Cost-benefit analysis of ALK diagnosis vs. non-diagnosis in patients with advanced non–small cell lung cancer in Spain

ABSTRACT

Introduction:

In recent years, target therapies to specific molecular alterations in advanced non–small cell lung cancer (NSCLC) have been identified and have shown superior efficacy compared to non-targeted treatments. Anaplastic lymphoma kinase (ALK) is one of the therapeutic targets; nevertheless, ALK diagnosis is not performed in all NSCLC patients in Spain. The objective of this study is to estimate in monetary terms the benefit for the Spanish society of ALK diagnosis in advanced NSCLC patients.

Methods:

A cost-benefit analysis of ALK diagnosis vs. non-diagnosis in advanced NSCLC patients was carried out from the Spanish social perspective, with a time horizon of 5 years. Costs, benefits and the cost-benefit ratio were measured. The analysis has considered the overall survival in advanced NSCLC patients treated with the ALK-tyrosine kinase inhibitor (TKI) alectinib. The natural history of NSCLC was simulated using a Markov model. A 3% discount rate was applied to both costs and benefits. The result was tested using a deterministic sensitivity analysis.

Results:

The cost of ALK diagnosis vs. non-diagnosis in the base case would be €10.19 million, generating benefits of €11.71 million. The cost-benefit ratio would be €1.15. In the sensitivity analysis, the cost-benefit ratio could range from €0.89 to €2.10.

Conclusions:

The results justify the universal application of ALK diagnosis in advanced NSCLC, which generates a benefit for Spanish society that outweighs its costs and allows optimal treatment with targeted therapies for these patients.

Introduction

Lung cancer (LC) is the most diagnosed cancer worldwide, with more than 2 million new cases in 2018, being the leading cause of death from malignancy (1). In Spain, LC is the fourth most diagnosed cancer, with an estimated incidence of 29,549 new cases in 2021. Due to its high mortality, its 5-year prevalence is low (35,815 patients in 2020) (2). Despite latest therapeutic advances, more than half of LC diagnosed patients die within 1 year of diagnosis and the 5-year survival is approximately 18% (3). Non–small cell lung cancer (NSCLC) accounts for approximately 85% of all LC (4).

Several molecular alterations have been identified in NSCLC, including rearrangements in the anaplastic lymphoma kinase (ALK) gene, which are present in about 5% of NSCLC (5). More than 40% of ALK-positive (ALK+) patients have brain metastasis (BM) at diagnosis, presenting a worse prognosis (6).

In patients with advanced NSCLC, targeted therapies based on driver genes improve survival (7). ALK-tyrosine kinase inhibitors (TKIs) such as alectinib, crizotinib, ceritinib, brigatinib and lorlatinib have been developed and authorized for the treatment of ALK+ NSCLC patients (8).

Treatment with ALK-TKIs relies on needs to perform a previous diagnostic test on NSCLC patients. From biopsy or cytological samples, the diagnostic test can identify various genetic alterations, including ALK rearrangements (9).

Therefore, in order to evaluate the efficiency of ALK diagnosis, the aim of this study was to estimate, in monetary terms, the benefit for the Spanish society of the ALK diagnosis in NSCLC patients vs. non-diagnosis.

Methods

A cost-benefit analysis (CBA) was carried out from the Spanish social perspective, with a 5-year time horizon and a 3% discount rate (10). To calculate the cost-benefit ratio, the benefit of ALK diagnosis in NSCLC patients was compared with non-diagnosis of ALK, regarding the additional cost of performing it.

According to the National Comprehensive Cancer Network (NCCN) and the European Society of Medical Oncology (ESMO) clinical practice guidelines published at the time of this analysis, alectinib is the preferred first-line treatment option for advanced ALK+ NSCLC patients. Therefore, it was assumed that these patients would be treated with alectinib. For non-diagnosed patients, it was assumed that they would be treated with chemotherapy and/or immunotherapy, which is the standard treatment in patients with unknown driver mutations (11,12).

The natural history of the disease was simulated using a Markov model based on three health states (stable, progression and death), with 6-month cycles (Fig. 1). The model starts with patients in stable state, every 6 months the patient state was reviewed to allocate the corresponding costs and benefits. States were modeled according to the alectinib survival curves of progression-free survival (PFS) and overall survival (OS), the non-diagnosed patient’s survival curves and the mortality risk in the general population by sex and age.

Fig. 1 -.

Markov model health states.

Data sources

Epidemiology data, survival rates, healthcare resource use, utilities, productivity and formal and informal care were obtained from a literature review, including national and international references (the latter were used whenever national data were not available). Databases consulted are included in Supplementary material (Supplementary Table S1). All extracted data were contrasted and validated by an expert group (a pathologist and three oncologists). To complete the necessary information about follow-up visits, medication, adverse events (AEs), disease progression and impact of ALK diagnosis on the different areas of patients’ lives, three telephone interviews were conducted with patients.

Furthermore, to quantify the tangible and intangible benefits, patients’ experience was considered, performing a focus group with seven patients and one caregiver in 2020.

Population

The candidate population (Fig. 2) for ALK diagnosis (7,724 patients) includes 28,833 patients diagnosed with LC in Spain in 2020 (13), with NSCLC (85%) (4) in stage IV (54.5%) (14), non-squamous (66.9%) and squamous (33.1%) (15) who have never smoked (16%) (16), and were tested for ALK (80.1%) (17). The target population (263 patients) was the subset of the candidate population for ALK diagnosis who obtained an ALK+ result (3.4%) in a molecular diagnostic test (17). The identification of ALK rearrangement allows the administration of personalized therapies that encompasses the strategy of matching this molecular subtype with effective targeted therapies, such as alectinib. The average age of ALK+ patients considered at diagnosis was 61 years, 40.6% were men, and 42.11% presented BM at diagnosis (Tab. I) (14).

Fig. 2 -.

Diagram of the target population for cost-benefit analysis (4,13-17). ALK = anaplastic lymphoma kinase; CBA = cost-benefit analysis; NSCLC = non–small cell lung cancer.

TABLE I -.

