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25.05.2011: Paclitaxel and gemcitabine versus Paclitaxel and Vinorelbine in patients with advanced non-small-cell lung cancer. A phase III study of the Hellenic Cooperative Oncology Group (HeCOG)

P.A.Kosmidis1, G. Fountzilas2, A.G. Eleftheraki3, H.P. Kalofonos4, G. Pentheroudakis5, D. Skarlos6, M. A. Dimopoulos7. D. Bafaloukos8, D. Pectasides9, E. Samantas10, J. Boukovinas11, S. Lambaki2,  N. Katirtzoglou12, C. Bakogiannis1 & K. Syrigos12.





1Department of Medical Oncology, Hygeia Hospital, Athens,
2Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
3 Section of Biostatistics, Hellenic Cooperative Oncology Group Data Office, Athens, Greece
4Division of Oncology, University Hospital of Patras, Patras, Greece
5Department of Medical Oncology, Ioannina University Hospital,Ioannina, Greece
6Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece
7Department of Clinical Therapeutics, Alexandra Hospital, University of Athens School of Medicine, Athens, Greece
8Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece
92nd Department of Internal Medicine-Propaedeutic, Oncology Section, University General Hospital Attikon, Athens, Greece
103rd Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece
11Department of Medical Oncology, Theagenio Hospital, Thessaloniki, 12Oncology Unit, 3rd Department of Medicine, Athens Medical School, Sotiria General Hospital, Athens, Greece


ABSTRACT

Background: Paclitaxel (Taxol) and vinorelbine  have shown synergism of cytotoxic effects in vitro and clinical activity in phase I and II studies. This combination was compared prospectively with the Paclitaxel/Gemcitabine regimen in non-operable Non-Small-Cell Lung Cancer.
Patients and methods: Chemotherapy-naïve patients, stage IIIBwet and IV with Performance Status (0-1), were randomized to receive paclitaxel 200mg/m² on day 1 plus gemcitabine 1gm/m² (Group A) on days 1 and 8 every 3 weeks or paclitaxel 80mg/m² plus vinorelbine 22.5mg/m² (Group B) on days 1, 8 and 15 every 4weeks.
Results: A total of 398 out of 415 patients were eligible for analysis on intent-to-treat basis (group A: 196, group B: 202). Progression-free survival (PFS) was 5.0months (95% Confidence Interval (CI), 4.3-5.6) and 4.4months (95% CI, 3.7-5.2) for groups A and B respectively (P=0.365). Median survival was 11.1months (95% CI, 9.2-13.0) and 8.6months (95% CI, 7.0-10.2) for groups A and B respectively (P=0.147). Grade 3/4 neutropenia and leucopenia were worse in group B (P<0.001, in both cases). Febrile neutropenia and severe infections were more prominent (P<0.001, P=0.029 respectively) in group B.  
Conclusion: Although response rate, PFS and survival were non-different in both groups, toxicity was significantly worse in group B and therefore further investigation of P-Vin is of no value.

