Cost-Effectiveness Analysis of Regorafenib versus Other Third-Line Treatments for Metastatic Colorectal Cancer

Figures & data

Figure 1 A flow diagram of articles identified and selection strategy based on inclusion criteria.

Table 1 General Characteristics of the Included Records

Author (Publication Year)	Country	Perspective	Evaluation Techniques	Model Analysis	Outcome Index
Kashiwa M et al (2018)^Citation20	Japan	Japanese health care payer	Cost-utility Analysis, CUA	Partitioned survival model	LYs, QALYs, ICER, Cost
Barzi A et al (2019)^Citation16	USA	US payer perspective	Cost-utility Analysis, CUA	Markov model	ICER
Guan X et al (2021)^Citation17	China	Chinese health care perspective	Cost-utility Analysis, CUA	Markov model	LYs, QALYs, ICER, Cost
Cho SK et al (2018)^Citation13	USA	US payer perspective	Cost-utility Analysis, CUA	Markov model	QALYs, ICER, Cost
Bullement A et al (2018)^Citation23	England and Wales	UK National Health Service perspective	Cost-utility Analysis, CUA	Partitioned survival model	LYs, QALYs, ICER, Cost
Goldstein DA et al (2015)^Citation14	USA	US payer perspective	Cost-utility Analysis, CUA	Markov model	LYs, QALYs, ICER, Cost
Kimura M et al (2016)^Citation21	Japan	NA	Cost-utility Analysis, CUA	Partitioned survival model	ICER, CER
Giuliani J et al (2021)^Citation22	Italy	NA	Cost-utility Analysis, CUA	Partitioned survival model	Cost
Gourzoulidis G et al (2021)^Citation24	Greece	A third-party payer perspective	Cost-effective Analysis	Partitioned survival model	LYs, QALYs, ICER, Cost
Ma Y et al (2023)^Citation18	China	Chinese health care perspective	Cost-effective Analysis	Markov model	LYs, QALYs, ICER, Cost
Zhang S et al (2020)^Citation19	China	Chinese health care perspective	Cost-utility Analysis, CUA	Markov model	LYs, QALYs, ICER, Cost
Mlcoch T et al (2018)^Citation25	Czech Republic	Czech Republic health care perspective	Cost-utility Analysis, CUA	Markov model	LYs, QALYs, ICER, Cost
Cho SK et al (2022)^Citation15	USA	United States (US) payer perspective	Cost-utility Analysis, CUA	Markov model	LYs, QALYs, ICER, Cost

Abbreviations: LYs, life years; QALYs, quality adjusted life-years; ICER, incremental cost-effectiveness ratio, NA, not applicable.

Table 2 Results Form the Quality of Health Economic Studies (QHES) Evaluation

Author (Publication Year)	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	Score
Kashiwa M et al (2018)^Citation20	√	√	√	×	√	√	√	×	√	√	√	√	√	√	√	×	89
Barzi A et al (2019)^Citation16	√	√	√	×	√	√	×	√	√	√	√	√	×	×	√	×	78
Guan X et al (2021)^Citation17	√	√	√	×	√	√	√	√	√	√	√	√	×	√	√	√	90
Cho SK et al (2018)^Citation13	√	√	√	×	√	√	√	√	√	√	√	√	√	×	√	×	90
Bullement A et al (2018)^Citation23	√	√	√	×	√	√	√	√	√	√	√	√	√	×	√	√	91
Goldstein DA et al (2015)^Citation14	√	√	√	×	√	√	√	×	√	√	√	√	√	×	√	√	84
Kimura M et al (2016)^Citation21	√	×	√	×	×	√	√	√	√	√	√	√	√	×	√	×	77
Giuliani J et al (2021)^Citation22	√	×	√	×	×	√	√	×	√	√	√	√	√	×	√	√	73
Gourzoulidis G et al (2021)^Citation24	√	√	√	×	√	√	√	√	√	√	√	√	√	√	√	√	99
Ma Y et al (2023)^Citation18	√	√	√	×	√	√	√	√	√	√	√	√	√	√	√	×	96
Zhang S et al (2020)^Citation19	√	√	√	×	√	√	×	√	√	√	√	√	×	×	√	×	78
Mlcoch T et al (2018)^Citation25	√	√	√	×	√	√	×	√	√	√	√	√	×	×	√	×	78
Cho SK et al (2022)^Citation15	√	√	√	×	√	√	√	√	√	√	√	√	√	×	√	×	90
Average score																	85.62