Epidemiology, median progression-free survival and patient characteristics

	Data inputs	References
Epidemiology of ALK-positive NSCLC
ALK+ NSCLC incidence (n)	263	(4,13-17)
Progression-free survival
Median PFS in ALK diagnosed patients with BM (months)	25.4	(6)
Median PFS in ALK diagnosed patients without BM (months)	38.6	(6)
Median PFS in ALK non-diagnosed patients with BM (months)	5.8	(6,18)
Median PFS in ALK non-diagnosed patients without BM (months)	8.9	(6,18)
Patient characteristics
Male (%)	40.6	(14)
Mean age at diagnosis (years)	61	(14)
Mean weight (kg)	71.08	(14,51)
Body surface (m2)	1.79	(14,51)
Creatinine level (mg/dL)	0.7	(52)
BM at diagnosis (%)	42.11	(6)

ALK = anaplastic lymphoma kinase; BM = brain metastasis; NSCLC = non–small cell lung cancer; PFS = progression-free survival.

The last updated median PFS in advanced ALK+ NSCLC patients treated with alectinib with and without BM in the ALEX trial was 25.4 and 38.6 months, respectively (6), and the last reported OS analysis of patients treated with alectinib is shown in Supplementary Table S2 (6). The median PFS and OS data of patients without molecular diagnosis have been estimated based on the median survival of patients treated with alectinib (6) and the hazard ratio (HR) of alectinib vs. chemotherapy estimated in a meta-analysis of ALK+ NSCLC patients (PFS HR: 0.23 [0.17; 0.030]; OS HR: 0.57 [0.39; 0.83]) (Tab. I and Supplementary Table S2) (18). The survival probability by age in the general population was estimated from all-cause mortality rates in the general population (Supplementary Table S3).

Cost and resource use

Costs were expressed in €2020, including direct healthcare costs (DHCs), direct non-healthcare costs (DNHCs) and indirect costs (ICs). Unit healthcare costs were the median value of the unit costs for each autonomous community in Spain (Median of the costs of the Official Gazettes of the Autonomous Communities, 2020). All prices corresponding to previous years were updated, using the general consumer price index (CPI) or medicines CPI (19).

DHCs included molecular diagnosis, imaging tests, drugs and their administration, palliative care, management of AEs and resources use. The diagnosis care process is shown in Supplementary Figure S1. It has been considered that ALK diagnosis was performed in parallel with LC diagnosis. The difference between groups was the re-biopsy when there was not enough tissue (77.1% of the invalid tests) (20), and also a first visit to the medical oncologist in the ALK diagnosis arm (21). The average cost of the ALK diagnosis test (€137.30), the cost of a consultation with the oncologist (€159.28), as well as the re-biopsy cost (€186.79) (Supplementary Tables S4 and S5) were also included in the ALK diagnosed arm.

The cost of ALK diagnosis test is applied to all the candidate population (7,724 patients), not just to the target population (263 patients). However, for the target population, resource use is different between ALK diagnosed and non-diagnosed patients, and depending on whether or not patients have BM (Supplementary Table S6). The unit DHCs are shown in Supplementary Table S5. The average annual cost for the ALK diagnosis arm was €4,907.72 per patient without BM and €15,054.61 per patient with BM. In the non-diagnosed ALK arm, costs were €4,625.11 and €14,605.79, respectively. In patients with BM, the costs related to neurosurgery (a neurosurgery consultation and hospitalization due to neurosurgery) were considered (€279.08). These costs are assumed only when performed (first 6 months).

The recommended drugs for the treatment of advanced NSCLC by ESMO guidelines and their market shares have been considered (Supplementary Table S7) (12). The respective dosages were obtained from the summary of product characteristics, the clinical trials submitted for the marketing authorization of the drug indication of interest, the ESMO Clinical Practice Guide (12) or the Therapeutic Positioning Guidelines of the Spanish Society of Hospital Pharmacy (SEFH) (Supplementary Table S8) (21). Drug costs were calculated using the list price (22), including Royal Decree Law 8/2010 deduction rate (23) and a 4% of the value-added tax (VAT) entitled for Spain (Supplementary Table S9). For intravenous drugs, the analysis also considered the cost of administration time for each drug in the day hospital (Supplementary Table S5). The administration time required is shown in Supplementary Table S10. The costs of treating AEs were also included, taking into account the different frequency and number of grade 1-2 and 3-4 AEs per year between the ALK diagnosed patients treated with alectinib and the non-diagnosed patients treated with chemotherapy and/or immunotherapy (Supplementary Table S11). The average unit cost of treating each AEs is shown in Supplementary Table S12.

The model also included the cost of palliative care. About 93.3% of patients received follow-up from primary care (PC) and 6.7% were assisted by a palliative home care team (24). The mean number of consultations required per week was 0.88, 0.38, 0.38 and 0.93 in home palliative care, PC physicians, PC nurses and nurse phone consultations, respectively (25). Supplementary Table S5 shows their unit costs. The drugs used in the palliative care phase were also considered (Supplementary Tables S13 and S14).

DNHCs included formal care (professional care financed by private or public funds), informal care (non-remunerated care from relatives/friends) and travel costs. About 0.50% of ALK diagnosed patients and 9.4% of non-diagnosed patients had a formal caregiver (26). Patients distinguished between informal care needs in the emotional sphere (support to face feelings such as fear, uncertainty, sadness, etc.) and in the functional sphere (help with limitations that affect functional activity and autonomy) (27). About 96.6% of patients, regardless of whether they were diagnosed or not, indicated that they had an informal caregiver related to the emotional sphere. However, no cost was assumed for that sphere. About 20% of diagnosed patients and 48.5% of non-diagnosed patients indicated that they had an informal caregiver in relation to the functional sphere (27). Based on interviews with patients, 2 hours of informal care was estimated in diagnosed patients. Based on published literature, 19.2 hours of informal care was used in non-diagnosed patients (28). A cost of €7.43/hour was assumed (minimum hourly wage for domestic workers) (29).

Traveling for follow-up visits, tests’ performance and day hospital for intravenous drugs administration implied a cost for patients, which amounts to €17.25 per trip (assuming an average 25 km/trip) (19,30-34). The number of day hospital visits for intravenous treatment administration was estimated depending on the type of treatment.

ICs included productivity loss (PL) due to attending consultations, performing tests and intravenous drug administration. The activity rate and the average salary of the general population were considered (Supplementary Table S15). The percentage of patients on sick leave at the time of diagnosis was 96.90% (35), assuming that 19% of the diagnosed patients would return to work after 4.5 months (36) and 11.20% of the non-diagnosed patients would return to work after 9 months (35). Based on this, the percentage of patients with NSCLC who work throughout the time horizon was estimated (Supplementary Table S16). It was assumed that, as the disease progresses, the percentage of patients on sick leave will increase. Based on the information obtained from the focus group and the patients’ interviews, a 1.5-hour PL was assumed for each test performed or visit to the hospital, including the traveling time and the time that they remained in the hospital. A PL was also assumed for visits to the day hospital to receive an intravenous treatment (Supplementary Table S10).

