ORIGINAL RESEARCH ARTICLE
Pharmacoeconomics 2002; 20 (5): 325-337 1170-7690/02/0005-0325/$25.00/0 © Adis International Limited. All rights reserved.
Economic Evaluation of Gemcitabine Alone and in Combination with Cisplatin in the Treatment of Nonsmall Cell Lung Cancer M. Lees,1 M. Aristides,2 N. Maniadakis,3 J. McKendrick,4 N. Botwood5 and D. Stephenson3 1 2 3 4 5
M-TAG, Sydney, New South Wales, Australia M-TAG, London, United Kingdom Eli Lilly and Co., Basingstoke, Hampshire, United Kingdom Eli Lilly and Co., Windlesham, Surrey, United Kingdom AstraZeneca, Kings Langley, Hertfordshire, United Kingdom1
Abstract
Objective: To evaluate the cost effectiveness of gemcitabine in the treatment of nonsmall cell lung cancer (NSCLC). Methods: Gemcitabine was compared with best supportive care and gemcitabine/cisplatin was compared with three standard chemotherapies and four other novel chemotherapy combinations. Costs and effectiveness measures were based on resource and outcome data from previously reported clinical trials. All direct costs associated with NSCLC treatment were included and adjusted to year 2000 values. Perspective: UK National Health Service. Results: Gemcitabine plus best supportive care was associated with an incremental cost per progression-free life year gained of £5228 compared with best supportive care alone. In comparison with standard chemotherapies, gemcitabine/cisplatin was associated with an incremental cost per progression-free life year gained of £1751 versus etoposide/cisplatin and cost per 1-year survival gain of £5681 versus mitomycin/vinblastine/platinum. Incremental cost per tumour response was £2032 relative to etoposide/cisplatin, £5169 relative to mitomycin/ifosfamide/cisplatin and £6240 relative to mitomycin/vinblastine/platinum. Compared with four novel (newer) combination chemotherapies gemcitabine/ cisplatin showed cost savings in each case, with the same or better outcome. Thus, gemcitabine/cisplatin showed improved cost effectiveness and dominance. Sensitivity analyses showed the results were robust to variations to the values of key parameters. Conclusion: Gemcitabine alone or in combination with cisplatin was assessed to be a cost-effective or cost-saving therapy when compared with best supportive
1 N. Botwood was an employee of Eli Lilly during this research. © Adis International Limited. All rights reserved.
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care, standard chemotherapy regimens and novel chemotherapy combinations. Chemotherapy regimens containing gemcitabine therefore represent good value for money and efficient use of healthcare resources in the treatment of advanced NSCLC.
Lung cancer is a significant cause of morbidity and mortality in England and Wales, with an incidence in 1997 of 33 000 cases; this represents 32% of all malignancies.[1] It is the leading cause of cancer deaths in men and currently ranks second for cancer deaths amongst women.[2] In 80 to 90% of cases lung cancer is caused by smoking[3,4] so the incidence is likely to remain high if the number of people who smoke remains high. The most common form of lung cancer is nonsmall cell lung cancer (NSCLC), which accounts for approximately 80% of cases. There are three categories of NSCLC, according to the type of cell from which they derived, but they are generally grouped together because the responses to treatments are broadly similar. Treatment of early stage disease with surgical resection or radiotherapy can be curative.[5] However, presentation is frequently late with extensive stage disease in over two thirds of cases. As such, the objective of treatment has historically been primarily palliative, with agestandardised 1-year survival of 19% and 5-year survival of only 5%.[6] Attitudes to chemotherapy for lung cancer have until recently been negative, as adverse effects of treatment often seemed to outweigh any potential benefits. However, a meta-analysis established that chemotherapy, particularly cisplatin-based combinations, has a significant impact on survival.[7] Despite this, only 10 to 15% of patients with NSCLC in England and Wales currently receive chemotherapy. Further, this average masks large regional differences. One possible reason for the low treatment rate is that current standard chemotherapy combinations may be considered too toxic for beneficial use in older and polymorbid patients. The introduction of newer agents, with improved efficacy and reduced toxicity, may alleviate such concerns. © Adis International Limited. All rights reserved.
