Japanese Journal of Clinical Oncology 31:596-600 (2001)
© 2001 Foundation for Promotion of Cancer Research
A Phase I/II Study of Cisplatin and Vinorelbine Chemotherapy in Patients with Advanced Non-small Cell Lung Cancer
Division of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: A combination of cisplatin and vinorelbine chemotherapy is effective in cases of advanced non-small cell lung cancer, but the optimum administration schedule for both drugs has not yet been defined. The aim of this study was to determine the maximum dose of vinorelbine that can be tolerated while receiving a fixed dose of cisplatin every 3 weeks and to observe the response in Japanese patients with advanced non-small cell lung cancer who had not previously received chemotherapy.
Methods: Cisplatin was given at a dose of 80 mg/m2 on day 1. Vinorelbine was administered on days 1 and 8 at a starting dose of 25 mg/m2 that was then increased by 5 mg/m2 increments. This treatment was repeated every 3 weeks.
Results: Twenty-one patients received a total of 54 chemotherapy cycles consisting of three different vinorelbine dosages. Toxicity and efficacy were evaluated in all of the patients. The main dose-limiting toxicity was neutropenia. Grades 3–4 leukopenia and neutropenia were observed in 57% and 86% of all cycles, respectively. These conditions were reversible and did not result in death from toxicity. The most severe non-hematological toxicity symptom was a grade 3 infection and reaction at the site of injection. The maximum tolerated dose of vinorelbine was 35 mg/m2. The objective response was noted in one of six patients at dose level 1, in four of 12 patients at dose level 2 and in two of three patients at dose level 3.
Conclusion: The recommended doses were 80 mg/m2 for cisplatin and 30 mg/m2 for vinorelbine. The combination of cisplatin and vinorelbine repeated every 3 weeks is well tolerated and has shown promising anti-tumor activity against non-small cell lung cancer.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Lung cancer, the leading cause of death from cancer in many countries, has a poor prognosis, with 5-year survival rates of 13% for all stages combined and 2% for stage IV diseases. Non-small cell lung cancer (NSCLC) accounts for 75–85% of all lung tumors (1). Although chemotherapy plays a critical role in improving survival in patients with NSCLC, only five drugs that produced a response rate of more than 15% against NSCLC were available prior to 1990 (2).
Recently, several new agents with novel mechanisms have been shown to be effective in treating lung cancer (3). Of these drugs, vinorelbine (VNB) is a unique semisynthetic Vinca alkaloid (4). A combination of cisplatin (CDDP) and VNB repeated every 4 weeks has been shown to produce a significant survival advantage over chemotherapy regimens using CDDP and vindesine, VNB alone or CDDP alone in two large randomized phase III studies (5,6). The optimum schedule for this combination, however, has not yet been defined.
Several recent studies using a 3-week cycle of CDDP and VNB treatment suggest that this schedule is less toxic than the conventional 4-week schedule. The frequency of grades 3 and 4 neutropenia was 11–38% using the 3-week cycle (7,8), compared with 75–88% for a 4-week cycle (5,6,9,10), although these figures were not obtained by randomized trials. Only a few randomized trials comparing 3- and 4-week schedules have been performed, but the 3-week schedule seems to have had a better toxicity profile and a higher dose intensity than the 4-week schedule when a combination of CDDP and gemcitabine was used (11).
The primary objective of this study was to determine the maximum tolerated dose (MTD) and the recommended dose for VNB when combined with CDDP every 3 weeks in chemo-naive Japanese patients with advanced NSCLC. The secondary objective was to observe the response of the tumor to this combination.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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All patients fulfilled the following eligibility criteria: pathologically proven advanced inoperable NSCLC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, age
74 years, no prior chemotherapy, presence of measurable or evaluable lesions, adequate hematological function (WBC count 
4000/µl, neutrophil count 2000/µl, hemoglobin level 9.0 g/dl, platelet count 10x104/µl), renal function (serum creatine 1.5 mg/dl, 24 h creatinine clearance 60 ml/min), hepatic function (total bilirubin 2.0 mg/dl, serum transaminases 2.0xupper limit of normal range) and pulmonary function (PaO2 60 Torr). Written informed consent was obtained from all of the patients. Patients with symptomatic brain metastases were excluded from the study. Baseline pretreatment evaluations included a complete history, physical examination and laboratory tests, chest X-ray, electrocardiogram, computed tomography (CT) scans of the chest and brain, ultrasonography or CT scan of the abdomen and a radionuclide bone scan, if medically indicated.
