Annals of Oncology Advance Access originally published online on October 25, 2006
Annals of Oncology 2007 18(2):331-337; doi:10.1093/annonc/mdl375
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© 2006 European Society for Medical Oncology
lung cancer |
Phase II trial of irinotecan/gemcitabine as second-line therapy for relapsed and refractory small-cell lung cancer: Cancer and Leukemia Group B Study 39902
1 University of Miami Miller School of Medicine, Miami, FL
2 CALGB Statistical Center, Durham, NC
3 Virginia Oncology Associates, Duke Oncology Network, Durham, NC
4 Southeast Cancer Control Consortium Inc. CCOP, Goldsboro, NC
5 University of Chicago, Chicago, IL
6 Care Alliance Roper Hospital, Charleston, SC, USA
* Correspondence to: C. M. Rocha-Lima, MD, Associate Professor of Medicine, University of Miami and Sylvester Cancer Center, 1475 NW 12th Avenue (D8-4), Suite 3310, Miami, FL 33136, USA. E-mail: crocha{at}med.miami.edu
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Abstract |
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Background: This phase II study evaluated the efficacy and safety of the irinotecan/gemcitabine combination in patients with relapsed/refractory small-cell lung cancer (SCLC).
Patients and methods: Patients with measurable tumor who had received one previous chemotherapy or chemotherapy/radiation regimen were eligible. Gemcitabine 1000 mg/m2 was administered i.v. over 30 min followed immediately by irinotecan 100 mg/m2 i.v. over 90 min, both on days 1 and 8 every 21 days. Patients were stratified based on response to initial treatment [i.e. primary sensitive disease with progression 
3 months (group A), or refractory disease (group B)].
Results: Seventy-three patients were enrolled but one never received treatment and one ineligible patient did not have SCLC. Median patient ages of the remaining patients were 61 and 63 years in groups A (n = 35) and B (n = 36), respectively, with performance status of 0 or 1 in 85% of 71 patients. Primary grade 3/4 toxic effects in groups A versus B were neutropenia (36% versus 43%), thrombocytopenia (36% versus 26%), nausea (12% versus 11%), vomiting (0 versus 11%), diarrhea (12% versus 9%), and pulmonary (12% versus 12%). Two patients had fatal events including pneumonitis (n = 1) and acute respiratory distress syndrome (n = 1). Responses occurred in 11 group A [two complete responses and nine partial responses (PRs)] and four group B (all PRs) patients, for response rates of 31% [95% confidence interval (CI) 17%, 49%) and 11% (95% CI 3%, 26%), respectively. Median survival and progression-free survival times were 7.1 (95% CI 6, 10.5) versus 3.5 (95% CI 3.1, 5.7) months, and 3.1 (95% CI 1.6, 5.3) versus 1.6 (95% CI 1.4, 2.8) months for group A versus B.
Conclusion: The irinotecan/gemcitabine combination is active and well tolerated as second-line therapy in SCLC patients. Additional studies are warranted as second-line therapy in patients who progressed 90 days or more after first-line therapy. However, the observed efficacy results in refractory SCLC patients indicate that this regimen should not be further explored in this population.
Key words: antimetabolite, combination chemotherapy, refractory, relapsed, SCLC, topoisomerase inhibitor
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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It is estimated that lung cancer will be diagnosed in >170 000 Americans, 15% of whom will have the small-cell histologic subtype [1]. Despite high response rates with first-line therapy for small-cell lung cancer (SCLC), most patients will eventually experience disease progression and become candidates for second-line therapy.
Previously treated SCLC patients can easily be divided into two groups, one more likely and the other less likely to respond to second-line chemotherapy. Patients who attain a response to initial therapy and have a treatment-free interval of at least 3 months between completion of their initial treatment program and the need to start second-line therapy are more responsive to second-line chemotherapy, either reinduction [2–4] or treatment with new active agents or combination [5, 6].
