original article N. Maniadakis 1 *, V. Fragoulakis 1, A. G. Pallis 2, E. Simou 1 & V. Georgoulias 2 introduction original article

Transcription

1 original article Annals of Oncology 21: , 2010 doi: /annonc/mdp551 Published online 17 December 2009 original article Economic evaluation of docetaxel gemcitabine versus vinorelbine cisplatin combination as front-line treatment of patients with advanced/metastatic nonsmall-cell lung cancer in Greece: a cost-minimization analysis N. Maniadakis 1 *, V. Fragoulakis 1, A. G. Pallis 2, E. Simou 1 & V. Georgoulias 2 1 Department of Health Services Management, National School of Public Health, Athens and 2 Department of Medical Oncology, University General Hospital of Heraklion, Heraklion, Greece Received 21 August 2009; revised 26 October 2009; accepted 27 October 2009 Background: An economic evaluation was undertaken, alongside a randomized phase III study, to assess docetaxel gemcitabine (DG) relative to vinorelbine cisplatin (VC) combination as front-line treatment of patients with advanced/metastatic non-small-cell lung cancer. Methods: No differences were found in efficacy, thus a cost-minimization analysis was carried out. Treatment cost accounts for the administration of first- and second-line chemotherapy, for concomitant medications, for laboratory and biochemical examinations, and for hospitalizations due to adverse events. Unit prices used reflect 2008 and are common among National Health Service hospitals in Greece. Results: The mean total cost of therapy in the DG group [ 14045, 95% uncertainty interval (UI) ], was significantly higher than in the VC group ( 8143, 95% UI ). Conclusions: Even though the combination VC has similar effectiveness compared with DG in patients with metastatic lung cancer, it is associated with a lower overall treatment cost and hence, it is preferable from an economic perspective. However, it should be noted that although VC is associated with lower cost, it is also more toxic than DG regimen, a significant parameter that should be considered in clinical decisions. Key words: cisplatin, docetaxel, economic evaluation, gemcitabine, lung cancer, vinorelbine introduction Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related death in both men and women in Western countries, accounting for 80% of lung cancer cases [1]. Surgery remains the only curative treatment modality of patients with NSCLC, but although one-third of them have resectable disease upon diagnosis, <5% of the patients are expected to be alive at 5 years [2,3]. Systemic chemotherapy for patients with advanced NSCLC has been proved to prolong survival and palliate symptoms compared with best supportive care alone [4]. Cisplatin-based chemotherapy has been the backbone of advanced NSCLC treatment for more than a decade, since a meta-analysis demonstrated an advantage of cisplatin-based chemotherapy, with a 27% reduction in risk of death and an increase in 1-year *Correspondence to: Dr N. Maniadakis, Department of Health Services Management, National School of Public Health, 196 Alexandras Avenue, Athens 11521, Greece. Tel: ; Fax: ; nmaniadakis@nsph.gr survival rate of 10% [5]. Moreover, the use of cisplatin has been indicated as an independent predictor of survival [6]. The combination of vinorelbine plus cisplatin (VC) is a frequently used first-line regimen in advanced NSCLC, with objective response rates ranging from 24.5% to 44% and a median survival ranging from 8.0 to 9.2 months. However, this regimen has considerable toxicity [7 10]. Cisplatin-related nausea and vomiting, renal toxicity, ototoxicity, and neuropathy limit its therapeutic ratio. On the other hand, several trials comparing platinum-based versus non-platinumbased chemotherapy regimens failed to demonstrate a statistically significant difference in terms of time to tumor progression or survival [11 14] and docetaxel gemcitabine combination represents an alternative first-line treatment of NSCLC. Recently, the Lung Cancer Working Group of the Hellenic Oncology Research Group conducted a prospective, multicenter, randomized, phase III trial to evaluate the vinorelbine cisplatin (VC) combination relative to the docetaxel gemcitabine (DG) combination in terms of efficacy and safety as first-line treatment of advanced NSCLC [13]. ª The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please journals.permissions@oxfordjournals.org

