1 Medical University of Gdask, Gda
sk, Poland; 2 Hygeia Center, Athens, Greece; 3 Lung Hospital, Poznan, Poland; 4 Aristotle University, Thessaloniki, Greece; 5 Kladno Hospital, Kladno, Czech Republic; 6 Belfort Hospital, Belfort; 7 Clinique Armoricaine de Radiologie, St Brieux, France; 8 Ospedale Maurizio, Bolzano, Italy; 9 Hospital Saint Faron, Meaux, France; 10 Tampere University Hospital, Tampere, Finland; 11 Institut de Recherche Pierre Fabre, Boulogne, France
Received 5 March 2003; revised 6 June 2003; accepted 8 August 2003
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Abstract |
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A phase II trial of alternating i.v. and oral vinorelbine in combination with cisplatin was designed to determine the response rate, safety profile, progression-free survival, overall survival and quality of life (QoL) in advanced non-small-cell lung cancer (NSCLC).
Patients and methods:
Fifty-six chemotherapy-naïve patients received cisplatin 100 mg/m2 and i.v. vinorelbine 25 mg/m2 on day 1, followed by oral vinorelbine 60 mg/m2 on days 8, 15 and 22, every 28 days.
Results:
After an independent review, the response rate was 33% [95% confidence interval (CI) 20% to 46%]. Median progression-free and overall survival were 5.5 months (95% CI 3.76.4) and 8.9 months (95% CI 8.811.7), respectively. The most frequent hematological toxicities were neutropenia (grade 34 in 73% of patients) and anemia (grade 34 in 11% of patients). Grade 34 infections and non-hematological toxicities occurred occasionally. QoL for lung cancer related symptoms was stable or improved.
Conclusions:
The efficacy and safety of the alternating vinorelbine schedule (i.v. on day 1, oral on days 8, 15 and 22) in combination with cisplatin in advanced NSCLC are similar to those of the standard regimen using exclusively i.v. vinorelbine, whereas ease of administration and patient comfort may favor the novel approach.
Key words: chemotherapy, cisplatin, non-small-cell lung cancer, oral vinorelbine
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Introduction |
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The choice of active cytotoxic agents in the treatment of advanced NSCLC is limited. Vinorelbine, a novel vinca-alkaloid, has generated in large phase III trials a response rate of 1220% and a median survival of 30 weeks [35]. The combination of vinorelbine and cisplatin is associated with response rates of 2540% and a median survival of 3340 weeks [46]. Traditionally, chemotherapy in NSCLC has been delivered intravenously. In an attempt to improve the comfort of patients, oral administrations have recently been investigated. The oral administration of active cytotoxic agents, apart from avoiding the peripheral vein irritation or discomfort of central venous access [7], may also provide economic savings associated with a reduction in the number of hospital visits.
The clinical development of vinorelbine oral formulation started in 1994 with a phase I dose-finding study in patients with advanced breast cancer [8]. The maximum tolerated dose was set at 100 mg/m2 weekly, and the recommended dose for further clinical investigations was 80 mg/m2 weekly. Dose-limiting toxicities included neutropenia, nausea/vomiting and constipation due to autonomic neuropathy. Preliminary evidence of activity was demonstrated in first- and second-line chemotherapy of advanced breast cancer; there were six objective responses out of 14 evaluable patients administered doses of 80 or 100 mg/m2/week. A comparative cross-over oral/intravenous (i.v.) study showed that the bioavailability of the oral administration (soft-gelatin capsules; 80 mg/m2) is 43 ± 14% of that with a 25 mg/m2 i.v. infusion [9]. The range of doses administered was derived from the established bioequivalence between the i.v. and the oral formulation: 30 mg/m2 i.v. was shown to correspond to 80 mg/m2 given orally and 25 mg/m2 to 60 mg/m2, respectively. A regimen with individual dose titration according to the hematological tolerance was demonstrated to be efficient and safe [9, 10]. In a recent randomized phase II study in advanced NSCLC [11], 115 patients with stage IIIB or IV disease were randomized (2 to 1) to receive oral vinorelbine at a dose of 60 mg/m2 for the first three administrations and then escalated to 80 mg/m2/week in the absence of severe neutropenia, or i.v. vinorelbine at 30 mg/m2/week. After external panel review, the response rates in evaluable patients were 14% in the oral arm and 12% in the i.v. arm. The median progression-free survival with oral and i.v. vinorelbine was 3.2 and 2.1 months, respectively, and the median survival 9.3 and 7.9 months, respectively. Safety profile was qualitatively comparable in both arms.
Since platinum-based combinations are a standard of care for stage IIIBIV NSCLC, the purpose of the present study was to evaluate the partial substitution of i.v. vinorelbine with its oral form in the established combination of vinorelbine plus cisplatin in advanced NSCLC. It should be noted that this was only a partial substitution due to the requirement for i.v. administration of cisplatin on day 1; venopuncture was avoided on days 8, 15 and 22 through the use of oral vinorelbine.