Gemcitabine is a novel antimetabolite that has become recognised internationally as a standard in the treatment of NSCLC, with at least 300 000 patients having been treated worldwide.[8,9] It can be prescribed as a single agent for patients considered unsuitable for cisplatin-based chemotherapy as it has at least equivalent efficacy and reduced toxicity compared with platinum-containing regimens. Administration of gemcitabine has a convenient schedule suitable for use on an outpatient basis. Due to its noncompeting toxicity profile it is also suitable for combination therapy. A considerable number of comparative studies have now established the use of gemcitabine alone[10-13] or in combination therapies[14-24] in the treatment of stage III or IV NSCLC. There is increasing pressure on healthcare resources that leads to concern about the economic impact of therapeutic alternatives. Information on relative cost effectiveness of new treatments is therefore required for the decision-making process. As part of a submission to the National Institute for Clinical Excellence (NICE) in England and Wales supporting the use of gemcitabine as treatment for NSCLC, a cost-effectiveness analysis was conducted. This analysis forms the basis of the present article, which contains an evaluation of gemcitabine/best supportive care relative to best supportive care (BSC) alone, and gemcitabine/cisplatin relative to other standard and alternative novel chemotherapeutic combinations. Methods Patients and Treatments
Outcome and resource utilisation data for the analysis were based on published head-to-head clinical trials, as best evidence for comparative clinical performance, and to minimise other potenPharmacoeconomics 2002; 20 (5)
Economic Evaluation of Gemcitabine in NSCLC
tial measurement biases. Although there is the possibility of protocol-driven costs being included in the analysis, the authors take the view that resource use reported in each trial, including hospitalisation and visits to healthcare professionals, represents the satisfaction of a health need rather than trial protocol. In the disease area under consideration, this is especially true for hospitalisations and hospital visits (two main cost drivers), which are due primarily to dealing with treatment-related adverse events. Furthermore, the analyst can introduce biases by selecting certain resources for inclusion and not others; hence the consideration of all data from the relevant trials. The evaluation of gemcitabine plus BSC versus BSC alone was based on a clinical trial of 300 patients.[10] All patients had symptomatic locally advanced or metastatic NSCLC not requiring immediate radiotherapy. Patients were randomised to receive gemcitabine (n = 150) for a maximum of six cycles (see table I for dose schedule) or BSC (n = 150).
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The economic evaluation of gemcitabine/cisplatin versus standard chemotherapies in patients with advanced NSCLC is based on three studies comparing this combination with etoposide/cisplatin,[14] mitomycin/ifosfamide/cisplatin (MIC)[15] and mitomycin/vinblastine/platinum (MVP).[16] In particular, the first comparison involved 135 chemotherapy naïve patients were randomised to receive either gemcitabine/cisplatin or etoposide/ cisplatin. In the second study 307 patients received either gemcitabine/cisplatin or mitomycin/ifosfamide/cisplatin and mesna on day 1. The third comparison of gemcitabine/cisplatin with standard chemotherapy was based on an interim analysis of 158 patients randomised to either gemcitabine/ cisplatin or mitomycin/vinblastine/cisplatin. The doses and treatment schedules are summarised in table I. For comparison of gemcitabine/cisplatin with other novel combinations, outcome and resource data were obtained from two large trials: one compared gemcitabine/cisplatin with different com-
Table I. Dosage regimens used in the comparative clinical studies Comparison of gemcitabine/best supportive care (BSC) versus BSC alone[10] Gemcitabine Gemcitabine 1000 mg/m2 on days 1, 8 and 15 of a 28-day cycle BSC alone
No chemotherapy regimen administered
Comparison of gemcitabine/cisplatin versus standard chemotherapy[14-16] Gemcitabine/cisplatin Gemcitabine 1250 mg/m2 on days 1 and 8, and cisplatin 100 mg/m2 on day 1 of a 21-day cycle Etoposide/cisplatin
Etoposide at 100 mg/m2 on days 1, 2 and 3 plus cisplatin 100 mg/m2 on day 1 of a 21-day cycle
Gemcitabine/cisplatin
Gemcitabine 1000 mg/m2 on days 1, 8 and 15 plus cisplatin 100 mg/m2 on day 1 (vs MVP) or day 2 (vs MIC), of a 28-day cycle
Mitomcyin/ifosfamide/cisplatin (MIC)
Mitomycin at 6 mg/m2, ifosfamide at 3000 mg/m2 and mesna on day 1, plus cisplatin at 100 mg/m2 on day 2 of a 28-day cycle
Mitomycin/vinblastine/platinum (MVP)
Mitomycin at 6 mg/m2 plus vinblastine at 6 mg/m2 on day 1, plus cisplatin at 100 mg/m2 on day 1 of a 28-day cycle
Comparison of gemcitabine/cisplatin versus novel chemotherapy[17,18]a Paclitaxel/cisplatin Paclitaxel 175 mg/m2 over 24h on day 1 plus cisplatin 75 mg/m2 on day 1 of a 21-day cycle Paclitaxel/carboplatin
Paclitaxel 225 mg/m2 over 3h on day 1 plus carboplatin at a dose of AUC 6 on day 1 of a 21-day cycle
Docetaxel/cisplatin
Docetaxel 75 mg/m2 on day 1 plus cisplatin 75 mg/m2 on day 1 of a 21-day cycle
Vinorelbine/cisplatin
Vinorelbine 30 mg/m2 once weekly plus cisplatin 120 mg/m2 on days 1 and 29 and then every 6 weeks
a
Gemcitabine/cisplatin regimen as in the comparison with MIC and MVP.
AUC = area under the curve.
