Japanese Journal of Clinical Oncology 30:435-439 (2000)
© 2000 Foundation for Promotion of Cancer Research
A Phase II Study of a Daily x4 Schedule of Vinorelbine Plus Cisplatin for Advanced Non-small Cell Lung Cancer
Departments of 1Internal Medicine and 2Radiology, College of Medicine, Catholic University of Korea, Seoul, Korea
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Because dose intensity may be important as a determinant response to vinorelbine, we explored the possibility of increasing the dose intensity of vinorelbine on a daily x4 schedule.
Methods: Between February 1998 and March 1999, 31 patients with previously untreated advanced non-small cell lung cancer were enrolled. Vinorelbine 15 mg/m2 and cisplatin 20 mg/m2 were administered intravenously daily for 4 days and repeated every 21 days.
Results: A total 96 cycles were administered (median 3, range 1–6); 42% of vinorelbine and 39% of cisplatin injections were dose-reduced or delayed owing to toxicity. The actual dose intensity (DI) of vinorelbine was 17.7 mg/m2/week and that of cisplatin was 24 mg/m2/week. These figures represent 88 and 90% of the theoretical DI, respectively. The overall response rate was 40% (12/30, one CR). The main toxicity was myelosuppression: granulocytopenia WHO grade 3 and 4 in 24 patients (77%) and thrombocytopenia grade 3 in two patients (6%). The non-hematological toxicity was mild and tolerable. After a median follow-up of 7.5 months (range 3–21 months), the median progression-free survival and overall survival times were 5 months (95% CI, 3.8–6.2) and 8 months (95% CI, 4.5–11.5), respectively.
Conclusions: This regimen has a comparable therapeutic activity in patients with advanced lung cancers. However, despite supportive care there were excessive hematological toxicities. In view of increased toxicity and similar efficacy, this regimen is not indicated outside a clinical trial.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Lung cancer is the leading cause of death from malignant diseases. More than 70% of patients with non-small cell lung cancer (NSCLC) are inoperable at the time of presentation because of either locally advanced or distant metastasis (1). The prognosis of patients with advanced NSCLC is poor and their treatment options are limited. However, treatment with chemotherapy has been associated with a modest but significant survival advantage when compared with the best supportive care (2–6). Recently, several new drugs such as vinorelbine, paclitaxel, docetaxel and gemcitabine have demonstrated a promising antitumor activity against NSCLC, with documented response ranging from 14 to 38% (7,8).
Vinorelbine (Navelbine, Pierre Fabre Medicament, Boulogne-sur-Seine, France) is a new semi-synthetic Vinca alkaloid with documented activity in NSCLC. Phase I studies of vinorelbine given on a weekly basis as an i.v. bolus indicated a maximum tolerated dose (MTD) ranging from 30 to 35 mg/m2/week (9). The recommended dose for phase II studies was a weekly i.v. bolus dose of 30 mg/m2. Thus far, only this schedule of administration has been extensively studied in current oncological practice (10–12). A few randomized trials showed that the combination of vinorelbine and cisplatin was superior to single-agent cisplatin or vinorelbine in the treatment of advanced NSCLC (10,13,14). Vinorelbine was usually given as a weekly i.v. bolus in these trials and the major dose-limiting toxicity when given weekly was myelosuppression with minimal neurological toxicity. Even with growth factor support, many patients were unable to receive vinorelbine on day 15 owing to neutropenia. In an attempt to ameliorate the neutropenia and dose delays encountered with weekly i.v. vinorelbine, alternative regimens of vinorelbine were conducted (15,16).
With a long half-life of 27.7–43.6 h (9), it is likely that daily x4 administration will lead to a progressive increase in vinorelbine level. A 4-day continuous i.v. infusion of vinorelbine was explored in patients with advanced breast cancer and the results showed that the response was correlated with dose intensity (17). Therefore, we initiated a phase II clinical trial of vinorelbine plus cisplatin given daily for four consecutive days every 3 weeks in patients with advanced NSCLC to explore the possibility of improving dose intensity. The objective was to determine the clinical activity and toxicity of this schedule.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patient Population
Patients with unresectable, histologically or cytologically confirmed, stage IIIB or IV NSCLC, with two-dimensionally measurable disease and who were less than 75 years of age were enrolled. Other eligibility criteria included World Health Organization (WHO) performance status 0–2; no prior chemotherapy; adequate bone marrow function [absolute granulocyte count (AGC) >1500/dl, platelets >120 x 109/l], normal renal (serum creatinine <1.5 mg/dl) and hepatic (serum bilirubin <1.5 mg/dl) function; absence of active infection; and no overt medical diseases. Prior radiation therapy was permitted, provided that the measurable lesions were outside the field of radiation. Brain metastases were not allowed. This trial was approved by the ethical committees of the hospital and all patients gave their informed consent to participate in the study.
