Japanese Journal of Clinical Oncology 34:245-249 (2004)
© 2004 Foundation for Promotion of Cancer Research
Gemcitabine and Vinorelbine as Second-line Therapy for Non-small Cell Lung Cancer after Treatment with Paclitaxel plus Platinum
Department of Internal Medicine, Korea Cancer Center Hospital, Seoul, Korea
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: To investigate the activity and feasibility of combination therapy of gemcitabine and vinorelbine for patients with advanced NSCLC after the failure of initial treatment with paclitaxel plus platinum.
Methods: From March 2000 to August 2002, 38 evaluable patients (median age 55 years) with NSCLC, who had failed to recover after treatment with paclitaxel plus platinum, received vinorelbine (30 mg/m2 i.v.) followed by gemcitabine (1000 mg/m2 i.v.), both being administered on days 1 and 8 and recycled every 3 weeks.
Results: Objective responses were as follows: partial response, 8/38 [21%; 95% confidence interval (CI) 8–23%]; and stable disease, 21/38 (55%). Median time to progression was 3.9 months and the median overall survival was 8.1 months. Grades III and IV neutropenia were seen in 17 and 11% of patients, respectively.
Conclusion: This combination chemotherapy with gemcitabine and vinorelbine is active and highly tolerable as a second-line therapy for NSCLC.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Lung cancer is a leading cause of death in the world, including Korea, where its incidence is still increasing (1,2). Only a few patients with lung cancer achieve long-term survival (1). During the 1990s, several new drugs with a single activity objective response rate of 15–25% in treating NSCLC were identified; these included docetaxel, paclitaxel, gemcitabine, irinotecan and vinorelbine (3). As a result of these new drug regimens, outcomes improved, with tolerable toxicity profiles, in patients with cancer recurrence or in refractory patients after first-line chemotherapy. Therefore, more patients are now candidates for some form of second-line treatment.
The role of second-line chemotherapy after an initial treatment with a platinum-based regimen remains largely undefined. However, the first result of a comparative randomized study with docetaxel versus best supportive care was reported (4), which showed for the first time significant prolongation of patient survival and symptom control.
Docetaxel was the first drug to show a favorable impact on the outcome of patients with NSCLC pretreated with chemotherapy (4). Although favorable responses were found in patients who were resistant to paclitaxel (5), we chose other drugs in the present study.
Gemcitabine used as a single drug showed significant activity and a response rate of 19% without relevant toxicity in patients who had been treated previously with platinum-containing chemotherapy (6). A few trials have evaluated the use of gemcitabine in previously treated NSCLC patients and response rates of 6–25% were observed (6–9).
Variable and conflicting results have been reported in studies of second-line vinorelbine therapy, where responses to single-agent vinorelbine have ranged from 0 to 20% (10–13).
The distinct mechanism of action and demonstrable single-agent activity support the rationale for adding vinorelbine to gemcitabine in treating patients with relapsed NSCLC. A phase III trial in elderly NSCLC patients compared single-agent vinorelbine therapy with gemcitabine plus vinorelbine. In this study, gemcitabine plus vinorelbine therapy showed improvements in both quality of life and median length of survival (14).
On the basis of these findings, we conducted this phase II trial, which aimed at evaluating the efficacy and feasibility of the gemcitabine plus vinorelbine combination regimen in NSCLC patients who had failed on a taxane plus platinum regimen.
The primary end-point of this study was response rate and secondary end-points were progression-free survival and overall survival.
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SUBJECTS AND METHODS |
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Patient Eligibility
Patients with histologically confirmed advanced NSCLC, stages IIIA/IIIB or IV at diagnosis, who had progressed on a paclitaxel plus cisplatin or carboplatin combination regimen and who had never received gemcitabine and vinorelbine were eligible. Eligibility criteria included: (i) ECOG Performance Status (PS)
2; (ii) life expectancy 
3 months; (iii) adequate hematopoietic, liver and renal functions; (iv) progression during or after the completion of prior chemotherapy with a paclitaxel plus cisplatin or carboplatin regimen; (v) absence of active coronary artery disease, unstable diabetes mellitus or peripheral neuropathy grade 2 by the National Cancer Institute Common Toxicity Criteria (NCI-CTC); (vi) no prior irradiation history; (vii) patients with asymptomatic brain metastasis were allowed to enroll, provided they had additional disease sites and did not require immediate whole brain irradiation; and (viii) the presence of two-dimensionally measurable disease. The study was approved according to institutional policies of our ethical committee and written informed consent was obtained from each patient before entry into the study.
