Topotecan and Paclitaxel in Previously Treated Patients with Relapsed Small Cell Lung Cancer: Phase II Trial of the North Central Cancer Treatment Group

Abstract

Small cell lung cancer (SCLC) is one of the most aggressive and lethal cancers in humans. It constitutes approximately 15 to 25% of all cases of primary lung cancers.1Laskin J Sandler A Johnson DH An advance in small-cell lung cancer treatment: More or less.J Natl Cancer Inst. 2003; 95: 1099-1101Crossref PubMed Scopus (13) Google Scholar Initial response rates of 70 to 90% for both limited and extensive stages of SCLC may be achieved using standard combination cytotoxic chemotherapy agents. The 5-year survival for limited-state SCLC is 15 to 25%, but patients with extensive-stage SCLC rarely survive 5 years. Even among patients who achieve a complete response, there is a high rate of relapse.2Jett JR Maksymiuk AW Su JQ et al.Phase III trial of recombinant interferon gamma in complete responders with small cell lung cancer.J Clin Oncol. 1994; 12: 2321-2326PubMed Google Scholar Until recently, there has been no well-established treatment available for patients with recurrent SCLC.3von Pawel J Schiller JH Shepherd FA et al.Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer.J Clin Oncol. 1999; 17: 658-667Crossref PubMed Google Scholar Topotecan is a camptothecin analogue that stabilizes the covalent adduct between topoisomerase I and DNA. In S-phase cells, these topo I-DNA adducts are converted into double-strand breaks that seem to be responsible for cytotoxicity.4Slichenmyer WJ Rowinsky EK Donehower RC et al.The current status of camptothecin analogues as antitumor agents.J Natl Cancer Inst. 1993; 85: 271-291Crossref PubMed Scopus (635) Google Scholar Several phase II5Ardizzoni A Hansen H Dombernowsky P et al.Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: A phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group.J Clin Oncol. 1997; 15: 2090-2096Crossref PubMed Scopus (405) Google Scholar, 6Depierre A von Pawel J Hans K et al.Evaluation of topotecan (HycamtinTM) in relapsed small cell lung cancer (SCLC): A multicentre phase II study.Lung Cancer. 1997; 18: 35Abstract Full Text PDF PubMed Google Scholar, 7Eckardt J Gralla R Palmer MC et al.Topotecan (T) as second-line therapy in patients (Pts) with small cell lung cancer (SCLC): A phase II study.Ann Oncol. 1996; 7: 107Google Scholar, 8Schiller JH Kim KM Hutson P et al.Phase II study of topotecan in patients with extensive-stage small-cell carcinoma of the lung: An Eastern Cooperative Oncology Group Trial.J Clin Oncol. 1996; 14: 2345-2352Crossref PubMed Scopus (204) Google Scholar trials as well as a phase III trial3von Pawel J Schiller JH Shepherd FA et al.Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer.J Clin Oncol. 1999; 17: 658-667Crossref PubMed Google Scholar have demonstrated antitumor efficacy, manageable toxicities, and acceptable safety profile of topotecan in both chemo-naive and previously treated patients with SCLC. Patients in the topotecan group derived significant palliative benefits in general symptoms (e.g., anorexia, fatigue, interference with daily activities, and pulmonary symptoms) over CAV chemotherapy in a randomized trial.3von Pawel J Schiller JH Shepherd FA et al.Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer.J Clin Oncol. 1999; 17: 658-667Crossref PubMed Google Scholar Although topotecan is currently approved for second-line therapy in SCLC at a starting dose of 1.5 mg/m2 by a daily 30-minute intravenous infusion for 5 consecutive days of a 21-day cycle, advanced age, extensive pretreatment, prior platinum therapy, prior radiotherapy, and renal impairment are potential risk factors for increased myelosuppression during topotecan therapy. Several studies suggest that the 1.0- and 1.25-mg/m2 doses of topotecan may be appropriate for patients with such high-risk factors.9Ardizzoni A Topotecan in the treatment of recurrent small cell lung cancer: An update.The Oncologist. 2004; 9: 4-13Crossref PubMed Scopus (47) Google Scholar, 10Perez-Soler R Glisson BS Lee JS et al.Treatment of patients with small-cell lung cancer refractory to etoposide and cisplatin with topoisomerase I poison topotecan.J Clin Oncol. 1996; 14: 2785-2790Crossref PubMed Scopus (120) Google Scholar, 11Takeda K Negoro S Sawa T et al.A phase II study of topotecan in patients with relapsed small-cell lung cancer.Clin Lung Cancer. 