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Pharmacoeconomics 2002; 20 (5)
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binations of taxanes and platinum agents,[17] and an interim analysis available from a second trial compared gemcitabine/cisplatin with vinorelbine/ cisplatin.[18] The first study used a randomised four-arm design and was the largest study to date of chemotherapy in NSCLC. A total of 1146 patients were enrolled and were stratified at entry by performance status, weight loss, disease stage and presence of brain metastases. The median age of the patients was 63 years, approximately two thirds were male, the majority (n = 1083) had ECOG (Eastern Cooperative Performance Group) performance status 0 to 1 and most (n = 968) had stage IV disease. Treatment combinations used were gemcitabine/cisplatin, paclitaxel/cisplatin, paclitaxel/carboplatin and docetaxal/cisplatin. The doses and treatment regimens used for each of the combination therapies are shown in table I. The second combination study randomised patients with NSCLC to gemcitabine/cisplatin or vinorelbine/cisplatin and the interim analysis was carried out when 60 patients per arm were evaluable for survival. Dosage regimens for the two therapies are also shown in table I. All patients had locally advanced or metastatic NSCLC (42% stage IIIB, 58% stage IV), were aged ≤70 years and had performance status ≤1. Study Methodology
Lees et al.
while hospitalisation costs are from the 2000 UK National Schedule of Reference Costs.[26] Chemotherapy administration and health professional costs were taken from a UK-based source of unit costs in healthcare[27] while the costs of radiotherapy and transfusions were taken from a previous economic evaluation of gemcitabine[28] All costs relate to the year 2000. Those not initially expressed in year 2000 values were adjusted for inflation using the composite NHS price inflation index.[27] As survival was low for the NSCLC patient populations, the majority of the costs were incurred within 1 year, so discounting was not considered necessary. Cost-minimisation and costeffectiveness analyses were performed. Sensitivity analyses were conducted for each of the economic evaluations by varying the value of key parameters in order to examine robustness of the cost-effectiveness ratios. Where 95% confidence intervals (CIs) were available for outcome measures these were used explore variation in treatment costs. The costs per episode of hospitalisation were taken from the UK National Schedule of Reference Costs. Each unit cost was based on a different Healthcare Resource Group (HRG). At baseline, the mean cost associated with the HRG was used, and in the sensitivity analyses the lower and upper cost bound for the HRG was used. Drug and other treatment costs were varied by up to 50% in each direction.
General Comments
Each economic evaluation was undertaken from the perspective of the national Health Service (NHS) in England and Wales, and includes only direct healthcare costs attributable to the NHS. Data on resource utilisation and outcomes from the clinical studies were combined with unit cost data from various national sources. Costs included those associated with chemotherapy acquisition and infusion, hospitalisation, visits to health professionals, use of concomitant medications, radiotherapy and hospice admissions. Wastage was incorporated into the analyses. Unit costs were taken from several sources. Costs of chemotherapy and other medications were taken from the British National Formulary,[25] © Adis International Limited. All rights reserved.
Gemcitabine Plus Best Supportive Care (BSC) Versus BSC Alone
The costing in this comparison was derived from the pivotal trial[10] where all of the resources listed previously were collected for each patient. This resource use collected from the trial was applied to the unit costs described above (see General Comments). It should be noted that gemcitabine was assumed to be administered at an outpatient clinic and did not require hospital admission. The study comparing gemcitabine plus BSC with BSC alone was designed to examine quality of life, from patient assessment of a pre-defined subset of commonly reported symptoms, and not survival advantage. Therefore, overall survival has Pharmacoeconomics 2002; 20 (5)
Economic Evaluation of Gemcitabine in NSCLC
not been evaluated but a progression-free survival measure was used, which is patient-relevant and allows comparison with other technologies. Incremental time to progression was evaluated for gemcitabine and BSC compared with BSC alone from the difference in area under the time to radiotherapy curves. Although the time to radiotherapy does not always correspond with time to progression and the results should be considered in this context, in this case it serves as an approximation in the absence of time to progression data. This is because a comparison of gemcitabine plus BSC and BSC alone is essentially a comparison of gemcitabine and no treatment as BSC is included in both arms. Gemcitabine/Cisplatin Versus Standard Chemotherapy
In these comparisons, resource use was also derived from pivotal trials. The cost of chemotherapy acquisition and administration was derived from the relevant trials for the etoposide/cisplatin[14] and MIC[15] comparisons, while the cost of MVP was based on the MVP regimen used in the UK. All other resource use was based on results from the trial comparing gemcitabine/cisplatin and etoposide/cisplatin.[14] It was assumed that the resource use associated with gemcitabine/cisplatin would be the same regardless of the comparator, while the non-chemotherapy costs associated with MIC and MVP were assumed to be the same as those for etoposide/cisplatin. Chemotherapy in all regimens was again administered in an outpatient clinic. Outcome measures in the study of gemcitabine/cisplatin versus etoposide/cisplatin were overall survival and progression-free survival, while the comparative study with MIC determined median survival time and the study versus MVP estimated 1-year survival after a median follow-up of 54 months. Overall tumour response was also determined in each of the three studies. Gemcitabine/Cisplatin Versus Novel Chemotherapy
There were two analyses performed. The first compared gemcitabine/cisplatin with the taxane/ © Adis International Limited. All rights reserved.