2 Annals of Oncology NSCLC affects many individuals and is associated with significant morbidity and mortality, both of which imply that its burden may be high upon the health services and society. In this light, an economic evaluation was undertaken alongside the clinical trial, in order to assess the therapeutic alternatives from the perspective of the third-party-payer perspective in Greece. The present paper presents the results of this economic analysis. methods patients and treatment schemes The present economic evaluation represents a cost-minimization analysis conducted alongside a clinical trial which recruited 389 patients who were randomly assigned to two different treatment arms. According to the inclusion criteria, eligible patients were chemotherapy naive, years of age, with histologically or cytologically confirmed inoperable stage IIIB (with pleural and/or pericardial effusion) or stage IV NSCLC. Additional inclusion criteria included the following: World Health Organization performance status (PS) of zero to two, negative pregnancy test in women of childbearing age and life expectancy >3 months. Central nervous system metastases were allowed provided that they had been irradiated and were clinically and radiologically stable. Prior radiotherapy was allowed provided that <25% of the total bone marrow had been irradiated and that treatment was completed at least 4 weeks before enrollment. Patients were excluded for severe cardiopulmonary insufficiency, severe uncontrolled angina pectoris, myocardial infarction within 6 months before enrollment, active infection, or severe malnutrition (loss of 15% of body weight). Eligible patients were randomly assigned to either DG: docetaxel (Taxotere; Sanofi-Aventis, Bridgewater, NJ) 100 mg/m 2 as a 1-h i.v. infusion on day 8 plus gemcitabine (Gemzar; Eli Lilly, Indianapolis, IN) 1000 mg/m 2 as a 30-min i.v. infusion on days 1 and 8 or VC: [vinorelbine (Navelbine; Pierre Fabre, Paris, France) 30 mg/m 2 as a 30-min i.v. infusion on days 1 and 8 plus cisplatin (Platinol; Bristol Meyers Squibb, Princeton, NJ) 80 mg/m 2 on day 8]. Recombinant human granulocyte colonystimulating factor (rhg-csf, 150 lg/m 2 /day s.c.; Granocyte; Sanofi- Aventis) was given prophylactically to all patients on days 9 through 15. Chemotherapy cycles were repeated every 3 weeks. Docetaxel and vinorelbine were given before gemcitabine and cisplatin, respectively. Patients receiving DG were administered standard dexamethasone premedication (8 mg orally before and after docetaxel administration). All patients received ondansetron and those receiving cisplatin were also administered 4 mg dexamethasone, adequate hydration, and forced diuresis. The DG regimen was administered on an outpatient basis, whereas most VC patients were admitted overnight for hydration. The study was conducted in accordance to ethical principles embodied in the Declaration of Helsinki and to good clinical practice guidelines. All patients were required to provide written informed consent and the study was approved by the ethics and scientific committees of each participating institution. Eligible patients were centrally registered and stratified according to age, PS, and disease stage and were randomly assigned to the different treatment arms which, as indicated in Table 1, were reasonably well balanced. type and perspective of evaluation Treatment effectiveness was measured in terms of mean patient survival per treatment group. Survival was calculated as the time from randomization to death from any cause or loss to follow-up or to the end of study period. According to the trial results, the two regimens produced comparable overall survival. In this light, a cost-minimization analysis, a variant of costeffectiveness analysis, is the most suitable methodology. In its context, alternative therapies are assessed only in terms of their total treatment cost, Table 1. Patient characteristics original article DG (n = 197) VC (n = 192) P value Age, mean 6 sd (years) All Male Female Number of patients, n (%) All 197 (50.6) 192 (49.4) Male 176 (89.3) 169 (88.0) Female 21 (10.7) 23 (12.0) Stage of disease, n (%) IIIB 78 (39.6) 71 (37.0) IV 119 (60.4) 121 (63.0) Performance status, n (%) (89.3) 173 (90.1) (10.7) 19 (9.9) Responses, n (%) CR 2 (1.0) 3 (1.6) PR 61 (31.1) 77 (40.1) SD 50 (25.4) 33 (17.2) PD 84 (42.6) 79 (41.1) NE 0 (0.0) 0 (0.0) PD was defined as a decrease of 50% or more in the sum of the longest diameters of all target lesions, CD was defined as disappearance of all target and non-target lesions. DG, docetaxel gemcitabine; VC, vinorelbine cisplatin; sd, standard deviation; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable. to