Cost-effectiveness analysis of bevacizumab combined with chemotherapy for the treatment of metastatic colorectal cancer in Japan

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Cost-Effectiveness Analysis of Bevacizumab Combined with Chemotherapy for the Treatment of Metastatic Colorectal Cancer in Japan Takeru Shiroiwa, MSc; Takashi Fukuda, PhD; and Kiichiro Tsutani, MD, PhD Department of Drug Policy and Management, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan ABSTRACT Background: Rapid progress has been made in the treatment of metastatic colorectal cancer (mCRC). New treatment regimens for mCRC include not only cytotoxic chemotherapy but also targeted monoclonal antibodies, including bevacizumab. However, bevacizumab is an expensive medication, which costs from ¥300,000 to ¥400,000 (US $2500–$3300) per month. Objective: The purpose of this cost-effectiveness analysis was to examine the economic efficiency of treating mCRC with bevacizumab plus chemotherapy versus chemotherapy alone in Japan. Methods: We searched an electronic database (MEDLINE, UpToDate, and American Society of Clinical Oncology [ASCO] Virtual Meeting; key terms: bevacizumab limited to randomized controlled trial; years: 2000 to present [June 29, 2007]) to detect randomized controlled trials (RCTs) that compared chemotherapy alone with chemotherapy plus bevacizumab. To analyze the cost-effectiveness of bevacizumab, we used the Weibull regression model and determined an expected treatment duration at each state using reported survival curves of RCTs. We included only the direct medical costs (2006) of these medications to estimate the expected values of incremental costs; thus, the analysis was conducted from the perspective of the health care payer. The incremental cost-effectiveness ratios (ICERs) were calculated from these expected values of incremental life-years and incremental costs. Results: We identified 5 articles using MEDLINE and 1 trial found on UpToDate and ASCO Virtual Meeting; these data composed the final analysis group. First-line chemotherapy regimens included in this analysis were bevacizumab + 5-fluorouracil/leucovorin (FU/LV), irinotecan/FU/LV (IFL), infusional FU/LV/ oxaliplatin (FOLFOX6), bolus FU/LV/oxaliplatin (bFOL), and capecitabine/oxaliplatin (CAPOX). The only 2256

second-line chemotherapy regimen included was FOLFOX4. The ICERs of additional bevacizumab when combined with FU/LV, IFL, FOLFOX6, bFOL, and CAPOX were ¥17.4 million (US $145,000), ¥11.9 million ($99,000), ¥13.5 million ($113,000), ¥16.9 million ($141,000), and ¥8.5 million ($71,000), respectively, per life-year gained; the ICER was ¥14.1 million ($118,000) with second-line FOLFOX4. Conclusions: In this cost-effectiveness analysis in Japan, the ICERs of bevacizumab + FU/LV combination treatment, IFL, and second-line FOLFOX4 were high compared with other chemotherapies for mCRC. It remains difficult to assess first-line therapies comprising bevacizumab with oxaliplatin-based regimens, especially CAPOX. Further information is needed to assess cost-effectiveness. (Clin Ther. 2007;29:2256–2267) Copyright © 2007 Excerpta Medica, Inc. Key words: cost-benefit analysis, colorectal neoplasms, antibodies monoclonal, neoplasm metastasis, drug therapy.

INTRODUCTION The prevalence of colorectal cancer is increasing in Japan. An increasingly westernized diet (increased intake of fat and meat) and a rapidly aging population are thought to be major factors in the increasing prevalence of this disease.1 In the past 20 years, the annual incidence of colorectal cancer–related death in Japan has doubled, increasing from 20,000 in 1985 to 40,000 in 2004.2 In Japan, colon cancer is the third leading cause of death from malignant neoplasm, after

Accepted for publication July 30, 2007. doi:10.1016/j.clinthera.2007.10.013 0149-2918/$32.00 Printed in the USA. Reproduction in whole or part is not permitted. Copyright © 2007 Excerpta Medica, Inc.

