 2-year survival rate is 40%. Ten to 30% of patients with progressive disease may respond to salvage chemotherapy regimens, but the responses are of short duration.


   Current Status of Chemotherapy
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 Abstract
 Introduction
 Current Status of Chemotherapy
The Search for New...
 Conclusion
 References
 
Commonly used combination chemotherapy regimens currently used to treat SCLC include cyclophosphamide, doxorubicin, and vincristine (CAV); cyclophosphamide, doxorubicin, and etoposide; and cisplatin and etoposide (PE). PE has been compared with CAV or CAV alternating with PE in two randomized trials.4 5 Investigators for the Southeastern Cancer Study Group showed no difference in response rates (51%, 61%, and 59%, respectively) or median survival (8.3, 8.6, and 8.1 months, respectively) with these three treatment arms in extensive-stage disease.4 In addition, four cycles of PE had equivalent activity to six cycles of CAV or CAV/PE. Fukuoka and coworkers5 noted a trend toward improved survival in the CAV/PE arm, 11.8 months, vs 9.9 months in the other two arms (p = 0.056), which was found to occur only among patients with limited-stage disease. No difference in survival (8 to 9 months) was noted among the patients with extensive-stage SCLC. Although nausea and vomiting were considerable with the PE regimen, there was less myelosuppression, neurotoxicity, and cardiac toxicity than with CAV. Based on these results, the PE regimen has become the most commonly used regimen to treat patients with SCLC.

Carboplatin has also been shown to be highly active against SCLC and less toxic than cisplatin.6 In one randomized trial, the combination of carboplatin and etoposide (CE) was compared to PE in treating 143 SCLC patients evaluable for response.7 Among 82 limited-disease patients, there was a 76% overall response rate, including a 44% CR in the PE treatment arm vs a 37% CR and an 86% objective response rate in the CE arm. The 62 patients with extensive-stage disease given PE had a 13% CR rate with an overall response rate of 60%, as compared to a 15% CR rate and a 69% objective response rate for patients receiving CE. Overall survival was 12.5 months for the PE group vs 11.8 months for the CE group. The CE regimen was shown to be less toxic than PE. Thus, CE has similar efficacy but less toxicity than PE, and is now often employed to treat patients with SCLC.


   The Search for New Agents
TOP
 Abstract
 Introduction
 Current Status of Chemotherapy
 The Search for New...
Conclusion
 References
 
Since the development of these active drugs and their addition to combination regimens, > 15 years have passed in trying to optimize SCLC therapy. However, even novel therapeutic programs using these agents—including maintenance therapy with more cycles of drugs, administering higher drug doses, or using drugs in alternating sequences—have been disappointing, yielding no change in survival rates. Instead, the hope for the future seems to come from six new agents having significant single-agent activity in SCLC. Two taxanes, paclitaxel and docetaxel; another mitotic spindle inhibitor, vinorelbine; two topoisomerase I inhibitors, irinotecan and topotecan; and one antimetabolite, gemcitabine, are being actively evaluated. Oral matrix metalloproteinase (MMP) inhibitors are being investigated as maintenance therapy in this disease.

Topotecan
Topotecan is the most extensively studied compound to date for the treatment of SCLC. Phase I testing identified myelosuppression as the dose-limiting toxicity and 1.5 mg/m2 IV over 30 min for 5 days every 21 days as the recommended dosage and schedule for phase II testing.8 Table 1 presents results from several phase II trials evaluating topotecan in SCLC.9 10 11 12 13 In the first trial, Schiller et al9 gave topotecan, 2 mg/m2, to 48 untreated patients with extensive-stage SCLC, adding granulocyte colony-stimulating factor (G-CSF) after the first 13 patients due to a high rate of grade 4 neutropenia (77%). The addition of growth factor reduced the neutropenia to 29%. Febrile neutropenia occurred in 8% of patients not receiving growth factor, and 11% of those were administered G-CSF. After treatment, 19 patients (39%) had a partial response (PR), median survival was 10 months, and 1-year survival rate was 39%. Watanabe et al10 administered dosages of 0.8 to 1.2 mg/m2/d for 5 days to 6 untreated and 15 previously treated patients, yielding responses in 2 of 6 untreated (33%) and 4 of 15 (27%) previously treated patients. Grade 4 neutropenia occurred only in previously treated SCLC patients (27%).


