Cisplatin plus weekly vinorelbine versus cisplatin plus vinorelbine on days 1 and 8 in advanced non-small cell lung cancer: A prospective randomized phase III trial of the G.O.I.M. (Gruppo Oncologico Italia Meridionale)
Introduction
Until recently, only a few antineoplastic chemotherapeutic agents have shown reliable clinical activity in excess of 15% overall response rate in advanced stage IIIB–IV non-small cell lung cancer (aNSCLC), which still remains a largely chemo-resistant malignancy [1]. New active, third-generation antineoplastic drugs have been recently developed and become available for the treatment of aNSCLC. Among these drugs, cisplatin (CDDP), gemcitabine, paclitaxel, docetaxel, and vinorelbine (VNR) have been the most frequently used both as single-agent and in various combinations [2]. The best combination regimens comprising these agents [2] have been able to yield a 30–40% overall response rate (ORR) with a small but clear impact on patients’ overall survival (OS). To date there is not a golden standard treatment among the various third-generation doublet regimens and oncologists’ choice of the chemotherapy regimen should be driven by patients’ characteristics, expected toxicity, convenience, and costs.
Vinorelbine (5′-nor-anydro-vinblastine; VNR) is a semisynthetic vinca alkaloid that demonstrated a high level of activity in clinical phase II and III studies with an interesting long-term survival rate [3], [4], [5], [6], [7], [8]. VNR has been successfully combined with CDDP yielding ORR ranging from 21 to 56% with a good toxicity profile [5], [8], [9], [10], [11]. A significant advantage in terms of overall survival (40 weeks versus 32 weeks) was first demonstrated by Le Chevalier et al. [12] for a weekly vinorelbine/cisplatin combination compared to vindesine/cisplatin and to vinorelbine alone. Other prospective randomized phase III trials have shown that the combination regimen of CDDP and VNR is more effective than either CDDP or VNR given as single agents [8], [9], and as active as carboplatin–paclitaxel, mitomycin/vindesine/CDDP, and mitomycin/ifosfamide/CDDP reference regimens with less toxicity [13], [14], [15]. On the other hand CDDP/VNR regimens have been shown as active as but more toxic than a CDDP-devoid regimen of docetaxel and gemcitabine [16]. For these reasons the CDDP/VNR regimen is considered one of the most active regimens for the management of aNSCLC and has been shown to be cost-effective when compared to other doublet regimens [17].
As reported in medical literature the CDDP/VNR regimen is not unique since it has been administered in at least two different schedules. One schedule employed CDDP 100 mg/m2 on day 1 plus weekly VNR 25 mg/m2 on day 1 and 8 and 15 every 4 weeks, and a second schedule used CDDP 80 mg/m2 on day 1 plus VNR 25–30 mg/m2 on day 1 and 8 every 3 weeks [13], [18]. Both schedules have been shown to be equiactive to the other third-generation doublets in terms of ORR, time-to-progression (TTP), overall survival and 1-year survival rate [19], [20], [21], [22].
A major criticism to the use of CDDP/VNR regimen came from the toxicity data reported in two large randomized phase III studies which compared the weekly VNR schedule (day 1, 8 and 15 every 4 weeks) plus CDDP to carboplatin/paclitaxel and CDDP/gemcitabine [19] or CDDP/docetaxel [20]. In these studies the regimen of CDDP plus weekly VNR has been associated with a statistically significant higher rate of severe neutropenia as compared to the other comparator doublet regimens of CDDP plus gemcitabine or paclitaxel [19] or docetaxel [20]. On the other hand these data have been counterbalanced by two other phase III trials employing the CDDP plus VNR day 1–8 schedule which reported hematological toxicity rates similar to those reported in the comparison arm with CDDP/gemcitabine [21], [22]. Moreover toxicity of the weekly VNR schedule had been previously reported in 1998 by the investigators of the SWOG who observed that the majority of patients treated with CDDP plus weekly VNR regimen suffered of severe granulocytopenia within three cycles of chemotherapy that resulted in a dose reduction of cisplatin [9]. In a subsequent randomized phase III trial published by the SWOG comparing CDDP plus weekly VNR to carboplatin/paclitaxel investigators underlined that the inability to deliver weekly VNR plus the significant toxicity observed in combination with CDDP probably accounted for the lower dose intensity on the CDDP/weekly VNR arm [13].
Overall the above-reported data may suggest that the weekly VNR schedule could be toxic to the point of causing a decrease in delivered dose intensity and an increase in treatment omissions and therapy discontinuations thus negatively affecting patients’ clinical outcome and quality of life (QoL). The optimization of chemotherapy scheduling has represented and still represents one of the most important research aims for medical oncologists. Therefore based on the above-reported scientific rationale we carried out a prospective, randomized, multicenter phase III trial with the aim of comparing the two above-reported schedules of the CDDP/VNR regimen in order to identify the one with the best therapeutic index.