VNB, diluted in 50 ml of normal saline, was administered intravenously over 10 min on days 1 and 8. The vein was then washed out with a further 100 ml of normal saline over a period of 20 min. Following the VNB injection, the CDDP was intravenously administered at a fixed dose of 80 mg/m2 over 1 h on day 1, with appropriate hydration. Serotonin agonist antiemetics and steroids were also administered prophylactically against drug-induced emesis. This treatment was repeated every 3 weeks. Three dose levels of VNB were planned. The starting VNB dose was 25 mg/m2; this dose was then increased in 5 mg/m2 increments.
Patients were treated with at least two cycles of chemotherapy unless their disease progressed, they developed unacceptable drug toxicity or they withdrew their consent. On day 1 of each 3-week cycle, patients had to exhibit a WBC count of 4000/µl, a neutrophil count of 2000/µl and a platelet count of 10x104/µl. The administration of VNB on day 8 was cancelled if the WBC count was <2000/µl or the platelet count was <5x104/µl.
Toxicity was graded according to the Japanese edition of the National Cancer Institute Common Toxicity Criteria, issued in 1999 (12). Six patients were scheduled to enter the study at each dose level and the MTD was defined as a dose level that produced any of the following dose-limiting toxicity (DLT) in three or more of six patients: any non-hematologic toxicities grade 3, except for alopecia, nausea and vomiting; platelet count 2x104/µl; grade 4 leukopenia; persistence of grade 4 neutropenia for more than 4 days; grade 4 neutropenia with fever 38°C or with infection; and the omission of VNB on day 8. If grade 4 leukopenia, neutropenia or febrile neutropenia was noted, the use of granulocyte colony-stimulating factor was permitted. The recommended dose was defined as the dose level below the MTD. All treatment cycles were analyzed to determine the DLT and MTD, although the decision to increase the dose was made at the end of the first cycle. The dose could be reduced for subsequent cycles in patients who experienced a DLT, but this decision was left to the discretion of the physician in charge of the patient.
The response was evaluated according to the World Health Organization’s (WHO) criteria, issued in 1979 (13). A minimum duration of 4 weeks was required to document a response. The best response was recorded for each patient. A complete response (CR) was defined as the disappearance of disease at all sites and a partial response (PR) was defined as a reduction of at least 50% in the sum of the products of the two largest perpendicular diameters of all measurable lesions initially selected as targets, without progression to any other site. A stable disease was defined as a decrease of <50% or an increase of <25% in the sum of the products of the two largest perpendicular diameters of all measurable lesions initially selected as targets. Progressive disease was defined as an increase of 25% in the sum of the products of the two largest perpendicular diameters of all measurable lesions initially selected as targets or the appearance of a new lesion.
The protocol was approved by the institutional review board of the National Cancer Center.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Twenty-one patients with advanced NSCLC were enrolled in this trial between March and October 2000. The patients’ characteristics are summarized in Table 1. A total of 54 chemotherapy cycles were administered, with a median number of three cycles per patient (range, one to four). Of 21 patients, 17 (81%) received more than two cycles of chemotherapy and four (19%) received only one cycle of chemotherapy. The reasons for discontinuation of the treatment in these patients were severe toxicity in one, decreased performance status in one and no therapeutic effect obtained in two patients. All patients and cycles were assessed for toxicity and response.
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The main toxicity of the combined chemotherapy regimen was myelosuppression (Table 2). Grade 4 neutropenia and leukopenia were observed in a dose-dependent manner. Anemia and thrombocytopenia were relatively mild and no transfusions were required.
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Febrile neutropenia occurred in one (17%) out of six patients receiving a level 1 dose, two (17%) out of 12 patients receiving a level 2 dose and two (67%) out of three patients receiving a level 3 dose. Of the three patients who received a level 3 dose, two also developed an infection (Table 3). These infectious episodes, however, were reversible and no deaths from toxicity occurred. The third patient who received a level 3 dose experienced a febrile episode, with a normal WBC count (4800/µl) but an elevated CRP value (6.6 mg/dl), on day 20 of the first cycle. We considered this symptom to be an infection and administered intravenous antibiotics, although the focus was unknown. Another patient who received a level 1 dose was unable to receive VNB on day 8, because he developed an infection.