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  		Table 1.. Phase II/III Clinical Trials With Topotecan in SCLC*

 
Two studies involved patients with refractory disease—defined as progressive disease while receiving first-line treatment or within 90 days of treatment—or sensitive relapse—progressive disease at least 90 days after first-line therapy.11 12 In both trials, topotecan, 1.5 mg/m2, was given for 5 days. Responses were rare among refractory patients in both trials (2% and 6%), with higher response rates observed in sensitive-relapse patients (14% and 38%). In the trial of Depierre et al,11 the lower response may have been because fewer courses of topotecan were administered. Several patients with stable disease after 2 to 3 cycles were given alternative chemotherapy. Neutropenia was the major toxicity in both trials. Perez-Soler et al13 evaluated topotecan, 1.25 mg/m2, given to 30 patients refractory to etoposide. Among 25 evaluable patients, 3 patients (12%) achieved a PR, and grade 3 and grade 4 neutropenia occurred in 69% of cycles. A composite of the data revealed a response rate of 38% among untreated patients, 24% in sensitive-relapse patients, and 5% for refractory patients.

Based on these encouraging results, a randomized phase III comparison of topotecan vs CAV in the treatment of patients who had relapses >= 60 days after completion of first-line therapy was initiated (Table 1) .14 At the time of analysis, there were 94 evaluable patients in each arm. Response rates, median time to progression, and median survival were similar between the two groups (21%, 3.3 months, and 5.8 months, respectively, for the topotecan arm; 15%, 3 months, and 5.5 months, respectively, for the CAV arm). The rates of neutropenia and febrile neutropenia also were similar in both arms, but more thrombocytopenia and anemia occurred in the topotecan arm (p < 0.001 and p < 0.003, respectively). There was no difference in the rates of nonhematologic toxicities between the two groups. Symptom relief was greater with topotecan than CAV. The investigators concluded that topotecan was active in this setting, and that the increased hematologic toxicity was manageable.

Currently, single-agent topotecan is being evaluated as part of a phase III trial conducted by the Eastern Cooperative Oncology Group (ECOG). In this trial, untreated patients with extensive-stage SCLC receive four cycles of PE and are then randomized to four cycles of topotecan or observation. Results are awaited. Combination trials incorporating topotecan into active regimens are also underway. Two institutions are performing a phase I trial of topotecan with PE, and a promising regimen of topotecan plus paclitaxel is discussed below.

Taxanes
Two phase II studies established the efficacy of paclitaxel in SCLC (Table 2 ).15 16 In an ECOG study, Ettinger and colleagues15 administered paclitaxel, 250 mg/m2 by 24-h infusion, to achieve a 53% response rate (11 of 32 untreated patients) and an 11-month median survival. The North Central Cancer Treatment Group conducted a similar trial and reported a 68% response rate in 37 patients and a median survival of 7.3 months.16 Grade 4 leukopenia was the major toxicity seen in both studies.


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  		Table 2.. Phase I/II Trials With Paclitaxel in SCLC*

 
To improve on the results with single-agent paclitaxel, several groups have combined paclitaxel with the platinum agents, cisplatin or carboplatin (Table 2) .17 18 19 20 21 22 23 24 25 Nair et al17 assigned patients with untreated extensive-stage SCLC to treatment with paclitaxel, 135 mg/m2 or 175 mg/m2, plus cisplatin, 75 mg/m2 on day 1. Fifteen of 21 evaluable patients receiving the lower dose of paclitaxel responded (71%), as did 39 of 44 patients (89%) on the higher dose arm. Median survival was 8.5 months vs 9.5 months and 1-year survival was 24% vs 38% on the low-dose and higher-dose paclitaxel arms, respectively, suggesting a dose-response effect for paclitaxel. Only one patient (2%) receiving the high-dose paclitaxel regimen experienced grade 4 neutropenia. Georgiadis et al18 conducted a dose-escalating trial of a 96-h infusion of paclitaxel plus cisplatin in patients with advanced lung cancer. Four of six patients (67%) with SCLC achieved an objective response. The maximally tolerated dose without growth factor support was paclitaxel, 120 mg/m2, with cisplatin, 80 mg/m2.