Benefits

The benefits in a CBA can be positive, negative, tangible, and intangible. To quantify intangible benefits, financial proxies (approximate value of something that does not have a specific market value) were used. Throughout the analysis, different benefits were detected related to: stigmatization and guilt of patients after diagnosis, quality of life (QoL) of patients and caregivers, impact of AEs in patients’ lives, time spent with the family and PL due to sick leave or premature death.

Patients with LC experience feelings of guilt and shame at the time of diagnosis (34.20%) (27,37). Based on the focus group and patients’ interviews, it was assumed that ALK diagnosis reduced this feeling by 75%. To quantify this benefit, it was assumed that patients suffering from these problems would need four visits to the psycho-oncologist after the diagnosis (in the first 6 months of the analysis).

The QoL loss associated with disease progression or death was estimated by utility loss as the disease progresses, which occurs earlier in the non-diagnosed patients (Supplementary Table S17). The economic proxy used was the cost-effectiveness threshold (cost per quality-adjusted life year [QALY] gained) recommended in Spain (€25,000) (38,39). After disease progression, patients who continued with active treatment (90% of diagnosed patients and 86.67% of non-diagnosed patients) lost 0.089 annual utilities, while patients who attended palliative care (10% of diagnosed and 13.33% of non-diagnosed patients) lost 0.344 annual utilities (40,41). Due to NSCLC mortality, both diagnosed and non-diagnosed patients lost an annual utility of 0.814 (40).

AEs, apart from generating a DHCs for their treatment, had an impact on different areas of patients’ lives: physical condition, self-care, autonomy, daily activities, leisure area, family and couple relationships, work environment, emotional sphere and care needs. These areas, as well as the percentage of patients affected, were identified through the focus group and patient interviews (Supplementary Table S18). According to the expert group, the impact of nausea and vomiting was considered only during the time of occurrence (3.5 days). Financial proxies used to quantify these impacts are shown in Supplementary Table S19.

Spending time with family has been recorded as a very important factor for cancer patients. Therefore, the time that patients who die are no longer with their family was quantified. In order to quantify this benefit, the analysis takes into account the minutes per day that couples spend doing activities together (42), which were quantified with a financial proxy (Supplementary Table S20).

Informal caregivers suffer an additional burden. After progression of the patients’ disease, there are changes in their treatment and worsening in their general condition. Therefore, informal caregivers have to spend more hours caring for these patients. Their mental and physical health worsens (43-45), as well as their social life (45). The benefits shown in Supplementary Table S21 were assumed per patient in disease progression with informal caregivers (96% had a caregiver in the emotional sphere in both groups and 20% and 48.5% of diagnosed and non-diagnosed patients had a caregiver in the functional sphere, respectively) (27). For the emotional sphere, the impact on mental and social health was included, and for the functional sphere the impact on health was included.

Finally, for those patients who were working at baseline, the PL due to disease progression or death was quantified as the lost wages (Supplementary Table S15).

Deterministic sensitivity analysis

A sensitivity analysis was carried out on the most relevant variables: 1) discount rate (0%; 5%); 2) price of ALK diagnosis tests (±20%); 3) HR of alectinib OS vs. chemotherapy OS (0.39; 0.83); 4) HR of alectinib PFS vs. chemotherapy PFS (0.17; 0.30); 5) cost per QALY gained (€22,000; €60,000); and 6) ±20% of the official rates of the autonomous communities in Spain.

Results

The cost results and the monetized benefits analyzed for diagnosed and non-diagnosed patients are detailed in Table II. The administration cost, the DHCs of treating AEs and the cost of formal and informal care were lower in the diagnosed patients’ arm, generating savings of €161,145, €625,958 and €1,111,823, respectively. Of the remaining additional costs, those that most affected the total cost were the anticancer drugs (67.74%), the follow-up (22.57%) and the ALK diagnosis (9.20%). The cost of traveling (visits, test and drug administration) and ICs had almost no effect in the total cost (Fig. 3A).

TABLE II -.

Costs and benefits for ALK diagnosed and ALK non-diagnosed patients with NSCLC

	Diagnosed patients	Non-diagnosed patients	Difference
Costs
ALK diagnosis	€1,111,783	€0	€1,111,783
Drugs	€50,792,934	€42,602,890	€8,190,044
Drug administration	€104,629	€265,774	−€161,145
Follow-up resources	€8,344,028	€5,615,785	€2,728,243
Treating adverse events	€374,265	€1,000,223	−€625,958
Formal care	€18,004	€42,931	−€24,927
Informal care	€745,014	€1,831,910	−€1,086,896
Traveling (visits and administration)	€422,944	€364,589	€58,355
Productivity loss due to attendance visits and follow-up tests	€7,184	€6,419	€766
Total costs	€61,920,785	€51,730,521	€10,190,265
Benefits
Stigmatization and guilt	−€17,686	−€63,540	€45,854
QoL loss associated with progression	−€513,869	−€469,177	−€44,692
QoL loss associated with mortality	−€8,174,452	−€14,183,585	€6,009,133
Adverse events	−€456,325	−€1,381,624	€925,299
Time to spend with the family	−€4,214,901	−€7,399,309	€3,184,408
QoL of caregivers	−€345,122	−€404,806	€59,684
Productivity loss due to sick leave	−€6,880,171	−€5,500,661	−€1,379,510
Productivity loss due to premature death	−€3,115,468	−€6,027,573	€2,912,105
Total benefits	−€2,371,799	−€35,430,276	€11,712,282
Cost-benefit ratio			€1.15

ALK = anaplastic lymphoma kinase; NSCLC = non–small cell lung cancer; QoL = quality of life.

Fig. 3 -.

Distribution of additional costs (A) and benefits (B). ALK = anaplastic lymphoma kinase.

The benefits related to utility loss associated with disease progression and the PL due to sick leaves were lower in the diagnosed patients’ arm than in the non-diagnosed arm (€44,692 and €1,379,510, respectively). Regarding the other benefits observed, the one that had the biggest impact was related to utility losses associated with mortality (45.75%) because the ALK diagnosed patients had a higher OS than the non-diagnosed patients (Fig. 3B). The next most important benefit was related to the PL due to premature death. Time spent with the family also had an important contribution (24.24%).

A cost increase of €10.19 million was obtained in the ALK diagnosed arm compared to the ALK non-diagnostic arm, which would generate benefits of €11.71 million. The cost-benefit ratio was €1.15.