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Patients and methods |
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The study was conducted in accordance with the ethical principles set out in the Declaration of Helsinki (Somerset West amendment) and was approved by the ethics committees of all participating institutions. All patients who entered the study gave written informed consent according to the requirements of the national legislation of the country in which they were treated.
Pretreatment evaluation consisted of physical examination, complete blood count, biochemical screen, electrocardiogram, chest X-ray, CT of the chest, brain and liver (if positive by ultrasound) and bone scintigraphy (with direct imaging of areas of increased uptake). Other imaging procedures and audiometry were performed if clinically indicated. Hematological monitoring was performed weekly and biochemical screens were repeated with every chemotherapy cycle. All imaging procedures were repeated every two cycles. Quality of life (QoL) assessments based on the EORTC QLQ-C30 and QLQ-LC13 questionnaires were performed before study entry, before each cycle and at the end of the study. A patient was evaluable for one type of questionnaire if it was completed just before the administration of the corresponding cycle and could be compared with the baseline evaluable questionnaire.
Treatment plan
Cisplatin was administered at a dose of 100 mg/m2 on day 1 of each cycle with prehydration according to routine practice of the individual center. Intravenous vinorelbine was supplied as a 10 mg/ml solution for injection on day 1 of each cycle at a dose of 25 mg/m2 (capped to a maximum of 50 mg). The drug was reconstituted to a total volume of 50 ml with N-saline, and then given into the site injection port of a freely flowing saline infusion over 610 min; the saline infusion was continued to flush the vein. Oral vinorelbine was supplied as soft gel capsules containing either 30 or 40 mg of the active drug and was administered at 60 mg/m2 (capped to a maximum of 120 mg) on days 8, 15 and 22 of each cycle. Treatment was planned to continue for a maximum of eight cycles unless halted by disease progression, unacceptable toxicity or patient refusal. Routine prophylactic antiemetics were administered to cover day 1 cisplatin/i.v. vinorelbine. Treatment was to be modified in the case of hematological and/or non-hematological toxicities according to a prespecified system. Hematological toxicity including neutropenia or thrombocytopenia at grade 2 on day 1 would result in treatment delay and reassessment after 1 week. On days 8, 15 or 22, the same levels of toxicity would result in the omission of the planned oral vinorelbine dose. Neurological toxicity at grade 2 would result in a 50% dose reduction, and at grade 3/4, in treatment discontinuation. Hepatic toxicity at grade 2 on day 1 would result in delay and reassessment 1 week later, and at grades 3 or 4, treatment would be discontinued. Renal toxicity was further assessed by creatinine clearance with modification of the cisplatin dose as follows:
55 ml/min, no modification; 4554 ml/min, 50% dose reduction; <45 ml/min, delay of both vinorelbine and cisplatin and reassessment 1 week later. Toxicity affecting hearing at grade 2 would result in a 50% reduction of the cisplatin dose, and at grade 3/4, in treatment discontinuation. Doses were not modified for nausea/vomiting unless these symptoms could not be controlled by the appropriate antiemetic therapy.
Response and toxicity criteria
All eligible patients were considered evaluable for toxicity and response by an intention-to-treat analysis. Response was assessed according to WHO criteria [12] with European Organisation for Research and Treatment of Cancer (EORTC) modifications [13]. In this study, the clinical response was additionally determined using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria [14]. All responses were reviewed by two independent radiologists. Toxicity was scored according to the NCICTC [15]. The design of Fleming [16] was used to determine the sample size of this two-stage phase II study; setting response rate limits of 1535% and and ß error limits of <10%, the total sample size required was 40 evaluable patients. An evaluation was required after 20 evaluable patients, with recruitment to continue if four or more responses and fewer than seven responses had been seen. Response rate in the intention-to-treat and evaluable population were presented with their 95% confidence intervals (CIs). Time-dependent parameters were assessed using the KaplanMeier method. The cut-off date for the survival analysis was 1 March 2002.
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Results |
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Treatment outcomes
One patient was ineligible according to the study entry criteria because of the presence of a brain metastasis at the time of inclusion. This patients overall response after four cycles was progressive disease. An additional four patients were considered to be non-evaluable for response because they were taken off study before their first tumor evaluation (one died at home after cycle one, cause of death unknown, two were taken off study with renal impairment after cycle one and received alternative treatment and one patient died of febrile neutropenia during cycle two before tumor evaluation).
After review by an independent panel, 17 partial responses (WHO criteria) were scored: 30% (95% CI 18% to 42%) in the intention-to-treat analysis and 33% (95% CI 20% to 46%) in 51 evaluable patients (Table 2). Scoring by RECIST criteria resulted in one change from a partial response by WHO criteria to no change. The median duration of follow-up was 14.8 months (range 1119.5). The median progression-free survival was 5.5 months (95% CI 3.76.4 months) (Figure 1), the median overall survival was 8.9 months (95% CI 8.811.7 months) (Figure 2), and the 1-year survival probability was 37% (95% CI 24% to 50%). Twelve patients (21%) were treated with at least one further chemotherapy regimen.