2003; 4: 224-228Abstract Full Text PDF PubMed Scopus (27) Google Scholar Paclitaxel is a chemotherapeutic agent that promotes the assembly and stabilization of microtubules. Such binding causes cells to form abundant arrays of disorganized and dysfunctional microtubules, leading to apoptosis. Although there is documented single-agent activity of paclitaxel in phase II studies among chemo-naive patients with SCLC with extensive disease,12Ettinger 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: 1430-1435Crossref PubMed Scopus (165) Google Scholar, 13Kirschling RJ Grill JP Marks RS et al.Paclitaxel and G-CSF in previously untreated patients with extensive stage small-cell lung cancer: A phase II study of the North Central Cancer Treatment Group.Am J Clin Oncol. 1999; 22: 517-522Crossref PubMed Scopus (49) Google Scholar response duration is short, which suggests that paclitaxel is not sufficient as a single agent. It is also widely accepted that combinations of cytotoxic drugs produce higher response rates and survival rates in patients with SCLC compared with single-agent therapy. The combination of topotecan and paclitaxel is rational as they have non-overlapping mechanisms of action and are both active agents in SCLC, as discussed previously. Moreover, there is demonstrable in vitro synergy of this combination in SCLC cell lines,14Bahadori HR Green MR Catapano CV Synergistic interaction between topotecan and microtubule-interfering agents.Cancer Chemother Pharmacol. 2001; 48: 188-196Crossref PubMed Scopus (42) Google Scholar, 15Jonsson E Fridborg H Nygren P et al.Synergistic interactions of combinations of topotecan with standard drugs in primary cultures of human tumor cells from patients.Eur J Clin Pharmacol. 1998; 54: 509-514Crossref PubMed Scopus (77) Google Scholar although there are insufficient data on sequence-specific synergy. Phase II trials of the combination of topotecan and paclitaxel that have been reported used a 5-day topotecan schedule as first-line treatment in patients with extensive SCLC.16Ramalingam S Belani CP Day R et al.Phase II study of topotecan and paclitaxel for patients with previously untreated extensive stage small-cell lung cancer.Ann Oncol. 2004; 15: 247-251Crossref PubMed Scopus (13) Google Scholar, 17Lyss AP Herndon II, JE Lynch Jr, TJ et al.Novel doublets in extensive-stage small-cell lung cancer: A randomized phase II study of topotecan plus cisplatin or paclitaxel (CALGB 9430).Clin Lung Cancer. 2002; 3: 205-210Abstract Full Text PDF PubMed Scopus (26) Google Scholar, 18Tweedy CR Andrews DF Ball T Topotecan and paclitaxel in extensive stage small cell lung cancer as initial therapy (Abstract).Proc Am Soc Clin Oncol. 1999; 18: 525Google Scholar, 19Schütte W Bork I Öhlmann K et al.Phase II study: First line treatment of stage IV small cell lung cancer with topotecan and paclitaxel (Abstract).Proc Am Soc Clin Oncol. 2001; 20: 283bGoogle Scholar A randomized phase II study evaluating four treatment combinations17Lyss AP Herndon II, JE Lynch Jr, TJ et al.Novel doublets in extensive-stage small-cell lung cancer: A randomized phase II study of topotecan plus cisplatin or paclitaxel (CALGB 9430).Clin Lung Cancer. 2002; 3: 205-210Abstract Full Text PDF PubMed Scopus (26) Google Scholar showed that paclitaxel (230 mg/m2 on day 1) plus topotecan (1 mg/m2 on days 1-5) produced excessive toxicity, with toxic deaths occurring in 25% of patients. Objective response rate was 54% with a median survival of 13.8 months. The toxicities were ameliorated in the treatment arm using an attenuated paclitaxel dose of 175 mg/m2, with treatment-related death occurring in 3% of patients. Objective response rate in this arm was 69% with a median survival of 9.9 months and 1-year survival of 40%, similar to standard etoposide plus cisplatin chemotherapy. Another phase II trial in patients with chemo-naive extensive SCLC used topotecan 1 mg/m2 (first three patients received 1.25 mg/m2) daily for 5 days and paclitaxel (135 mg/m2) on day 5 via a 24-hour infusion every 4 weeks.16Ramalingam S Belani CP Day R et al.Phase II study of topotecan and paclitaxel for patients with previously untreated extensive stage small-cell lung cancer.Ann Oncol. 