Sensitivity analysis results

The results of the sensitivity analysis are shown in Figure 4. The most relevant parameters were the variations in OS (−13.58%; 82.78%) and PFS (−22.37%; 71.07%), as well as the cost per QALY gained (−6.11%; 71.29%). A total of 83% of the sensitivity analysis performed showed that the implementation of ALK diagnosis in NSCLC patients is cost-beneficial for society, demonstrating the robustness of the result obtained in the base case. This result could increase by 82.78% and reach a cost-benefit of €2.10.

Fig. 4 -.

Tornado diagram of total cost-benefit ratio. ACs = autonomous communities; HR = hazard ratio; OS = overall survival; PFS = progression-free survival; QALY = quality-adjusted life year.

Discussion

To our knowledge, this is the first study that has determined the CBA of ALK diagnosis in NSCLC patients. Until now, the economic evaluation of biomarker diagnosis in NSCLC has been studied only in terms of cost-effectiveness without showing a complete overview of their impact on patients’ lives and their informal caregivers (46). Furthermore, this is the first economic evaluation that includes intangible patient outcomes such as the stigmatization, the time that they lost with their families or the consequences that AEs have in all aspects of their daily life (self-care, autonomy, etc.).

Cost-effectiveness is a very common criterion by which to evaluate healthcare interventions. It compares costs with outcomes (effectiveness) in a long-term analysis. On the other hand, CBA, where both costs and outcomes are measured in monetary units is hardly used in the field of healthcare (47). The CBA can provide shorter-term results since it allows us to observe the social value of the healthcare intervention. For example, our analysis with a 5-year time horizon shows how the diagnosis of ALK rearrangements can affect relevant social aspects for the patient, such as leisure (travel, going to restaurants, theaters, etc.).

The cost-benefit ratio of €1.15 obtained in this analysis means that for each €1 invested in ALK diagnosis in NSCLC patients, a social benefit of €1.15 would be obtained. The relevant benefits (QoL loss associated with mortality, time to spend with the family and PL due to premature death) are associated with an increased OS in patients treated with targeted therapies, reaching almost double. These results demonstrate that financing the ALK diagnosis by the Spanish National Health System would generate a benefit for Spanish society. Patients with NSCLC harboring ALK fusions can be successfully treated with ALK-TKIs that could substantially improve their QoL. Therefore, treatment with ALK-TKIs is recognized as the standard-of-care for these patients, with alectinib indicated by multiple national treatment guidelines as the preferred option until 2020 (6,11,48).

Several limitations must be acknowledged. The monetary value of some items in the study was scattered. Consequently, many data sources had to be considered in order to estimate a median. It was also necessary to make approximations or even assumptions for some items in which no accurate data were found. Secondly, the data obtained from the focus group of patients and caregivers may not be representative of the total number of patients and caregivers, given the small number of participants included. Another limitation of the study is the small number of interviews conducted with patients. However, it was not possible to include more patients or caregivers in the focus group, or interview more patients, due to the small number of patients with NSCLC ALK+ in Spain (n = 263). In addition, the real prices (financed prices) of the drugs have not been used since these are not public, so it has been decided to use the accessible prices (list prices). Finally, the absence of a probabilistic sensitivity analysis is also considered a limitation of the study.

Conclusions

The results suggest that ALK diagnosis in NSCLC is cost-beneficial, as it generates a benefit for the Spanish society that outweighs its costs, justifying the universal application of this diagnosis, which allows patients to be treated with effective and tailored options like targeted therapies.

Declarations

Ethics approval and consent to participate: The present study conforms with the ethical principles of the Declaration of Helsinki 1975/83. This study did not require approval by any ethics committee. According to the Spanish law (“Ley 14/2007, de 3 de julio, de Investigación biomédica” updated on June 2, 2011), research projects carried out on human beings or their biological material have to be approved by a Research Ethics Committee, excluding observational studies where any patient treatment or intervention is not modified (49). Moreover, according to the Spanish law (“Ley 41/2002, de 14 de noviembre, básica reguladora de la autonomía del paciente y de derechos y obligaciones en materia de información y documentación clínica el consentimiento informado” updated on December 6, 2018), the informed consent has to be signed only when the activity of the study can affect patients’ health status (50). As the present study did not affect the patients’ health status, it was not necessary for patients to sign an informed consent form.

Table S1.

Databases used for the literature review

Databases
Medline
Pubmed
Embase
Medes
Spanish National Institute of Statistics (INE)
Official Bulletins of the Spanish Autonomous Communities
Drugs Database of the General Council of Pharmaceutical Colleges
Spanish Society of Hospital Pharmacist (SEFH)
European Medicines Agency (EMA)
Spanish Medicines and Sanitary Products Agency (AEMPS)
Statistical Site of the Spanish Ministry of Health, Consumer Affairs and Social Welfare (MSCBS)
Spanish Society of Palliative Care (SECPAL)
WHO Collaborating Centre for Drug Statistics Methodology
Spanish Institute for Older Persons and Social Services (IMSERSO)
Spanish Ministry of Labour and Social Economy (MITES)

Table S2.

Overall survival in non-small cell lung cancer

Overall survival (years)	ALK diagnosis patients treated with alectinib	No diagnosis patients
0.5	90.9%	51.8%
1	84.3%	48.1%
1.5	78.2%	44.6%
2	72.5%	41.3%
2.5	69.0%	39.3%
3	67.0%	38.2%
3.5	67.0%	38.2%
4	65.3%	37.2%
4.5	63.4%	36.1%
5	62.5%	35.6%

References: (1,2).

ALK: anaplastic lymphoma kinase.

Table S3.