There have been four studies in which investigators added paclitaxel to the active regimen of PE. Kelly et al19 recently completed a phase I trial in which escalating doses of paclitaxel, 135 to 200 mg/m2 IV over 3 h; cisplatin, 50 to 80 mg/m2; and etoposide, 50 to 80 mg/m2 IV day 1, with 100 to 160 mg/m2 orally on days 2 and 3, was given to untreated patients with extensive-stage SCLC. With this regimen, 19 of 23 evaluable patients (83%) achieved a response. The median survival for all 28 patients was 10.8 months, and the 1-year survival rate was 46%. Dose-limiting neuropathy occurred with paclitaxel, 200 mg/m2; cisplatin, 80 mg/m2; and etopside, 80 to 160 mg/m2. Grade 4 neutropenia was frequent in cycle 1 (82%), but febrile neutropenia was uncommon. Based on these encouraging results, the Southwest Oncology Group (SWOG) is enrolling SCLC patients in a phase II trial to receive paclitaxel, 175 mg/m2; cisplatin, 80 mg/m2; and etopside, 80 to 160 mg/m2 with G-CSF.

In a similar design, Glisson et al20 administered paclitaxel, 130 mg/m2 by a 3-h infusion, on day 1, plus cisplatin, 75 mg/m2, and etoposide, 80 mg/m2 IV, on days 2 to 4. In this setting, 25 of 26 patients (96%) achieved a response, including 5 patients (19%) with a CR. The estimated median overall survival was 15.5 months. Grade 4 neutropenia was frequent (48% of courses), but febrile neutropenia occurred in only 6% of courses.

Levitan et al21 administered paclitaxel, 135 to 200 mg/m2, with cisplatin, 60 mg/m2 on day 1, and etoposide, 80 mg/m2 on days 1 to 3, to eight patients with extensive-stage SCLC. Among seven evaluable patients, one experienced a CR and six had a PR, for an overall response rate of 88%. Bremnes et al22 also treated eight SCLC patients with paclitaxel, 175 mg/m2 IV over 1 h; cisplatin, 50 mg/m2; and etoposide, 100 mg/m2 IV day 1 and 100 mg orally bid on days 2 to 5. All patients had limited-stage disease and received concurrent radiation beginning with cycle 3. Seven patients had a CR, and one had a PR (100%). Four patients developed grade 3 or grade 4 leukopenia after cycle 1, three patients had reversible grade 3 peripheral neuropathy, and one patient experienced grade 3 esophagitis from the radiation. Presently, the Radiation Treatment Oncology Group (RTOG) and ECOG are conducting phase II trials with paclitaxel, cisplatin, and etoposide plus concurrent radiation to treat patients with limited-stage disease. In the RTOG study, the concurrent therapy begins on day 1; in the ECOG study, it begins with cycle 3.

Hainsworth et al23 have conducted the largest trial combining paclitaxel with CE in the treatment of SCLC. Their study included 38 patients, 15 with limited-stage disease and 23 with extensive-stage disease who received paclitaxel, 135 mg/m2 IV over 1 h; carboplatin, at an area under the plasma concentration-vs-time curve (AUC) of 5; and etoposide, 50 mg alternating with 100 mg orally on days 1 through 10. Patients with limited-stage disease received concurrent radiation beginning with cycle 3. This regimen resulted in an objective response in 14 patients (93%) with limited-stage disease and 15 patients (65%) with extensive-stage disease. Median survival was 17 months and 7 months in limited- and extensive-stage SCLC, respectively. The regimen was extremely well tolerated: only 8% of courses resulted in grade 3 or grade 4 neutropenia. Thus, an additional 79 patients were treated with the paclitaxel dose escalated to 200 mg/m2, resulting in objective responses in 40 of 41 patients (98%) with limited-stage SCLC and 32 of 38 patients (84%) with extensive-stage SCLC. Median survival was 10 months for patients with extensive-stage disease, and has not been reached for those with limited-stage disease. Grade 3 and grade 4 neutropenia increased to 38% of courses with the higher dose of paclitaxel.