2004; 15: 247-251Crossref PubMed Scopus (13) Google Scholar Despite prophylactic G-CSF administration, this combination was associated with a high incidence of myelosuppression and febrile neutropenia, with 31 of 32 patients experiencing grade 4 neutropenia, albeit brief and not associated with life-threatening febrile neutropenia. Thirty episodes of febrile neutropenia occurred in 22 patients. Overall objective response rate was 69%. The median survival was 54 weeks. The 1-, 2-, and 3-year survival rates were 50%, 10%, and 3%, respectively. Accordingly, because of the activity observed as front-line therapy, we initiated a phase II trial to investigate the efficacy of the combination of topotecan and paclitaxel in relapsed or refractory small-cell lung cancer. Recognizing that second-line treatment is not curative and that these patients have a limited survival, we elected to use a 3-day regimen of topotecan and paclitaxel in anticipation that it would be more convenient and less toxic than the 5-day topotecan regimen and would prove to be more effective because of the addition of a second active agent. Eligibility included patients aged ≥18 years with Eastern Cooperative Oncology Group performance score (PS) of 0-2 who had relapsed or refractory disease after one prior treatment regimen for a histologically or cytologically confirmed diagnosis of small-cell lung cancer. Patients with tumors exhibiting mixed histology were not eligible. Patients were required to have measurable disease, defined as at least one lesion whose longest diameter could be accurately measured as ≥2 cm. Adequate hematologic (absolute neutrophil count [ANC] ≥1500/μl; platelet count ≥100,000/μl; hemoglobin ≥9.0 g/dl), renal (serum creatinine ≤1.5 times the upper normal limits), and hepatic functions (serum total bilirubin ≤1.5 times the upper normal limits or direct bilirubin less than or equal to the upper normal limits) were required for enrollment. Patients were excluded from the study if they had a concurrent malignancy or history of another malignancy (except skin cancer or localized prostate cancer) within the preceding 3 years, uncontrolled symptoms from central nervous system metastasis (i.e., patients with treated central nervous system metastasis who were clinically stable were eligible), uncontrolled infection or precarious cardiovascular reserve (e.g., unstable angina pectoris, myocardial infarction, or class III/IV heart failure within the preceding 3 months). Patients were also excluded if they had undergone major surgery or preceding systemic chemotherapy within 21 days or radiation therapy within 14 days before treatment. Because the study involved investigational agents whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn were unknown, men or women of child-bearing potential who were unwilling to use adequate contraception were excluded, as were pregnant or nursing women. All patients signed an informed consent that was approved by the respective institutional review boards. Patients were categorized into two groups depending on their prior response to treatment. Arm A included patients progressing after <3 months of first-line therapy, and arm B included patients progressing ≥3 months after completing one previous treatment regimen. We aimed to maintain paclitaxel dose intensity, as sequential Phase II studies had suggested a possible dose-response effect with paclitaxel when administered with other cytotoxic agents.20Hainsworth JD Gray JR Stroup SL et al.Paclitaxel, carboplatin, and extended-schedule etoposide in the treatment of small-cell lung cancer: Comparison of sequential phase II trials using different dose-intensities.J Clin Oncol. 1997; 15: 3464-3470PubMed Google Scholar Topotecan dose reductions, however, are not necessarily associated with decreased efficacy.21Fields SZ Eckardt JR Zhang L et al.Efficacy of reduced dose of IV topotecan in relapsed small cell lung cancer patients.Lung Cancer. 