Volume 29 Number 10

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T. Shiroiwa et al. lung and stomach cancer.2 Reducing the risk for death in patients with colon cancer has therefore become an important public health issue in that country. Significant progress in the treatment of colon cancer has been made in recent years.3,4 In metastatic colorectal cancer (mCRC), with the development of systematic chemotherapy, including 5-fluorouracil, oxaliplatin, and irinotecan, disease progression has been slowed and survival time has increased.3 Until ~2000, combination 5-fluorouracil/leucovorin (FU/LV)5 was the only regimen used worldwide. In 2000, some Phase III trials6–8 found a survival benefit with combination irinotecan/FU/LV (IFL) (irinotecan 120 mg/m2 q2w and Mayo regimen6) or infusional FU/LV/irinotecan (FOLFIRI) (irinotecan 180 mg/m2 q2w and de Gramont regimen or AIO regimen7), and infusional FU/oxaliplatin infusional FU/LV/oxaliplatin (FOLFOX4) (oxaliplatin 85 mg/m2 q2w and de Gramont regimen8) compared with FU/LV monotherapy (median overall survival [OS]: IFL, 14.8 vs 12.6 months [P = 0.04]; FOLFIRI, 17.4 vs 14.1 months [P = 0.031]; FOLFOX4, 16.2 vs 14.7 months [P = 0.12]). In a randomized controlled trial (RCT) in 220 patients with unresectable metastases, sequential administration of an oxaliplatin-based regimen (FOLFOX6) (oxaliplatin 85 mg/ m2 q2w and sLV5FU2 regimen) and an irinotecanbased regimen (irinotecan 180 mg/m2 q2w and sLV5FU2 regimen) was associated with increased median OS to ~20 months after metastasis compared with other chemotherapies.9 Targeted monoclonal antibody therapy has also contributed to the recent progress in the treatment of mCRC; angiogenesis inhibitors may reduce tumor cell growth and reduce overall tumor size.10 Bevacizumab— an angiogenesis inhibitor and a recombinant humanized monoclonal antibody—blocks the activity of vascular endothelial growth factor (VEGF). VEGF is a growth factor ligand that binds to specific cells and stimulates new blood vessel formation. Bevacizumab has been approved for the treatment of mCRC in the United States (in 2004) and the European Union (in 2005) and in April 2007 was approved by the Ministry of Health, Labor and Welfare in Japan, where its use is expected to increase. The American National Comprehensive Cancer Network11 has recommended the use of bevacizumab plus chemotherapy as first-line treatment of mCRC. In patients with mCRC, bevacizumab + IFL combination,12 FU/LV,13–15 and an oxaliplatin-based regimen16,17 have been associated with increased progressionOctober 2007

free survival (PFS) and OS compared with chemotherapy alone. However, bevacizumab is an expensive medication (¥300,000–400,000 [US $2500–$3300] per month) and may lead to rising health care costs. Thus, we conducted a cost-effectiveness analysis of the efficiency of distribution of medical resources and use of bevacizumab plus chemotherapy compared with chemotherapy alone in the treatment of mCRC in Japan.

MATERIALS AND METHODS Data Collection We searched MEDLINE,18 UpToDate online version 14.2,19 and American Society of Clinical Oncology (ASCO) Virtual Meeting20 for RCTs that studied the efficacy of bevacizumab, as measured by both PFS (or disease-free survival) and OS. The MEDLINE search was performed using the key words bevacizumab limited to randomized controlled trial and using the years 2000 to present (June 29, 2007).

Calculation of Direct Medical Costs The framework of our analysis was based on the methods described by Siegel et al.21 This analysis was conducted from the perspective of the health care payer, and thus we calculated only the direct medical costs. Neither the indirect costs (eg, work loss) nor the direct nonmedical costs (eg, transportation costs) were considered. The cost price of bevacizumab in Japan is ¥50,291 for 100 mg and ¥191,299 for 400 mg. In Japan, cetuximab has not been approved for the treatment of mCRC, and therefore the market price has not yet been determined by the Ministry of Health, Labor and Welfare. Because the price of cetuximab in Japan is unknown, we used the UK price £136.5 for 100 mg to calculate cetuximab treatment costs. We estimated only direct medical costs based on the per-unit drug tariff in Japan22 and the reimbursement schedule from 2006.23 It was assumed that patients weighed 60 kg and had a body surface area of 1.7 m2.