Keywords: chemotherapy, gemcitabine, NSCLC, paclitaxel, vinorelbine
 


INTRODUCTION
Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer–related mortality in Western countries and the incidence is increasing among women [1]. Platinum–based chemotherapy offers a survival benefit in advanced NSCLC as compared with best supportive care and represents the standard of care [2,3]. Non-platinum combinations have been also tested and are considered alternative regimens for those who cannot tolerate platinum–based chemotherapy [4,5,6]. During the past few years, several novel drugs including paclitaxel (Taxol), docetaxel, gemcitabine and vinorelbine have shown significant activity against NSCLC. Doublets of the above so-called third – generation compounds or combinations of a platinum compound with a novel drug have been tested in advanced NSCLC, without significant difference in activity among them [7]. Our group has published two-phase III studies comparing various doublets with platinum-based and non – platinum based combinations in advanced NSCLC [4,5]. In a phase III study, a combination of carboplatin at an area under the time-concentration curve 6mg and paclitaxel 200mg/m2, both given on day 1 every 3 weeks, was found equally active to a non-platinum combination of paclitaxel 200mg/m2 on day 1 and gemcitabine 1000mg/m2 given on days 1 and 8 every 3 weeks. The toxicity profile was similar for both combinations [4]. Therefore, the paclitaxel – gemcitabine combination was used as the standard arm in this study based on the fact that non-platinum regimens are acceptable alternatives to platinum-based combinations in first-line treatment of NSCLC. Paclitaxel and vinorelbine have tubulin as their common intracellular target, but inhibit growth by binding to different sitesd. The in vitro antiproliferative activity of both agents have been evaluated and in most cell lines synergism has been found [8,9]. Concurrent vinorelbine and paclitaxel were synergistic in four of six lines when the exposure was extended to 96h [9]. Clinical phase I studies in lung, esophageal and breast cancer have shown activity with neutropenia but not neurotoxicity as a dose limiting factor [10]. Clinical phase II studies in lung cancer are very limited and the value of this combination is basically lacking [11,12]. Our group in an effort to further explore the efficacy of non-platinum regimens selected this poorly studied combination as the experimental arm. The schedule of the combination differs in the very few published reports. Similarly, dose density varies in these studies. We elected to use the schedule and dose density of the combination paclitaxel and vinorelbine based not only on these studies but also on our preliminary experience with a few patients. Novel-targeted agents especially bevacizumab combined with chemotherapy have proven efficacy and promising results in some studies [13]. However, toxicity from chemotherapy remains an unresolved problem. Combinations with better toxicity profile but with equal or improved efficacy are eagerly needed. Specifically, efficacy in certain subgroups of patients is intensively investigated. Hellenic Cooperative Oncology Group (HeCOG) initiated this studying order to compare the combination of paclitaxel and vinorelbine with the combination of paclitaxel and gemcitabine in a phase III randomized study in NSCLC patients stage IIIbwet (IIIb with pleural effusion) and IV with good performance status (PS) (0-1).

PATIENTS AND METHODS
Eligibility criteria
Chemotherapy – naïve patients, older than 18 years of age, with histologically or cytologically confirmed NSCLC stage IIIbwet or IV, according to the American Joint Committee on Cancer Criteria, were included. An Eastern Cooperative Oncology Group PS of zero or one was required. Additional inclusion criteria were measurable or evaluable disease in non – irradiated fields, a life expectancy of at least 3 months and adequate bone marrow, kidney and liver functions. Patients with stable brain metastases were eligible. Exclusion criteria were a past or current history of other malignant disease, except for basal cell carcinoma of the skin or carcinoma in situ of the cervix, active cardiac disease or active infection and pre–existing motor or sensory neuropathy grade > 2 according to World Health Organization (WHO).
The clinical protocol was approved by the Hellenic Cooperative Oncology Group (HeCOG) Protocol Review Committee, by appropriate Institutional Review Boards at participating Institutions and by the National Organization for Medicines, Division of Pharmaceutical Studies and Research. Written informed consent was obtained from all patients. The study was registered at the Australian New Zealand Clinical Trials Registry (ACTRN12609000946213).