The topoisomerase I inhibitor topotecan has been compared with best supportive care (BSC) as second-line chemotherapy in SCLC [7]. This trial included 141 patients with limited or extensive-stage SCLC that had progressed between 45 and 90 days subsequent to initial therapy. The randomization consisted of oral topotecan 2.3 mg/m2/day for 5 days on a 21-day cycle plus BSC, or BSC alone. Median overall survival (OS) was 25.9 weeks in the topotecan arm, compared with 13.9 weeks in the BSC alone arm [hazards ratio (HR) 0.64, P = 0.014]. Topotecan received regulatory approval for the second-line management of SCLC patients based on a phase III trial comparing its i.v. formulation with cyclophosphamide, doxorubicin, and vincristine (CAV) in SCLC patients progressing >60 days after first-line treatment [8]. Topotecan was associated with similar response rates and median survival as CAV. Single-agent topotecan, however, led to improvement in disease-related symptoms compared with CAV. Several cytotoxic agents that have demonstrated activity in chemotherapy-naive SCLC patients are being tested alone or in combination in the salvage setting, including taxanes, vinorelbine, gemcitabine, and camptothecins, in hopes of improving outcome for SCLC patients with relapsed and refractory disease [9].
Gemcitabine is a pyrimidine antimetabolite that is phosphorylated intracellularly to its active diphosphate and triphosphate forms, which inhibit DNA and RNA repair and synthesis. Single-agent activity has been demonstrated in chemotherapy-naive and previously treated SCLC patients. A 27% response rate [all partial responses (PRs)] to single-agent gemcitabine was reported among 26 previously untreated SCLC patients, with a mean response duration of 12.5 weeks [10]. The Eastern Cooperative Oncology Group reported results of a phase II trial in SCLC (trial 1597), in which 12% of 42 assessable patients responded to second-line gemcitabine monotherapy [11]. Patients in this trial were stratified based on having primary refractory or primary sensitive disease. Response rates were 6% versus 17% in the two groups, respectively (P = 0.37), and median survival was 7.1 months overall. On another phase II trial in 38 assessable patients with refractory SCLC previously treated with at least one chemotherapeutic regimen, single-agent gemcitabine resulted in a response rate of 13% [12]. In this trial, median time to progression and median survival were 8 weeks and 17 weeks, respectively.
Irinotecan is a camptothecin analogue prodrug. Its active metabolite, SN-38, inhibits topoisomerase I activity by stabilizing the topoisomerase I DNA-cleavable complex formed during enzymatic relaxation of DNA tortional strain, thus resulting in double-strand DNA breakage and cell death. This agent has established first-line activity in SCLC and demonstrated efficacy as salvage therapy as well [13–15]. Treatment with irinotecan 100 mg/m2/week resulted in response rates of 50% in 33 previously untreated and 33% in eight previously treated patients, with a median response duration of 50 days [13]. Other trials from Japan using the same weekly irinotecan dose in SCLC demonstrated response rates of 47% in 16 cisplatin-pre-treated patients [14] and 50% among 16 patients refractory to etoposide-containing chemotherapy [15].
Preclinical data demonstrated dose-dependent synergistic interactions between gemcitabine and irinotecan [16]. The recommended doses for phase II studies of gemcitabine given first at 1000 mg/m2 immediately followed by irinotecan 100 mg/m2 given on days 1 and 8 every 21-day cycle were established in a phase I trial in solid tumor patients (none with SCLC) [17].
The phase II study reported in this article evaluated the gemcitabine/irinotecan combination in previously treated SCLC patients based on response to previous chemotherapy (i.e. primary sensitive with relapse, or primary refractory). The main study objective was to determine treatment response, and secondary objectives included OS and progression-free survival (PFS) times, response durations, and safety of the irinotecan/gemcitabine combination as second-line therapy for SCLC.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Patient registration and data collection were managed by the Cancer and Leukemia Group B (CALGB) Statistical Center. Data quality was ensured by careful review of data by CALGB Statistical Center staff and by the study chairperson. As part of the quality assurance program of the CALGB, members of the Data Audit Committee visit all participating institutions at least once every 3 years to review source documents. The auditors verified compliance with federal regulations and protocol requirements, including those pertaining to eligibility, treatment, adverse events, tumor response, and outcome in a sample of protocols at each institution. Such on-site review of medical records was carried out for a subgroup of 15 patients (21.7%) of the 69 patients treated under this study. Statistical analyses were carried out by CALGB statisticians.
Patients at least 18 years old with histologically or cytologically proven relapsed SCLC who had received one previous chemotherapy or chemotherapy/radiotherapy regimen were eligible. Inclusion required at least one site of disease measurable in at least one dimension, and National Cancer Institute Common Toxicity Criteria (NCI–CTC) performance status 0 to 2. No previous gemcitabine or irinotecan treatment was allowed. Patients were excluded if they had other malignancies in the past 5 years, except curatively treated carcinoma in situ of cervix or inactive basal cell or squamous skin carcinoma. Adequate laboratory values including granulocyte count 1500/µl, platelet count 100 000/µl, creatinine level 
2.0 mg/dl, and bilirubin level 1.5 mg/dl were required. Women who were pregnant or breast-feeding were excluded. The human protection committees of participating institutions approved the protocol, and all patients provided written informed consent.