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platinum regimens on the basis of a comparative trial.[17] Chemotherapy acquisition and administration costs were based on the specifications for each regimen and the number of treatment cycles in the trial results. All administrations except for paclitaxel/cisplatin, where paclitaxel was administered over 24 hours, were performed in an outpatient clinic. Hospital costs were derived from the percentage of patients hospitalised due to neutropenic fever and a need for intravenous antibacterials. Visits to general practitioners were assumed to occur once per month during treatment and prior to disease progression, and twice per month after disease progression. There was no available data regarding the use of the other three resource components: radiotherapy, transfusions and use of concomitant medications. It was assumed that these resources would have the same cost as the gemcitabine/cisplatin arm in the comparison of gemcitabine/cisplatin and standard chemotherapy. The second analysis compared gemcitabine/ cisplatin with vinorelbine/cisplatin on the basis of a comparative trial.[18] Chemotherapy acquisition and administration costs were based on the specifications for each regimen and the number of treatment cycles in the trial. It showed that 70% of gemcitabine/cisplatin recipients received an initial two cycles of chemotherapy (8 weeks), while the remaining 30% received four cycles (16 weeks). On the other hand, 75% of vinorelbine/cisplatin patients received the initial two cycles (10 weeks), while the remaining 25% received four (20 weeks). All administrations were performed in an outpatient clinic. Due to a lack of available data on the other resource components, it was assumed that the costs associated with these resources in vinorelbine/cisplatin recipients was the same as for gemcitabine/cisplatin recipients. For the study comparing gemcitabine/cisplatin with the three taxane/platinum regimens, overall survival, response rates and time to progression were documented for each combination. In the interim analysis of the comparison with vinorelbine/cisplatin, mean survival time and rates of rePharmacoeconomics 2002; 20 (5)
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sponse to the two treatment regimens were assessed. Results Gemcitabine as a Single Agent
This represents a gain of 0.314 years of life without disease progression due to gemcitabine. In addition, tumour response was reported for 18.5% of the patients given gemcitabine but there was no response to BSC alone. Cost Effectiveness
Costs
The costs associated with gemcitabine plus BSC, BSC alone and the incremental costs as the difference between the two treatments are summarised in table II. Gemcitabine plus BSC was associated with more resource use than BSC alone, essentially due to the cost of chemotherapy drugs. This incremental cost was partially offset by the increased use of concomitant medications, radiotherapy and surgical procedures that is associated with BSC alone. Patients given BSC alone also received chemotherapy with drugs other than gemcitabine and this resource use was incorporated into the concomitant medications component. Outcomes
At the median follow-up of 25.3 months, less than 10% of patients in the study remained alive and there was no significant difference in median survival time between treatments. However, the study was not designed to assess survival and during the study 49% of patients given gemcitabine plus BSC received radiotherapy, compared with 79% of those receiving BSC alone. The outcome results from the study (table III) showed that the median time to radiotherapy was 288 days for gemcitabine plus BSC and 173 days for BSC alone.
The cost-effectiveness ratios are also displayed in table III. These demonstrate that the incremental cost per progression-free life year gained was £5228 for gemcitabine plus BSC compared with BSC alone. The incremental cost per additional tumour response among gemcitabine patients was £8873. Several sensitivity analyses were conducted to test the robustness of the baseline results. When only the costs of gemcitabine acquisition and administration were included in the analysis, thereby removing all cost offsets, the incremental cost per progression-free life year increased to £7885 and the incremental cost per tumour response to £13 382. On the other hand, when outcomes were varied using the 95% CIs, the resulting incremental cost per progression-free life year gained ranged from £2942 to £23 451 and the incremental cost per tumour response ranged from £6314 to £12 628. Varying unit costs of chemotherapy administration gave an incremental cost per progression-free life year gained with gemcitabine ranging from £3715 to £6741 and an incremental cost per tumour response from £6305 to £11 442.
Table II. Average costs (£; 2000 values) per patient of gemcitabine plus best supportive care (BSC) or BSC alone and the incremental costs Resource component
Gemcitabine plus BSC
BSC alone
Incremental cost
Chemotherapy drugsa
1525
NA
1525
Chemotherapy administration
NA
950
1400
1471
–71
Hospice admissions
465
231
234
Radiotherapy and surgical procedures
325
492
–167
Hospitalisations
950
Visits to health professionals
137
152
–15
Concomitant medications
700
1514
–814
5502
3861
1642
Total costs a
Patients in the BSC alone arm did receive some non-gemcitabine chemotherapy. This resource use is incorporated into the concomitant medications component.