Patient Evaluation
Pretreatment evaluation included a complete medical history and physical examination; a complete blood cell (CBC) count with differential and platelet count; a standard biochemical profile; an electrocardiogram; chest X-rays; computed tomographic scans of the chest, abdomen and brain; and a bone scan. During treatment, a CBC count with differential and platelet count was performed weekly; in the case of grade 4 neutropenia or thrombocytopenia, the CBC count was performed daily until the AGC was >1000/dl and platelets were >50 000/dl. A detailed medical history was taken and a complete physical examination was performed before each course of treatment to document symptoms of disease and toxicities of treatment. Biochemical tests, ECG and chest X-rays were performed every 3 weeks. Lesions were measured after each cycle if they were assessable by physical examination or by chest X-ray; lesions assessable by computed tomographic scans were evaluated after every two courses.
Treatment
Vinorelbine was given at a dose of 15 mg/m2 by rapid intravenous injection over 6–10 min and cisplatin at 20 mg/m2 by intravenous infusion over 60 min daily for four consecutive days, and this was repeated every 21 days. Patients were given pretreatment intravenous hydration of at least 1 l over a 4 h period. Owing to the emetogenic potential of cisplatin, ondansetron was given 8 mg intravenously 30 min before the start of the cisplatin infusion. Patients with progressive disease at any time were withdrawn from the study; patients with stable disease received a maximum of six cycles, whereas patients with a complete or partial response were treated until disease progression. Dose-adjustment criteria were based on hematological parameters. Patients were required to have an AGC of 
1500/µl and a platelet count of 100 000/µl to begin the next cycle of chemotherapy. If a patient’s neutrophil and platelet counts did not meet these criteria on day 21, therapy was delayed until adequate count recovery. For patients who required 28 days to recovery, doses of vinorelbine were reduced by 25% in the subsequent treatment cycle. Granulocyte colony-stimulating factor (G-CSF) was permitted but not mandated after the first course of treatment for patients with grade 3 or 4 neutropenia or febrile neutropenia. G-CSF was given at a dose of 5 µg/kg/day beginning 24 h after completion of chemotherapy and continuing until the total granulocyte count was >1000/µl. G-CSF was not given on the day chemotherapy was administered.
Response and Toxicity Criteria
Standard WHO criteria were used for response determination. A complete response (CR) required the disappearance of all measurable and assessable disease in all disease sites, including normalization of abnormal laboratory values with no new lesions. A partial response (PR) required a >50% decrease in the sum of the products of the perpendicular diameters of all measurable lesions and sites evaluated. Both CR and PR had to be maintained for >4 weeks. Stable disease (SD) was defined as a decrease of <50% an increase of <25% in the sum of the products of measurable lesions without the appearance of any new lesion. Progressive disease (PD) was defined as an increase of >25% in the sum of the products of the measurable disease or the appearance of any new lesions. Toxicities were graded according to the WHO guidelines.
Criteria for removal of patients from study included progression of disease, unacceptable toxicity, a delay in treatment of >4 weeks, requirement for palliative radiotherapy or patient refusal. Appropriate procedures were followed with regard to reporting all unexpected or fatal toxicities.
Statistical Methods
A two-stage design (18) was adopted. The objective response rate was the primary efficacy end-point. After the first 15 patients assessable for response, response status was assessed. If extreme results (
1 or 5 responders) were observed, the study would have been terminated. If at first-stage analysis 2–4 responders were observed, 15 additional patients could be included so that the maximum number of response-assessable patients would be 30. Response rates were calculated as the ratio between the number of responders and number of patients assessable for tumor response. Duration of response, time to progression and survival were estimated using the Kaplan–Meier method. Survival was calculated from the first day of treatment to death. Patients still alive were censored at the last day the patient was known to be alive. Time to progression was calculated from the first day of treatment to the date that disease progression was reported. Duration of response was calculated for all responders from the date of first treatment until the date that progressive disease was noted. Confidence intervals (CI) were constructed around the Kaplan–Meier estimates using Greenwood’s variance equation (19). The 95% confidence intervals for response rate were calculated using methods for exact binomial confidence intervals. Dose intensity was calculated by using the method of Hryniuk and Bush (20).