Neill et al24 are conducting a trial of paclitaxel, 200 mg/m2 IV over 3 h; carboplatin, AUC of 6; and etoposide, 80 to 100 mg/m2 IV on days 1 to 3 plus growth factor, in patients with advanced lung cancer. Seventeen of 20 patients with SCLC obtained a major response (85%). Grade 4 neutropenia developed in 24% of patients. Gatzemeier and coworkers25 have reported preliminary results with a similar three-drug combination for limited-stage SCLC. Patients received paclitaxel, 175 mg/m2 by 1-h infusion; carboplatin, AUC of 5; and oral etoposide, 100 mg on days 2 to 8. Thirty-one of 35 patients (86%) achieved a response, including 13 CRs (37%). Grade 4 neutropenia occurred in 31% of patients. Significant thrombocytopenia, peripheral neuropathy, and other nonhematologic toxicities were infrequent in all three trials.

Paclitaxel in combination with platinum-based chemotherapy regimens appears to produce a higher response rate in SCLC than previously observed. Thus, the Intergroup plans to initiate a trial comparing paclitaxel plus PE to the standard regimen of PE for extensive-stage SCLC to determine if there is a survival benefit with the three-drug regimen.

Other combinations with paclitaxel are under investigation. Jett et al26 are evaluating paclitaxel, 130 mg/m2 IV over 24 h on day 5, plus topotecan, 1 mg/m2 IV on days 1 to 5, with G-CSF support when administered to previously untreated patients with extensive-stage SCLC (Table 2) . Among 12 evaluable patients receiving this combination, there were two CRs (17%) and nine PRs (75%), for an overall response rate of 92%. The 1-year rate was 50%. Grade 3 or grade 4 leukopenia occurred in 51% of courses, but other toxicities were minimal. In a phase I trial, Strauss and colleagues27 are testing the combination of 24-h infusional paclitaxel, 75 to 225 mg/m2; ifosfamide, 2,000 mg/m2 on days 1 to 3; carboplatin, 300 mg/m2 on day 2; and etoposide, 75 mg/m2 on days 2 to 3 with G-CSF support, for the treatment of advanced lung cancer (Table 2) . Among the six patients with SCLC, the investigators observed two CRs and three PRs (83%). Perez28 is evaluating the efficacy of paclitaxel, 150 mg/m2 given on day 10, plus oral etoposide, 50 mg bid for 10 days. With 16 of the 50 planned patients entered in the study, the regimen appears to be well tolerated and the response rate is encouraging.

Studies with the other taxane, docetaxel, are limited. Smyth et al29 administered docetaxel, 100 mg/m2, to 28 previously treated patients with SCLC and reported a 25% response rate. Grade 4 neutropenia developed in 71% of patients. Burris et al30 treated 46 chemotherapy-naive patients with docetaxol, 100 mg/m2, to achieve eight PRs (17%) and a median survival of 9 months. Grade 4 leukopenia was noted in 8% of patients. The University of Colorado is conducting a phase I clinical trial using docetaxel in a combination regimen for the treatment of limited-stage SCLC. Eligible patients receive two cycles of carboplatin, AUC of 5, day 1, and etoposide, 50 mg/m2 IV on day 1 and 100 mg/m2 orally on days 2 to 3, with escalating doses of docetaxel starting at 50 mg/m2, day 1, before and after chemoradiotherapy.

Gemcitabine
Gemcitabine is a new potent antimetabolite shown to be active against SCLC. Cormier and coworkers31 used gemcitabine, 1,000 to 1,250 mg/m2 administered weekly for 3 of 4 weeks, to treat 29 previously untreated patients with SCLC. They observed a 27% response rate (7 of 26) among evaluable patients, a median duration of response of 12.5 weeks, and a 12-month median survival. Toxicities were mild, with only 18% of courses (13 of 72) leading to grade 3 or grade 4 myelosuppression.