2000; 29: 10Abstract Full Text PDF Google Scholar To be cautious, the toxicity profile was evaluated for the first six patients enrolled into the study at four selected institutions (six patients may be from arm A or arm B or any combination) treated with a topotecan dose of 1.0 mg/m2 days 1-3, after which paclitaxel 200 mg/m2 was administered on day 3, with a cycle length of 28 days. The doses were not escalated on subsequent cycles. After demonstrating good tolerance at that dose, the topotecan dose was escalated to 1.25 mg/m2 daily for 3 days, which was our target dose and was 75% of the dose of topotecan usually used in phase II trials. Treatment remained at this dose if grade 3+ infection, grade 4 neutropenia that was either prolonged (>5 days) or associated with fever, or grade 4 thrombocytopenia occurred in one or none of the second cohort of the six patients. If two or more of the six patients experienced the aforementioned toxicities, the dose of 1.0 mg/m2 would be used throughout the rest of the study. Dose modification guidelines for non-hematologic grade 3 or 4 toxicities (other than neuropathy) required a 25% dose reduction of either or both drugs. If treatment delay for adequate recovery of blood counts or serum creatinine required >4 weeks, patient would be removed from the study and go to event monitoring. G-CSF/GM-CSF was not to be used with the initial cycle of chemotherapy because of the expense associated with G-CSF support and the shorter schedule of topotecan (3-day rather than standard 5-day regimen tested in phase II trials). If the patient experienced excessive myelosuppression, the dosage reductions were followed per guidelines. Use of G-CSF/GM-CSF for subsequent cycles was at the discretion of the attending physician. Patients who developed metastases in the central nervous system as the only site of disease progression were not required to leave the study but could receive therapeutic whole-brain radiation therapy and thereafter continue on the protocol. Imaging studies were scheduled to be obtained after every other 28-day cycle. Response Evaluation Criteria in Solid Tumors criteria were used in the evaluation of treatment response.22Therasse P Arbuck SG Eisenhauer EA et al.New guidelines to evaluate the response to treatment in solid tumors.J Natl Cancer Inst. 2000; 92: 205-216Crossref PubMed Scopus (13980) Google Scholar All responses were confirmed for at least 4 weeks. Patients who achieved a complete response received a maximum of six cycles of the combination chemotherapy on study. The Common Toxicity Criteria version 2.0 was used for adverse event monitoring and reporting. This study used a two-staged study design based on Simon23Simon R Optional two-stage designs for phase II clinical trials.Control Clin Trials. 1989; 10: 1-10Abstract Full Text PDF PubMed Scopus (2873) Google Scholar for each patient group (arm A: patients progressing <3 months after previous treatment; arm B: patients progressing ≥3 months after previous treatment). This study was designed to detect an increase in response rate from 15% in each arm with a 5% type I error rate and power of 80% for detecting a true response probability of 30%. For each study arm, 19 patients were enrolled into the study and evaluated. This included the six patients already evaluated for toxicity at the same dose level. If three or fewer responses were observed on a given arm, accrual to the study arm would be stopped for lack of efficacy. Otherwise, patient accrual would continue into stage 2 analysis, into which an additional 36 patients (total of 55 patients per arm) were enrolled. To be considered an active treatment in an arm, confirmed responses must have been observed in at least 13 of the first 55 evaluable patients on that arm. Between July 1998 and March 2002, 84 patients were accrued to the study. Two of these patients refused to participate before receiving any treatment and four others were deemed ineligible by pathology review, leaving 78 patients evaluable for the primary end point of response. Six of these patients (three on each arm) were treated at a lower dose of topotecan before escalating the dosage for the remaining patients. Table 1 lists the demographic data of the 78 evaluable patients. Most patients (87%) had PS ≤1. Baseline characteristics were comparable except for the male to female ratio inversion between the two groups. Except for seven patients in arm B for whom information about prior therapy was missing (i.e., specific drugs used, administration of thoracic radiation and/or prophylactic cranial irradiation), all patients received a platinum-containing regimen for first-line therapy. We did not collect data on response status to prior therapy.TABLE 1Patient DemographicsArm A (n = 23)Arm B (n = 55)Total (n =78)Characteristicsn%n%n%Age62(38–79)62(42–82)62(38–82) (median and range) Gender Male1565.22240.03747.4 Female834.83360.04152.6Race White23100.05396.47697.4 Black00.011.811.3 Native American00.011.811.3Performance scorean = 71 (arm A: n = 23; arm B: n = 48). TRT, thoracic radiation; PCI, prophylactic cranial irradiation. 