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Table III. Outcome measures and associated costs (£; 2000 values) for gemcitabine plus best supportive care (BSC) compared with BSC alone as treatment for nonsmall cell lung cancer Outcome
Gemcitabine plus BSC
BSC alone
Time to radiotherapy (days)
288
173
Incremental 115
Progression-free life years
0.789
0.474
0.314 (95% CI: 0.070-0.558)
Cost per progression-free life year
6974
8145
5228
Overall tumour response (%)
18.5
0.0
18.5 (95% CI: 13-26)
Cost per tumour response
29 743
NA
8873
CI = confidence interval; NA = not applicable.
compared with etoposide/cisplatin (4.3 months; p = 0.01), while estimated 1-year survival was greater in patients receiving gemcitabine/cisplatin (36%) than MVP (17%; p < 0.05). For each of the three comparisons, tumour response was greater with gemcitabine/cisplatin.
Gemcitabine/Cisplatin Versus Standard Chemotherapies Costs
Average costs per patient for gemcitabine/ cisplatin and the three standard NSCLC chemotherapies, etoposide/cisplatin, MIC and MVP, are shown in table IV. The gemcitabine/cisplatin regimen was associated with a higher level of resource use in each case. This was due to higher costs of chemotherapy acquisition and administration in patients receiving gemcitabine, although these were partially offset by higher hospitalisation and transfusion costs in patients receiving the standard chemotherapy regimens.
Cost Effectiveness
Cost-effectiveness ratios calculated on the basis of cost and outcome results discussed above are also displayed in table V. These ratios suggest that gemcitabine/cisplatin is a cost-effective alternative to standard chemotherapy for NSCLC. The incremental cost per progression-free life year gained with gemcitabine/cisplatin compared with etoposide/cisplatin was £1751, while the incremental cost per percentage gain in 1-year survival compared with MVP was £5681. Using the only outcome measure common to the three comparisons, the incremental cost per additional tumour response with gemcitabine/cisplatin is £2032 com-
Outcomes
The outcome results from those studies comparing gemcitabine/cisplatin with standard chemotherapy for advanced NSCLC are displayed in table V. Progression-free survival was significantly increased with gemcitabine/cisplatin (6.9 months)
Table IV. Average costs (£; 2000 values) per patient of resource use for gemcitabine/cisplatin versus three standard chemotherapy regimens and the incremental costs (£) in each case Resource component
GC
Incremental
GC
Chemotherapy drugs
1384
EP 465
Incremental 919
GC 1900
MIC 857
1043
1900
MVP 733
Incremental 1167
Chemotherapy administration
999
421
578
1442
748
694
1442
424
1018
Hospitalisations
–883
1157
2051
–894
1157
2051
–894
1140
2023
Radiotherapy
3
0
3
3
0
3
3
0
3
Transfusions
414
618
–204
414
618
–204
414
618
–204
62
58
4
62
58
4
62
58
4
123
149
–25
123
149
–26
123
149
–26
4142
3762
380
5101
4481
620
5084
4005
1079
Visits to health professionals Concomitant medications Total treatment costs
EP = etoposide/cisplatin; GC = gemcitabine/cisplatin; MIC = mitomycin/ifosfamide/cisplatin; MVP = mitomycin/vinblastine/platinum.
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pared with etoposide/cisplatin, £5169 compared with MIC and £6240 compared with MVP. Sensitivity analyses were conducted to assess the robustness of the baseline results. Only the analyses that demonstrated the most noticeable impact on baseline results were reported here. As such, in the comparison of gemcitabine/cisplatin and etoposide/cisplatin exclusion of all non-chemotherapy costs resulted in an incremental cost per progression-free life year of £6907, while increasing each hospitalisation cost to its upper HRG bound as specified in the National Schedule of Reference Costs resulted in a cost saving per patient of over £300 with gemcitabine/cisplatin. Conversely, in the comparison of gemcitabine/cisplatin with MVP the upper limit of incremental cost per percent gain in 1-year survival was £15 847 when costs of chemotherapy administration were increased by 50%. The lower limit of incremental cost per percent gain in 1-year survival in this comparison was £1676 when hospitalisation costs were increased by 50%. The incremental cost per tumour response for gemcitabine/cisplatin versus MIC ranges from an upper limit of £14 475, when all non-chemotherapy costs were excluded, to a cost saving with gemcitabine/cisplatin if costs of hospitalisation were increased by 50%. In the comparisons of gemcitab-