Patients were stratified at registration into one of two groups, based on whether disease had progressed or relapsed at least 90 days after having responded [complete response (CR) or PR] to first-line chemotherapy or chemotherapy/radiation (group A—primary sensitive with relapse), or whether disease progressed during or within 90 days of completing initial treatment (group B—primary refractory).
evaluations
Pre-treatment evaluations included history and physical examination, including vital signs, height and weight, performance status, and complete blood cell counts. These were repeated on day 1 of each treatment cycle, and after treatment at least every 3 months for 1 year, every 6 months for 2 years, and yearly for 3 years. Up to 10 target lesions were identified at baseline and measured by X-ray, computed tomography (CT), or magnetic resonance imaging (MRI) scan. If palpable, tumors were remeasured on day 1 of each treatment cycle; otherwise, X-rays or scans for tumor status were repeated every two cycles. Other ‘non-target’ lesions, including small or non-measurable lesions (e.g. bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, abdominal masses, and cystic lesions) were identified at baseline and followed as appropriate. All patients had baseline chest X-ray, and CT scan or MRI of chest and upper abdomen. Complete blood cell count with differential and platelet counts were obtained on days 1, 8, and 15 of the first treatment cycle, and on days 1 and 8 for subsequent cycles. Serum creatinine, aspartate transaminase, alkaline phosphatase, and bilirubin levels were also repeated on day 1 of each cycle. Other laboratory studies were carried out as needed. Tumor response was assessed every 6 weeks using standard response criteria. In patients with PR or CR, confirmatory scans were required 4 weeks following initial documentation of objective response. Toxic effects were evaluated using NCI–CTC version 2.0 on day 1 of each treatment cycle and during post-treatment follow-up evaluations.
treatment
Treatment consisted of gemcitabine 1000 mg/m2 administered i.v. over 30 min on days 1 and 8, immediately followed by irinotecan 100 mg/m2 i.v. over 90 min on days 1 and 8. Patients received 5 hydroxytriptamine receptor antagonist and dexamethasone prior to each treatment. Irinotecan dose could be increased to 115 mg/m2 in subsequent cycles if no hematologic toxicity >grade 3 or non-hematologic toxicity >grade 2 (except nausea/vomiting, alopecia, anorexia, or fever) was observed during the first cycle. Courses were repeated every 3 weeks for at least four cycles beyond achievement of response or stable disease, or until documentation of disease progression or unacceptable toxicity occurred. Doses of study medications were delayed or modified for hematologic, gastrointestinal, and other toxic effects. Growth factors were not recommended, but could be used at the physician's discretion. For management of potential delayed diarrhea, patients were instructed to take loperamide at the earliest signs of diarrhea and/or abdominal cramping that occurred at least 24 h after irinotecan administration.
statistical considerations
This study evaluated second-line irinotecan/gemcitabine activity based on patient response to initial treatment (i.e. relapsed or refractory). Within each stratum, a two-stage phase II design was used. For patients with sensitive but relapsed SCLC, the study was designed to differentiate between a response rate (CR or PR) of 10% and 30%. After accruing 
18 patients in the first stage, a test of the alternative hypothesis at the 0.01 level of significance was conducted. When the criteria for continued accrual was satisfied, additional patients were enrolled so that a total of at least 33 patients were enrolled in this stratum. When a total of 35 patients were accrued during stages 1 and 2, the treatment regimen was to be considered active among patients with relapsed disease if 7 or more patients responded. The type I and II errors were <0.10.
For patients with refractory disease, a two-stage design that differentiated between a response rate of 5% and 20% was used. After accruing 18 patients in the first stage, a test of the alternative hypothesis at the 0.02 level of significance was conducted. When the criterion for continued accrual was satisfied, enrolment was to be continued so that a total of 40 patients would be accrued during stage 1 and 2. With a total of 36 patients accrued, the treatment regimen was to be considered active for the treatment of patients with refractory disease if four or more patients responded. The type I and II errors were <0.10.