Table 3 Cost Analysis of the Included Publications

Author (Publication Year)	Types of Clinical Trials	Health Outcomes	Time Horizon (Years)	Discounting	Cost Expense
					Direct Cost	Indirect Cost
Kashiwa M et al (2018)^Citation20	RCT: CORRECT, CONCUR, RECOURSE	OS, PFS	5	2%	(1)(2)(3)(4)	NA
Barzi A et al (2019)^Citation16	Randomized Phase II trial	NA	NA	5%	(1)(2)(3)	NA
Guan X et al (2021)^Citation17	RCT: FRESCO, CONUR	PFS, OS	NA	5%	(1)(2)(3)	NA
Cho SK et al (2018)^Citation13	RCT: RECOURSE, CORRECT	PFS, MOS	5	5%	(1)(2)(3)(4)	NA
Bullement A et al (2018)^Citation23	RCT: RECOURSE, CORRECT, J003-10,040,030	OS, PFS, HRQL	10	3.5%	(1)(2)(3)(4) (5)	NA
Goldstein DA et al (2015)^Citation14	RCT (CORRECT)	OS	NA	NA	(1)(2)	NA
Kimura M et al (2016)^Citation21	RCT: CORRECT, RECOURSE	MST	<1	NA	(1)(2)(3)(4)	NA
Giuliani J et al (2021)^Citation22	RCT: RECOURSE, ReDOS	OS	NA	NA	(1)	NA
Gourzoulidis G et al (2021)^Citation24	RCT: RECOURSE, CORRECT, Phase II clinical trial	OS, PFS	10	3.5%	(1)(2)(3)(4)	NA
Ma Y et al (2023)^Citation18	RCT (ASTRUM-010, CONCUR)	OS, PFS	Lifetime	5%	(1)(2)(3)(4) (5)	NA
Zhang S et al (2020)^Citation19	RCT (CONCUR)	NA	NA	5%	NA	NA
Mlcoch T et al (2018)^Citation25	RCT (CORRECT)	OS, PFS	2.5	3%	NA	NA
Cho SK et al (2022)^Citation15	RCT: CORRECT, RECOURSE, ReDOS, Phase 2 clinical trials	OS, PFS	3	5%	(1)(2)(3)(4) (5)	NA

Notes: Cost expense: (1) drugs, (2) Adverse events, (3) Pallicare per day, (4) Outpatient chemotherapy, (5) Terminal care.

Abbreviations: RCT, randomized controlled trials; OS, overall survival; PFS, progression-free survival; MST, median survival time.

Table 4 Health Output Assessment of Included Publications

Author (Publication Year)	Treatment Protocol	Results from Economic Evaluation				Willingness to pay Threshold
		QALYs	LYs (Years)	ICER/QALY	Cost
Kashiwa M et al (2018)^Citation20	Regorafenib versus TAS-102	0.249 vs 0.344	0.280 vs 0.421	$432,734 vs $131,799	$107,781 vs $45,291	$135,869.57
Barzi A et al (2019)^Citation16	Regorafenib (ReDOS) versus regorafenib (standard)	NA	NA	$112,705 vs $384,687	NA	$150,000
Guan X et al (2021)^Citation17	Regorafenib versus fruquintinib	0.79 vs 0.74	1.10 vs 1.02	$231,697	$32,224 vs $22,888	$75,758
Cho SK et al (2018)^Citation13	Regorafenib versus TAS-102	0.397 vs 0.437	NA	$395,223 vs $399,740	$26,657 vs 43,264	$150,000
Bullement A et al (2018)^Citation23	Regorafenib versus TAS-102	0.11 vs 0.17	0.16 vs 0.26	£133,561 vs £51,194	£14,613 vs £8,479	NA
Goldstein DA et al (2015)^Citation14	Regorafenib versus BSC	0.04	0.13	>$550,000	$40,000	$900,000
Kimura M et al (2016)^Citation21	Regorafenib versus TAS-102	NA	NA	¥477,330.9/MST	¥705,330.3 vs ¥371,198.7	NA
Giuliani J et al (2021)^Citation22	ReDO versus TAS-102	NA	NA	Per month OS-gain: €510.41 vs €1167.50	€3,879.12 vs €5,818.68	NA
Gourzoulidis G et al (2021)^Citation24	Regorafenib versus TAS-102	0.50 vs 0.57	0.78 vs 0.89	€51,000 vs €49,326	€10,850 vs €10,087	€51,000
Ma Y et al (2023)^Citation18	Serplulimab versus Regorafenib	6.00 vs 0.69	7.43 vs 1.03	$5385.94	$68,722 vs $40,106	$36,036
Zhang S et al (2020)^Citation19	Regorafenib versus BSC	0.62 vs 0.44	0.85 vs 0.61	$63,154.63	$26,795.62 vs $15,184.05	$27,576
Mlcoch T et al (2018)^Citation25	Regorafenib versus BSC	0.572 vs 0.351	NA	€43,122	€9,904 vs €362	€47,000
Cho SK et al (2022)^Citation15	ReDO vs RSD	0.571 vs 0.394	NA	$104,308	$71,701 vs $ 53,323	$150,000
	ReDO vs TAS-102	0.571 vs 0.435		$37,966	$71,701 vs $ 66,545
	ReDO vs TAS-BEV	0.571 vs 0.511		Dominant^a	$71,701 vs $ 124,746

