Vinorelbine alternating oral and intravenous plus carboplatin in advanced non-small-cell lung cancer: results of a multicentre phase II study

M. E. R. O’Brien1,*, A. Szczesna2, H. Karnicka3, P. Zatloukal4, T. Eisen5, W. Hartmann6, P. Kasan7, B. Longerey8 and F. Lefresne8

1 Royal Marsden Hospital and Kent Cancer Centre, UK; 2 Regional Lung Hospital, Otwock; 3 PCK Maritime Hospital, Gdynia, Poland; 4 Charles University, Faculty Hospital Na Bulovce, Prague, Czech Republic; 5 North Middlesex Hospital, London, UK; 6 Central Hospital, Bremen, Germany; 7 National Institute, Bratislava, Slovak Republic; 8 Institut de Recherche Pierre Fabre, France

Received 15 August 2003; revised and accepted 18 February 2004


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background:

Vinorelbine and carboplatin are both active agents in the treatment of non-small-cell lung cancer (NSCLC). Vinorelbine has recently been developed in an oral formulation, which is as active as the intravenous (i.v.) form.

Patients and methods:

Fifty-two chemonaive patients with unresectable localised or metastatic NSCLC received i.v. vinorelbine 25 mg/m2 plus carboplatin (AUC 5) on day 1 and oral vinorelbine 60 mg/m2 on day 8 (or day 15 if neutrophils <1500/mm3) every 3 weeks in an open-label, multicentre phase II study.

Results:

A total of 224 cycles were given, with the median number per patient of four (range one to eight). Eight responses out of 52 enrolled patients were documented and validated by an independent panel review, yielding a response rate of 18.2% [95% confidence interval (CI) 6.8–29.6%] in the evaluable population. This response rate was balanced by a high rate of disease control (78.9% in the intention-to treat population and 90.9% in the evaluable population). The median progression-free and median survival were 5.1 months (95% CI 4.3–8.1) and 9.3 months (95% CI 6.8–11.4), respectively. Overall, the safety profile of the combination regimen alternating i.v. and oral vinorelbine appeared similar to that expected for each individual agent. Some lung cancer-specific items (pain, dyspnoea) improved or were stabilised by assessment using the EORTC QLQ-C30 and QLQ-LC13 questionnaires.

Conclusions:

The combination of carboplatin with an alternating regimen of i.v./oral vinorelbine is a well tolerated regimen with a low level of toxicity and a low rate of serious adverse events. A high rate of disease control (partial response + no change) was achieved. Progression-free survival and overall survival fell within the expected range. This regimen is convenient and safe for the treatment of patients with locally advanced or metastatic NSCLC patients.

Key words: carboplatin, chemotherapy, non-small-cell lung cancer, oral vinorelbine


    Introduction
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Lung cancer is one of the most commonly occurring malignancies in the world, with a death rate greater than that attributed to colorectal, breast and prostate cancers combined, leading to 1.1. million deaths in the year 2000 [1].

Chemotherapy for stage IV non-small-cell lung cancer (NSCLC) has been shown to prolong survival when compared with best supportive care [2]. Palliative chemotherapy for advanced stages of NSCLC is normally a platinum (cisplatin or carboplatin) combined with an agent such as vinorelbine, gemcitabine or a taxane [3]. This gives response rates of ~20% and median survival of 8 months in patients with good performance status of 0–1 [4].

Oncology is one of the few areas of medicine where most patients are treated with intravenous (i.v.) rather than oral drugs [5]. Work from Liu et al. [6] indicated that ~90% of cancer patients treated outside a clinical trial setting expressed a preference for oral chemotherapy over i.v., predominantly because of the convenience of administration or their concerns about previous problems with i.v. access [6]. From a patient perspective, the availability of oral agents would make a significant contribution to their quality of life, provided that the efficacy and toxicity of these agents were comparable to those of their i.v. counterparts.