Treatment Plan
Eligible patients were treated as follows: vinorelbine was administered at 30 mg/m2 diluted in 100 ml of 0.9% normal saline within 5 min by i.v. infusion, followed by i.v. infusion of gemcitabine at 1000 mg/m2 diluted in 250 ml 0.9% normal saline over 30 min. Both vinorelbine and gemcitabine were administered on the first and eighth days of each cycle and the regimen was recycled every 21 days.
Dose adjustment criteria were based on hematological parameters. Both vinorelbine and gemcitabine doses were 25% reduced for patients with grade 2 neutropenia. Treatment was delayed 1 week for patients with grades 3–4 neutropenia or thrombocytopenia. Treatment was discontinued if the patient experienced grade 2 toxicity more than twice, unacceptable toxicity, refused treatment or withdrew consent.
Response and Toxicity Criteria
Complete and differential blood counts and biochemistry were performed on day 21. A complete evaluation, including physical examination, chest X-ray, complete blood count and laboratory test, had been performed when the patient visited for treatment of their fever or other problems.
The responses of the patients were evaluated according to RESIST guidelines. Tumor response was assessed by clinical evaluation and computed tomography (CT) scans every two treatment cycles. Standard criteria were used for response assessments and all patients were considered as assessable for efficacy and toxicity. Complete response (CR) was defined as the disappearance of all target lesions; partial response (PR), a decrease of at least 30% in the sum of the longest diameters of target lesion; progressive disease (PD), an increase of at least 20% in the sum of the longest diameters of target lesions or the appearance of one or more new lesion; and stable disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Patients with CR or PR required a confirmatory disease assessment at least 4 weeks later. Patients with no confirmed tumor response were not regarded as responders.
Toxicities were assessed according to the National Cancer Institute (NCI) Common Toxicity Criteria 2.0.
Statistical Methods
The trial was designed using Gehan’s two-stage testing procedure. Assuming a true response rate of 10%, 22 patients were initially included. If at least one response was observed, enrollment would then continue to 30 evaluable patients, with a target minimum response of 30% and a maximum width of 36% for the 95% CI. However, the number of patients enrolled was increased to 42 to provide a more accurate estimate of response rate. Progression-free survival and overall survival were measured from the date of first treatment administration to the date of disease progression or death for the former and the date of death for the latter. The Kaplan–Meier method was employed to determine medians and 95% CIs of the time-related parameters.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients’ Characteristics
From March 2000 to August 2002, 46 patients with NSCLC who had recurrent cancers or whose treatment with paclitaxel plus platinum had failed were enrolled into this study at the Korea Cancer Center Hospital.
Characteristics of the patients and their tumors are summarized in Table 1. The median age of the patients was 55 years (range 30–69 years). There were 31 patients with good performance status (ECOG scale 1). Of 40 patients enrolled, one patient rejected further chemotherapy after one cycle and one patient died before the start of chemotherapy. The 38 patients eligible for response and toxicity evaluations underwent 119 cycles of chemotherapy. There were 11 patients (29%) with progressions after first-line chemotherapy and 27 (71%) who were no-response or refractory to first-line chemotherapy (SD or PD). Adenocarcinoma was the most common histopathological finding (58%). Twenty-four patients (63%) had a performance status of 1. All patients received paclitaxel plus platinum chemotherapy (cisplatin 82%, carboplatin 18%) as first-line chemotherapy. Metastases occurred in the liver, bone, lymph nodes and pleura.
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Response and Survival
The overall response rate was 21% (8/38; 95% CI 8–23%). No CR was seen. We defined patients who progressed after response to previous chemotherapy as ‘chemosensitive’ and those with no response to previous chemotherapy as ‘chemoresistant’. Responses were seen in three of 11 chemosensitive patients and five of 27 with no-response and refractory tumors. Stable disease was observed in 21/38 patients (55%) and progressive disease in 9/38 patients (24%).
The median time to progression for all patients was 3.9 months (range 0–21.7+ months) (Fig. 1). For the eight responders, the median time to progression was 7.5 months (range 0–21.7+ months), but for the non-responders, the median time to progression was 2.4 months (range 1.9–14.2+ months) [log-rank, not significant (N.S.)].
