Costs of adverse events associated with erlotinib or afatinib in first-line treatment of advanced EGFR-positive non-small cell lung cancer

Figures & data

Table 1 Frequency of adverse events with erlotinib and afatinib

Adverse events	Erlotinib			Afatinib (Haaland et al)^Citation14			Afatinib (clinical trials)^Citation27,Citation28
	Average (%)	LL 95% CI (%)	UL 95% CI (%)	Average (%)	LL 95% CI (%)	UL 95% CI (%)	Average (%)	LL 95% CI (%)	UL 95% CI (%)
Adverse events grade <2
Anemia	7.0	4.0	11.0	3.0	1.0	4.0	7.0	6.1	7.0
Asthenia (fatigue)	20.0	3.0	59.0	16.0	13.0	19.0	21.4	19.7	23.1
Anorexia	31.0	22.0	37.0	18.0	15.0	20.0	21.5	15.1	27.9
Arthralgia	10.0	6.0	17.0	0.0	0.0	0.0	3.5	0.0	7.0
Diarrhea	37.0	20.0	57.0	86.0	88.0	79.0	89.3	89.1	89.5
Rash	71.0	63.0	68.0	74.0	72.0	73.0	67.8	62.9	72.8
Stomatitis/mucositis	12.0	8.0	15.0	65.0	61.0	67.0	29.7	21.8	37.6
Constipation	0.0	0.0	0.0	3.0	1.0	4.0	8.4	3.8	13.1
Infection	16.0	1.0	19.0	0.0	0.0	0.0	28.5	15.1	41.9
Leukopenia	0.0	0.0	0.0	2.0	1.0	2.0	4.7	2.6	6.7
Nausea	0.0	0.0	0.0	17.0	13.0	20.0	18.5	11.7	25.3
Neurotoxicity	9.0	5.0	12.0	0.0	0.0	0.0	0.0	0.0	0.0
Neutropenia	1.0	0.0	13.0	1.0	0.0	1.0	3.4	1.3	5.4
Pruritus	0.0	0.0	0.0	19.0	14.0	22.0	15.7	11.3	20.1
Cheilitis (lips inflammation)	0.0	0.0	0.0	12.0	9.0	15.0	18.2	12.2	24.3
Thrombocytopenia	2.0	1.0	4.0	0.0	0.0	0.0	1.3	0.0	2.5
Vomiting	0.0	0.0	0.0	14.0	12.0	16.0	15.6	13.4	17.9
Adverse events grade ≥3
Anemia	1.0	0.0	4.0	0.0	0.0	2.0	0.0	0.0	0.0
Asthenia (fatigue)	1.0	0.0	14.0	1.0	0.0	4.0	0.9	0.0	1.7
Anorexia	0.0	0.0	4.0	3.0	1.0	6.0	0.9	0.8	0.9
Arthralgia	1.0	0.0	6.0	0.0	0.0	0.0	0.0	0.0	0.0
Diarrhea	3.0	1.0	7.0	9.0	4.0	18.0	3.7	0.8	6.6
Rash	6.0	2.0	19.0	15.0	12.0	19.0	0.4	0.0	0.8
Stomatitis/mucositis	1.0	0.0	7.0	7.0	5.0	10.0	0.2	0.0	0.4
Constipation	0.0	0.0	4.0	0.0	0.0	2.0	0.2	0.0	0.4
Infection	1.0	0.0	7.0	0.0	0.0	0.0	3.9	2.1	5.7
Leukopenia	0.0	0.0	0.0	0.0	0.0	2.0	0.0	0.0	0.0
Nausea	0.0	0.0	0.0	1.0	0.0	3.0	0.2	0.0	0.0
Neurotoxicity	1.0	0.0	6.0	0.0	0.0	0.0	0.0	0.0	0.0
Neutropenia	0.0	0.0	2.0	0.0	0.0	2.0	0.6	0.4	0.8
Pruritus	0.0	0.0	0.0	0.0	0.0	2.0	0.0	0.0	0.0
Cheilitis (lips inflammation)	0.0	0.0	0.0	0.0	0.0	2.0	0.0	0.0	0.0
Thrombocytopenia	0.0	0.0	2.0	0.0	0.0	0.0	0.0	0.0	0.0
Vomiting	0.0	0.0	0.0	3.0	1.0	6.0	2.8	0.8	4.8

Abbreviations: CI, confidence interval; LL, lower limit; UL, upper limit.

Table 2 Unit costs of outpatient and in-hospital management of the adverse events (AEs) validated by the panel of experts