Notes: ^aReDO dominant over TAS-BEV, providing a higher QALY at a lower cost.

Table 5 Sensitivity Analyses, Conclusions and Limitations of Included Studies

Author (Publication Year)	Sensitivity Analyses	Conclusions	Limitations
Kashiwa M et al (2018)^Citation20	One-way and probability sensitivity analysis, scenario analysis	Regorafenib is less cost-effective than TAS-102	1) Lack of local data and direct clinical evidence; 2) Selection of partitioned survival analysis may affected clinical and CE outcomes.
Barzi A et al (2019)^Citation16	Univariate and probabilistic sensitivity analyses	Regorafenib (ReDOS) was more cost-effective than regorafenib (standard)	NA
Guan X et al (2021)^Citation17	One-way and probabilistic sensitivity analyses	Regorafenib is less cost-effective versus fruquintinib	Lack of primary health utility data to measure patients’ quality of life in the different arms.
Cho SK et al (2018)^Citation13	Univariate and probabilistic sensitivity analyses, scenario analysis	Neither TAS-102 nor regorafenib are cost effective at standard willingness-to-pay thresholds	1) The uncertainty of methods for fitting survival data; 2) The cost of toxicities were from of estimation, while economic and clinical impact of most toxicities were previously studied.
Bullement A et al et al (2018)^Citation23	One-way sensitivity analysis	TAS-102 is more clinically and cost-effective than regorafenib	Lack of directly measured HRQL data, and assumptions made regarding the comparative efficacy of regorafenib.
Goldstein DA et al (2015)^Citation14	Univariate and probabilistic sensitivity analyses	Regorafenib provides minimal incremental benefit at high incremental cost per QALY	The limitation of data availability, and lack of efficacy data to support dosing strategy
Kimura M et al (2016)^Citation21	NA	TAS-102 is more cost-effective than regorafenib	The study did not take quality of life into account, it was not possible to accurately determine the CE in the common units ¥/QALI.
Giuliani J et al (2021)^Citation22	NA	Regorafenib escalation-dose strategy is more cost-effective than TAS-102	NA
Gourzoulidis G et al (2021)^Citation24	One-way and probabilistic sensitivity analyses	Regorafenib is less cost-effective than TAS-102	Lack of local data and direct clinical evidence
Ma Y et al (2023)^Citation18	One-way and probability sensitivity analysis, scenario analysis	Regorafenib is less cost-effective than serplulimab in patients with previously treated mCRC in China	1) Lack of appropriate comparator; 2) The increased risk of death and other parameters were derived based on expert opinion might involve uncertainty.
Zhang S et al (2020)^Citation19	Univariate and probabilistic sensitivity analyses	Regorafenib is not cost-effective at the WTP threshold of $27,576 when compared with placebo group.	NA
Mlcoch T et al (2018)^Citation25	Probabilistic sensitivity analysis	Regorafenib is a cost-effective therapy based on registry/RCT data in the CZ.	NA
Cho SK et al (2022)^Citation15	One-way and probabilistic sensitivity analyses	The optimum dosing strategy for regorafenib has improved relative cost-effectiveness compared to RSD, TAS-102, and TAS-BEV.	1) Lack of head-to-head trials; 2) The study utilized published drug costs, while the actual price of the treatments may vary across health plans.

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Data Sharing Statement

The datasets used and/or analyzed during the present study are available from the corresponding author upon reasonable request.