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The median overall survival time for all 38 patients, who had a median follow-up period of 14 months, was 8.1 months (range 0.8–23.5+ months) (Fig. 2). For the eight responders, the median overall survival time was 11.1 months (range 2.4–15.9+ months) and for the non-responders, it was 7.9 months (range 0.8–23.5+ months) (log-rank, N.S.).
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The 1 year survival rate was 13.2%. Because of the limited statistical power due to the small subgroup numbers, there were no significant effects of gender, age, disease status at second chemotherapy, performance status, number of metastatic sites and other demographic findings on response and survival.
Toxicity
Toxicities observed during 119 cycles of chemotherapy are shown in Table 2. The median number of cycles received was three (range one to six). The median delivered dose was 890 mg/m2 per week for gemcitabine and 27 mg/m2 per week for vinorelbine, which corresponds to a relative dose intensity of 0.88.
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The principal hematological toxicity observed was neutropenia. Grades 3 and 4 neutropenia were found in 17 and 11 of all chemotherapy cycles, respectively, but febrile neutropenia was seen in only three of 119 cycles in two patients. No treatment-related death was observed. Anemia was common and grades 1 and 2 anemia was seen in 66% of chemotherapy cycles. However, grade 3 anemia was seen in only two patients. Grades 1 and 2 thrombocytopenia were found in 5% of chemotherapy cycles and grades 3 or 4 thrombocytopenia were absent. Mild nausea and vomiting were seen in 35 cycles in 30 patients. Grades 1 and 2 neuropathy were seen in 27 cycles for six patients. This was considered as vinorelbine-induced neuropathy, although the contribution of previously treated paclitaxel cannot be excluded reliably.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The administration of second-line treatment for advanced NSCLC is limited and deserves careful scrutiny because of its poor performance in patients with uncontrollable disease or prolonged disability from prior therapy. Until recently, second-line therapy for patients with advanced NSCLC has not been given much consideration because of its notoriously poor outcome. However, the first randomized trial showing a benefit over best supportive care (BSC) was reported in 1999 (6).
Several conflicting results have been reported in the studies of second-line gemcitabine plus vinorelbine therapy. In one phase II trial, only one of 16 patients showed a response and the projected median survival was 25 weeks (15). However, the relative dose intensity of gemcitabine was 0.73. This result was probably due to scheduling: gemcitabine 1200 mg/m2 was infused on days 1, 8 and 15, but most of the drug due to be administered on day 15 was skipped because of persistent neutropenia, although there was no severe cytopenia. By contrast, in a Greek trial with infusion on the days 1 and 8 and a 3-week cycle, a 22.5% response rate with a median time to progression of 4.5 months was reported (16). The results of those studies indicate that a 3-week repeat schedule of twice-weekly infusions may be appropriate for gemcitabine plus vinorelbine combination second-line chemotherapy. In another trial, using this combination as second- or third-line chemotherapy, 17% of patients achieved a partial response (17). However, even in patients with poor outcomes, toxicities were mild and the therapy was well tolerated (15–17). In our study, combination chemotherapy with gemcitabine and vinorelbine showed a good response rate (21%) with a tolerable toxicity profile. Both gemcitabine and vinorelbine were delivered at relative dose intensities exceeding 0.8.
In a recent phase III trial, the combination of vinorelbine plus gemcitabine was not more effective than single-agent vinorelbine or gemcitabine for elderly NSCLC patients (18). Although this result will be of interest to those involved in clinical practice and will result in savings in terms of costs and toxicity, this trial was for elderly patients in a first-line setting.
As above, the toxicities in this study were milder than in other second-line chemotherapies (19). Other gemcitabine and vinorelbine second-line chemotherapies for NSCLC showed similar good therapeutic outcomes with feasible toxicity profiles (20–22) compared with this study. Therefore, we are going to proceed to phase III trials of gemcitabine plus vinorelbine versus docetaxel alone for patients with NSCLC previously treated with first-line chemotherapy.
In conclusion, non-platinum, non-taxane regimens with active agents such as gemcitabine and vinorelbine could well suit second-line chemotherapy for NSCLC.
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FOOTNOTES |
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+ For reprints and all correspondence: Yeon Hee Park, Division of Medical Oncology, Korea Cancer Center Hospital, 215–4, Gongneung-Dong, Nowon-ku, Seoul 139-706, Korea. E-mail: yhpark{at}kcch.re.kr
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Received January 5, 2004; accepted March 7, 2004
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