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients’ Demographics
From February 1998 to March 1999, 31 consecutive patients with previously untreated advanced NSCLC were registered. Patients’ characteristics are listed in Table 1; 68% of the patients had a WHO performance status of 0–1 and 52% had stage IV disease. All patients had no prior treatment.
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Response to Treatment
Of 31 eligible patients, 30 were assessable for response. One patient refused clinical and radiological follow-up after the first treatment and was therefore not assessable for response. One CR was observed and 11 patients achieved a PR (overall response, 40%; 95% CI, 21–58%), whereas 12 patients (40%) had SD and six patients (20%) had PD (Table 2). The median duration of response was 4 months (range 1–20 months); the median time to disease progression was 5 months (range 2–21 months). The median overall survival was 8 months (range 3–21 months) and 13 patients died after a median follow-up period of 7.5 months (range 3–21 months); the actuarial 1-year survival was 31% (95% CI, 14–48%) (Fig. 1).
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Compliance with Treatment
A total of 96 chemotherapy cycles were administered with a median number of three cycles per patient (range 1–6 cycles); the median interval between cycles was 21 days (range 21–37 days). Thirty-seven cycles (39%) were delayed for 6–16 days (median 7 days). The reasons for treatment delay were grade 4 neutropenia (27 cycles), grade 3 thrombocytopenia (four cycles), grade 2 asthenia (four cycles) and a patient’s request unrelated to the disease or treatment (two cycles). A 25% dose reduction of vinorelbine was applied in three cycles (3%) because of the prolonged grade 4 neutropenia. At the time of analysis, all patients had stopped treatment for the following reasons: completion of treatment (eight patients) and deterioration of performance status and/or progressive disease (23 patients). The administered average dose intensity for vinorelbine and cisplatin was 17.7 and 24 mg/m2/week, respectively, which correspond to 88 and 90% of the planned dose for each drug.
Hematologic and Non-hematologic Toxicity
Toxicity was evaluated in all patients and in all cycles. Hematologic toxicities are listed in Table 3. Grade 3 anemia and thrombocytopenia were observed in six patients (19%) and two patients (6%), respectively. Grade 3 and 4 neutropenia was observed in three (10%) and 21 (68%) patients, respectively. Nine of these patients developed febrile neutropenia. Twenty-one patients received G-CSF. There were two (6%) toxic deaths because of pneumonia and sepsis during severe neutropenia. Non-hematologic toxicities were generally mild (Table 4). Alopecia was common. Nausea and vomiting occurred frequently; grade 3 or 4 nausea/vomiting occurred in eight patients (26%). Grade 3 constipation and diarrhea occurred in four (13%) and two (6%) patients, respectively. Grade 2 asthenia occurred in two patients (6%). Mild liver enzyme derangement was observed in four patients (13%) and mild renal abnormalities occurred in two patients (6%). Supraventricular ectopic beats were recorded in one patient (3%).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Vinorelbine has shown its most promising clinical activity when administered weekly in clinical trials and early clinical evaluations of vinorelbine predominantly used a weekly i.v. bolus schedule. However, the survival outcomes remain unsatisfactory in advanced lung cancer patients, and the optimal dose and schedule of vinorelbine are yet to be determined (10,13,14).
Over the past decades, the development of cell cycle-dependent agent administration has been pursued on the basis that the prolonged exposure of cancer cells to the agent might be provided by an increase in the therapeutic index. Vinorelbine is a cell cycle-dependent antimitotic agent blocking progression in the G2 and M phases (9,21). Moreover, it has a long terminal half-life, with average values ranging from 27.7 to 43.6 h. It is expected that daily administration might result in prolonged tumor exposure to cytotoxic concentrations and enhanced antitumor activity (9). Jackson (22) reported that the cytotoxicity of Vinca alkaloids appears to be critically dependent on drug concentration. Because we wanted to increase therapeutic efficacy by using different schedules of administration, we initiated this phase II study of daily vinorelbine plus cisplatin for four consecutive days and explored the possibility of the dose intensity of this schedule. Hoffman et al. were able to administer 30 mg/m2 daily x3, which suggests that daily bolus infusion is not associated with unacceptable toxicity in advanced NSCLC patients (23). Toussaint et al. suggested that 4-day continuous infusion of vinorelbine showed that the response was correlated with dose intensity in advanced breast cancer patients (17). However, we chose daily bolus infusion rather than continuous infusion to prevent vesicant complications. The usual recommended infusion time of vinorelbine is within 10 min because of its serious vesicant effect.