Studies in non-small cell lung cancer combining gemcitabine with cisplatin have shown an acceptable toxicity profile. SWOG, therefore, is currently conducting a phase II trial involving untreated patients with extensive-stage SCLC who will receive gemcitabine, 1,250 mg/m2 on days 1 and 8, plus cisplatin, 75 mg/m2 on day 1, given every 21 days.32 33

Vinorelbine
Vinorelbine, a semisynthetic vinca alkaloid, has been evaluated as a single agent for the treatment of SCLC by five investigators, as shown in Table 3 .34 35 36 37 38 Depierre et al34 administered vinorelbine, 30 mg/m2 weekly, to 30 patients with untreated advanced disease, achieving a PR in 8 of 30 patients (27%). Myelosuppression was observed in 12 patients (40%) as was the dose-limiting toxicity; 3 patients experienced grade 3 or grade 4 constipation. In a smaller trial by Tummarello and coworkers,35 vinorelbine, 25 mg/m2 weekly, yielded no responses among six previously untreated patients. In previously treated patients, Furuse and colleagues36 noted responses in 3 of 24 patients (13%) treated with vinorelbine, 25 mg/m2, and 60% of patients developed grade 3 or grade 4 leukopenia. In a similar population, Jassem et al37 treated 26 sensitive-relapse patients with vinorelbine, 30 mg/m2 weekly. Four of 25 evaluable patients (16%) achieved an objective response. Neutropenia—the predominant toxicity—occurred in 32% of patients. Finally, Lake and colleagues38 evaluated the activity of vinorelbine, 30 mg/m2 every week for 3 of 4 weeks, when administered to 34 sensitive-relapse patients. Five of 31 patients with measurable disease had documented PR (15%), with a median survival of 5 months. Grade 4 neutropenia was noted in 40% of patients.


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  		Table 3.. Phase II Trials of Vinorelbine in SCLC*

 
In a phase II trial, vinorelbine was combined with PE to treat 14 previously untreated patients with limited-stage (n = 9) and extensive-stage (n = 5) SCLC (Table 4 ).39 Patients received the combination of cisplatin, 75 mg/m2 on day 1; etoposide, 60 mg/m2 on days 1 to 3; and vinorelbine, 20 mg/m2 on days 1 and 8, repeated every 28 days. Patients with limited-stage disease received concurrent radiation beginning with cycle 3. All patients were evaluable for response and toxicity. In this setting, seven of nine patients (78%) with limited-stage SCLC, and two of five patients (40%) with extensive-stage SCLC achieved a response. Median survival was 13.4 months and 7 months, respectively, for limited-stage and extensive-stage patients. Neutropenia was observed in 7% of patients.


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  		Table 4.. Phase II Trials of Irinotecan in SCLC*

 
In Italy, a phase II trial was designed to evaluate the activity of carboplatin plus vinorelbine in extensive-stage SCLC (Table 4) .40 Treatment with carboplatin, 300 mg/m2 on day 1, and vinorelbine, 25 mg/m2 on days 1 and 8, repeated every 4 weeks, yielded an objective response in 23 patients (70%), with 24% having a CR. Treatment was well tolerated, with 4% grade 4 neutropenia and 4% grade 3 thrombocytopenia.

Irinotecan
Irinotecan is a camptothecin derivative similar to topotecan with single-agent activity in SCLC (Table 4) .41 42 43 44 Negoro and coworkers41 treated 35 patients (27 had received previous therapy) with irinotecan, 100 mg/m2 weekly. Nine previously treated patients (33%) and four of eight untreated patients (50%) responded. When Masuda et al42 administered the same dose and schedule to 16 patients with relapses, 7 of 15 achieved an objective response (47%). Le Chevalier and colleagues43 used a 3-week schedule of irinotecan, 350 mg/m2, to treat 32 chemotherapy-naive SCLC patients. An objective response was observed in five patients (16%), and the median survival was 4.5 months. The major toxicities in all trials were neutropenia and diarrhea.