AE	Outpatient management cost (€)	DRG	Cost of DRG/process (€)	Hospital admission rate AE grade ≤2 (%)	Hospital admission rate AE grade ≥3 (%)	Total cost AE grade ≤2 (€)*	Total cost AE grade ≥3 (€)*	References
Anemia	149.81	574	6,379.64	3.3	5.3	360.34 (288.27–432.40)	487.93 (390.34–585.51)	Isla et al^Citation30
Asthenia/fatigue	1.21	–	685.38	0	1.8	1.21 (0–1.45)	171.34 (0–342.69)	Isla et al^Citation30
Anorexia	10.05	–	242.50	3.3	6.7	10.05 (0–16.01)	10.05 (0–32.50)	Isla et al^Citation30
Arthralgia	–	–	–	–	–	16.80 (13.44–20.16)	261.09 (16.80–505.39)	Llibre-Codina et al^Citation31
Diarrhea	0	522	6,894.66	13.3	22.0	916.99 (550.19–1,100.39)	1,516.83 (995.51–1,820.19)	Isla et al^Citation30
Rash	2.06	272, 273, 283, 284, 563	3,235.25	0	0	2.06 (1.65–2.48)	2.06 (1.65–2.48)	Isla et al^Citation30
Stomatitis/mucositis	–	–	–	–	–	137.47 (109.98–164.97)	1,321.35 (931.64–1,711.06)	Ojeda et al^Citation32
Constipation	0.77	522	6,894.66	0	0	0.77 (0.61–0.92)	0.77 (0.61–0.92)	Isla et al^Citation30
Infection	278.74	79, 80, 418, 540, 541	4,767.30	7	31.7	612.45 (489.96–734.94)	1,789.98 (1,431.98–2,147.97)	Isla et al^Citation30
Leukopenia	–	–	–	–	–	671.33 (537.06–805.60)	1,566.40 (671.33–2,461.47)	Llibre-Codina et al^Citation31
Nausea	23.37	552	6,894.66	0	6.7	212.80 (170.24–407.21)	485.31 (388.25–582.38)	Isla et al^Citation30
Neurotoxicity	–	–	–	–	–	462.54 (370.03–555.05)	1,171.35 (462.54–1,880.16)	Llibre-Codina et al^Citation31
Neutropenia	266.90	574	6,379.64	0	0	266.90 (213.52–320.28)	266.90 (213.52–320.28)	Isla et al^Citation30
Pruritus	0	272, 273, 283, 284, 563	3235.25	0	0.3	0 (0–0)	9.71 (7.76–11.65)	Isla et al^Citation30
Cheilitis	0	–	–	–	–	0 (0–0)	0 (0–0)	Ojeda et al^Citation32
Thrombocytopenia	141.49	–	6,379.64	1.7	12.0	249.94 (199.95–299.93)	907.04 (725.63–1,088.45)	Isla et al^Citation30
Vomiting	23.37	552	6,894.66	0	20	212.80 (170.24–407.21)	1,402.30 (1,121.84–1,682.77)	Isla et al^Citation30

Notes: Costs updated to 2015.

* The minimum and maximum costs were obtained directly from the indicated sources. When not available, they were calculated as ±20% the mean price. The panel of experts reviewed the hospital admission rates described by Isla et al,³⁰ as well as those AEs that have a relevant economic impact.

Abbreviation: DRG, diagnosis-related group.

Table 3 Cost of management of the adverse event (AE) grades ≤2 and ≥3

Adverse event	Cost management AE grade ≤2			Cost management AE grade ≥3
	Mean (€)	Minimum (€)	Maximum (€)	Mean (€)	Minimum (€)	Maximum (€)
Anemia	362.46	289.97	434.96	490.06	392.04	588.07
Asthenia/fatigue	1.21	0.00	1.45	171.34	0.00	342.69
Anorexia	10.05	0.00	16.17	10.05	0.00	32.33
Arthralgia	16.80	13.44	20.16	261.09	16.80	505.39
Diarrhea	919.29	551.57	1,103.15	1,516.83	995.51	1,820.19
Rash	2.06	1.65	2.48	2.06	1.65	2.48
Stomatitis/mucositis	137.47	109.98	164.97	1,321.35	931.64	1,711.06
Constipation	0.77	0.61	0.92	0.77	0.61	0.92
Infection	612.45	489.96	734.94	1,789.98	1,431.98	2,147.97
Leukopenia	671.33	537.06	805.60	1,566.40	671.33	2,461.47
Nausea	212.80	170.24	407.21	485.31	388.25	582.38
Neurotoxicity	462.54	370.03	555.05	1,171.35	462.54	1,880.16
Neutropenia	479.55	383.64	575.46	1,861.81	1,489.45	2,234.17
Paronychia	0.00	0.00	0.00	0.00	0.00	0.00
Pruritus	0.00	0.00	0.00	9.71	7.76	11.65
Cheilitis	0.00	0.00	0.00	0.00	0.00	0.00
Thrombocytopenia	249.94	199.95	299.93	907.04	725.63	1,088.45
Vomiting	212,80	170,24	407,21	1,402.30	1,121.84	1,682.77

Notes: The costs include both the outpatient and in-hospital management of the AEs. Calculation was made from the works of Isla et al,³⁰ Llibre et al,³¹ and Ojeda et al,³² with validation by the panel of experts.

Table 4 Cost per patient of management of the adverse events (AEs) according to the Monte Carlo simulation

AE severity	Erlotinib	Afatinib	Difference (95% CI)*
AE grade ≤2	€550.86	€980.63	€−429.76 (€−292.48 to −536.40)
AE grade ≥3	€106.58	€291.52	€−184.95 (€−50.08 to −344.89)
All AEs	€657.44	€1,272.15	€−614.71 (€−342.57 to −881.29)

Note:

* The negative values indicate savings with erlotinib versus afatinib.

Abbreviation: CI, confidence interval.

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