The most significant toxicity in trials of a weekly schedule was granulocytopenia. Most of the protocols were amended to allow vinorelbine dose adjustments based on neutropenia. Typically, the vinorelbine dose had to be reduced in week 3 and patients were able to receive 71–77% of the projected vinorelbine dose (10–14). We planned the dose intensity of vinorelbine as 20 mg/m2/week in this study based on the actual dose intensity of weekly schedule trials and we wished to avoid using G-CSF routinely.
Both the high dosage of cisplatin given in a single day and the weekly administration of full doses of vinorelbine resulted in frequent refusals to continue the treatment. Severe emesis, constipation, fatigue and sometimes renal toxicity were the main reasons for this non-compliance (10,13,14). We chose daily x4 infusion of cisplatin rather than single-day infusion to decrease the highly emetogenic toxicity of cisplatin and to increase the convenience of the regimen.
Overall, the response rates for vinorelbine plus cisplatin ranged from 32 to 49% in non-comparative trials (10–14). The trial by Le Chevalier et al. (13) demonstrated a survival advantage with the combination over vinorelbine monotherapy (median survival duration, 40 vs 31 weeks). The survival duration ranged from 22 to 52 weeks with vinorelbine plus cisplatin in comparative trials (10–14). In this trial, a 40% response rate (95% CI, 21–58%) was observed in 30 patients. The median survival time was 8 months. Although it is difficult to compare phase II studies from an efficacy standpoint, the overall survival and response rates for daily vinorelbine plus cisplatin are consistent with the results observed in other phase II trials. The actual dose intensity was 17.7 mg/m2/week for vinorelbine and 24 mg/m2/week for cisplatin in this study. These figures represent 88 and 90% of the planned dose, respectively. However, the actual dose intensity of vinorelbine in this study is only 59 or 71% of the theoretical dose of a standard weekly schedule of 30 or 25 mg/m2/week, respectively. These results with a daily schedule substantiate the proposal that dose intensity–response relationships are schedule dependent with vinorelbine and suggest that a daily schedule may increase the therapeutic index of vinorelbine. However, a more severe hematological toxicity pattern was revealed with this schedule. The most significant toxicity in this trial was granulocytopenia. This was an anticipated side effect based on previous trials with vinorelbine and growth factor was used at the discretion of the clinical investigator to prevent granulocytopenia. However, a significantly higher proportion of patients (78%) than in other comparable trials experienced grade 3 or 4 neutropenia and 29% experienced febrile episodes requiring hospitalization. Thirty-four cycles out of a total of 96 cycles required a dose reduction or delay in chemotherapy due to grade 3 or 4 myelosuppression. Two deaths occurred, one as result of sepsis and the other pneumonia, despite the fact that growth factor was used prophylactically. The high incidence of severe hematologic toxicity, inability to increase dose intensity, a relatively smaller proportion of patients with good performance status (WHO PS = 0) and poor compliance of continuing chemotherapy due to toxicity may interfere with the improvement of overall survival. The non-hematologic toxicity of this regimen was trivial. Alopecia was universal but reversible. Nausea and vomiting were moderate but manageable. The neurological tolerance appears better than with a weekly schedule, with <10% of grade 1–2. However, a distinctive side effect of this schedule was moderate asthenia. Two patients experienced grade 2 asthenia, which necessitated a delay in chemotherapy.
The data generated by this study resulted in the conclusion that this 4-day schedule of vinorelbine and cisplatin has comparable therapeutic activity. However, despite supportive care there were excessive hematologic toxicities. In view of the increased toxicity and similar efficacy, this regimen is not indicated outside a clinical trial.
Acknowledgment
This study was supported by Boo Kwang Pharmaceutical Company of Korea.
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FOOTNOTES |
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+ For reprints and all correspondence: Kyung Shik Lee, Department of Internal Medicine, College of Medicine, Catholic University of Korea, Kangnam St. Mary’s Hospital, 505 Banpo-dong, Seocho-gu, Seoul 137–040, Korea. E-mail: jymama@cmc.cuk.ac.kr
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Received June 26, 2000; accepted July 25, 2000.
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