Kaplan–Meier [18] curves were used to describe OS and PFS, where survival was defined as the time between randomization and death, and PFS was defined as the time between randomization and disease progression or death.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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From May 2000 to September 2001, a total of 73 patients were enrolled in the study. One patient never received treatment, and one ineligible patient did not have SCLC. Of the remaining 71 patients, 35 had primary sensitive disease that had relapsed (group A) after initial therapy, and 36 had primary refractory disease (group B) with initial therapy. Baseline patient characteristics are shown in Table 1. Thirty-eight patients were male and 33 were female. The median patient age was 61 years in group A (range, 40–76 years) and 63 years in group B (range, 35–85) years. Seven of 71 (10%) patients were non-Caucasian, and the remainder Caucasian. The majority (68%) had extensive disease at the time of original diagnosis, including 18 of 35 (51%) relapsed patients and 30 of 36 (83%) refractory patients. Performance status was good (0 or 1) in 85% of all patients. Approximately 65% of relapsed and refractory patients had <5% weight loss in the previous 6 months and about 21% of patients had 5%–10% weight loss. Pleural effusion was present in 24% of patients (37% of relapsed group A and 11% of refractory group B patients). A total of 50 (70%) patients had achieved objective response to previous therapy (77% group A, 64% group B).
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response to irinotecan/gemcitabine
Table 2 shows response to irinotecan/gemcitabine therapy based on whether patients had primary sensitive disease with relapse after initial therapy (group A) or primary refractory disease (group B). Four patients, two in each group, died within 30 days from study entry from disease-related respiratory failure (n = 1), pneumonia (n = 1), and progressive disease (n = 2). Irinotecan/gemcitabine treatment resulted in two CRs and nine PRs in group A and zero CRs and four PRs in group B, for overall response rates (CR + PR) of 31% [95% confidence interval (CI) 0.17–0.49) in group A and 11% (95% CI 0.03–0.26) in group B. OS of 71 patients is shown on Figure 1. All patients have died. Median survival time was 7.1 months (95% CI 6.0–10.5 months) for group A compared with 3.5 months (95% CI 3.1–5.7 months) for group B. Figure 2 depicts PFS, which has a median of 3.1 months (95% CI 1.6–5.3 months) and 1.6 months (95% CI 1.4–2.8) in groups A and B patients, respectively.
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toxicity
A total of 68 patients (33 in group A and 35 in group B) were included in the toxicity analysis. Two patients in each group were not assessable because of lack of data. The most common toxic effects were hematologic or gastrointestinal in nature. Table 3 shows maximum toxic effects
grade 3 that were considered treatment related or possibly treatment related. Among patients in groups A (relapsed) and B (refractory), respectively, grades 3 and 4 toxic effects included neutropenia in 36% and 43%, thrombocytopenia in 36% and 26%, fatigue in 15% and 9%, nausea in 12% and 11%, vomiting in 0 and 11%, and diarrhea in 12% and 9%. One patient in each group had grade 5 (lethal), treatment-related pulmonary effects consisting of pneumonitis (n = 1) and acute respiratory distress syndrome (n = 1). Other pulmonary toxic effects were grade 3 in three patients in each group, consisting of cough (n = 1), dyspnea (n = 3), pneumonitis (n = 1), and voice changes (n = 1); and grade 4 dyspnea in one patient in each group. Six patients had neurologic effects consisting of grade 3 neurosensory (n = 2), neuromotor (n = 2), or mood alteration/anxiety (n = 1); one patient (group B) had grade 4 neuromotor effects. In all 68 patients, the maximum toxicity was grade 3 in 32 (47%) patients and grade 4 in 13 (19%) patients. A total of 73% (24/33) of group A and 60% (21/35) of group B patients had maximum toxicity of grade 3 or 4
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The efficacy of second-line chemotherapy in SCLC depends on multiple factors [2–6, 19]. The interval between cessation of primary therapy and detection of recurrence and the nature of the response to primary therapy are particularly important in predicting the response to second-line therapy. The longer the interval from cessation of primary treatment to the beginning of second-line chemotherapy, the greater is the probability of a response [2, 5]. In circumstances where >12 months have elapsed since completion of induction chemotherapy, retreatment with the original drug regimen may produce a second tumor regression [4, 6]. In contrast, a short period between completion of induction therapy and recurrence usually portends a poor outcome, especially if the interval is <3 months. Patients who responded to primary chemotherapy are more likely to respond to second-line therapy [2, 6, 19]. On the other hand, patients who progress during primary chemotherapy rarely respond to second-line therapy.
