Japanese Journal of Clinical Oncology Advance Access originally published online on July 26, 2006
Japanese Journal of Clinical Oncology 2006 36(9):547-551; doi:10.1093/jjco/hyl062
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© 2006 Foundation for Promotion of Cancer Research
Phase II Study of Combination Chemotherapy with Gemcitabine and Irinotecan in Patients with Advanced Non-Small-Cell Lung Cancer Previously Treated with Platinum-Containing Chemotherapy Regimens
1 Thoracic Oncology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, 2 Respiratory Medicine, Kanazawa University Hospital, Kanazawa, 3 Department of Respiratory Medicine, International Medical Center of Japan, Tokyo, 4 Department of Respiratory Medicine, Kouseiren Takaoka Hospital, Takaoka, Toyama and 5 Department of Internal Medicine, Fukui Saiseikai Hospital, Fukui, Japan
For reprints and all correspondence: Makoto Nishio, Thoracic Oncology Center, Cancer Institute Hospital, Ariake 3-10-6, Koto-ku, Tokyo 135-8550, Japan. E-mail: mnishio{at}jfcr.or.jp
Received November 5, 2005; accepted June 8, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Objective: The aim of this study was to evaluate the efficacy and toxicity of gemcitabine combined with irinotecan in patients with previously treated non-small-cell lung cancer (NSCLC).
Methods: Patients who failed to respond to platinum-containing first-line chemotherapy were enrolled and treated with gemcitabine 1000 mg/m2 and irinotecan 150 mg/m2 on days 1 and 15. Cycles were repeated every 4 weeks.
Results: Twenty-seven of 30 registered patients were evaluated. There were previous combination treatments of platinum and taxane regimens in 21 out of 27 patients, with 17 patients treated with carboplatin and paclitaxel and 4 patients treated with cisplatin or carboplatin and docetaxel. A total of 87 cycles was administered and the median number of cycles administered per patient was 3.5 cycles. Objective responses were observed in 5 out of 27 patients (18.5%). No severe hematologic and non-hematologic toxicities were observed (grade 3 leukopenia in 3 patients; grade 3 anemia in 3 patients; grade 3 thrombocytopenia in 2 patients; grade 3 diarrhea in 1 patient). The median survival time was 7.7 months and 1-year survival rate was 34.8%.
Conclusion: Bi-weekly gemcitabine and irinotecan was well tolerated and had an acceptable response rate and a reasonable median survival time for patients with NSCLC who had previously been treated with platinum-based chemotherapy.
Key Words: gemcitbabine • irinotecan • phase II
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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First-line cisplatin-based chemotherapy has been shown to confer a survival advantage in inoperable locally advanced and metastatic non-small-cell lung cancer (NSCLC) (1). In the last decade, several third-generation chemotherapy agents, such as paclitaxel, gemcitabine, docetaxel, vinorelbine and irinotecan, have shown a good single-agent activity with favorable toxicity profiles and innovative, non-overlapping mechanisms of action. Their use may allow for novel approaches to second-line chemotherapy for recurrent NSCLC (2,3). The combination regimens of these agents with a platinum compound are considered as the standard first-line treatment based on results of recent phase III studies (4,5). Two recent randomized studies have demonstrated that second-line docetaxel prolonged the survival and clinical benefit, as well as improved the quality of life compared with best supportive care (6) or monotherapy with vinorelbine or ifosfamide (7). However, these benefits of docetaxel are limited. The most common first-line combined regimen is platinum and taxane (paclitaxel or docetaxel) (4). If taxane is used as the first-line treatment, there is no consensus on the optimum second-line treatment for NSCLC. Therefore, development of clinically effective novel second-line chemotherapy for patients treated with taxane and platinum is necessary.