Oral vinorelbine belongs to the new generation of oral drugs that achieve reliable blood exposure. In a phase I study with a cross-over design, Marty et al. [7] demonstrated that the oral form of vinorelbine was rapidly absorbed, with an absolute bioavailability of ~40%. The inter-individual variability was not increased with the oral form. Equivalent oral and i.v. doses were established to achieve equivalent blood exposure: 80 mg/m2 oral corresponding to 30 mg/m2 i.v. and 60 mg/m2 oral to 25 mg/m2 i.v. In a randomised phase II study of oral versus i.v. vinorelbine in advanced NSCLC, Jassem et al. [8] showed that the activity of both formulations was comparable. 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. Moreover, the safety profiles looked qualitatively similar. Neutropenia was the most frequent dose-limiting toxicity, but the incidence of complicated neutropenia was similar and very low in both arms. The incidence of gastrointestinal toxicities, especially nausea, vomiting and anorexia, seemed to be more frequent with the oral formulation. In subsequent studies of oral vinorelbine, primary prophylaxis with oral 5-HT3 antagonist was used and was shown to control easily the occurrence of nausea and vomiting [9]. Neurological toxicity was observed with the same frequency in both arms, except for neuroconstipation, which seemed to be more frequent in the i.v. arm.

Carboplatin is a platinum analog with a different toxicity profile to the parent compound cisplatin. It is less likely to induce nephrotoxicity and neurotoxicity, or to produce gastrointestinal symptoms. Furthermore, a shorter infusion period with no need for pre- or posthydration renders carboplatin more suitable for outpatient-based regimens. The combination of i.v. vinorelbine and carboplatin has been demonstrated to be an active combination with reduced toxicity in patients with NSCLC. Different phase II studies of i.v. vinorelbine in combination with carboplatin have been evaluated using a 3-weekly schedule [1018]. This combination was generally well tolerated, with few major side-effects. The objective response rates ranged from 18–45%, with survival comparable to other more toxic regimens. On the basis of these results, a phase II combination study of carboplatin with an alternating regimen of i.v./oral vinorelbine was developed. The schedule consisted of a conventional dose of carboplatin area under the curve (AUC) 5 on day 1, 25 mg/m2 of i.v. vinorelbine on day 1 and 60 mg/m2 of oral vinorelbine on day 8. The i.v. administration of vinorelbine on day 1 was justified due to the concomitant use of i.v. carboplatin. Oral vinorelbine was used with cisplatin in another phase II study [19] and achieved the same level of efficacy as previously reported for i.v. vinorelbine and cisplatin.

In the present phase II study, the administration of alternating oral (day 8) and i.v. (day 1) formulations of vinorelbine in combination with carboplatin was investigated. Owing to the correlation between AUC and the degree of myelosuppression, especially thrombocytopenia, carboplatin AUC 5 was selected. The aim of this study was to develop a conveniently scheduled and administered regimen while providing similar activity and safety in comparison with the fully i.v. combinations.


    Patients and methods
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Eligibility and evaluation
Eligible patients fulfilled all the following criteria: age between 18 and 75 years; histologically proven NSCLC (any subtype) with inoperable stage IIIb–IV disease (after multidisciplinary meeting discussion) or delayed relapse of any stage becoming unresectable; Karnofsky performance status ≥80%; life expectancy ≥12 weeks; and adequate bone marrow, hepatic and renal functions defined as neutrophils ≥2 x 109/l, platelets ≥100 x 109/l, haemoglobin >11 g/dl or 6.8 mmol/l, total bilirubin ≤1.5x the upper limit of normal (ULN), transaminases <2.5x ULN, alkaline phosphatases <5x ULN, serum creatinine ≤ULN or, in case of borderline value of the serum creatinine, calculated creatinine clearance ≥35 ml/min. Patients may have had previous surgery for NSCLC but must have had no systemic chemotherapy or immunotherapy; prior radiotherapy was permitted if there were measurable lesions outside the irradiated area. Patients were excluded if they had brain metastases. Patients were required to have at least one bidimensionally measurable indicator lesion. Physical examination, ultrasound and chest X-ray were not considered as objective tumour assessments. All sites of disease, measurable and non-measurable, were recorded and followed using the World Health Organization (WHO) and Response Evaluation Criteria in Solid Tumors (RECIST) criteria for assessment. The protocol was submitted and approved by the relevant ethics committees. The study was conducted in accordance with the ethical principles set out in the Declaration of Helsinki. Written informed consent was obtained from each participating patient prior to entry into the study.