choose the least costly as the preferable one. The economic evaluation was carried out from a third-party-payer (Social Security Sickness Funds) perspective in Greece. In this context, only direct health care reimbursement costs were included. costing methodology The trial collected patient data on safety and efficacy as well as on resource utilization associated with each therapeutic option. Patient-level resource utilization data were combined with unit cost data and they were then aggregated to compute total treatment cost for each patient. There was variation in resource utilization, but not in unit costs, given that the reimbursement tariffs, which we obtained from the official Government Gazette, are common to all public hospitals and public payers in Greece. All price data and economic estimates refer to the year Discounting was unnecessary because of the limited time horizon of the study. Patient-specific data on chemotherapy doses delivered in each cycle were multiplied with drug prices to compute the cost of chemotherapy. It was assumed that there was no drug wastage because in the case of surplus from a vial the drug was used for the next patient, a common practice in Greece and other countries [15 19]. Administration costs were based upon the number of cycles delivered on a hospital basis multiplied by the cost per visit. The cost of other medications accounts for drugs such as antiemetics, growth factors, antibiotics, etc., which were given either during chemotherapy administration or subsequently for the treatment of adverse events. The cost of hospitalizations due to adverse events was based upon the product of the number of inpatient days and the cost per day for each patient. Visits to oncologists occurred at the administration of the treatment regimen, every 3 months thereafter and in cases of adverse events. The cost of examinations in each cycle accounts for diagnostic imaging such as computed tomography scans and X-rays and for laboratory tests Volume 21 No. 7 July 2010 doi: /annonc/mdp

3 original article such as full blood cell count with differential and platelet count as well as full biochemistry tests (alanine aminotransferase, aspartate aminotransferase, c-glutamyltransferase, albumin, bilirubin, sodium, potassium, lactate dehydrogenase, alkaline phosphatase, uric acid, serum creatinine, etc.). For patients who had to undergo radiotherapy, there was a calculation of total cost based upon the duration of treatment and the cost per session. Analysis was performed on an intent-to-treat basis. Table 2 depicts the unit price data used in the economic analysis. analysis Cost data are truncated at zero and they do not follow normal distributions (are skewed because of very expensive patients) and hence hypothesis testing is invalid if done with conventional approaches. Furthermore, in studies such as the present, another methodological issue concerns the handling of the censored data. More specifically, the survival time data used in this study were right censored in total by 20.8% and 24.5% in DG and VC, respectively, due to loss of follow-up or due to the fact that some of its patients were still alive at the time of completion. Although the present study encounters light-censoring, that is, <25%, classical hypothesistesting procedures which are based upon strong parametric assumptions may be biased and unreliable to support robust conclusions [20,21]. To deal with such cases, one may choose among a wide range of parametric and nonparametric approaches each of which has not only strengths but also limitations [21 25]. Nonparametric models have the advantage that they do not require prior assumptions concerning the distribution and the pattern of the variables of interest, in this case treatment cost. However, they are deterministic and do not account for random effects. On the other hand, parametric approaches require such assumptions, but they provide valuable information on the pattern of cost accumulation and are easily used to make predictions to various settings. For instance, the Lin parametric approach can provide information on the pattern of cost accumulation by assessing individual covariates (i.e. sex, age, PS, etc.). However, if the set of available covariates has been determined by their clinical rather than economic importance, the validity and the power of the Lin parametric model remain unclear [26]. In this light, a two-stage regression approach, proposed by Carides et al. [24] is employed to assess the mean