Cumulative survival and mortality by age in general population

Age	Survival	Mortality	Age	Survival	Mortality	Age	Survival	Mortality	Age	Survival	Mortality
100	0.94%	99.06%	75	81.31%	18.69%	49	98.08%	1.92%	24	99.71%	0.29%
99	5.20%	94.80%	74	82.95%	17.05%	48	98.32%	1.68%	23	99.74%	0.26%
98	4.74%	95.26%	73	84.74%	15.26%	47	98.50%	1.50%	22	99.78%	0.22%
97	5.51%	94.49%	72	85.84%	14.16%	46	98.69%	1.31%	21	99.76%	0.24%
96	6.46%	93.54%	71	87.11%	12.89%	45	98.86%	1.14%	20	99.78%	0.22%
95	8.46%	91.54%	70	87.68%	12.32%	44	99.06%	0.94%	19	99.82%	0.18%
94	10.38%	89.62%	69	88.86%	11.14%	43	99.02%	0.98%	18	99.78%	0.22%
93	13.24%	86.76%	68	90.09%	9.91%	42	99.17%	0.83%	17	99.84%	0.16%
92	16.95%	83.05%	66	91.10%	8.90%	41	99.22%	0.78%	16	99.84%	0.16%
91	19.33%	80.67%	65	91.86%	8.14%	40	99.29%	0.71%	15	99.88%	0.12%
90	23.55%	76.45%	64	92.36%	7.64%	39	99.37%	0.63%	14	99.89%	0.11%
89	28.38%	71.62%	63	92.84%	7.16%	38	99.43%	0.57%	13	99.92%	0.08%
88	33.37%	66.63%	62	93.33%	6.67%	37	99.50%	0.50%	12	99.93%	0.07%
87	38.06%	61.94%	61	93.87%	6.13%	36	99.51%	0.49%	11	99.93%	0.07%
86	43.00%	57.00%	60	94.38%	5.62%	35	99.52%	0.48%	10	99.94%	0.06%
85	48.01%	51.99%	59	94.88%	5.12%	34	99.54%	0.46%	9	99.94%	0.06%
84	52.26%	47.74%	58	95.21%	4.79%	33	99.62%	0.38%	8	99.92%	0.08%
83	57.43%	42.57%	57	95.68%	4.32%	32	99.65%	0.35%	7	99.94%	0.06%
82	61.32%	38.68%	56	96.02%	3.98%	31	99.62%	0.38%	6	99.93%	0.07%
81	64.85%	35.15%	55	96.33%	3.67%	30	99.63%	0.37%	5	99.90%	0.10%
80	67.95%	32.05%	54	96.60%	3.40%	29	99.63%	0.37%	4	99.90%	0.10%
79	71.63%	28.37%	53	97.06%	2.94%	28	99.66%	0.34%	3	99.89%	0.11%
78	74.00%	26.00%	52	97.42%	2.58%	27	99.75%	0.25%	2	99.89%	0.11%
77	77.65%	22.35%	51	97.59%	2.41%	26	99.68%	0.32%	1	99.80%	0.20%
76	79.88%	20.12%	50	97.83%	2.17%	25	99.75%	0.25%	0	97.42%	2.58%

Reference: (3)

Table S4.

Percentage use of screening techniques

	Percentage use
Fluorescent “in situ” hybridization (FISH)	11.63%
Immunohistochemistry (IHQ)	37.21%
IHQ+FISH	46.51%
Next Generation Sequencing (NGS)	4.65%

Reference: (4)

Table S5.

Unit direct healthcare costs

	Costs	References
Screening techniques
Fluorescent “in situ” hybridization (FISH)	€111.36	(5)
Immunohistochemistry (IHQ)	€60.28	(5)
Next Generation Sequencing (NGS)	€475.00	(5)
Consultations
Emergencies (external consultation)	€182.25	(6–24)
Medical Oncology (first visit)	€159.28	(6–23,25)
Medical Oncology (Subsequent visit)	€88.72	(6,7,9–23,25,26)
Neurosurgery, in the year of the operation (first visit)	€159.28	(6–23,25)
Neurosurgery, in the year of the operation (Subsequent visit)	€88.72	(6,7,9–23,25,26)
Nursing (telephone consultation)	€15.00	(10,20,21)
Pharmacy (external consultation)	€88.72	(6,7,9–23,25,26)
Primary care nursing (external consultation)	€25.81	(6,7,9–24,26)
Primary care physician (external consultation)	€51.88	(6,7,9–24,26)
Psycho-oncologist (first visit)	€159.28	(6–23,25)
Psycho-oncologist (Subsequent visit)	€88.72	(6,7,9–23,25,26)
Radiation oncology (first visit)	€159.28	(6–23,25)
Radiation oncology (Subsequent visit)	€88.72	(6,7,9–23,25,26)
Support team in home palliative care	€221	(5,11,20,63)
Hospitalizations
Neurosurgery	€2542.80	(6,27)
Medical oncology hospitalization	€1723.27	(6,27)
Radiation oncology hospitalization	€446.05	(6,27)
Tests
Biochemistry	€4.41	(6,7,10,12,20–22,28)
Biopsy*	€186.79	(6,7,9–12,14,15,17–24,29)
Blood count	€4.41	(6,7,10,12,20–22,28)
Brain computed tomography	€190.00	(6,8,9,13,15,20–22)
Brain magnetic resonance imaging	€308.69	(6,8,20–22)
Chest x-ray	€21.23	(6–12,15,17–23,30)
Chest / abdomen computed tomography	€289.68	(7,10,11,17,23,24)
Positron Emission Tomography - Computed Tomography	€691.00	(6–8,10,20,22,23,29)
Surgical resection	€320.95	(7)
Others
Day hospital (per minute)	€0.57	(6,9–24)
Holocranial radiotherapy	€1223.67	(7)
Radiosurgery or stereotactic radiation therapy	€7252.24	(6–12)
Thoracentesis	€174.08	(6,7,9,10,13,15,17–19,21–23)

*The cost of the liquid biopsy is assumed as €0, because it is not funded by the Spanish National Health System and is performed within clinical trials, that is, it does not involve any cost for the patient.

Table S6.

Use of resources in diagnosed and non-diagnosed patients

	Patients without brain metastases		Patients with brain metastases
	Patients (%)	Tests/year (n)	Patients (%)	Tests/year (n)
Specific procedures for the treatment of brain metastasis in diagnosed and non-diagnosed patients
Holocranial radiotherapy	NA	NA	15%	5
Radiosurgery or stereotactic radiation therapy	NA	NA	35%	3
Surgical resection	NA	NA	2%	3
None	NA	NA	48%	0
Hospitalizations in diagnosed and non-diagnosed patients
Medical oncology	10%	1 (5 days)	20%	1 (5 days)
Neurosurgery	0%	0	10%	1 (7 days)
Radiation oncology	0%	0	2%	3 (5 days)
External consultations in diagnosed and non-diagnosed patients
Primary care (PC)	100%	5	100%	5
Pharmacy consultations	100%	12	100%	12
Emergencies	100%	3	100%	5
Medical oncology	100%	12	100%	15
Radiation oncology	0%	0	15%	8
Neurosurgery (in the year of the operation)	0%	0	10%	2
Laboratory tests in diagnosed and non-diagnosed patients
Blood count	100%	12	100%	12
Biochemistry	100%	12	100%	12
Imaging tests/other treatments in diagnosed and non-diagnosed patients
Chest x-ray	5%	2	5%	2
Thoracentesis	10%	1	10%	1
Positron Emission Tomography - Computed Tomography	50%	1	50%	1
Neurosurgery hospitalizations	0%	0	10%	1 (7 days)
Other specific tests in diagnosed patients
Brain magnetic resonance imaging	20%	2	50%	3
Computed tomography of chest / abdomen	100%	3	100%	4
Brain computed tomography	70%	2	50%	3
Other specific tests in non-diagnosed patients
Brain magnetic resonance imaging	10%	1	20%	3
Chest / abdomen computed tomography	100%	3	100%	4
Brain computed tomography	40%	1	20%	3

References: (5,31).