Treatment plans and dose modifications
Eligible patients were centrally randomized at the HeCOG data office to receive either paclitaxel (Taxol, Bristol-Myers Squibb Co, Princeton, NJ) 200mg/m² as a 3h infusion on day 1 in combination with a 30-min infusion of gemcitabine 1 g/m² on days 1 and 8 (group A) every 3 weeks or paclitaxel 80 mg/m² in  combination with intravenous vinorelbine 22.5mg/m² on days 1, 8 and 15 every 4 weeks (group B).
Paclitaxel was always given before gemcitabine with premedication of 20mg dexamethasone 12h and 1h before administration, diphenydramine 50mg and cimetidine 50mg i.v., 30min before paclitaxel were administered. Ondasentron, 16mg i.v., was given 15min before chemotherapy, followed by 8mg bid orally for the next 3 days. Treatment was repeated every 3 weeks until maximum response plus two cycles or unacceptable toxicity. In the situation of stable disease, patients received a maximum of four cycles.
Dose modifications were planned according to hematologic and severe non-hematologic toxic effects. Once the doses reduced, they were not reescalated. Patients were treated at four dose levels (0, -1, -2 and -3) as follows. All patients were started at dose level 0, in which they received gemcitabine 1000mg/m² combined with paclitaxel 200mg/m² (group A) or vinorelbine 22.5mg/m² combined with paclitaxel 80mg/m² (group B). If WHO grade 3 neutropenia and/or thrombocytopenia, grade 2 neurotoxicity and hepatotoxicity, or grade 3 diarrhea occurred, doses were reduced to level -1 (gemcitabine 900mg/m² and paclitaxel 175mg/m² or vinorelbine 20mg/m² and paclitaxel 70mg/m²). If grade 4 neutropenia and/or thrombocytopenia or grade 3 hepatotoxicity occurred, the drugs were reduced to level -2 (gemcitabine 800mg/m² and paclitaxel 150mg/m² or vinorelbine 17.5mg/m² and paclitaxel 60mg/m²). If neutropenic fever was observed, doses were further decreased to level -3 (gemcitabine 700mg/m² and paclitaxel 140mg/m² or vinorelbine 15mg/m² and paclitaxel 50mg/m²). For patients who did not achieve hematologic recovery on the scheduled day of treatment, a full blood count was taken twice weekly until the absolute neutrophil count reached 1500/μl and the platelet count reached 100.000/l. If hematologic recovery was not achieved by day 35 of treatment, the patient was withdrawn from the study. Patients were also withdrawn from the study and discontinued treatment if they had symptomatic arrhythmia or atrioventricular block, grade 3 neurotoxicity or grade 4 hepatotoxicity that was not reversible within 15 days.




Baseline and follow-up assessments
Pretreatment evaluation included a complete medical history, physical examination, complete blood count and standard biochemical profile. Bidimensionally measurable disease was assessed with chest X-rays and  computed tomographic scans of chest and abdomen. Bone scanning was carried out as baseline test and then at the discretion of the treating physician.
Tumor assessments for response were carried out at least every 6 weeks.
Patients receiving at least two cycles of chemotherapy were considered assessable for response. Patients receiving at least one cycle of chemotherapy were assessable for toxicity. Standard WHO criteria were applied for assessment of response. Toxicity was evaluated according to the WHO grading system.


Statistical analysis
The primary endpoint of the study was to compare survival between the two arms and secondary were response, progression free survival (PFS) and toxicity. All end points except toxicity and treatment characteristics were analyzed according to the intent-to-treat (ITT) principle. Treatment characteristics and safety analyses were based on the actual treatment administered.
For a two-sided test at the 5% level of significance and power of 80%, the number of patients required to detect a 10% difference in survival rate, to a baseline rate of 47% at the 1-year time point, were 420 patients. The study accrual rate was estimated at 130 patients per year.
The maximum study duration was estimated to be 5.5 years, while assuming that either the null or the alternative hypothesis holds leads to an expected duration of 4.4 years and 4.9 years respectively. An interim analysis according to the O’Brien Fleming boundary based on the Lan-DeMets alpha spending function would be performed when 50% of the endpoints (190 deaths) had been reached. The study would end prematurely if either a significant difference was detected or the alternative was rejected at the interim analysis. No significant difference in survival was detected (P=0.280) and the study was continued to completion.
Summary statistics were provided for all variables. Categorical variables were summarized by frequencies and corresponding percentages, while continuous variables by median and range. Differences between groups were evaluated by Fisher’s exact test for categorical variables and Mann-Whitney U test for continuous variables. Response rates (RRs) are summarized as percentages along with exact binomial confidence intervals.
Survival was calculated from the randomization date to the date of death or of last contact. PFS was defined as the time interval between randomization and objective tumor progression or death. The median survival and the PFS time were estimated with the Kaplan-Meier method, whereas the log-rank test was used to compare time-to-event distributions.
Cox proportional hazards regression models were used to assess the influence on survival and PFS outcome of treatment group (P-Gem versus P-Vin), age categories (70 versus >70), gender (female versuss male), PS (0 versus 1), prior radiation therapy (no versus yes), prior lung surgery (no versuss yes), stage of disease (IIIbwet versus IV), tumor histology (squamous versus adenocarcinoma versuss other histology), number of metastatic sites at entry (<3 versuss 3), symptoms (no versuss yes), vena cava symptoms (no versus yes), weight loss (no versus yes), palpable mass (no versus yes), cough (no versus yes), hemoptysis (no versus yes), dyspnea (no versus yes), fatigue (no versus yes), fever (no versus yes), pain (no versus yes), lymphnodes involvement (no versus yes), pleura involvement (no versus yes), liver metastasis (no versus yes), bone metastasis (no versus yes), brain metastasis (no versus yes), other lung metastasis (no versus yes) and adrenal glands metastasis (no versus yes). A backward selection procedure with removal criterion P>0.10 was used to select the predictors included in the final Cox multivariate model. All tests were two sided and the level of significance was set at a=5%.The SPSS 15.0 software was used for statistical analysis.