One Japanese phase II combination trial (investigators brochure) examined irinotecan, 80 mg/m2 on days 1, 8, and 15; and cisplatin, 60 mg/m2 on day 1, every 28 days to treat 75 previously untreated patients with SCLC. Among 40 patients with limited-stage SCLC, the response rate was 83% (33 of 40 patients), including 12 CRs (30%). The response rate in 35 patients with extensive-stage SCLC was 86% (30 of 35 patients), with 10 CRs (29%).

MMP Inhibitors
The MMP inhibitors are a new class of drugs that break down extracellular matrix and disrupt tissue architecture that is associated with tumor progression.44 Specific MMPs, MMP-2 and MMP-9, have been isolated in lung tumors. MMP inhibitors have been shown to inhibit tumor invasion in vitro and in vivo and block tumor-induced neovascularization.

Two MMP inhibitors are being examined in SCLC as maintenance therapy in phase III clinical trials. Responding patients with limited- or extensive-stage SCLC are randomly assigned to an oral MMP inhibitor or placebo treatment. In one study, patients take the medication for a maximum of 18 months, while the other study allows patients to take the medication until the cancer progresses. In phase I testing, MMPs are extremely well tolerated, with the major side effects being myalgias, arthralgias, and headache.


   Conclusion
TOP
 Abstract
 Introduction
 Current Status of Chemotherapy
 The Search for New...
 Conclusion
References
 
In conclusion, the antitumor activity of these new agents against SCLC has renewed our optimism that survival can be prolonged for this group of patients. Perhaps most encouraging is the possibility that patients with limited-stage disease might be cured with new agents in combination with radiotherapy. Defining the optimum combinations of these new agents to impact survival is just beginning, but the future appears promising.


   Footnotes
 
Abbreviations: AUC = area under the plasma concentration-vs-time curve; CAV = cyclophosphamide, doxorubicin, and vincristine; CE = carboplatin and etoposide; CR = complete response; ECOG = Eastern Cooperative Oncology Group; G-CSF = granulocyte colony-stimulating factor; MMP = matrix metalloproteinase; PE = cisplatin and etoposide; PR = partial response; RTOG = Radiation Treatment Oncology Group; SCLC = small cell lung cancer; SWOG = Southwest Oncology Group


   References
TOP
 Abstract
 Introduction
 Current Status of Chemotherapy
 The Search for New...
 Conclusion
 References
 

  1. Landis, SH, Murray, T, Bolden, S, et al (1998) Cancer statistics 1998. CA Cancer J Clin 48,6-29[Abstract]
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  11. Depierre, A, von Pawel, J, Hans, K, et al (1997) Evaluation of topotecan (Hycamtinô) in relapsed small cell lung cancer (SCLC): a multicentre phase II study [abstract 126]. Lung Cancer 18(suppl1),35[ISI][Medline]
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  18. Georgiadis, MS, Brown, JE, Schuler, BS, et al (1995) Phase I study of a four day continuous infusion of paclitaxel followed by cisplatin in patients with advanced lung cancer [abstract 1072]. Proc Am Soc Clin Oncol 14,353
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  20. Glisson, BS, Kurie, JM, Fox, NJ, et al (1997) Phase I-II study of cisplatin, etoposide, and paclitaxel (PET) in patients with extensive small cell lung cancer (ESCLC) [abstract 1635]. Proc Am Soc Clin Oncol 16,455A
  21. Levitan, N, McKenney, J, Tahsildar, H, et al (1995) Results of a phase I dose escalation trial of paclitaxel, etoposide, and cisplatin followed by filgrastim in the treatment of patients with extensive stage small cell lung cancer [abstract 1177]. Proc Am Soc Clin Oncol 14,379
  22. Bremnes, RM, Sundstrom, S, Aasebo, U, et al (1997) Treatment of limited small cell lung cancer (SCLC) with paclitaxel, cisplatin, etoposide and radiation therapy [abstract 206]. Lung Cancer 18(suppl1),54
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