NA: not applicable.

Table S7.

Market share of treatments

Treatment	ALK+ diagnosed patients		Without diagnosis
	First-line				In progression		First-line	In progression
	Squamous	Non-squamous	Squamous	Non-squamous
	PD-L1=50%	PD-L1<50%	PD-L1=50%	PD-L1<50%	PD-L1=50%	PD-L1<50%			PD-L1=50%	PD-L1<50%
Alectinib (monotherapy)	100%	0%	0%	0%	0%	0%	0%	0%	0%	0%
Atezolizumab	0%	0%	0%	0%	0%	0%	0%	20%	0%	20%
Cisplatin + Gemcitabine	0%	0%	0%	12.5%	0%	0%	12.5%	0%	0%	0%
Cisplatin + Pemetrexed	0%	40%	0%	0%	0%	9.4%	0%	0%	30%	0%
Cisplatin + Pemetrexed + Pembrolizumab	0%	0%	0%	0%	0%	37.5%	0%	0%	0%	0%
Cisplatin + Vinorelbine	0%	0%	0%	12.5%	0%	0%	12.5%	0%	0%	0%
Carboplatin + Gemcitabine	0%	0%	0%	12.5%	0%	0%	12.5%	0%	0%	0%
Carboplatin + Paclitaxel	0%	0%	0%	50%	0%	0%	50%	0%	0%	0%
Carboplatin + Paclitaxel + Bevacizumab	0%	10%	0%	0%	0%	6.3%	0%	0%	10%	0%
Carboplatin + Pemetrexed	0%	40%	0%	0%	0%	9.4%	0%	0%	60%	0%
Carboplatin + Pemetrexed + Pembrolizumab	0%	0%	0%	0%	0%	37.5%	0%	0%	0%	0%
Carboplatin + Vinorelbine	0%	0%	0%	12.5%	0%	0%	12.5%	0%	0%	0%
Docetaxel	0%	0%	0%	0%	0%	0%	0%	20%	0%	10%
Docetaxel + Nintedanib	0%	0%	0%	0%	0%	0%	0%	0%	0%	10%
Nivolumab	0%	0%	0%	0%	0%	0%	0%	20%	0%	20%
Pembrolizumab	0%	0%	100%	0%	100%	0%	0%	20%	0%	20%
Palliative care	0%	10%	0%	0%	0%	0%	0%	20%	0%	20%

Note: 33.10% of patients are squamous and 66.9% are non-squamous (32). 25.5% have an expression of PD-L1=50% and 74.5% have a PD-L1<50% (33).

ALK: anaplastic lymphoma kinase; AUC: Area under the curve; NSCLC: non-small cell lung cancer.

Table S8.

Dosage regimen of treatments

	Treatment	Dose	Regimen	Cycle duration (days)	Maximum number of cycles	References
ALK+ diagnosed patients	Alectinib (monotherapy)
	Alectinib	1200 mg	600 mg twice daily	30	Up to progression	(34)
	Carboplatin + Pemetrexed
	Carboplatin	636.92 mg	AUC 5 mg/mL	21	4	(35–37)
	Pemetrexed	894 mg	500 mg/m2	21	Up to progression
	Cisplatin + Pemetrexed
	Cisplatin	134 mg	75 mg/m2	21	4	(35–37)
	Pemetrexed	894 mg	500 mg/m2	21	Up to progression
	Carboplatin + Paclitaxel + Bevacizumab
	Carboplatin	764.30 mg	AUC 6 mg/mL	21	6	(35,38)
	Paclitaxel	358 mg	200 mg/m2	21	6
	Bevacizumab	1066 mg	15 mg/Kg	21	Up to progression
Non-ALK diagnosed NSCLC patients	Carboplatin + Pemetrexed
	Carboplatin	636.92 mg	AUC 5 mg/mL	21 days	4 cycles	(35,37,39)
	Pemetrexed	894 mg	500 mg/m2	21 days	Up to progression
	Cisplatin + Pemetrexed
	Cisplatin	134 mg	75 mg/m2	21 days	4 cycles	(35,37,39)
	Pemetrexed	894 mg	500 mg/m2	21 days	Up to progression
	Carboplatin + Paclitaxel + Bevacizumab
	Carboplatin	764.30 mg	AUC 6 mg/mL	21 days	6 cycles	(40,41)
	Paclitaxel	358 mg	200 mg/m2	21 days	6 cycles
	Bevacizumab	1066 mg	15 mg/Kg	21 days	Up to progression
	Pembrolizumab (monotherapy)
	Pembrolizumab	200 mg	200 mg	21 days	Up to progression	(42)
	Carboplatin + Paclitaxel
	Carboplatin	764.30 mg	AUC 6 mg/mL	21 days	6 cycles	(35,43)
	Paclitaxel	358 mg	200 mg/m2	21 days	6 cycles
Non-ALK diagnosed NSCLC patients	Carboplatin + Gemcitabine
	Carboplatin	764.30 mg	AUC 6 mg/mL	21 days	6 cycles	(35,44,45)
	Gemcitabine	1788 mg	1000 mg/m² days 1 and 8 of the cycle	21 days	6 cycles
	Cisplatin + Gemcitabine
	Cisplatin	179 mg	100 mg/m2	21 days	6 cycles	(46,47)
	Gemcitabine	2235 mg	1250 mg/m2 days 1 and 8 of the cycle	21 days	6 cycles
	Carboplatin + Vinorelbine
	Carboplatin	509.53 mg	AUC 4 mg/mL	21 days	3 cycles	(35,44,48)
	Vinorelbine	45 mg	25 mg/m2 days 1 and 8 of the cycle	21 days	3 cycles
	Cisplatin + Vinorelbine
	Cisplatin	179 mg	100 mg/m2	21 days	6 cycles	(35,44,49)
	Vinorelbine	54 mg	30 mg/m2 days 1 and 8 of the cycle	21 days	6 cycles
	Carboplatin + Pemetrexed + Pembrolizumab
	Carboplatin	636.92 mg	AUC 5 mg/mL	21 days	4 cycles	(35,39)
	Pemetrexed	894 mg	500 mg/m2	21 days	Up to progression
	Pembrolizumab	200 mg	200 mg	21 days	Up to progression
	Cisplatin + Pemetrexed + Pembrolizumab
	Cisplatin	134 mg	75 mg/m2	21 days	4 cycles	(35,39)
	Pemetrexed	894 mg	500 mg/m2	21 days	Up to progression
	Pembrolizumab	200 mg	200 mg	21 days	Up to progression
	Nivolumab (monotherapy)
	Nivolumab	240 mg	240mg	14 days	Up to progression	(50)
	Atezolizumab (monotherapy)
	Atezolizumab	840 mg	840 mg	14 days	Up to progression	(51)
	Docetaxel (monotherapy)
	Docetaxel	134 mg	75 mg/m2	21 days	6 cycles	(52,53)
	Docetaxel + nintedanib
	Docetaxel	134 mg	75 mg/m2	21 days	4 cycles	(54–56)
	Nintedanib	400 mg	200 mg twice daily	21 days	Up to progression