RESULTS
Patient and tumor characteristics
From April 2004 to January 2008, 415 patients were registered in this study. Seventeen (4%) patients were found ineligible and were therefore not included in the analysis: PS 2 (6 patients), stage II or IIIb (10 patients) and concurrent gastric cancer (1 patient). A total of 398 eligible patients were included in the analysis according to the ITT principle. Eighteen of them never started treatment and for five patients the medical records were considered incomplete.  The progress of patients through the various stages of the trial is shown in the flow chart (Figure 1), according to the Consolidated Standards of Reporting Trials[14].
The two groups were well balanced with respect to selected basic patient and tumor characteristics, as presented in Table 1.

Treatment characteristics
One hundred eighty-four patients discontinued chemotherapy with significantly more patients in group B (71 (36%) versus 113 (56%) in group B, p<0.001). The most common reason for treatment discontinuation was progressive disease (39 patients in arm A versus 47 in arm B). Additional more frequent reasons for treatment discontinuation were toxicity (12 versus 17), death (6 versus 20) and voluntary withdrawal (5 versus 9) (Table 2).
A total of 804 and 614 cycles of chemotherapy were given in groups A and B, respectively. The median number of cycles administered was 4 (1-9) and 3 (1-6) in groups A and B, respectively.
Significantly more cycles in group A were administered at full dose (group A: 92% versus group B: 15%, P<0.0001).
The relative dose intensity (RDI) of paclitaxel was 0.86 (0.1 – 1.54) in group A and 0.55 (0.19 – 0.89) in group B. The RDI for gemcitabine was 0.85 (0.33 – 1.06) and for vinorelbine 0.58 (0.20 – 0.90) (Table 3).



Response
There were no significant differences between arms A and B in overall response rate (ORR). RR was calculated in the intention-to-treat population (Table 4). Four complete responses (CRs) and 50 partial responses (PRs) were achieved in group A for an ORR of 27.5% (95% confidence Interval (CI), 21.4% to 34.4%). Two CRs and 46 PRs were achieved in group B for an ORR of 24% (95% CI, 18.1% to 30.2%).