ine cisplatin with etoposide/cisplatin and MVP, the variations in incremental cost per tumour reported in the sensitivity analyses were almost identical to the variations in the other ratios reported in the previous paragraph. Gemcitabine/Cisplatin Compared with Other Novel Therapies Costs
The costs per patient for resource use for gemcitabine/cisplatin and the other novel chemotherapy combinations are shown in tables VI and VII. The incremental total treatment cost due to gemcitabine/cisplatin compared with each of the other therapies is shown in table VIII. The gemcitabine/cisplatin combination was associated with slightly reduced resource use compared with docetaxel/cisplatin (–£242) and vinorelbine/cisplatin (–£571). The reductions were greater when compared with paclitaxel/cisplatin (–£3506), due to reduced costs for both chemotherapy and administration, and compared with paclitaxel/carboplatin (–£2907) due to reduced costs of chemotherapy drugs. It is important to note that although the acquisition cost of vinorelbine per administration was lower than that of gemcitabine, vinorelbine was used more intensively than gemcitabine in the studies on which this evaluation was based. As
Table V. Outcome measures and associated costs (£; 2000 values) for gemcitabine/cisplatin compared with standard chemotherapy regimens for nonsmall cell lung cancer Outcome
Gemcitabine/cisplatin
Comparator combination
Incremental
Versus etoposide Progression-free survival (years)
0.575
0.358
0.217 (p = 0.01)
Cost per progression-free life-year
7203
10 508
1751
Tumour response (%)
40.6
21.9
18.7 (p = 0.02)
Cost per tumour response
10 201
17 177
2032
Versus mitomycin/ifosfamide/cisplatin (MIC) Tumour response (%) 39.6
27.6
12.0 (p = 0.029)
Cost per tumour response
£16 235
£5169
£12 882
Versus mitomycin/vinblastine/platinum (MVP) 1-year survival (%) 36.0
17.0
19.0 (p < 0.05)
Cost per % gain in 1-year survival
23 554
5681
14 121
Tumour response (%)
54.0
36.7
17.3 (p < 0.05)
Cost per tumour response
9414
10 910
6240
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Pharmacoeconomics 2002; 20 (5)
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Table VI. Average costs (£; 2000 values) per patient associated with gemcitabine/cisplatin and other taxane/platinum combinations in treatment of nonsmall cell lung cancer Resource component
Gemcitabine/cisplatin
Paclitaxel/cisplatin
Paclitaxel/carboplatin
Docetaxel/cisplatin
Chemotherapy drugs
3338
4317
6981
4129
Chemotherapy administration
1088
3353
379
372
372
627
321
548
Hospitalisations Radiotherapy
3
3
3
3
Transfusions
414
414
414
414
Visits to health professionals
199
206
223
190
Concomitant medications
123
123
123
123
5537
9043
8444
5779
Total treatment costs
such, a lower acquisition unit cost of vinorelbine does not translate to a lower overall cost. Outcomes
Survival was very similar between treatments in the study of gemcitabine/cisplatin compared with the taxane/platinum combinations.[17] Response rate was also similar for gemcitabine/cisplatin (21.0%) and paclitaxel/cisplatin (21.3%) although greater than for docetaxel/cisplatin (17.3%) or paclitaxel/carboplatin (15.3%). However, time to progression of disease was clearly greater for gemcitabine/cisplatin compared with each of the other combinations, as shown in table IX In the second study, slightly greater values were observed with gemcitabine/cisplatin compared with vinorelbine/cisplatin in the median survival time (42 weeks versus 35 weeks) and response rates (30% versus 25%). Significance testing was not conducted on these interim data but it is noteworthy that the vinorelbine/cisplatin arm was stopped due to an early stopping rule for unfavourable survival.
Cost Effectiveness
The costs and outcomes from the two studies above[17,18] indicate that gemcitabine/cisplatin is cost saving and in some cases dominant relative to the other combinations based on novel therapies or that it is at least a very cost-effective option. In particular, it is clear that gemcitabine/cisplatin dominates the taxane/platinum combinations, with lower costs of between £242 and £3506 and significantly higher progression-free survival. In addition, gemcitabine/cisplatin is a more cost-effective NSCLC therapy than vinorelbine/cisplatin. It is £571 less expensive per patient and at least equal in efficacy to this vinorelbine combination. Sensitivity analyses for these evaluations were mainly reported as changes in incremental cost, rather than incremental cost-effectiveness. This is for the obvious reason that the gemcitabine/cisplatin regimen is cost saving relative to the other novel regimens. In the costing of paclitaxel/cisplatin the study protocol used a 24-hour infusion of paclitaxel, which is rarely the case in the UK.