0–12087.04287.56287.3 2313.0612.5912.7Presence of stable brain metastases at study entryan = 71 (arm A: n = 23; arm B: n = 48). TRT, thoracic radiation; PCI, prophylactic cranial irradiation.313.0714.61014.1Previous chemotherapy23100.055100.078100.0Previous chemotherapy + TRT1521.73368.83853.5Previous chemotherapy + TRT + PCIan = 71 (arm A: n = 23; arm B: n = 48). TRT, thoracic radiation; PCI, prophylactic cranial irradiation.28.71939.62129.6a n = 71 (arm A: n = 23; arm B: n = 48). TRT, thoracic radiation; PCI, prophylactic cranial irradiation. Open table in a new tab The first three patients entered into each arm received a lower dose of topotecan (1.0 mg/m2) as an initial evaluation of toxicities that may be encountered. This dose was well tolerated. Nonhematologic toxicities were grade 1 and 2 (alopecia, myalgia, arthralgia, fatigue, nausea, and sensory neuropathy were the most common), except for grade 3 sensory neuropathy that occurred in one patient. Although five of the first six patients had grade 3 to 4 neutropenia occurring throughout most cycles of treatment, the prespecified conditions for subsequent dose reduction to 1.0 mg/m2 (see Treatment Schema) did not occur and thus the topotecan dose was maintained at the target dose of 1.25 mg/m2 for the remaining patients. The median number of treatment cycles for arms A and B were three and four, respectively. The toxicity analysis includes all evaluable patients (n = 78). The most frequently encountered grade 3 and 4 toxicities were neutropenia (92%), leukopenia (77%), thrombocytopenia (29%), fatigue (22%), and dyspnea (10%). GCSF was given on 42 cycles (15% of cycles) to 22 patients (28% of patients). Neutropenia (grades 3 and 4) was comparable in the cycles with and without GCSF. Cycles during which GCSF was administered had similar rates of grade 3 and 4 overall hematologic toxicities, although grade 3 or 4 thrombocytopenia was increased in the cycles in which GCSF was administered. Two deaths from neutropenic infections occurred in arm B. Grade 3 or 4 nonhematologic toxicities occurred in 51% of patients (Table 2). Of the patients, 38% required dose reductions (35% in arm A, 40% in arm B), and 19% required treatment delay (17% in arm A, 20% in arm B) because of toxicities.TABLE 2Grade 3+ Toxicities Most Frequently Encountered (All Cycles of Treatment)Data are expressed as percentages.ToxicityArm AArm BTotalGrade 3Grade 4Grade 3Grade 4Grade 3Grade 4HematologicLeukopenia481745364631Neutropenia137415801478Thrombocytopenia224229218Non-hematologicFatigue170203193Dyspnea4011191Myalgia903050Nausea903050Sensory neuropathy904060 Open table in a new tab Arm A was closed to further accrual after interim analysis of results from 23 patients revealed insufficient activity of the combination in chemo-refractory patients with SCLC to meet stage I decision criteria for protocol continuation (Table 3). Among the first six patients who received topotecan at the 1.0-mg/m2 dose level, there was only one response seen in arm B. Seven patients had documented brain metastases after initiation of study treatment. Only three of these seven patients remained on the protocol after completing whole-brain radiation, receiving one, two, and four additional cycles, respectively, for stable extracranial disease. These patients were coded as having stable disease. The four remaining patients had progressive clinical deterioration or developed brain metastases after being off study treatment because of extracranial disease progression. The study was not powered to examine gender differences in responses; Fisher's P values for both arms when examining response versus gender were >0.50.TABLE 3Response Rate by Treatment Arm (n = 78)Response rateArm A (refractory) (n = 23)Arm B (sensitive) (n = 55)n (%)95% CIn (%)95% CIComplete response1 (4.3)(0.1,22.0)4 (7.3)(2.0,17.6)Partial response1 (4.3)(0.1,22.0)11 (20.0)(10.4,33.0)Total2 (8.7)(1.1,28.0)15 (27.3)(16.1,41.0) Open table in a new tab The overall objective response rate of patients with refractory disease was 8.7%; median time to progression was 2.8 months (95% CI, 2.0–3.7). The overall objective response rate of patients in “sensitive” relapse was 27.3%; median time to progression was 3.7 months (2.2–5.3). Survival outcomes for both groups are