lifetime treatment cost, in an approach where the total cumulative cost is modeled as a function of failure time. This estimator is described as a two-stage estimator because at the first stage of the assessment, the expected cost at any given point in time is estimated as a function of failure time (uncensored cases) and at the second stage, the estimated expected cost at a given point in time is weighted by the Kaplan Meier probability of death at this point in time [24]. A simple linear model is used but other specifications are employed in the sensitivity analysis. Moreover, in order to deal with uncertainty, the bootstrap method is utilized to derive standard error estimates for the total cost in both arms. Specifically, from the raw dataset containing cost and failure time, 5000 new datasets were drawn using random sampling with replacement. Exact values for the regression parameters of interest (b 0,b 1 for linear model) were obtained from each dataset and were used to construct a new matrix with observations. The obtained mean values of the bootstrapped dataset represent unbiased estimators and their variability measures were also used to estimate uncertainty intervals (UIs) for total cost using the percentile method [27]. All clinical data were held in the main electronic trial database and were analyzed using the SPSS (version 16.0) program and the Visual Basic of Microsoft Office results Median survival was 9.0 and 9.7 months (P = 0.965) for DG and VC arms, while the corresponding 1-year survival rates Annals of Oncology were 34.3% and 40.8%, respectively. Overall response rate was 30% [95% confidence interval (CI) 23.9% to 36.3%] and 39.2% (95% CI 32.5% to 45.9%; P = 0.053) for DG and VC, respectively. Mean overall survival was (95% CI ) and (95% CI ; P = 0.903) for the DG and VC arm, respectively. A total of 829 DG and 810 VC cycles were administered with 88 DG patients (45%) and 76 VC patients (40%) receiving six or more cycles. The median number of cycles was 4 (range 1 9) in both DG and VC arms. The median interval between cycles was 22 days for both arms. Treatment was delayed in 190 DG cycles (23%) and 194 VC cycles (24%; P = 0.664) for hematologic (DG: 22 cycles; VC: 49 cycles; P = ) and non-hematologic (DG: 24 cycles; VC: 14 cycles; P = 0.076) toxicity. All other cycles were delayed for reasons unrelated to treatment or toxicity [13]. Fifty-seven DG patients (29%) and 46 VC patients (24%) received second-line chemotherapy. Cytotoxic drugs administered in second line were carboplatin, topotecan and irinotecan. Table 3 shows the results of the regression analysis on the basis of the linear model, which following the related literature includes as an independent variable, apart from the constant, the time measured in terms of monthly units. The coefficient b 0 reflects the constant and b 1 captures the effect of time. Both estimators are statistically significant (P < and P < 0.001, respectively). Table 4 includes data on the total cost of treatment and its components per treatment arm and Table 5 includes data on the cost differences between treatment arms for the linear model. Data presented in Table 4 are those obtained after bootstrapping at the second stage of the analysis. As indicated in Figure 1 for the case of total treatment cost per therapy, these data follow almost a normal distribution and hence their UIs and consequently the inferences on the basis of them are robust. The total treatment cost (Euro) in the DG group was (95% UI ) and in the VC group 8143 (95% UI ), a difference of 5902 (95% UI ; P value < 0.001), favoring the VC treatment. The difference in the total treatment cost in between the two groups is mainly due to the cost of chemotherapy, which is the main item driving the total therapy cost. In particular, the mean cost of chemotherapy in patients receiving DG was 7805 (95% UI ) while in the VC group, it was 1035 (95% UI ), a statistically significant difference of 6770 (95% UI ; P < 0.001), favoring VC. In terms of the other items, there were no statistically significant differences in between arms, though the cost of second-line drugs in the DG arm was lower [2 903 (95% UI to 111)]. Hence, chemotherapy accounts for 55.6% of the total cost of treatment in DG arm, followed by G-CSF which accounts for 21.9% of the cost and the remaining items account for 22% of the cost. On the other hand, in VC arm, G-CSF accounts for more than the cost of chemotherapy. However, no statistically significant difference in the cost of G-CSF was observed between the two treatment arms (DG: 3074 versus VC: 3016, P < 0.001). Details on each of the components of the total treatment cost are depicted in Figure Maniadakis et al. Volume 21 No. 7 July 2010