ALK: anaplastic lymphoma kinase; AUC: Area under the curve; NSCLC: non-small cell lung cancer.

Table S9.

Drugs unit costs

	mg	Vials or tablets	Administration types	List price - Discount RDL 8/2101 + VAT (€)	References
Alectinib	150	224	Oral	5401.00	(34,57,58)
	150	240	Oral	5786.81
Carboplatin	50	1	Intravenous	7.95	(57–59)
	150	1	Intravenous	23.84
	450	1	Intravenous	71.51
	600	1	Intravenous	95.35
Pemetrexed	100	1	Intravenous	230.88	(37,57,58)
	500	1	Intravenous	1154.40
Cisplatin	10	1	Intravenous	2.32	(57,58,60)
	50	1	Intravenous	11.60
	100	1	Intravenous	23.19
Paclitaxel	30	1	Intravenous	40.84	(57,58,61)
	100	1	Intravenous	136.13
	150	1	Intravenous	204.19
	300	1	Intravenous	408.38
Bevacizumab	100	1	Intravenous	272.93	(40,57,58)
	400	1	Intravenous	1003.99
Pembrolizumab	100	1	Intravenous	3430.49	(42,57,58)
Gemcitabine	200	1	Intravenous	9.09	(47,57,58)
	1000	1	Intravenous	45.45
	1500	1	Intravenous	68.17
	2000	1	Intravenous	90.90
Vinorelbine	10	1	Intravenous	6.55	(57,58,62)
	50	1	Intravenous	32.76
Vinorelbine	20	1	Oral	28.20	(57,58,63)
	30	1	Oral	42.31
Nivolumab	40	1	Intravenous	548.34	(50,57,58)
	100	1	Intravenous	1370.85
Atezolizumab	1200	1	Intravenous	4318.18	(51,57,58)
Docetaxel	20	1	Intravenous	45.73	(53,57,58)
	80	1	Intravenous	182.92
	140	1	Intravenous	320.10
	160	1	Intravenous	365.83
Nintedanib	100	120	Oral	2312.50	(54,57,58)

VAT: value-added tax.

Table S10.

Treatment administration time

	Treatment	Administration time	References
ALK+ diagnosed patients	Carboplatin + Pemetrexed	40 minutes
	Carboplatin	30 minutes	(35,36)
	Pemetrexed	10 minutes
	Cisplatin + Pemetrexed	160 minutes
	Cisplatin	120 minutes	(35–37)
	Pemetrexed	10 minutes
	Time between doses	30 minutes
	Carboplatin + Paclitaxel + Bevacizumab	353 minutes
	Carboplatin	23 minutes	(35,38)
	Paclitaxel	180 minutes
	Bevacizumab	60 minutes
	Time between doses	90 minutes
	Treatment	Administration time	References
Non-ALK diagnosed NSCLC patients	Carboplatin + Pemetrexed	48 minutes	(35,39)
	Carboplatin	38 minutes
	Pemetrexed	10 minutes
	Cisplatin + Pemetrexed	160 minutes	(35,37,39)
	Cisplatin	120 minutes
	Pemetrexed	10 minutes
	Time between doses	30 minutes
	Carboplatin + Paclitaxel + Bevacizumab	263 minutes	(40,41)
	Carboplatin	23 minutes
	Paclitaxel	180 minutes
	Bevacizumab	60 minutes
	Pembrolizumab (monotherapy)	30 minutes	(42)
	Pembrolizumab	30 minutes
	Carboplatin + Paclitaxel	203 minutes	(35,41,43)
	Carboplatin	23 minutes
	Paclitaxel	180 minutes
	Carboplatin + Gemcitabine	90 minutes	(35,44,45)
	Carboplatin	60 minutes
	Gemcitabine	30 minutes
	Cisplatin + Gemcitabine	90 minutes	(46,47,64)
	Cisplatin	60 minutes
	Gemcitabine	30 minutes
	Carboplatin + Vinorelbine	70 minutes	(35,44,48)
	Carboplatin	60 minutes
	Vinorelbine	10 minutes
	Cisplatin + Vinorelbine	75 minutes	(35,44,49)
	Cisplatin	60 minutes
	Vinorelbine	15 minutes
	Carboplatin + Pemetrexed + Pembrolizumab	78 minutes	(35,39)
	Carboplatin	38 minutes
	Pemetrexed	10 minutes
	Pembrolizumab	30 minutes
	Cisplatin + Pemetrexed + Pembrolizumab	190 minutes	(35,37,39)
	Cisplatin	120 minutes
	Pemetrexed	10 minutes
	Pembrolizumab	30 minutes
	Time between doses	30 minutes
	Nivolumab (monotherapy)	30 minutes	(50)
	Nivolumab	30 minutes
	Atezolizumab (monotherapy)	30 minutes	(51)
	Atezolizumab	30 minutes
	Docetaxel (monotherapy)	60 minutes	(52,53)
	Docetaxel	60 minutes
	Docetaxel + nintedanib	60 minutes	(54–56)
	Docetaxel	60 minutes
	Nintedanib	Oral

Note: the administration time shown in this table does not take into account the 30 minutes of preparation and observation of the patient.

ALK: anaplastic lymphoma kinase. NSCLC: non-small cell lung cancer

Table S11.