Pharmacoeconomic Analysis We used the Weibull regression model,24–26 which is based on a report from Tappenden et al,24 to analyze the cost-effectiveness of treating patients with mCRC with bevacizumab plus chemotherapy versus chemotherapy alone. This statistical method was ap2257

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Clinical Therapeutics plied to the economic evaluation of colon cancer by the National Institute for Health and Clinical Excellence (NICE)24,25 in the United Kingdom instead of other standard models, such as the Markov model. Because clinical trials cannot follow up all patients until death, mean PFS or OS could be estimated by extrapolating incomplete (right-censored) data using parametric (Weibull) curves.26 It is known that survival curves are generally wellfitted to Weibull curves. By approximating empirical survival curves by Weibull and estimating the 2 parameters, the expected value of PFS or OS was analytically derived. In the Weibull regression model,24 the hazard is expressed as a function of time: Hazard: λ(t) = abtb – 1 (a,b : constant) ... (1) Survival function: S(t) = exp(–atb) ... (2) Survival curves were obtained from publications and presentations. We obtained the survival rate at each time point by scanning these curves using TechDig.24 From these 2-dimensional data, the parameters a and b in the second equation were estimated using nonlinear Weibull regression analysis using R version 2.3.1. Expected value of OS (EO) or PFS (EP) time, used to calculate the duration of each stage, was obtained by the formula: E[S(t)] = (1/a)(1/b) 䡠 Γ[1 + (1/b)] [Γ(x):gamma function] Let tij was the duration time of the ith (i = 1 ... n) state, treatment j (j = 1,2), and Cij was the costs per time of the ith state, treatment j. EOj was the expected value of OS obtained by the Weibull regression. The incremental cost-effectiveness ratio (ICER) was given as: n

n

Σ ti1 䡠 Ci1 – iΣ= 1ti2 䡠 Ci2 i=1

ICER = _____________________________ (Eo1 – Eo2) EO and EP were assumed to follow a 2-dimension normal distribution in probabilistic sensitivity analysis. The variance was calculated as: (1/a)(2/b){Γ[2 + (1/b)] – Γ2[1 + (1/b)]}/n, where n was the sample size. 2258

Actual Model of this Analysis In this model, we considered 4 states.

State 1 Patients in state 1 continued to receive both chemotherapy and monoclonal antibody until intolerable adverse events (AEs) or disease progression occurred. The duration of state 1 was thought to be equivalent to time to treatment failure (TTF) in Table I. The costs are shown in Table II.

State 2 In this state, patients discontinued chemotherapy because of unacceptable AEs or complete response, although they continued to receive only monoclonal antibody. The duration time of state 2 was calculated as EP – TTF.

State 3 This is the state in which patients were cured by second-line or subsequent chemotherapy after disease progression despite chemotherapy. EO – E P was the time patients were in state 3. The costs per month of this state were calculated as follows. For first-line bevacizumab, patients received second-line chemotherapy, third-line chemotherapy, and palliative care based on standard treatment algorithms we constructed reflecting Japanese practice patterns (Figure 1). For the costs of this state, we used the average costs of second-line, third-line, and palliative care (assumed by experts’ opinions as ¥300,000 per month, subject to sensitivity analysis) by weighting each stay time, which was also computed from Weibull regression. Durations of second-line, third-line, and palliative care were estimated using data from the Tournigand et al9 and Bowel Oncology with Cetaximab antibody (BOND) trials.27 For second-line bevacizumab, the costs per month were the mean of third-line and palliative care weighted for each stay time.

State 4 In state 4, the patient has died and no costs were incurred. It was difficult to discount costs and effectiveness in the Weibull model. Tappenden et al24 did not discount costs and effectiveness because the omission is unlikely to have a substantial impact on the estimates of cost-effectiveness in this short time-horizon. We agreed with this argument, and therefore did not discount costs or benefits. Volume 29 Number 10

October 2007

10.6

20.3

9.4

PFS or TTP

OS

TTF

6.4

15.6

6.2 7.2

16.6

9.2

W/O B With B (n = 411) (n = 104)

4.9

12.9

5.5

W/O B (n = 105)

FU/LV10

5.8

26.0

9.9

With B (n = 71)