shown in Table 4. Figure 1 is a graphic representation of the comparative Kaplan-Meier survival curves for both treatment groups.TABLE 4Survival Outcomes by Treatment ArmArm A (refractory) (n = 23)Arm B (sensitive) (n = 55)SurvivalPoint estimate95% CIPoint estimate95% CIOverall Survival1 year13.0%(4.5%, 37.5%)30.9%(20.8%, 45.9%)2 year4.3%(0.6%, 29.6%)7.3%(2.8%, 18.7%)Median survival (months)5.7(4.3, 7.5)6.9(5.8, 8.4)Progression-free survival6 months13.0%(4.5%, 37.5%)22.7%(13.8%, 37.3%)12 months4.3%(0.6%, 29.6%)3.8%(1.0%, 14.7%) Open table in a new tab Phase II trials of the combination of topotecan and paclitaxel as first-line treatment in patients with extensive SCLC have been reported.16Ramalingam S Belani CP Day R et al.Phase II study of topotecan and paclitaxel for patients with previously untreated extensive stage small-cell lung cancer.Ann Oncol. 2004; 15: 247-251Crossref PubMed Scopus (13) Google Scholar, 17Lyss AP Herndon II, JE Lynch Jr, TJ et al.Novel doublets in extensive-stage small-cell lung cancer: A randomized phase II study of topotecan plus cisplatin or paclitaxel (CALGB 9430).Clin Lung Cancer. 2002; 3: 205-210Abstract Full Text PDF PubMed Scopus (26) Google Scholar, 18Tweedy CR Andrews DF Ball T Topotecan and paclitaxel in extensive stage small cell lung cancer as initial therapy (Abstract).Proc Am Soc Clin Oncol. 1999; 18: 525Google Scholar, 19Schütte W Bork I Öhlmann K et al.Phase II study: First line treatment of stage IV small cell lung cancer with topotecan and paclitaxel (Abstract).Proc Am Soc Clin Oncol. 2001; 20: 283bGoogle Scholar These trials used a 5-day topotecan schedule at doses of 1.0 to 1.25 mg/m2 in combination with paclitaxel 175 to 230 mg/m2 or 135mg/m2 infusion on day 1 or 5, respectively, every 3 or 4 weeks. These combinations were thought to demonstrate efficacy similar to standard platinum-based therapy. However, treatment-related deaths and myelosuppression were frequent despite G-CSF support, particularly with the higher paclitaxel dose. Even with single-agent topotecan, hematologic toxicities occurred frequently, with Grade 3 or 4 neutropenia encountered in up to 75% of courses. Patients with recurrent disease typically have cumulative toxicities from prior chemotherapy exposure, which may predispose these patients to myelosuppression. An alternate dosing regimen for topotecan in combination with paclitaxel is thus rational in the hopes of ameliorating myelosuppression associated with topotecan treatment, particularly in a pretreated population. However, despite the modification from a standard 5-day to a 3-day topotecan schedule, the combination of topotecan with paclitaxel in our study was still associated with a high rate of myelosuppression.3von Pawel J Schiller JH Shepherd FA et al.Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer.J Clin Oncol. 1999; 17: 658-667Crossref PubMed Google Scholar, 5Ardizzoni A Hansen H Dombernowsky P et al.Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: A phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group.J Clin Oncol. 1997; 15: 2090-2096Crossref PubMed Scopus (405) Google Scholar West et al.24West W Birch R Schnell F et al.Phase I study of paclitaxel and topotecan for the first-line treatment of extensive-stage small cell lung cancer.The Oncologist. 2003; 8: 76-82Crossref PubMed Scopus (13) Google Scholar reported the results of a dose-escalation phase IB trial in patients with chemo-naive SCLC treated with intravenous paclitaxel 135 to 175 mg/m2 over 1 hour on day 1, followed by intravenous topotecan 1.25 to 1.5 mg/m2 over 30 minutes on days 1 to 3 of a 21-day course. Dose-limiting neutropenia was seen in three of five patients treated with topotecan 1.5 mg/m2 and paclitaxel 175 mg/m2. Topotecan 1.5 mg/m2 with paclitaxel 135 mg/m2 was thus determined to be the maximal tolerated dose. In contrast to our studies and the aforementioned phase II combination trials, only 24% (4 of 17) of patients in West et al.'s phase IB trial experienced grade 3 or 4 neutropenia, most of whom received paclitaxel 175 mg/m2 and topotecan 1.5 mg/m2. Routine G-CSF support was not used. The overall response of 53% (nine patients with partial response of 17 evaluable patients) was similar to response rates observed among previously untreated patients using the 5-day topotecan regimen in combination with other agents. These toxicity and efficacy results should be interpreted with caution because of differences in patient characteristics (previously untreated patients versus patients with relapsed disease) and the limited number of patients enrolled. Nevertheless, the results seemed to indicate that a 3-day topotecan regimen in combination with lower-dose paclitaxel is feasible and still has clinically relevant activity despite lower dose intensity by preserving relative dose density with a 21-day versus a 28-day cycle interval. Response to second-line therapy is influenced by the progression-free interval from cessation of initial therapy.5Ardizzoni A Hansen H Dombernowsky P et al.Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: A phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group.J Clin Oncol. 1997; 15: 2090-2096Crossref PubMed Scopus (405) Google Scholar, 6Depierre A von Pawel J Hans K et al.Evaluation of topotecan (HycamtinTM) in relapsed small cell lung cancer (SCLC): A multicentre phase II study.Lung Cancer. 1997; 18: 35Abstract Full Text PDF PubMed Google Scholar Patients who relapse within 3 months are considered to have refractory disease and typically have response rates to second-line therapy that are inferior to patients considered to have sensitive disease, generally defined as those who experience relapse more than 3 months after therapy.5Ardizzoni A Hansen H Dombernowsky P et al.Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: A phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group.J Clin Oncol. 1997; 15: 2090-2096Crossref PubMed Scopus (405) Google Scholar Our results were not clearly inferior to those reported in a phase II trial testing the combination of paclitaxel (175 mg/m2 by a 3-hour intravenous infusion) and carboplatin (AUC = 7) among 35 patients with SCLC who experienced relapse within 3 months of first-line treatment with cyclophosphamide doxorubicin and etoposide.25Groen HJ Fokkema E Biesma B et al.Paclitaxel and carboplatin in the treatment of small-cell lung cancer patients resistant to cyclophosphamide, doxorubicin, and etoposide: A non-cross-resistant schedule.J Clin Oncol. 1999; 17: 927-932PubMed Google Scholar Although the published objective response rate was 73.5% (95% CI 59% to 88%) and median survival was 31 weeks, the high response rate can be attributed to the difference in patient selection: the patients in the latter trial were not previously exposed to any platinum agent, whereas nearly all of our patients had a platinum-based regimen for first-line therapy. Moreover, the 1-year survival rates are similar between the two studies, highlighting the dismal prognosis for this group of patients. Nonetheless, the combination we tested was not effective in patients with SCLC with chemo-refractory disease. Our study outcomes were similar to those of single-agent topotecan when comparing the historical objective response rate of 2 to 11% and median overall survival time of 16 to 21 weeks among chemo-refractory patients.4Slichenmyer WJ Rowinsky EK Donehower RC et al.The current status of camptothecin analogues as antitumor agents.J Natl Cancer Inst. 1993; 85: 271-291Crossref PubMed Scopus (635) Google Scholar, 5Ardizzoni A Hansen H Dombernowsky P et al.Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: A phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group.J Clin Oncol. 1997; 15: 2090-2096Crossref PubMed Scopus (405) Google Scholar, 6Depierre A von Pawel J Hans K et al.Evaluation of topotecan (HycamtinTM) in relapsed small cell lung cancer (SCLC): A multicentre phase II study.Lung Cancer. 1997; 18: 35Abstract Full Text PDF PubMed Google Scholar, 7Eckardt J Gralla R Palmer MC et al.Topotecan (T) as second-line therapy in patients (Pts) with small cell lung cancer (SCLC): A phase II study.Ann Oncol. 1996; 7: 107Google Scholar, 10Perez-Soler R Glisson BS Lee JS et al.Treatment of patients with small-cell lung cancer refractory to etoposide and cisplatin with topoisomerase I poison topotecan.J Clin Oncol. 1996; 14: 2785-2790Crossref PubMed Scopus (120) Google Scholar Among patients considered to have sensitive relapsed disease, the antitumor activity of the regimen in our study performed variably compared with other agents. The objective response rate among our patients in sensitive relapse seems to be better than the historical objective response rate of 16.7% obtained with single-agent gemcitabine26Masters GA Declerck L Blanke C et al.Phase II trial of gemcitabine in refractor or relapsed small cell lung cancer: Eastern Cooperative Oncology Group Trial 1597.J Clin Oncol. 