Survival and PFS
At the time of the analysis, after a median follow-up of 37.6 months (range 0.1 – 55.8), 334 patients (84%), 165 in group A and 169 in group B, had died and 315 (79%), 162 in group A and 153 in group B, had relapsed. Survival and PFS did not differ significantly between treatment groups (Table 5). Survival data were updated in October 2009.  
Overall, median survival was 11.1 months (range 0.7 – 49.9 months, 95% CI 9.2 – 13.0) for group A and 8.6 months (range 0.1 – 47.0 months, 95% CI 7.0 – 10.2) for group B (P=0.147) (Figure 2).
The 1-year survival rate was 45.8% in group A and 38.3% in group B. PFS was 5.0 months (range 0.5 – 49.9 months, 95% CI  4.3 – 5.6) for group A and 4.4 months (range 0.1 – 42.6 months, 95% CI 3.7 – 5.2) for group B (P=0.365) (Figure 2). The respective 1-year progression-free survival rates were 15.4% and 13.3% respectively.
The COX multivariate analysis for survival revealed that several prognostic factors including PS [1 versus 0: hazard ratio (HR) = 1.52, 95% CI 1.22 – 1.91, P<0.001], number of metastatic sites [3 versus <3: HR=1.74, 95% CI 1.35 – 2.24, P<0.001], weight loss [yes versus no: HR=1.45, 95% CI 1.06 – 1.99, P=0.021], other lung metastasis [yes versus no: HR=0.62, 95% CI 0.48 – 0.80, P<0.001] and treatment arm [P-Vin versus P-Gem: HR=1.32, 95% CI 1.06 – 1.65, P=0.015] were related to significantly poorer survival. (Table 6)
Also, the COX multivariate analysis for PFS revealed that the hazard of disease progression at any time was significantly higher for patients with prior radiotherapy (HR=1.44, 95% CI 1.12 – 1.87, P=0.005), with weight loss (HR=1.48, 95% CI 1.10 – 1.99, P=0.01), with liver metastasis (HR=1.37, 95% CI 1.05 – 1.79, P=0.021) and with adrenal gland metastasis (HR=1.46, 95% CI 1.12 – 1.92, P=0.005). Squamous versus non-squamous histology did not reveal any significance neither for survival nor for PFS.

Toxicity
The rates of severe leucopenia differed significantly between the two groups (8% in group A versus 47% in group B, P<0.001). Also, severe neutropenia was significantly worse in group B (A=15% versus B=70%, P<0.001). Febrile neutropenia differed significantly between the two groups (2% in A and 14% in B, P= <0.001). Similarly severe infections occurred significantly more in patients of group B (A=4% versus B=11%, P=0.029) (Tables 7 and 8).



DISCUSSION
In this phase III randomized study, we targeted the population of patients with NSCLC, stage IIIbwet and IV and specifically those with a PS zero to one. We initiated this trial during a period in which targeted treatment was unavailable to our group. Therefore, we tested two non-platinum combinations of third generation compounds, namely paclitaxel – gemcitabine versus paclitaxel – vinorelbine. Median survival was not statistically significantly different (11.1 versus 8.6 months, P=0.147) between the two groups.  Moreover, the 1-year survival rate was 38.3% for group A and 45.8% for group B. Median PFS was also similar in the two groups (5.0 versus 4.4 months). Finally, ORR were 27.5% for group A and 24% for group B based on an intention-to-treat analysis.  Due to these results the study failed to meet each primary point.
These results are in accordance with those of our previous randomized trial, which compared the non-platinum combination of paclitaxel and gemcitabine with a combination of carboplatin and paclitaxel [4]. This was also consistent with the results from other randomized studies [5,6]. It is well known from a meta-analysis comparing platinum-based versus non-platinum-based chemotherapy in advanced NSCLC confirmed that there is a marginal 1-year survival benefit with platinum-based regimens which is lost when platinum therapies are compared with third – generation – based combination regimens [14, 15]. In our study histology played no role in the activity of either regimen. Regarding clinical prognostic factors, low PS, weight loss and three and more metastatic sites in other lung were related with poor survival. Similarly for the PFS, factors such as weight loss, hepatic and adrenal gland metastasis as well as prior radiotherapy increased significantly the hazard for disease progression. These results are not different from previous studies [4,5].  
Toxicity profile was different between the two groups in this study. Neutropenia and infections were statistically worse in the patients who received the combination paclitaxel – vinorelbine. Otherwise, no differences were found between the two groups. It must be emphasized that the dose density of the paclitaxel-vinorelbine combination that we decided to use was not well tolerated by our patients regarding myelotoxicity. Dose modifications were necessary, which certainly affected the dose intensity.
Based on these results, non-platinum combinations can be used alternatively to platinum-based regimens on certain occasions; however,  toxicity is an important parameter for selecting the proper combination. Paclitaxel–vinorelbine is equally active to other non-platinum combinations; however, the toxicity is significantly worse and further investigation is of no value.