Gemcitabine, a nucleoside analog, and irinotecan (CPT-11), a water-soluble camptothecin derivative, have been reported to have first-line treatment response rates (RRs) ranging from 20 to 30% in patients with locally advanced or metastatic NSCLC (4,8,9). In addition, a synergistic effect has been demonstrated in an experimental study that used a combination of these two drugs (10). We previously conducted a phase I study that administered the gemcitabine combined with CPT-11 using every 2-week administration regimen. Only minor toxicities were noted for the 1000 mg/m2 gemcitabine and 150 mg/m2 CTP-11 combination regimen. In addition, there was also good adherence of treatment and this combination was found to be potentially active for NSCLC (11). Based on our phase I study, this phase II trial was conducted to evaluate the efficacy and the safety of bi-weekly gemcitabine and CPT-11 combination in patients with NSCLC who were previously treated with platinum-based chemotherapy by an open-label, non-randomized and multi-institutional trial.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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PATIENTS
Patients with histologically or cytologically confirmed unresectable or metastatic NSCLC, were entered into the trial, provided that they their age was between 20 and 74 years of age, had a performance status (PS) of 0–2 (Eastern Cooperative Oncology Group), a life expectancy of at least 3 months and adequate bone marrow function (leukocyte count >4000/µl, neutrocyte count >2000/µl, platelet count >100 000/µl and hemoglobin level >9.5 g/dl), hepatic function (AST and ALT levels <3.0 times the normal upper range limit and bilirubin levels < the normal upper range limit) and renal function (creatinine level < the normal upper range limit), and gave written informed consent to participate. Patients with concurrent severe cardiac, metabolic or infectious diseases, symptomatic peripheral neuropathy, watery diarrhea, paralytic ileus, intestinal obstruction, and massive pleural effusion or ascitic fluid were excluded. Patients were eligible if they had received one or more platinum-based chemotherapy regimens, regardless of their response to previous treatments.
PRETREATMENT EVALUATION
Staging was conducted within 4 weeks before registration. All patients underwent a medical history and physical examination. Assessment included complete blood cell counts, renal and liver function tests, urinalysis, performance status evaluation, height and weight determination (including weight loss), chest X-rays, chest computed tomography (CT) scans, abdominal echo or CT scans, brain CT scans or magnetic resonance imaging (MRI).
Treatment-related hematological toxicity was evaluated at least once a week and daily in patients with grade 3–4 neutropenia or thrombocytopenia. Patients who received at least one chemotherapy cycle were assessed for toxicity.
Before each cycle, we repeated medical histories, physical examinations, laboratory assessments and toxicity evaluations (NCI-CTC version 2.0).
TREATMENT
Gemcitabine and CPT-11 were purchased from Eli Lilly Japan, Inc., (Kobe, Japan) and Yakult Honsha Co., Ltd., (Tokyo, Japan), respectively. Gemcitabine and CPT-11 were diluted in 100 mL of normal saline and 250 mL 5% glucose, respectively. CPT-11 150 mg/m2 was administered intravenously (i.v.) over a 90-min infusion, followed by gemcitabine 1000 mg/m2 (i.v.) during a 30 min infusion on days 1 and 15. Cycles were repeated every 4 weeks. All patients received prophylactic antiemetic therapy (dexamethasone 8 mg, and serotonin receptor antagonist (5-HT3 antagonist), which was given i.v. over a 30 min period before administration of CPT-11.
The dose levels and treatment schedule were modified to avoid severe adverse effects. If a WBC count less than 3.0 x 109/l, platelet count less than 75 x 109/l, grade 1 or higher, diarrhea, fever higher than 38°C, or a performance status 3 or 4 were observed on the treatment day, treatment was withheld until patients recovered from these toxicities. If there was recovery from the toxicities within 1 week, a reduced dose (125 mg/m2) of CPT-11 and 1000 mg/m2 of gemcitabine were given in the following cycle. Patients who required delays of more than 1 week were withdrawn from the study. During the treatment, if there was grade 4 neutropenia or leukopenia lasting longer than 3 days, neutropenic fever, grade 4 thrombocytopenia, grade 2 peripheral neurotoxicity, grade 3 liver toxicities or grade 3 diarrhea, the dose of CPT-11 was reduced to 125 mg/m2 in the following cycle. Patients requiring more than one dose reduction were removed from the study.