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In the first subpopulation, the comparison of functional score scales between baseline and the first evaluation showed a worsening of physical, role and social scores, the other items having slightly worsened. In the second subpopulation, functional scores were stable except for physical and social scores. The symptom scales showed an improvement of some lung-cancer specific symptoms (pain, dyspnea) and sleep disturbance. As expected with this combination, nausea/vomiting and diarrhea scales worsened in the two subpopulations. The item QoL remained globally stable.
The analysis of the QLQ-LC13 questionnaire in the two subpopulations showed stabilization, or a slight improvement, of all lung-cancer-specific items (dyspnea, coughing, hemoptysis, dysphagia and pain), whereas specific treatment-related toxicities (alopecia and peripheral neurosensory) worsened (Figure 3).
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Discussion |
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In this phase II study, a response rate of 33% in the evaluable population was achieved after independent panel review. Other major outcomes included a median progression-free survival of 5.5 months, a median survival of 9 months and a 1-year survival probability of 37%. Previous phase II studies of i.v. vinorelbine in combination with cisplatin in a 4-week schedule showed overall response rates ranging from 33 to 42% (evaluable population) [1821]. However, response rates in these studies were not verified by independent panel review. Similar efficacy has also been shown in two large randomized phase III South West Oncology Group (SWOG) trials using i.v. vinorelbine and cisplatin [6, 19, 22]. Indeed, the first of them, including 206 NSCLC patients treated with i.v. vinorelbine 25 mg/m2/week and cisplatin 100 mg/m2, demonstrated a response rate of 26% (intention-to-treat analysis) with a median survival of 8 months [6]. Another study including 202 patients reported a response rate of 28% and a median survival of 8 months [22]. It should be noted that both studies included confirmed and unconfirmed responses.
The most frequent adverse events in our series were neutropenia and anemia, both observed in 88% of patients. Grade 34 neutropenia was reported in 73% of patients and was associated with complications in seven patients (five cases of febrile neutropenia leading to one death and two cases of neutropenic infection). Similar to the 4-week schedule using only i.v. vinorelbine [6], a high incidence of vinorelbine cancellations (63%) was observed on day 15 of the cycle, secondary to a high rate of neutropenia on that day of the cycle. The relative dose intensity of oral vinorelbine was lower in comparison to that of i.v. vinorelbine and cisplatin. This could be explained by the dose-modification rules used in the present study. Indeed, no dose reduction of oral and i.v. vinorelbine was allowed and the drug could not be administered when the neutrophil count was <1500/mm3. Intravenous vinorelbine administrations could be delayed in cases of hematological toxicity, whereas oral vinorelbine administration could not be delayed and therefore was just canceled. On the other hand, in the two SWOG trials using cisplatin and i.v. vinorelbine [6, 22], patients could receive a reduced dose when neutrophil counts were between 1000 and 1500/mm3. The most frequent non-hematological toxicities included nausea and vomiting. Grade 34 was observed in less than 10% of patients. Neurological symptoms occurred in 16% of patients and led to study withdrawal in two. Renal toxicities and ototoxicity, typical of cisplatin-based regimens, were rare but led to treatment discontinuation in three patients and dose reduction of cisplatin in another two. Importantly, no unexpected adverse events were reported. The toxicity profile of this combination was not different from that observed in the two SWOG trials using i.v. vinorelbine [6, 22].
Administration of oral chemotherapy has several potential advantages: greater patient convenience and acceptance, as well as significant cost savings, both in terms of treatment costs and lost wages incurred by patients and family during the physicians visits [23]. In this study, oral vinorelbine had to be given in the presence of a physician or a nurse. No major treatment violations were observed. One advantage of oral vinorelbine is the once-weekly schedule that reduces the risk of lack of compliance. Indeed, poor patient compliance has been reported with a multiday oral regimen [24]. There is evidence that with regular patient education and monitoring, adequate patient compliance to oral medications may be achieved [17]. In the future, this may allow the prescribing oral vinorelbine as a home-based therapy, which would have social benefits and give the patient an increased feeling of control over their treatment.
In conclusion, this study has demonstrated that partial substitution of i.v. vinorelbine by its oral form in combination with cisplatin maintains the efficacy and safety of the standard 4-week regimen using i.v. vinorelbine exclusively [6, 22]. Given the relatively high number of oral vinorelbine omissions on day 15 of the 4-week cycle, an alternative option including cisplatin and i.v. vinorelbine on day 1 followed by oral vinorelbine on day 8 in a 3-weekly schedule warrants further evaluation, preferably in a randomized study with i.v. vinorelbine in the control arm. A desirable approach would be a fully oral vinorelbine regimen in combination with another active oral agent. Such an ambulatory administered regimen would clearly be a very welcome development in the palliative setting of NSCLC, provided its safety and efficacy are similar to standard i.v. combinations. In addition to the development in this indication, a range of clinical studies are in progress with paclitaxel, docetaxel, capecitabine and cyclophosphamide. Oral vinorelbine offers a new therapeutic option, both in monotherapy and in combination with traditional cytotoxic agents.
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Acknowledgements |
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Footnotes |
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References |
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