The primary objective of the study was to determine the response rate of vinorelbine (alternating i.v. and oral) in combination with carboplatin as first-line chemotherapy in patients with unresectable localised or metastatic NSCLC, using the WHO criteria. The secondary objectives were to determine the response rate, using the RECIST criteria, to determine the duration of response, progression-free survival and overall survival time, and to characterise the toxicity of the regimen of vinorelbine in combination with carboplatin.

Statistics
This study was an open-label, multicentre, non-comparative phase II trial. The one-sample multiple testing procedure of Fleming for phase II clinical trials was used [20]. A minimum of 25 evaluable patients and a maximum of 45 evaluable patients were required depending on the response rate observed in the first 25 subjects. The reference response rates, acceptable error probabilities, and number of tests selected for this study were as follows: Po = 0.15, PA = 0.30, {alpha} ≤0.10, ß ≤0.20, k = 2. This assumed that 15% was the minimum desirable response rate for an active combination therapy in this population. Continuous data were summarised by frequency, median and range. Categorical data were summarised by frequencies, percentages and 95% confidence intervals (CIs) where relevant. Times to dependent parameters were analysed with the Kaplan–Meier method.

Efficacy analyses included response rate, duration of response, progression-free survival and overall survival. These analyses were performed on both the intention-to-treat and evaluable populations. The criteria for response used in this study were both WHO [21] and RECIST [22]. The duration of response was measured from the date of registration until the date of progression, lost to follow-up or the start date of a new antineoplastic treatment. If none of these events occurred, the duration of response was censored at the date of last contact. Progression-free survival was calculated from the registration date until the date of progression, lost to follow-up or death due to any cause. If a patient had not progressed or died, progression-free survival was censored at the time of last contact. Survival was defined as the time elapsed from registration date to death or lost to follow-up. If a patient was not known to have died, survival was censored at the time of last contact.

Maximum National Cancer Institute Common Toxicity Criteria grade per cycle and per patient were tabulated on the intention-to-treat population. For quality of life data, change from baseline for each of the 15 scales derived from the EORTC QLQ-C30 questionnaire was studied.

Treatment plan
Owing to the correlation between AUC and the degree of myelosuppression, especially thrombocytopenia, carboplatin was administered at the dose in milligrams to produce an AUC of 5 mg/ml/min on day 1; the dose was calculated by Calvert’s formula using a calculated creatinine clearance with the Cockcroft–Gault formula [23]. I.v. vinorelbine was administered at the dose of 25 mg/m2, on day 1 every 3 weeks. Oral vinorelbine was administered at a dose of 60 mg/m2 on day 8 of each cycle. Treatment was modified for haematological and/or non-haematological toxicities. The duration of each cycle was not to exceed 5 weeks, two consecutive delays of 1 week were accepted for day 1, and only a 1-week delay for day 8 oral vinorelbine administration (which did not increase the duration of the cycle). Treatment could be administered for a maximum of eight cycles, unless there was documented disease progression or unacceptable toxicity, or because of patient refusal. Preventive antiemetic treatment was recommended for each carboplatin infusion and was given according to the investigational centre’s standard policies. Systematic antiemetic treatment was recommended with oral vinorelbine as secondary prophylaxis. Metoclopramide was given for nausea/vomiting and 5-HT3 antagonists for metoclopramide failures.

The study enrolment started on 11 August 2000 and was ended on 9 April 2001 after the inclusion of 52 patients.