Table VII. Average costs (£; 2000 values) per patient associated with gemcitabine/cisplatin and vinorelbine/cisplatin as treatment for nonsmall cell lung cancer Resource component
Gemcitabine/cisplatin
Vinorelbine/cisplatin
Chemotherapy drugs
2538
2611
Chemotherapy administration
827
1325
Hospitalisations
373
373
Radiotherapy
3
3
Transfusions
414
414
Visits to health professionals
199
199
Concomitant medications
123
123
4477
5048
Total treatment costs
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Table VIII. Incremental costs (£; 2000 values) for gemcitabine/cisplatin versus other novel combination chemotherapies for nonsmall cell lung cancer Treatment
Gemcitabine/cisplatin
Comparator cost
Incremental cost
Paclitaxel/cisplatin
5537
9043
–3506
Paclitaxel/carboplatin
5537
8444
–2907
Docetaxel/cisplatin
5537
5779
–242
Vinorelbine/cisplatin
4477
5048
–571
Administration of paclitaxel over 3 hours reduced the cost saving associated with gemcitabine/cisplatin to £579. Conversely, the cost of each chemotherapy drug was calculated using the mean number of cycles but calculation on the median number of cycles increases the cost saving with gemcitabine/cisplatin to £4011. In the comparison of gemcitabine/cisplatin versus paclitaxel/carboplatin, the baseline cost saving of £2907 was reduced to £1569 if the carboplatin dose was reduced to that of cisplatin. Again, calculating the cost of each chemotherapy drug on the median rather than the mean number of cycles increased the cost saving associated with gemcitabine/cisplatin to £4314. Compared with docetaxel/cisplatin the cost saving associated with the gemcitabine/cisplatin regimen was £242. If costs of chemotherapy administration are increased by 50%, however, the result is an incremental cost associated with gemcitabine/cisplatin of £116. This corresponds to an incremental cost per progression-free life year gained of £1158. No other sensitivity analysis results in an incremental cost associated with gemcitabine/cisplatin. The baseline cost saving associated with gemcitabine/cisplatin in the comparison against vinorelbine/cisplatin was £571. Assuming that the two treatments have the same number of administrations decreases this cost saving to £140. On the other hand, it was conservatively assumed that hospital resource use is the same for both treatments. This is unlikely to be true, however, as gemcitabine/cisplatin showed a better toxicity profile than vinorelbine/cisplatin in the study. If it is assumed that vinorelbine/cisplatin recipients use hospital resources at the same level as paclitaxel/cisplatin patients, the cost saving associated with gemcitabine/cisplatin increases to £826. © Adis International Limited. All rights reserved.
Other sensitivity analyses were conducted for each of these comparisons. These include such analyses as adjusting each resource cost by 50% in either direction. All other sensitivity analyses result in total cost savings within the ranges indicated above. The values quoted are therefore the upper and lower values of cost savings for gemcitabine/ cisplatin compared with other novel chemotherapy combinations. Discussion Clinical studies have shown that gemcitabine is an effective and safe agent for use as first-line treatment of patients with advanced NSCLC. It can be used either alone or in combination with other agents and its low toxicity profile enables it to be used in patients with advanced stage of disease and in elderly patients.[23,24] The present economic evaluation showed that single-agent gemcitabine is cost effective in preventing disease progression. The incremental cost per progression-free lifeyear gained when comparing gemcitabine plus BSC to BSC alone was £5228. Sensitivity analyses demonstrated these results to be robust. This finding is supported by the results of a similar evaluation in Canada, which looked at survival with gemcitabine versus best supportive care.[29] They found that at 1993 rates the cost per life-year gained ranged from $632 Canadian dollars ($Can) to $Can9285 (year 2000 UK equivalent £340 to £4995) and concluded that gemcitabine was a costeffective intervention. Further support for this finding comes from other evaluations that compared gemcitabine as single agent therapy with standard palliative combination treatments. These evaluations showed gemcitabine to be cost saving while improving quality of life.[30-32] Pharmacoeconomics 2002; 20 (5)
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When compared with standard chemotherapy for advanced NSCLC i.e. MIC, etoposide/cisplatin and MVP, gemcitabine/cisplatin was again shown to be value for money. Although overall survival is similar between treatments, progression-free survival is increased relative to etoposide/cisplatin and 1-year survival is increased versus MVP, while tumour response is improved relative to each standard therapy. In these comparisons, the incremental cost per additional tumour response ranged between £2032 and £6240, though it is acknowledged that tumour response must be interpreted cautiously as an outcome of lung cancer therapy. The cost per progression-free life year for gemcitabine/cisplatin was £2032 relative to etoposide/cisplatin and the cost per 1-year survival benefit was £5681 relative to MIC. The gemcitabine/cisplatin regimen was also shown to be value for money relative to other novel combination chemotherapies. In most cases the gemcitabine/cisplatin regimen dominated the other novel regimens, with superior progression-free survival and incremental cost savings ranging from a saving of £242 versus docetaxel/cisplatin to £3506 versus paclitaxel/cisplatin. This regimen is also more cost effective than vinorelbine/cisplatin, with efficacy assumed to be equal and a cost saving per patient of £571. These cost savings were shown to still be present using sensitivity analyses with highly negative assumptions. The only instance where gemcitabine/cisplatin was more expensive was against docetaxel/cisplatin after administration costs were increased by 50%. In this case the incremental cost per progression-free life-year is £1158, which would still indicate gemcitabine/cisplatin to be good value for money.