6.4

19.2

8.7

W/O B (n = 49)

FOLFOX613

5.5

20.7

8.3

With B (n = 70)

4.9

17.9

6.9

W/O B (n = 50)

bFOL13

5.5

27.0

10.3

With B (n = 72)

4.4

17.2

5.9

5.0

12.9

7.2

4.0

10.8

4.8

W/O B (n = 284)

FOLFOX414 W/O B With B (n = 48) (n = 287)

CAPOX13

IFL = irinotecan/5-fluorouracil/leucovorin; FU/LV = 5-fluorouracil/leucovorin; FOLFOX = infusional FU/LV/oxaliplatin; bFOL = bolus FU/LV/oxaliplatin; CAPOX = capecitabine/oxaliplatin.

With B (n = 402)

Parameter

IFL8

10:36 AM

Second-Line

11/2/07

First-Line

Table I. Observed progression-free survival (PFS) or time to progression (TTP), overall survival (OS), and time to treatment failure (TTF) with chemotherapy regimens with (test) or without (control) bevacizumab (B) in the final analysis group. Values are mean months.

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Table II. Costs* of chemotherapy regimens with (test) or without (control) bevacizumab (B). Values are medians. Cost/Mo (in Thousands) Treatment First-line IFL With B W/O B FU/LV With B W/O B FOLFOX6 With B W/O B bFOL With B W/O B CAPOX With B W/O B B Second-line FOLFOX4 With B W/O B FOLFIRI Third-line C + IR First month After first month Palliative care

¥

US $

500 200

4.2 1.7

510 200

4.3 1.7

780 460

6.5 3.8

660 350

5.5 2.9

690 360 330

5.8 3.0 2.8

730 410 240

6.1 3.4 2.0

870 810 300

7.3 6.8 2.5

IFL = irinotecan/5-fluorouracil/leucovorin; FU/LV = 5fluorouracil/leucovorin; FOLFOX = infusional FU/LV/ oxaliplatin; bFOL = bolus FU/LV/oxaliplatin; CAPOX = capecitabine/oxaliplatin; FOLFIRI = infusional FU/LV/ irinotecan; C + IR = cetuximab + irinotecan. *Values were obtained by multiplying the unit cost by the consumption of medical resources, which was based on the dose and schedule in Table III. We assumed coefficient of variation of 0.1 (arbitrary but chosen to ensure a large SD).

The outcome measure of this analysis was incremental cost (in Japanese yen [¥]) per incremental lifeyear gained (LYG), which is equivalent to the ICER. We used the exchange rate US $1 = ¥120. 2260

RESULTS The MEDLINE search yielded 23 reports. We excluded 16 papers that dealt with diseases other than mCRC, 1 paper in which both groups were given bevacizumab, and 1 paper that did not report original trial data. Patients reported in 5 papers obtained via MEDLINE and an additional single trial found on UpToDate and ASCO Virtual Meeting composed the final analysis group (Table I). Details of the chemotherapy + bevacizumab combinations are listed in Table III. The first-line chemotherapy regimens to which bevacizumab was added included IFL, FU/LV, FOLFOX6, bFOL, and CAPOX. The second-line chemotherapy regimen consisted of FOLFOX4. We calculated the cost-effectiveness of each regimen.

First-Line Bevacizumab Several RCTs examined several chemotherapeutic combinations containing bevacizumab used as first-line treatment. Three RCTs studied bevacizumab/FU/LV: Kabbinavar et al,13 Kabbinavar et al,14 and Hurwitz et al.15 However, we used only the data from Kabbinavar et al14 to calculate the cost-effectiveness of bevacizumab because the trial by Kabbinavar et al13 was small, and in the study by Hurwitz et al,15 the chemotherapy regimen administered in the control group was different from that administered in the trial group. Kabbinavar et al14 compared bevacizumab (5 mg/kg q2w) plus FU/LV (5-FU, 500 mg/m2; LV, 500 mg/m2, once a week for 6 weeks, cycle repeated every 8 weeks) to FU/LV alone. In the study by Hurwitz et al,12 813 untreated patients were randomly allocated to combination treatment with bevacizumab plus IFL or monotherapy with IFL. Bevacizumab was administered at a dose of 5 mg/kg q2w, and irinotecan (125 mg/m2), 5-FU (500 mg/m2), and LV (20 mg/m2) were injected once a week for 4 weeks. This cycle was repeated every 6 weeks and disease progression was observed. These 2 chemotherapy regimens are relatively mild. Often, more intensive chemotherapy regimens that include oxaliplatin are used. The TREE1 and TREE216 trials examined the tolerability and efficacy of oxaliplatin-based regimens (TREE1) and bevacizumab plus oxaliplatin-based regimens (TREE2). Fluorinated pyrimidine was administered 3 different ways in combination with oxaliplatin or bevacizumab plus oxaliplatin: (1) by bolus and infusion FU/LV (FOLFOX6), Volume 29 Number 10