Treatment evaluation
For tumour assessment, the following examinations were required: physical examination, chest X-ray, chest computed tomography (CT) scan, bone scintigraphy, liver ultrasound completed by liver CT if deemed necessary by the investigator, and brain CT scan. All positive imaging procedures at study entry had to be repeated every two cycles [22]. Responses were reviewed by an independent panel. Complete blood counts (including a differential and platelet count) were to be assessed every cycle on days 1, 8 and 15, within 24 h prior to dosing. In case of delay in drug administration, blood counts had to be repeated on the scheduled day for drug administration. Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, creatinine, glucose and electrolytes including calcium and total proteins were assessed every cycle. Blood samples had to be taken within 24 h of the drug administration. An ECG had to be performed and recorded prior to initial administration and repeated if any cardiac event occurred.

Quality of life assessments based on the EORTC QLQ-C30 and lung-specific 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.


    Results
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Patient characteristics
Fifty-two patients with metastatic NSCLC were included in this study analysis, of whom 51 were evaluable for safety (one patient was lost to follow-up after first dose of i.v. treatment and was considered not evaluable). Two patients were considered not eligible (one patient with no measurable lesion, one with brain metastases) and 44 were evaluable for efficacy. Demographic data on the intention-to-treat population are shown in Table 1.


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Table 1. Demographic data for the intention-to-treat population
 
Treatment administration
A total of 224 cycles were administered during the study (median number of cycles four; range one to eight). Among the 52 treated patients, the relative dose intensity for i.v. and oral vinorelbine was 97.1% and 93.5%, respectively. For carboplatin, the relative dose intensity was 98%. Cycles were delayed (>3 days) in 22 patients (42.3%) and in 38 cycles (22.1%). Administrations of oral vinorelbine on day 8 were delayed (>3 days) in three patients (5.8%) and in three cycles (1.3%). Cancellations of administrations on day 8 were reported in 13 patients (25%) and in 18 cycles (8%). Grade ≥2 neutropenia was the main haematological toxicity responsible for delayed administration on day 1 and cancelled administrations on day 8.

Treatment outcomes
A total of 52 patients were recruited in the study, finally yielding 44 evaluable patients for whom the responses are shown inTable 2. The reasons for non-evaluability in the eight patients were: two ineligible patients; five patients who discontinued the study during the first cycle [because of diarrhoea (one patient), grade 4 dyspnoea (one patient), consent withdrawal (one patient), lost to follow-up (one patient), concomitant disease (one patient)]; and one patient left the study after two cycles and was not reassessed for response. In the intention-to-treat population, eight patients achieved a partial response, yielding a response rate of 15.4% (95% CI 5.6–25.2%). In the evaluable patients, eight patients achieved a partial response, yielding a response rate of 18.2% (95% CI 6.8–29.6%). Disease control rate (partial response + no change) was achieved in 78.9% of the patients in the intention-to-treat analysis and in 90.9% of the evaluable patients. The response rate according to WHO was slightly inferior to the one according to RECIST criteria (15.4% with WHO, 17.3% with RECIST criteria) in the intention-to-treat population. Median duration of response in the 52 patients was 7.9 months (95% CI 5–14.2), median progression-free survival was 5.1 months (95% CI 4.3–8.1) and the median survival time was 9.3 months (95% CI 6.8–11.4).


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Table 2. Overall response rate (after panel review)
 