DEFINITION OF RESPONSE
Patients who received at least 1 cycle of therapy were assessed for response. All patients receiving treatment were assessed for toxicity and survival. Treatment response was classified in accordance with the standard World Health Organization criteria for solid tumor (12). A complete response (CR) required the disappearance of all measurable and assessable disease in all disease sites, which included the normalization of abnormal laboratory values and the absence of any new lesions. A partial response (PR) required a greater than 50% decrease in the sum of the products of the perpendicular diameters of all measurable lesions and sites evaluated. Both the CR and PR should be continued for more than 4 weeks. Stable disease (SD) was defined as a decrease of less than 50% as well as an increase of less than 25% in the sum of the products of measurable lesions without the appearance of any new lesions. Progressive disease (PD) was defined as an increase of more than 25% in the sum of the products of the measurable disease or the appearance of any new lesions or the reappearance of any lesion that had disappeared.
STATISTICAL CONSIDERATIONS
The primary end point was the objective tumor RR.
A Simon's minimax two-stage phase II design (13) was used. A target RR of 30% was deemed sufficient to warrant further study, whereas an RR 10% was insufficient for further investigation. This trial design therefore called for 15 assessable patients to be entered onto the first stage of the trial. If one or more responses were observed among these initial patients, an additional 10 assessable patients would be entered. If five or more responses were observed among 25 assessable patients, the treatment would be considered worthy of further consideration. If fewer than five responses were observed, this combination chemotherapy would not be considered for further testing. Assuming a dropout rate of 20%, a sample size of 30 patients provided an 
error = 0.05 and ß error = 0.2. The accuracy of estimating objective RR provided a maximum 95% confidence interval (CI) width of 34.6%. Survival curves were estimated by the method of Kaplan and Meier.
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RESULTS |
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PATIENT CHARACTERISTICS
From October 2001 to February 2003, 30 pretreated patients with NSCLC were enrolled. Patient characteristics are listed in Table 1. Of the 30 patients enrolled, 3 patients were ineligible because 2 patients had no measurable disease and a patient had started the treatment before registration. The median age was 61 years (range, 34–74 years). PS values were 0 in 7 patients, 1 in 14 patients and 2 in 6 patients. Sixteen patients had adenocarcinoma and 6 had squamous cell carcinoma.
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All patients had previously received platinum-based chemotherapy, and 21 of the 27 patients had been treated with a combination of taxane and platinum compound regimens. Seventeen patients received carboplatin and paclitaxel and four patients were treated with cisplatin or carboplatin and docetaxel. Responses to prior chemotherapy were no CR, 14 PR, 6 SD and 10 PD. Fourteen patients concluded prior chemotherapy less than 12 weeks before entering this study and 13 patients concluded prior chemotherapy more than 12 weeks before entering this study. Median duration from prior chemotherapy was 11.6 weeks.
RESPONSE AND SURVIVAL RATE TO TREATMENT
Twenty-seven patients were assessable for response. Five patients (18.5%) achieved PR, 9 patients (33.3%) had SD and 13 (48.1%) had PD. No CR was observed. Overall RR was 18.5% (95% CI, 3.9–33.2%). Prior responses of 5 PR patients were 2 SD and 3 PR. Duration from prior chemotherapy of 5 PR patients were 38, 18, 11, 9 and 10 weeks, respectively.
The median overall survival time (MST) was 7.7 months (range, 1–18 months), and 13 patients (49%) were dead after a median follow-up period of 12 months (range, 1–15 months). The actuarial 1-year survival was 34.8% (Fig. 1).
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ADHERENCE TO TREATMENT
A total of 87 chemotherapy cycles were administered. The median number of cycles administered was 3.5 (range, 1–12 cycles). Twenty cycles (22.7%) were delayed for 1–14 days (median, 3 days). The reasons for the treatment delays were requests by patients unrelated to the disease or treatment (15 cycles), grade 2 leukopenia (2 cycles) and non-neutropenic infections (3 cycles). Dose reduction was necessary in 4 patients, (2 patients due to leukopenia; 1 patient due to grade 3 diarrhea; 1 patient due to non-neutropenic infection).