4 Annals of Oncology original article Table 2. Unit price data used to estimate treatment cost Cost item Cost ( ) Chemotherapy Docetaxel 20 mg Docetaxel 80 mg Gemcitabine 1 g Gemcitabine 200 mg 21.8 Vinorelbin/Ebewe C/S 10 mg 16.3 Vinorelbin/Ebewe C/S 50 mg 74.5 Cisplatin 50 mg/100 ml 22.0 Cisplatin 10 mg/20 ml 4.4 Second-line chemotherapy Carboplatin 150 mg 55.5 Irinotecan 40 mg 63.1 Irinotecan 100 mg Etoposide 100 mg 6.82 Topotecan 20 mg Radiotherapy Radiotherapy planning Radiotherapy adjustment Radiotherapy cost/session 14.0 G-CSF (per package) Lenograstim Filgrastim Antibiotics (per package) Ciprofloxacin 21.2 Amoxycillin + clavulanic acid 6.2 Roxithromycin 17.1 Cefuroxime axetil 7.3 Cefuroxime 5.8 Azithromycin 18.0 Piperacillin + tazobactam 11.5 Sulfamethoxazole + trimethoprim 1.8 Moxifloxacin 23.6 Metronidazole 4.0 Loracarbef 19.6 Clarithromycin 43.1 Itraconazole 8.7 Clindamycin 4.1 Laboratories and diagnostic tests Hematology and biochemistry test 72.8 CT scan 80.6 X-ray 15.0 Hb 4.0 ESR 2.0 AST 9.0 ALT 9.0 c-gt 5.0 Creatinine 4.1 Albumin 5.9 Bilirubin 2.9 Na 5.2 K 5.2 LDH 4.8 ALP 5.0 Hospitalization Day of hospitalization 73.4 Outpatient chemotherapy administration 30.0 G-CSF, granulocyte colony-stimulating factor; CT, computed tomography; Hb, hemoglobin; ESR, erythrocytes sedimentation rate; AST, aspartate aminotransferase; ALT, alanine aminotransferase; c-gt, c-glutamyltransferase; LDH, lactate dehydrogenase; ALP, alkaline phosphatase. Table 3. Estimated regression parameters a for the two-stage regression model Linear model Coefficient SE t Statistic P VC (R 2 = 29.5%) b b DG (R 2 = 37.2%) b b a b 1 expresses the time estimator and is measured in months. SE, standard error; DG, docetaxel gemcitabine; VC, vinorelbine cisplatin. Table 4. Treatment costs per item and therapy group Linear model Total cost Chemotherapy Hospitalization Diagnostics DG VC DG VC DG VC DG VC B-mean B-sd B-95% LUI B-95% UUI B-min B-max Laboratories G-CSF Toxicity Second-line drugs DG VC DG VC DG VC DG VC B-mean B-sd B-95% LUI B-95% UUI B-min B-max B indicates measures on the basis of 5000 bootstraps. DG, docetaxel gemcitabine; VC, vinorelbine cisplatin; sd, standard deviation; LUI, lower uncertainty interval; UUI, upper uncertainty interval; G-CSF, granulocyte colony-stimulating factor. sensitivity analysis Similar results were obtained when other models, such as the log linear, were employed. Correction bias for the total cost in this case is smaller and standard deviations of the various components are higher. Under this approach, the mean total treatment cost in patients receiving DG was (95% UI ), while that for patients receiving VC was 7182 (95% UI ), a statistically significant difference of 5305 (95% UI ; P < 0.001) favoring VC. The cost of chemotherapy in patients receiving DG was 6570 (95% UI ) and in the VC group 928 (95% UI ), a difference of 5642 (95% UI ). The cost of G-CSF in the DG arm was 2720 (95% UI ), while that of patients receiving VC was 2741 (95% UI ); thus, there was not any significant difference. Furthermore, often in economic analysis such as the present, there is no correction for censoring and instead bootstrapping is directly used to draw datasets from the original matrix of total patient treatment cost which is not time dependent. To estimate the impact of correcting for this bias and to find Volume 21 No. 7 July 2010 doi: /annonc/mdp

5 original article Table 5. Cost differences between treatment arms Linear model Mean 6 sd ( ) Difference (95% UI) DG (n = 197) VC (n = 192) Total cost (4237 to 7528) a Chemotherapy (5899 to 7.622) a Second-line drugs (21695 to 111) Diagnostics (256 to 72) Laboratory (283 to 111) Hospitalization (284 to 112) G-CSF (2357 to 477) Toxicity (hospitalization) (2195 to 83) a Statistically significant difference in 95% level of significance. sd, standard deviation; DG, docetaxel gemcitabine; VC, vinorelbine cisplatin; UI, uncertainty interval; G-CSF, granulocyte colony-stimulating factor. Figure 1. Distribution of mean total treatment cost ( ). Figure 2. Components of total treatment cost ( ) per group of therapy. whether the results hold true in this context, this approach was used in the sensitivity analysis. It was estimated using this approach that the mean total cost of treatment in the DG group was and in the VC group 5185, which