Toxicity
Throughout the study period, neutropenia was observed in 40 out of the 51 (78%) patients evaluable for safety (Tables 3 and 4). Grade 3 and 4 neutropenia were seen in five (10%) and 22 (43%) patients, respectively. Anaemia was recorded in 84% of the patients, corresponding to 76% of cycles, but was mainly grade 1 and 2. Only 5% of cycles required blood products. The overall incidence of thrombocytopenia represented 61% of patients, corresponding to 29% of cycles, and was never severe. Febrile neutropenia, defined as grade 4 neutropenia concomitant with grade ≥2 fever, was observed in one patient (2%). Infection concomitant with grade 3–4 neutropenia was observed in two patients (4%), both of whom experienced pneumonia. Nausea was the most frequent gastrointestinal toxicity, and was reported in 28% of patients and 15% of cycles. Vomiting was observed in 22% of patients. No grade 3 or 4 emesis was observed. Constipation was observed in 24% of patients, and only one patient experienced a grade 3 event. Diarrhoea was observed in 18% of patients (7% of cycles) and was never severe. The incidence of neurosensory symptoms was low (8% of patients; grade 1). Alopecia was observed in only 14% of patients. No patient died during the treatment study, or during the 30 days after the last administration of study drug. No clinically relevant modifications of liver function tests were seen. An increase of creatinine (grade 1) was reported in one patient.


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Table 3. Haematological toxicity
 

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Table 4. Main non-haematological toxicities (by patient)
 
Quality of life
Evaluation of changes in quality of life was assessed using only the QLQ-C30 tool, as the QLQ-C13 questionnaire was not available in the Polish centres. Baseline questionnaires were filled in on time by 51 patients (98%). At the first, second and third evaluations, 91%, 80% and 74% of the population, respectively, were evaluable. An improvement of emotional and cognitive scores (functional scales), as well as financial impact and sleep disturbance (symptom scales) was observed. Some lung cancer-specific items (pain, dyspnoea) improved or were stabilised. Some more specific treatment-related toxicities (nausea/vomiting) remaining globally stable. On the other hand, the incidence of diarrhoea (18%) had a slight impact on the quality of life (slight worsening during the first two evaluations and a stabilisation at the third evaluation).

Figures 1 and 2 show the evolution of functional and symptom scales in the population of patients who completed the first two evaluations before cycle 2 and before cycle 3.



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Figure 1. Mean difference of functional scores for each evaluation.

 


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Figure 2. Mean difference of symptom scores for each evaluation.

 

    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
The use of orally administered anticancer therapy is likely to increase in the coming years. Agents such as tamoxifen, prednisone and oral cyclophosphamide have long been part of the management of many malignancies. More recently, oral chemotherapy formulations, including fluoropyrimidines, idarubicin, etoposide, vinorelbine, oral taxanes and fludarabine have become available [24]. Oral chemotherapy is more convenient for patients, and its advantages include ease of administration, greater patient convenience and reduced need for hospitalisation [6].

In the 52 enrolled patients, a response rate of 15.4% in the intention-to-treat population and 18.2% in the 44 evaluable patients were reached, according to the review panel. This response rate was balanced by the high disease control rate in 78.9% of the intention-to-treat population and 90.9% of the evaluable population. This is the only combination trial of carboplatin and vinorelbine with an independent radiology panel review. Three patients initially considered as partial responses by the investigators were assessed as stable disease, and one patient in stable disease became a responder after the panel review. Phase II studies have been already published with the same schedule and dose of carboplatin [1518]. In Bueltzingsloewen’s trial [15], 106 patients received vinorelbine at 30 mg/m2 on day 1 and day 8, with carboplatin AUC 5 on day 1. The response rate was achieved in 22% of patients in this monocentric study [15]. In the ‘CarNavel’ trial [16], 53 patients were enrolled, initially at carboplatin AUC 6 (21 patients), and then at AUC 5 (32 patients) when carboplatin AUC 6 proved unexpectedly toxic. With carboplatin AUC 5 and vinorelbine 25 mg/m2 given on days 1 and 8, the response rate was 25%, with a median survival of 9 months. The AUC 5 dose level was better tolerated in comparison with the toxicities observed in the initial population treated with carboplatin AUC 6. In a larger phase II study [17] with vinorelbine given at 30 mg/m2, the median survival reached 7.3 months in 344 patients. Of note, 16% of patients were performance status 2–3 and 26% experienced a weight loss of >5%, which could explain the lower survival duration observed. In Maquire et al.’s trial [18], a response rate of 37.3% was achieved in the evaluable population, using the RECIST criteria. These patients were treated with the same dose of vinorelbine and carboplatin as in our study. Toxicity included neutropenic sepsis in 18% and anaemia requiring blood transfusion in 26%. There were four treatment-related deaths. About half of the patients were performance status 2 and 40% were >70 years old; however, the author concluded that patients age >70 years at start of treatment were more likely to require blood transfusions but were not at increased risk of neutropenic sepsis or treatment related death. Patients with performance status 2 were more likely to have to discontinue treatment before completion of three cycles, but had a similar overall survival. The response rate was not validated by an independent panel in any of these trials.