HEMATOLOGIC AND NON-HEMATOLOGIC TOXICITY
Toxicity was evaluated in 27 patients and in 87 chemotherapy cycles (Table 2). There was no severe hematologic toxicity. Grade 3 leukopenia was observed in only 3 patients (10%) and no patients developed febrile neutropenia. Grade 3 anemia was observed in 4 patients (13.3%) and grade 3 thrombocytopenia occurred in 2 patients (6.7%). No patient required transfusions and no thrombopenic episode was complicated by hemorrhage. Non-hematologic toxicity was also mild (Table 2). Grade 3 nausea/vomiting was observed in 1 patient (3.3%), grade 3 diarrhea in 1 patient (3.3%) and grade 3 liver toxicities in 1 patient (3.3%). One patient (3.3%) reported grade 3 dyspnea. There were no grade 4 hematologic or nonhematologic toxicities and no deaths occurred due to toxicity.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Recently, there has been an extension of the role of second-line chemotherapy in the treatment for NSCLC. This treatment strategy is mainly due to the availability of third-generation agents that have a favorable toxicity profile as well as non-overlapping mechanisms of action. Through this study, we would like to address the feasibility and efficacy of doublets (CPT-11 and gemcitabine) of third-generation anti-neoplastic agents in patients with previously treated NSCLC. The rationale for the development of this study includes the results that have been observed for the in vitro synergistic interactions for these two agents when given in combination (10,14). Furthermore, the toxicities of these agents have been shown not to overlap [i.e. dose limiting toxicity (DLT) for CPT-11 is diarrhea while the DLT for gemcitabine is thrombocytopenia] (15–17).
Our present study showed that there was an acceptable safety profile for this combination with no severe toxicities. Notable points observed were the low rate of myelosuppression and diarrhea (2 patients with grade 3 thrombocytopenias; 3 patients with grade 3 leukopenias; 1 patient with grade 3 diarrhea). Mild myelosuppression could potentially be explained by the lower dose intensity of gemcitabine used (two-thirds of the recommended single-agent dose). Although dose density of CPT-11 (150 mg/m2 bi-weekly) was the same as the recommended single-agent dose (100 mg/m2 weekly), a low incidence of diarrhea was observed. This reason could be explained by the bi-weekly administration of CPT-11. Despite the tolerability of this regimen, our bi-weekly combination achieved good efficacy in patients with previously treated NSCLC. Notably, there was favorable response to NSCLC patients who were given platinum and taxane as their first-line treatment (4 of 21 patients had PR).
Several phase I and II studies that examined the combination of gemcitabine and CPT-11 in NSCLC have been reported (18–20). In these studies, the doses of CPT-11 and gemcitabine were 150–180 mg/m2 and 1000–1500 mg/m2, respectively, and these studies reported similar results with an RR of 11–18.5%, MST of 7–8.1 months and a 1-year survival rate of 20–36%. Toxicity profiles were also noted to be mild and the adherence of these studies was favorable.
Because our study was a phase II study, it was not possible to draw conclusions regarding a potential higher efficacy for the combination administration, comparing the 75 mg/m2 single-agent docetaxel administered every 3 weeks. However, the high RR (18.5%), MST of 7.7 months and 1-year survival rate of 34.8% are notable, especially considering the low toxicities. Therefore, our regimen is encouraging for further pursuing randomized phase III evaluations in patients with previously treated NSCLC.
Also of interest is a recently reported meta-analysis of non-platinum-based chemotherapy, in which comparisons with platinum-based chemotherapy resulted in a similar 1-year survival in advanced NSCLC patients and a better tolerability (21). Therefore, this low toxic and active non-platinum-based chemotherapy regimen might be a kind of treatment option for the first-line chemotherapy in NSCLC patients who are not suitable for cisplatin-containing regimens because of functional status or comorbid diseases in elderly patients.
In conclusion, bi-weekly CPT-11/gemcitabine is an active combination regimen with mild toxicity that can be used in advanced NSCLC patients who were previously treated with platinum-containing chemotherapy.
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References |
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