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First-line

IFL + B

Second-line

FU/LV + B

FOLFOX + B

bFOL + B

FOLFOX

CAPOX + B

FOLFIRI

Third-line

C + IR

Palliative care

Figure 1. Standard treatment algorithms reflecting routine clinical practice in Japan. IFL = irinotecan/5-fluorouracil/ leucovorin; B = bevacizumab; FU/LV = 5-fluorouracil/leucovorin; FOLFOX = folinic acid/infusional FU/LV/ oxaliplatin; bFOL = bolus FU/LV/oxaliplatin; CAPOX = capecitabine/oxaliplatin. FOLFIRI = infusional FU/LV/ irinotecan; C + IR = cetuximab + irinotecan.

Table III. Details of the chemotherapy regimens with (test) or without (control) bevacizumab (B). Regimen IFL IFL + B FU/LV FU/LV + B FOLFOX6 FOLFOX6 + B

Dose and Schedule IR 125 mg/m2, FU 500 mg/m2, and LV 20 mg/m2 qw for 4 wk of every 6 wk Same dose and schedule as with IFL + B 5 mg/m2

FU 500

mg/m2

(bolus), LV 500

mg/m2

10

mg/m2

10

q2w

(bolus), FU 2400

mg/m2

Same dose and schedule as with FOLFOX6 + B 5

mg/m2

LV 400 FU 400 OX 85 mg/m2q2w mg/m2

mg/m2

8

qw for 6 wk of q8w

Same dose and schedule as with FU/LV + B 5 mg/m2,

q2w

(46-h infusion), 13

mg/m2

OX 85 q2w, FU 500 of every 4 wk

bFOL + B

Same dose and schedule with FOLFOX6 + B 5 mg/m2 q2w

CAPOX + B FOLFOX4 FOLFOX4 + B

OX 135

mg/m2

OX 135

mg/m2

q3w, CAP 850

mg/m2,

mg/m2

q3w, CAP 1000

OX 85 FU 400 LV 200 mg/m2 q2w

(bolus), LV 20

q2w

mg/m2

bFOL

CAPOX

8

mg/m2

mg/m2

13

qw for 3 wk

13

for 14 d q21d

13

for 14 d q21d, B 5

(bolus), FU 600

mg/m2

Same dose and schedule as with FOLFOX4 + B 10

13

mg/m2

q2w

13

(22-h infusion), 14

mg/m2

q2w

14

IFL = irinotecan/5-fluorouracil/leucovorin; FU/LV = 5-fluorouracil/leucovorin; FOLFOX = infusional FU/LV/oxaliplatin; bFOL = bolus FU/LV/oxaliplatin; CAPOX = capecitabine/oxaliplatin.

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Clinical Therapeutics (2) by bFOL, and (3) by oral CAPOX for previously untreated mCRC. No significant differences between these 3 regimens were observed in either the TREE1 and TREE2 trials, but the addition of bevacizumab to oxaliplatin-based regimens decreased risk for death (median [95% CI] survival, 20.4 [21.4–26.8] months vs 18.2 [14.5–21.6] months).