The evaluations undertaken here are based on the schedules and doses outlined in table I. However, such analysis may underestimate the cost effectiveness of gemcitabine/cisplatin, since the regimen used may not have been optimal, in light of studies which have suggested that when combined with gemcitabine administration of cisplatin on days 2 and 15 significantly increased survival compared with administration on days 1, 8 and 15.[33] Nonetheless, the evidence from this evaluation is supported by other published studies. An economic evaluation of gemcitabine/cisplatin compared with etoposide/cisplatin found no difference in total costs but suggested a favourable cost effectiveness due to increased response rates and time to disease progression with gemcitabine/cisplatin.[34] Average cost effectiveness for gemcitabine/cisplatin in an Italian study also suggested no significant difference compared with MIC, etoposide/cisplatin or vinorelbine/cisplatin.[35] In that study, mean tumour response was highest with the gemcitabine/cisplatin combination than each of the other treatments and was significantly better compared with the etoposide/cisplatin regimen. Not all patients with NSCLC are eligible for first-line chemotherapy and a significant proportion will refuse chemotherapy, die before treatment can be initiated or will not be suitable for other reasons. At present, in England and Wales, the number of patients receiving chemotherapy for NSCLC is estimated to be approximately 2700 patients per year. Of these, 10% will be treated with gemcitabine alone and 20% with gemcitabine/cisplatin.[7] Projected impact on the NHS in England and Wales of a change in these numbers was calculated for the year 2001. With no increase in the
Table IX. Progression-free life-years gained with gemcitabine/cisplatin compared with other novel combination therapiesa Treatment
Gemcitabine/ cisplatin
Comparator
Incremental
Gemcitabine/cisplatin vs paclitaxel/cisplatin
0.375
0.292
0.083 (p < 0.01)
Gemcitabine/cisplatin vs paclitaxel/carboplatin
0.375
0.300
0.075 (p < 0.05)
Gemcitabine/cisplatin vs docetaxal/cisplatin
0.375
0.275
0.100 (p < 0.05)
Gemcitabine/cisplatin vs vinorelbine/cisplatinb
0.808
0.673
0.135
a
Based on two trials.[17,18]
b
Statistical significance not tested.
© Adis International Limited. All rights reserved.
Pharmacoeconomics 2002; 20 (5)
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number of patients with NSCLC receiving chemotherapy but the proportion receiving gemcitabine/ cisplatin increasing from 20 to 30%, the increased cost to the NHS would be £430 000. The maximum impact would occur if there was an additional 10% of patients receiving chemotherapy, with an increased cost to the NHS of £6.8 million. However, this is a large overestimate as it excludes offsets due to reductions in hospitalisation, radiotherapy or palliation. These analyses are based fundamentally on cost and outcome drivers from head-to-head studies. It is acknowledged that there are limitations to the generalisability of analyses which are based on trials. However, any limitations with this approach must be considered in the light of limitations of alternative approaches where analysts make systematic adjustments to the data or pursue predominantly modelled analyses. These analytical ‘trade-offs’ are recognised in the Australian pharmacoeconomic guidelines for reimbursement.[36] In these guidelines, analyses based on head-tohead trials are seen as a pivotal step in value-formoney assessment which can later be complemented by modelled analyses. Overall, a claim for cost effectiveness of gemcitabine regimens in the treatment of advanced NSCLC is supported for each setting examined in this economic evaluation. When compared with best supportive care and standard therapies they consume more resources but have a significant impact on health outcomes. In each of these settings, the high cost of chemotherapy acquisition and administration with gemcitabine/cisplatin is offset by reductions in the cost of hospitalisation due to adverse events and visits to healthcare professionals, among other resource savings. These savings are observed from use of resources reported in the trials due to patient need rather than any protocol requirements. Therefore, they represent real savings likely to be observed with treatment in the community. In each case a small additional outlay of public funds is likely to significantly improve progression-free survival and tumour response relative to standard therapies. © Adis International Limited. All rights reserved.
Lees et al.
Compared with other novel chemotherapies, the combination of gemcitabine plus cisplatin is generally cost saving. Even in the worst situation the incremental cost-effectiveness ratio is very low, indicating that gemcitabine/cisplatin is a cost-effective alternative. Savings from nonchemotherapy resource use are again important. Hospitalisation costs may be underestimated as only neutropenic fever and intravenous antibacterial costs were included. It is likely that more hospitalisations from a wider range of causes may have occurred. In addition, the adverse effect profile of vinorelbine/cisplatin is inferior to that of gemcitabine/cisplatin, which would indicate a higher number of adverse event–related hospitalisations for vinorelbine/cisplatin. However, a lack of evidence regarding actual hospitalisations means that it was assumed that hospital costs for gemcitabine/cisplatin and vinorelbine/cisplatin were identical. Conclusions In summary, gemcitabine alone or in combination with cisplatin represents a cost-effective treatment for NSCLC compared to BSC, standard chemotherapy and novel chemotherapy strategies, in the context of the UK NHS. Its use represents good value for money and efficient use of health care resources for the small portion of patients with NSCLC that are eligible for chemotherapy. Acknowledgements This study was carried out with a research grant from Eli Lilly and Company.
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Correspondence and offprints: N. Maniadakis, Lilly Research Centre, Sunninghill Road, Erl Wood Manor, Windlesham, GU20 6 PH, United Kingdom.
Pharmacoeconomics 2002; 20 (5)