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One patient who received a level 2 dose experienced severe superficial phlebitis with ulceration during the first cycle (grade 3 reaction at the site of injection); this patient was cured of the reaction and did not have any functional defect. Grade 3 hyponatremia during the first cycle of each dose level was reversible. Another patient who received a level 1 dose developed paroxysmal atrial fibrillation on day 2 of the first cycle. She had a past history of the same attack and the condition improved with the administration of digoxin after a few days. No other severe non-hematological toxicity symptoms were observed. Consequently, DLT was observed in two of six patients receiving a level 1 dose (febrile neutropenia and omission of VNB on day 8), two of 12 patients receiving a level 2 dose (grade 4 leukopenia and grade 3 reaction at injection site) and all three patients receiving a level 3 dose during the first cycle (febrile neutropenia, febrile neutropenia and grade 3 infection).
To avoid excessive toxicities in subsequent cycles, dose modification was performed in only two (4.3%) of the 46 cycles of level 1 and 2 doses, but in five (62.5%) of the eight cycles of level 3 doses. The second cycle could be initiated on the planned day of the first cycle (day 22) in 50 and 58% of patients receiving level 1 and 2 doses, respectively. We finally decided that the MTD and recommended dose for VNB were 35 and 30 mg/m2, respectively.
An overall response was observed in one of six patients receiving a level 1 dose, four of 12 patients receiving a level 2 dose and two of three patients receiving a level 3 dose.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The present study demonstrated that a combination of CDDP and VNB repeated every 3 weeks was well tolerated and showed promising anti-tumor activity for the treatment of advanced NSCLC.
The frequency of grades 3–4 neutropenia in this trial was much higher than that in other trials using the same schedule (7,8). In addition, the frequency of febrile neutropenia was also slightly higher than previously reported (16.7% for dose level 2, Table 4), although the condition was reversible and no deaths from toxicity occurred. This difference in toxicity between Japanese and European populations might arise from racial differences in the activity of CYP3A4, by which VNB is predominantly metabolized (14). However, the frequency of variant alleles of the CYP3A4 gene, the amount of CYP3A4 protein in liver specimens and the level of CYP3A4 activity measured by nifedipine oxidation does not differ between Caucasian and Japanese populations (15–19). Hence the cause of the difference in myelotoxicity severity remains unclear.
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Of the non-hematological toxicity, phlebitis is one of the most common conditions associated with VNB toxicity. The frequency of phlebitis at the injection site can be reduced by shortening the infusion time from 20 min to between 6 and 10 min (20). Smaller volumes of solution in which VNB is diluted have also been reported to reduce the incidence of phlebitis (21). Based on these observations, we injected the VNB dose over 10 min diluted in 50 ml of normal saline. In addition, the vein was then washed with normal saline. In spite of the reported prophylactic measures for phlebitis, however, a toxic response of grade 2 or more was observed in 33% of the patients. Hence further studies are needed to lessen the incidence of phlebitis.
The MTD in this trial was determined to be dose level 3. Although the toxicity observed at dose level 2 was reversible and tolerable, the second cycle was initiated on the planned day in only seven (58%) of the 12 patients receiving this dosage. This finding results from our strict criteria for initiating the second cycle, particularly our criteria that the WBC count be 4000/µl and the neutrophil count 2000/µl on day 1. If our criteria for initiating the second cycle of treatment had been a WBC count of 3000/µl or a neutrophil count of 1500/µl, as documented in other reports (6,7), the second cycle of treatment would have been initiated on the planned day in 10 (83%) of the 12 patients receiving a level 2 dose. Thus, we defined the recommended VNB dose as a level 2 dose (30 mg/m2) on days 1 and 8.
This recommended dose of VNB determined in the combination chemotherapy was higher than the approved maximum dose of a single agent of VNB, 25 mg/m2/week when used weekly (22). This discrepancy might result from (i) the difference in administration schedule of VNB, (ii) the patients’ variability because of the small sample size or (iii) the difference in the criteria and definition of dose-limiting toxicity (DLT), MTD or recommended dose.
In conclusion, this phase I/II study showed that CDDP and VNB could be administered in a 3-week cycle with an acceptable toxicity level in Japanese patients to produce a significant response rate in patients with advanced NSCLC.
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FOOTNOTES |
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+ For reprints and all correspondence: Ikuo Sekine, Department of Medical Oncology, National Cancer Center Hospital, 1–1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan. E-mail: isekine@.gan2.ncc.go.jp
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Received June 1, 2001; accepted September 3, 2001.
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