Single-agent topotecan in the pivotal phase III trial in SCLC patients progressing >60 days after first-line treatment resulted in a response rate of 24.3% and a median survival of 6.2 months [8]. The combination of topotecan and gemcitabine has been studied in 37 assessable SCLC patients, where 68% had sensitive and 32% had refractory disease [20]. The preliminary results for all patients (the authors did not report the results in refractory and sensitive patients separately) included response rates of 24%, median time to progression of 2.1 months and median survival of 4.1months.
In this current phase II trial, second-line irinotecan/gemcitabine treatment in chemotherapy-sensitive patients resulted in response rates of 31%, and median survival of 7.1 months. The efficacy results observed in chemotherapy refractory patients, however, included a response rate of 11%, median survival of 3.5 months, and median PFS of 1.6 months. These results confirm poorer efficacy among patients with disease refractory to first-line therapy.
The combination was well tolerated, with hematologic toxicity, primarily neutropenia and thrombocytopenia, and diarrhea as the primary adverse effects. These effects are expected based on toxic effects observed with gemcitabine or irinotecan monotherapy.
Two other studies of the irinotecan/gemcitabine regimen in previously treated SCLC patients have been reported with more attractive efficacy results [21, 22]. Domine et al. [21] used an irinotecan dose of 150 mg/m2 i.v. over 90 min followed by gemcitabine 1500 mg/m2 over 30 min on day 1, with cycles repeated every 2 weeks. They reported response rates of 28% in 29 assessable patients, with 31% versus 25% of patients with sensitive versus refractory disease responding. Median response duration was 3.3 months, time to disease progression was 5.3 months, and median survival was 9.3 months [21]. Toxicity was mild, with no grade 3–4 hematologic toxicity, and grade 3–4 non-hematologic effects in only 1.5% of cycles. Agelaki et al. [22] also evaluated irinotecan plus gemcitabine in 31 pre-treated SCLC patients, of whom 16 had sensitive and 15 had resistant disease. Gemcitabine 1000 mg/m2 was administered on days 1 and 8 and irinotecan 300 mg/m2 on day 8 only, every 21 days. Three patients (10%) had PR, with median survival of 6 months and 1-year survival rate of 17%. The primary grades 3 and 4 toxic effects were neutropenia in 29%, thrombocytopenia in 13%, and diarrhea in 10% of patients.
The results of this phase II cooperative group trial indicate that additional studies in patients with chemotherapy sensitive SCLC is warranted. The disappointing efficacy results in chemotherapy refractory patients, however, indicate that further studies in this population of patients are not recommended.
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Acknowledgements |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The research for Cancer and Leukemia Group B (CALGB) 39902 was supported, in part, by grants from the National Cancer Institute (CA31946) to the CALGB (R. L. Schilsky, MD, Chairman). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. The following institutions participated in this study: CALGB Statistical Center, Durham, NC—S. George, PhD, supported by CA33601; Dana Farber-Partners, Boston, MA—G. P Canellos, MD, supported by CA32291; Duke University Medical Center, Durham, NC—Jeffrey Crawford, MD, supported by CA47577; Green Mountain Oncology Group CCOP, Bennington, VT—L. H. Maurer, MD, supported by CA35091; Missouri Baptist Medical Center, St Louis, MO—A. P. Lyss, MD, N/A; Rhode Island Hospital, Providence, RI—W. Sikov, MD, supported by CA08025; Roswell Park Cancer Institute, Buffalo, NY—E. Levine, MD, supported by CA02599; Southeast Cancer Control Consortium Inc. CCOP, Goldsboro, NC—J. N. Atkins, MD, supported by CA45808; State University of New York Upstate Medical University, Syracuse, NY—S. L. Graziano, MD, supported by CA21060; The Ohio State University Medical Center, Columbus, OH—C. D. Bloomfield, MD, supported by CA77658; University of Chicago, Chicago, IL—G. Fleming, MD, supported by CA41287; University of Iowa, Iowa City, IA—G. Clamon, MD, supported by CA47642; University of Nebraska Medical Center, Omaha, NE—A. Kessinger, MD, supported by CA77298; University of North Carolina at Chapel Hill, Chapel Hill, NC—T. C. Shea, MD, supported by CA47559; University of Tennessee Memphis, Memphis, TN—H. B. Niell, MD, supported by CA47555; Vermont Cancer Center, Burlington, VT—H. B. Muss, MD, supported by CA77406; Wake Forest University School of Medicine, Winston–Salem, NC—D. D. Hurd, MD, supported by CA03927.
Received for publication May 24, 2006. Revision received August 15, 2006. Accepted for publication August 30, 2006.
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References |
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