Section snippets
Eligibility criteria
Before entry into the study all patients had to fulfill the following eligibility criteria: informed consent as required by the ethical committees of participating institutions; histologically confirmed diagnosis of locally advanced, inoperable stage IIIB with cytology positive pleural effusion and/or metastatic supraclavicular nodes or metastatic stage IV NSCLC; age > 18 but < 75 years; performance status (PS) of 0–1 according to the ECOG criteria; life expectancy of at least 3 months; adequate
Patient population
The main clinical and demographic characteristics of enrolled patients are depicted in Table 1. Briefly, a total of 278 eligible chemotherapy-naïve patients were enrolled into the trial between January 2003 and December 2004 from ten institutions. In both arms there was a prevalence of male patients over females with a male: female ratio of about 3:1. Overall 54% of enrolled patients had poor prognosis stage IIIB NSCLC, and 56% had metastatic stage IV disease. The treatment arms were well
Discussion
Even in the era of biologic targeted therapies systemic chemotherapy is still widely considered the first-line therapy of choice in the majority of patients affected by aNSCLC which cannot receive anti-angiogenesis agents [25], [26]. Published data on newer third-generation regimens have also shown a small but positive impact of new antineoplastic drugs on patients’ QoL and survival [26]. Current knowledge on the treatment of aNSCLC suggests that there is not a doublet regimen of choice but a
References (33)
- et al.
Vinorelbine (Navelbine) in the treatment of non small cell lung cancer: studies with single-agent therapy and in combination with cisplatin
Ann Oncol
(1999) - et al.
Vinorelbine versus vinorelbine plus cisplatin in advanced non-small cell lung cancer: a randomized trial
Ann Oncol
(1994) - et al.
GLOB-1: a prospective randomised clinical phase III trial comparing vinorelbine-cisplatin with vinorelbine–ifosfamide–cisplatin in metastatic non-small-cell lung cancer patients
Ann Oncol
(2002) - et al.
Gemcitabine–docetaxel versus cisplatin–vinorelbine in advanced or metastatic non-small-cell lung cancer: a phase III study addressing the case for cisplatin
Ann Oncol
(2005) - et al.
Gemcitabine and cisplatin versus vinorelbine and cisplatin versus ifosfamide and gemcitabine followed by vinorelbine and cisplatin versus vinorelbine and cisplatin followed by ifosfamide and gemcitabine in stage IIIB-IV non small cell lung carcinoma: a prospective randomized phase III trial of the Gruppo Oncologico Italia Meridionale
Lung Cancer
(2003) - et al.
Multicentre randomised phase III study comparing the same dose and schedule of cisplatin plus the same schedule of vinorelbine or gemcitabine in advanced non-small cell lung cancer
Eur J Cancer
(2005) - et al.
Factorial phase III randomised trial of rofecoxib and prolonged constant infusion of gemcitabine in advanced non-small-cell lung cancer: the GEmcitabine-COxib in NSCLC (GECO) study
Lancet Oncol
(2007) - et al.
Treatment of non-small cell lung cancer, stage IV: ACCP evidence-based clinical practice guidelines (2nd edition)
Chest
(2007) - et al.
Randomized study of vinorelbine–gemcitabine versus vinorelbine–carboplatin in patients with advanced non-small cell lung cancer
Lung Cancer
(2005) - et al.
Comparison of docetaxel- and vinca alkaloid-based chemotherapy in the first-line treatment of advanced non-small cell lung cancer: a meta-analysis of seven randomized clinical trials
J Thorac Oncol
(2007)
Chemotherapy in non-small lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials
Br Med J
A randomized phase III trial of four chemotherapy regimens in advanced non-small cell lung cancer
N Engl J Med
A phase II study of Navelbine (vinorelbine) in the treatment of non-small cell lung cancer
Am J Clin Oncol
Randomized trial of vinorelbine compared with fluorouracil plus leucovorin in patients with stage IV non-small cell lung cancer
J Clin Oncol
Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small cell lung cancer: results of a European multicenter trial including 612 patients
J Clin Oncol
Non-small cell lung cancer: a study of long-term survival after vinorelbine monotherapy
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2013, Thoracic Surgery ClinicsCitation Excerpt :In addition, dose reduction and incomplete chemotherapy administration were more likely in patients who had undergone pneumonectomy, were older, or were female. For advanced NSCLC, a randomized trial demonstrated that a 3-week cycle of vinorelbine on days 1 and 8 and cisplatin on day 1 had better tolerance and similar efficacy to the less convenient weekly regimen administered in the adjuvant setting.17 In situations where constraints preclude the use of the weekly schedule of administration, practitioners might prescribe the more convenient intravenous regimen tested for advanced disease or even oral vinorelbine for patients living far from the hospital.18