indicate that there is a statistically significant difference favoring VC in line with the figures of the main analysis (P < 0.001). discussion The amount of money spent each year on drugs for the treatment of advanced/metastatic NSCLC is significant. This is the composite product of multiple factors, such as the high prevalence of the disease, the considerable share of patients undergoing chemotherapy, the length of treatment, the high prices of drugs involved, and the therapy-induced toxic effects. Given that several treatments have become available, it is paramount to consider the cost relative to the clinical benefits associated with alternative therapy options for NSCLC in Greece. The analysis here showed that the two alternatives considered have comparable survival times and hence the focus was shifted on their cost differences, from the perspective of Social Insurance Funds which are the payers on behalf of patients. Thus, a cost-minimization analysis was undertaken to compare the use of two alternative first-line chemotherapy options for patients with metastatic lung cancer. The economic analysis was on the basis of a prospectively designed randomized phase III clinical trial. Apart from efficacy and safety, comprehensive sets of resource utilization data were gathered from the participating centers in the context of the trial. In the context of the analysis, direct medical reimbursed costs were estimated. Because of the perspective, indirect costs such as productivity losses were not considered. The study did not include quality-of-life data. However, as survival was similar in the two arms, only significant differences in terms of quality of life could alter the results and the conclusions. In the presence of right censoring, which is a common issue in this kind of studies, a two-stage regression estimator, proposed by Carides et al. (2000), in which the total cumulative cost is modeled as a function of failure time, was employed. At the first stage, a linear model is used to assess treatment cost as a function of survival time. At the second stage, bootstrapping is employed to deal with uncertainty and to derive standard error and interval estimates for the mean cost. This approach has advantages as it deals with the issue of censoring and uncertainty but it also has limitations which relate to the fact that the form of the cost function is presupposed and that estimates are heavily on the basis of the uncensored data. Thus, in the sensitivity analysis, other approaches were used to find out whether the results remain constant. It is notable that in all cases, the VC combination was associated with significantly lower average cost compared with the DG combination, mainly due to lower chemotherapy cost and despite the fact that a higher incidence of severe neutropenia in the VC arm required a higher and more prolonged use of rhg-csf, increasing the treatment cost in this arm. Furthermore, it should be noted that this trial used docetaxel at a dose of 100 mg/m 2, instead of the 75 mg/m 2 dose which is more frequently used. In case a lower dose of docetaxel had been used, different results might have been observed. Nevertheless, the obtained results are in accordance with the specific trial protocol and could not be extrapolated to other dosage scheme. conclusions Annals of Oncology The findings of the clinical trial indicate that the two alternative treatment options considered have similar efficacy in terms of survival; however, they also indicate that the DG option has a more favorable toxicity profile, which supports its use as 1466 Maniadakis et al. Volume 21 No. 7 July 2010

6 Annals of Oncology first-line chemotherapy, especially in patients who cannot tolerate cisplatin and/or in patients with severe comorbidities. On the other hand, this economic evaluation provides a further decision criterion, on the basis of cost considerations. Specifically, on the basis of this criterion, the DG regimen represents a more costly approach in the management of patients and this should be considered in the medical decisionmaking process. In this context, the VC combination could be recognized as the preferred treatment regimen and the significantly higher cost of the DG regimen is an issue that should be taken into account for the final therapeutic decision. One may wonder whether the extra toxicity benefit justifies the significant additional cost, which supports an argument for lowering the price of the DG combination. 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