Second-Line Bevacizumab The use of bevacizumab/oxaliplatin for second-line treatment of mCRC was examined in the Eastern Cooperative Oncology Group 3200 trial.17 In that study, 829 patients with mCRC previously treated with regimens that did not include bevacizumab were randomly allocated to receive FOLFOX4 (oxaliplatin 85 mg/m2, LV 200 mg/m2, FU 400 mg/m2 [bolus], and 600 mg/m2 [22-hour infusion] q2w) plus high-dose bevacizumab (10 mg/m2 q2w) or monotherapy with bevacizumab or FOLFOX4. Treatment with bevacizumab monotherapy was discontinued because of poor OS and PFS compared with other groups. The combination therapy group was found to have improved OS and PFS. Based on the literature search, there were no available data concerning second-line treatment with bevacizumab in patients who had been previously treated with it.

Costs The values in Table II were obtained by multiplying the unit cost by the consumption of medical resources, which was based on the dose and schedule in Table III. This included the cost of supportive care (eg, antiemetic agents28), routine follow-up, diagnostic imaging, blood tests, infusion pump, and pharmacy costs. In the probabilistic sensitivity analysis, all cost data were modeled as normal distributions with the basecase value as the mean. In the E3200 trial, the dose of bevacizumab was 10 mg/kg higher than the standard dose (5 mg/m2). We predicted that if the cost of bevacizumab was calculated using the higher dose, the value of the ICER would be unacceptably high. We therefore used the costs of the standard dose (5 mg/m2), the efficacy of which was thought to be the same as with the higher dose.

Parameter Estimation and ICER Table IV shows the results of the Weibull regression (estimated parameters “a” and “b” and estimated mean PFS and OS) and cost-effectiveness analysis (incremental effectiveness, incremental costs, and ICERs) 2262

of each regimen. Kaplan Meier curves of observed OS and estimated OS Weibull curves are shown for each treatment group in Figure 2. ICER of additional bevacizumab was ¥11.9 million (US $99,000) when combined with IFL, ¥17.4 million ($145,000) with FU/LV, ¥13.5 million ($113,000) with FOLFOX6, ¥16.9 million ($141,000) with bFOL, ¥8.5 million ($71,000) with CAPOX, and ¥14.1 million ($118,000) with second-line FOLFOX4. ICERs for all the combinations except CAPOX plus bevacizumab exceeded ¥10.0 million ($83,000) per LYG. Sensitivity analysis showed that the ICER was insensitive to palliative costs; over the range of ¥0 to ¥600,000, the ICER hardly changed. Probabilistic sensitivity analysis was carried out to determine the robustness of the results and acceptability curves are shown in Figure 3. The probability that the ICER of additional bevacizumab is less than ¥ 10.0 million was 15%, 14%, 19%, 24%, 63%, and 5% in combination with IFL, FU/LV, FOLFOX6, bFOL, CAPOX, and second-line FOLFOX4, respectively.

DISCUSSION This study consisted of a cost-effectiveness analysis of bevacizumab using the Weibull regression model and found that the ICER of almost all the regimens except CAPOX plus bevacizumab was >¥10.0 million (US $83,000) per LYG, and that the probability of the ICER being <¥10.0 million ($83,000) per LYG is low. In the United Kingdom, NICE suggests that the ICER threshold should be £20,000 to £30,000 (¥4.0 million–¥6.0 million) per quality-adjusted life-year (QALY).29 In the United States, $50,000 to $100,000 (¥5.0 million–¥10.0 million) per QALY is often used as the threshold. In Japan, however, there is no established cost-effectiveness threshold, so the question of whether the use of bevacizumab is cost-effective remains difficult to determine. Additionally, there are no previous costeffectiveness studies of mCRC chemotherapy. In January 2007, NICE issued a statement in which bevacizumab and cetuximab were not recommended as treatment options for patients with mCRC.30 The base-case costs per QALY gained were £62,857 for bevacizumab combined with IFL compared with IFL alone, and £88,436 for bevacizumab combined with 5-FU/LV compared with 5-FU/LV alone. The likelihood that the ICER of additional bevacizumab is <£30,000 is close to zero. Our analysis found results similar to the results of NICE. Volume 29 Number 10