The median survival (9.3 months) in our study was in the range described with vinorelbine in combination with other platinum agents, such as cisplatin [19, 25, 26]. Twelve patients received at least one further cycle of chemotherapy. Among the 22 patients with locally advanced disease at baseline, 11 were treated with further radiotherapy.

These results were achieved without encountering some of the toxicities commonly noted with cisplatin, and with relative ease of administration as evidenced by the good relative dose intensities of each drug. Indeed, the administration of each drug could be delayed, without dose reduction, for 1–2 weeks because of the occurrence of toxicities, as described previously. Grade 3–4 neutropenia was reported in 53% of patients, and was associated with serious complications in only five patients.

Thrombocytopenia was observed in 61% of patients, but grade 3 was rare (10%). The principal gastrointestinal events included nausea (28%) and vomiting (22%), but they were generally of mild to moderate intensity. Neurological symptoms were uncommon and observed in <10% of patients. Of note, only six patients experienced a drug-related serious adverse event. Moreover, no fatal event occurred during the study. No unexpected adverse events were reported. Overall, the safety profile of the combination regimen alternating i.v. and oral vinorelbine appeared similar to that expected for each individual agent [8, 21].

In a study conducted by Silvestri et al. [27], 81 lung cancer patients who had received chemotherapy were interviewed to learn about their treatment preferences with a range of survival benefits. Several patients would choose chemotherapy for a survival benefit of as little as 1 week, while others would not choose chemotherapy even when offered a survival benefit of 24 months. Most patients would not choose chemotherapy for a likely survival benefit of 3 months, but would if it improved quality of life. Perspectives of the use of oral chemotherapy differ between the patient, the oncologist, the pharmaceutical industry and the funders of health care [5]. A clear majority of patients (≥80%) prefer oral chemotherapy, but only provided this is not at the expense of efficacy. The preference for oral chemotherapy stems largely from the greater convenience of treatment at home and avoidance of venepunctures. According to our protocol, oral vinorelbine was given only on day 8 in the presence of a physician or a nurse, after a blood examination. This type of regimen will allow the patient to take oral vinorelbine at home in the future, with local haematological monitoring, and to come to the cancer centre only for the first day of each cycle.

Compliance is a major consideration for treatment with oral drugs. In general, compliance is higher in older, better educated patients, and is improved by limiting the number of tablets, making them easy to swallow and using a simple dosing schedule [5]. The advantages of oral vinorelbine are the once-weekly schedule and the low number of capsules to swallow (two to four, depending on the body surface area). In this study, no major treatment violation was observed for the administration of oral vinorelbine.

In conclusion, this combination study with carboplatin and partial substitution of i.v. vinorelbine by its oral form is a well tolerated regimen with few toxicities, and hospitalisation is usually not required. This regimen may be given on an outpatient basis, and achieved a high disease control rate. Progression-free survival and overall survival fell in the range reported for other cisplatin- or carboplatin-containing regimens.


    Acknowledgements
 
This study was supported by an unrestricted grant from the Institut de Recherche Pierre Fabre, Boulogne, France.


    FOOTNOTES
 
* Correspondence to: Dr M. E. R. O’Brien, Royal Marsden Hospital, Downs Road, Sutton, Surrey, UK. Tel: +44(0)208-661-3278; Fax: +44(0)208-643-0373; E-mail: maryo{at}icr.ac.uk Back


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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
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