2003; 21: 1550-1555Crossref PubMed Scopus (98) Google Scholar among patients considered to have chemo-sensitive relapsed SCLC. Combinations of vinorelbine with gemcitabine or doxorubicin induced partial responses of 25 to 26.5% among patients in published phase II studies,27Hainsworth JD Burris III, HA Erland JB et al.Combination chemotherapy with gemcitabine and vinorelbine in the treatment of patients with relapsed or refractory small cell lung cancer: A phase II trial of the Minnie Pearl Cancer Research Network.Cancer Invest. 2003; 21: 193-199Crossref PubMed Scopus (16) Google Scholar, 28Johnson E Lake D Herndon II, JE et al.Phase II trial of vinorelbine plus doxorubicin in relapsed small-cell lung cancer: CALGB 9332.Am J Clin Oncol. 2004; 27: 19-23Crossref PubMed Scopus (6) Google Scholar similar to our findings. Likewise, the historical objective response rate of 21.7% among this group of patients treated with CAV in a phase III trial is comparable to our findings.2Jett JR Maksymiuk AW Su JQ et al.Phase III trial of recombinant interferon gamma in complete responders with small cell lung cancer.J Clin Oncol. 1994; 12: 2321-2326PubMed Google Scholar Phase II trials of irinotecan-based combinations with or without cisplatin did, however, produce apparently better objective response rates of 37.5 to 78% among patients previously exposed to platinum, but not better survival rates.29Naka N Kawahara M Okishio K et al.Phase II study of weekly irinotecan and carboplatin for refractory or relapsed small-cell lung cancer.Lung Cancer. 2002; 37: 319-323Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 30Ando M Kobayashi K Yoshimura A et al.Weekly administration of irinotecan (CPT-11) plus cisplatin for refractory or relapsed small cell lung cancer.Lung Cancer. 2004; 44: 121-127Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 31Goto K Sekine I Nishiwaki Y et al.Multi-institutional phase II trial of irinotecan, cisplatin, and etoposide for sensitive relapsed small-cell lung cancer.Br J Cancer. 2004; 91: 659-665PubMed Google Scholar, 32Ichiki M Gohara R Rikimaru T et al.Combination chemotherapy with irinotecan and ifosfamide as second-line treatment of refractory or sensitive relapsed small cell lung cancer: A phase II study.Chemotherapy. 2003; 49: 200-205Crossref PubMed Scopus (20) Google Scholar Finally, the modest activity seen in our study among patients with SCLC in sensitive relapse was not evidently better than results seen from early studies with single-agent topotecan in several trials in terms of objective response rate, which ranged from 14 to 38%, and median survival, which ranged from 25 to 36 weeks. This may be explained in part by treatment delays because of toxicity. In conclusion, the dose schedule used in this study was associated with high rates of myelosuppression and modest clinical efficacy. Although this regimen is not recommended for further study, the combination of paclitaxel and topotecan is active, and the value of alternative dosing and scheduling schemes, such as weekly topotecan or paclitaxel, should be further investigated. Given the refractory state of relapsed SCLC to conventional chemotherapy, trials are needed to explore treatment with novel therapeutic agents. This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service grants CA-25224, CA-37404, CA-15083, CA-35195, CA-63849, CA-35269, CA-35431, CA-52352, CA-35113, CA-35103, CA-35101, CA-35103, CA-35415, CA-35448, CA-35272, and CA-63848. Additional participating institutions include: Mid Dakota Clinic, Bismarck, North Dakota (Edward Wos, MD); Iowa Oncology Research Association CCOP, Des Moines, Iowa (Roscoe Morton, MD); Sioux Community Cancer Consortium, Sioux Falls, South Dakota (Loren K. Tschetter, MD); Toledo Community Hospital Oncology Program CCOP, Toledo, Ohio (Paul L. Schaefer, MD); Geisinger Clinic and Medical Center CCOP, Danville, Pennsylvania (Suresh Nair, MD); Altru Health Systems, Grand Forks, North Dakota (Tudor Dentchev, MD); Saskatoon Cancer Centre, Saskatoon, Saskatchewan, Canada; Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (Muhammad Salim, MD); Ochsner CCOP, New Orleans, Louisiana (Carl Kardinal, MD); Michigan Cancer Consortium, Ann Arbor, Michigan (Philip Stella, MD)