October 2007

99

11.9

4.8 2.9 to 7.6

0.40 0.17 to 0.63

11.9

1.99

–

–

– –

–

–

7.1

1.59

145

17.4

2.2 –0.2 to 5.3

0.13 –0.28 to 0.50

8.8

1.59

0.0010 1.49 19.08

–

–

– –

–

–

6.6

1.46

0.039 1.11 17.52

113

13.5

3.7 0.4 to 8.2

0.27 –0.32 to 0.86

12.6

2.04

0.0011 2.06 24.48

0.0071 1.97 10.92

With B

–

–

– –

–

–

8.9

1.77

0.0044 1.71 21.24

0.015 1.88 8.52

W/O B

FOLFOX6

141

16.9

4.6 0.1 to 8.0

0.27 –0.34 to 0.88

11.9

1.97

0.0050 1.62 23.64

0.023 1.69 7.32

With B

CAPOX

–

–

– –

–

–

7.3

1.70

0.014 1.38 20.40

0.040 1.53 8.52

0.043 1.45 8.04

71

8.5

7.4 3.0 to 12.9

0.86 0.08 to 1.64

15.6

2.70

–

–

– –

–

–

8.2

1.84

0.0093 0.028 1.31 1.14 32.40 22.08

0.023 1.46 12.24

W/O B With B W/O B

bFOL

118

14.1

3.6 2.0 to 5.6

0.17 0.07 to 0.43

9.0

1.48

0.012 1.56 15.84

0.026 1.67 7.92

–

–

– –

–

–

5.4

1.31

0.016 1.56 12.84

0.053 1.61 5.52

–

–

– –

–

–

–

–

– – –

0.043 1.86 4.80

–

–

– –

–

–

–

–

– – –

0.120 1.58 3.48

–

–

– –

–

–

–

–

0.032 1.44 9.84

0.150 1.18 4.68

With B W/O B FOLFOX FOLFIRI C + IR

FOLFOX4

IFL = irinotecan/5-fluorouracil/leucovorin; FU/LV = 5-fluorouracil/leucovorin; FOLFOX = infusional FU/LV/oxaliplatin; bFOL = bolus FU/LV/oxaliplatin; CAPOX = capecitabine/oxaliplatin; FOLFIRI = infusional FU/LV/irinotecan; C + IR = cetuximab + irinotecan; LYG = life-years gained; IE = incremental effectiveness; IC = incremental costs; ICER = incremental cost-effectiveness ratios.

$/LYG (in thousands)

ICER ¥/LYG (in millions)

IC, ¥ (in millions) Mean 95% CI

IE, y Mean 95% CI

Cost per LYG, (in ¥ millions)

LYG, y

0.0063 0.012 1.55 1.44 23.88 19.08

0.055 1.44 6.84

a b OS, mo

0.050 1.16 12.60

0.013 1.70 11.28

a b PFS, mo

0.052 1.36 7.92

With B W/O B With B W/O B

FU/LV

ThirdLine

10:36 AM

Parameter

IFL

Second-Line

11/2/07

First-Line

Table IV. Estimated parameters “a” and “b,” progression-free survival (PFS), and overall survival (OS) (Weibull regression) and cost-effectiveness analysis of chemotherapy regimens with (trial) or without (control) bevacizumab (B). Values are means.

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A

IFL (first-line)

B

1.0

FU/LV (first-line) 1.0

IFL + B (Weibull) IFL (Weibull) Observed data

0.8

FU/LV + B (Weibull) FU/LV (Weibull) Observed data

0.8

0.6

OS

OS

0.6

0.4

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Figure 2. Kaplan-Meier curves of observed overall survival (OS) and estimated OS (Weibull curves) for each treatment. IFL = irinotecan/5-fluorouracil/leucovorin; B = bevacizumab; FU/LV = 5-fluorouracil/leucovorin; FOLFOX = infusional FU/LV/oxaliplatin; bFOL = bolus FU/LV/oxaliplatin; CAPOX = capecitabine/oxaliplatin.

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IFL (first-line) FU/LV (first-line) FOLFOX6 (first-line) bFOL (first-line) CAPOX (first-line) FOLFOX4 (second-line)

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% Cost-Effectiveness

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Willingness to Pay (¥ [in millions]) Figure 3. Cost-effectiveness (acceptability) curves (probabilistic sensitivity analysis). IFL = irinotecan/ 5-fluorouracil/leucovorin; FU/LV = 5-fluorouracil/leucovorin; FOLFOX = infusional FU/LV/oxaliplatin; bFOL = bolus FU/LV/oxaliplatin; CAPOX = capecitabine/oxaliplatin.

Other studies have evaluated the economics of mCRC treatments.31,32 In one,32 the ICER of first-line FOLFOX compared with IFL was $80,410/LYG, and the researchers concluded that the ICER of FOLFOX was acceptable. Another study looked at cetuximab plus irinotecan compared with active/best supportive care and found an ICER of £42,975/LYG. The authors noted that the ICER was high compared with other health care interventions.29 Using data from those 2 studies and the decision making in NICE as benchmarks, we conclude that the ICERs obtained in this analysis are high. In particular, the ICER of bevacizumab with IFL and FU/LV, and second-line bevacizumab with FOLFOX4, were higher than those found with other chemotherapy or treatments. In the E3200 trial, patients did not receive first-line bevacizumab. This raises the question as to whether second-line bevacizumab therapy for patients who did not previously receive bevacizumab would be cost-effective. We cannot answer with certainty, but the probability that this October 2007

will meaningfully improve the cost-effectiveness seems low. It is difficult to assess first-line bevacizumab with oxaliplatin-based regimens because the ICER of CAPOX with bevacizumab tended to be lower than that with bevacizumab with other regimens. In addition, the sample size in the TREE trial was small and not randomized between TREE1 and TREE2, although they did randomize within TREE1 and TREE2. The larger NO16966 trial is currently in progress and will compare the tolerability and efficacy of FOLFOX, CAPOX, FOLFOX + bevacizumab, and CAPOX + bevacizumab. We will therefore reserve our conclusions until the results of that trial are released. The estimated mean PFS and OS were longer (Table IV) than the observed median PFS and OS (Table I) because the median value is insensitive to the influence of long-term survivors. Because using the median value underestimates the OS, the mean OS, which cannot be calculated from the observed data without modeling, should be used in cost-effectiveness analyses. 2265

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Clinical Therapeutics The limitation of this result is that our end point is LYG, and not QALY. In Japan there are no healthrelated quality-of-life data from patients with colorectal cancer that we could use in our analysis. We decided it was better to use LYG than QALYs because QALYs are necessarily calculated using non-Japanese, utility values. The measurement of utility values aimed at patients who received adjuvant bevacizumab is a challenge for the future. Some researchers, though, insist that cost-effectiveness should be estimated by costs and primary health outcomes, not QALYs, which are not sufficiently accurate or reliable for decision making.33 However, if we adjusted the LYG by utility value, it is highly possible that the incremental effectiveness would become lower and the ICER higher. In addition, costs were calculated by the construction of a standard therapy model and not analyzed using data from actual patients. This is also a limitation of this model-based result. The study took the perspective of the health care payer, not including indirect costs. The median age of metastatic patients in these studies was ~60 years. Some of these patients were able to work. The delay of disease progression by administering bevacizumab may reduce work loss, although the degree of that reduction is unknown. The LYGs we estimated using the Weibull regression model were consistent with the results from the study by Tappenden et al.24 They estimated the LYG of IFL, IFL + bevacizumab, FL, FL + bevacizumab to be 1.57, 1.97, 1.41, and 1.59, respectively, using data from the same clinical trials. The estimated LYGs of cetuximab plus irinotecan in this study was 0.82, and that from Tappenden et al was 0.81, suggesting that their study findings were reproducible. It remains difficult to assess the first-line therapies comprising bevacizumab with oxaliplatin-based regimens, especially CAPOX. No conclusions can be drawn until the results of the ongoing NO16966 trial—a large study with >2000 participants—are finally released.

CONCLUSIONS In this cost analysis, the ICER of bevacizumab with IFL and FU/LV and second-line bevacizumab with FOLFOX4 were high compared with other health care interventions. Further information is needed to assess the cost-effectiveness of the first-line bevacizumab with oxaliplatin. 2266

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Address correspondence to: Takeru Shiroiwa, MSc, 7-3-1 Hongo, Bunkyoku, Tokyo 113-0033, Japan. E-mail: [email protected] 2267