Percentage of grades 1/2 and 3/4 adverse events and number of events per year

Adverse event	GRADE 1/2				GRADE 3/4
	Diagnosed patients	No. of events	Non-diagnosed patients	No. of events	Diagnosed patients	No. of events	Non-diagnosed patients	No. of events
Nausea and vomiting	20.39%	1	89.35%	3.5	0.66%	0.5	4.73%	0.5
Constipation/diarrhea	11.84%	2	12.43%	4.5	0.00%	0	0.59%	1
Fatigue	7.24%	1	59.17%	6	0.00%	0	3.55%	2
Peripheral edema	-	-	-	-	0.00%	0	0.59%	1
Anemia	15.13%	1	23.08%	4	4.61%	1	8.88%	1
Neutropenia	0.00%	0	14.79%	1	0.00%	0	15.38%	1
Increased Alanine transaminase (ALT)	-	-	-	-	4.61%	1	1.18%	1
Increased Aspartate transaminase (AST)	-	-	-	-	5.26%	1	1.18%	1
Increased bilirubin	-	-	-	-	1.97%	1	0.00%	0
Leukopenia	0.00%	0	10.06%	1	0.00%	0	5.33%	1
Thrombocytopenia	0.00%	0	11.83%	1	0.00%	0	6.51%	1

References: (5,65,66)

Table S12.

Average cost of treating an adverse event by type and grade

Adverse event	GRADE 1/2		GRADE 3/4
	Cost (€)	Reference	Cost (€)	Reference
Nausea and vomiting	216.94	(67)	216.94	(67)
Constipation/diarrhea	934.85	(67)	1546.37	(67)
Fatigue	1.23	(67)	174.68	(67)
Peripheral edema	-	-	495.34	(31)
Anemia	367.36	(67)	497.43	(67)
Neutropenia	272.10	(67)	272.10	(67)
Increased ALT	-	-	1329.37	(31)
Increased AST	-	-	631.06	(31)
Increased bilirubin	-	-	1098.37	(31)
Leukopenia	684.40	(67)	1596.91	(67)
Thrombocytopenia	254.81	(67)	924.70	(67)

AST: Aspartate transaminase; ALT: Alanine transaminase

Table S13.

Medication use and daily dose in palliative care

Drugs	Medication use (%)	Daily dose (mg)
Midazolam	100	0.03 mg/kg/h
Morphine	26	100 mg
Diazepam	25	10 mg
Metoclopramide	45	30 mg
Haloperidol	43	8 mg
Lactulose	100	30 mg

References: (68–76)

Table S14.

Medication costs in palliative care

Drugs	Presentations	List price + VAT (€)
Midazolam	Midazolam EFG (5 mg/ml, 5 phials 3 ml)	1.94
Morphine	MST Continus (100 mg, 60 prolonged-release tablets)	0.69
Diazepam	Diazepam EFG (10 mg, 30 tablets)	1.92
Metoclopramide	Metoclopramida EFG (10 mg, 60 tablets)	2.83
Haloperidol	Haloperidol EFG (2 mg/ml, oral drops solution 30 ml)	2.50
Lactulose	Lactulosa EFG (666 mg/ml oral solution, 1 bottle 200 ml)	3.50

Note: The presentation that best conforms to the defined daily dose (DDD) was selected. Additionally, in those cases in which several presentations could be selected, a conservative selection was made, selecting the one with the lowest price per mg.

VAT: value-added tax.

Table S15.

Activity rate and average salary by age

Age (years)	Activity rate (%)		Average salary (€)
60 – 64	41.83		26,170.28
65 – 69	6.52		24,676.30
≥ 70	0.81		24,676.30

References: (77,78).

Table S16.

Percentage of working NSCLC patients by age

	Age (years)	Baseline (%)	At 6 months (%)	At 1 year and until the end of the time horizon (%)
Diagnosed patients with ALK+	60 – 64	1.30	3.22	3.22
	65 – 69	0.20	0.50	0.50
	≥ 70	0.03	0.06	0.06
Non-diagnosed patients	60 – 64	1.30	1.30	3.57
	65 – 69	0.20	0.20	0.56
	≥ 70	0.03	0.03	0.07

ALK: anaplastic lymphoma kinase; NSCLC: non-small cell lung cancer

Table S17.

Health state utility of NSCLC patients

Condition of the patient	Utility (annual)
Stable	0.814 (0.79;0.84)
After progression, active treatment	0.725 (0.70; 0.75)
After progression, palliative care	0.47 (0.38;0.57)

References: (79,80)

NSCLC: non-small cell lung cancer

Table S18.

Impact of adverse events on different areas of patient’s life

Area of life*	Nausea or vomiting	Tiredness / weakness (fatigue)	Altered sense of taste	Altered sight
Physical state	16.3 %	14.1 %	0.0 %	0.0 %
Self-care	5.3 %	8.2 %	8.7 %	0.0 %
Autonomy	16.7 %	11.1 %	0.0 %	0.0 %
Daily life activities	16.7 %	13.9 %	21.7 %	33.3 %
Leisure activities	7.9 %	11.1 %	34.8 %	33.3 %
Family or partner relationships	3.1 %	3.0 %	21.7 %	33.3 %
Working life	8.8 %	14.7 %	0.0 %	0.0 %
Emotional sphere	10.6 %	14.9 %	13.0 %	0.0 %
Care needs	14.5 %	9.0 %	0.0 %	0.0 %

Source: Own preparation from the ‘focus group’ and interviews with patients.

*Note: Physical condition (pain, discomfort), self-care (hygiene, dressing), autonomy (mobility, leaving home, traveling), daily activities (shopping, cleaning), leisure area (going to the movies, theater, dinner), emotional sphere (anxiety or depression).

Table S19.

Financial proxies for every area of patient’s life

Area of patient’s life	Financial proxies	References
Physical state	One visit per week to the physiotherapist. Cost per visit: €37.50	(81)
Self-care	Two hairdressing sessions at home per week. Cost of a hairdressing session: €45.00	(82)
Autonomy	Average daily expenditure of the Spanish population on travel (leisure, recreation and vacation): €0.79	(83)
Daily life activities	Four hours a week from a household employee. Cost per hour: €7.43	(84)
Leisure	Average daily spending on leisure of the Spanish population: €1.81	(85)
Family and / or partner relationships	Average daily spending on traveling to visit family and friends of the Spanish population: €0.41	(83)
Working life	Not applicable. It is imputed in the benefit related to the loss of productivity due to sick leave.	-
Emotional sphere	One visit to the psycho-oncologist for diagnosis and, thereafter, one every 2 months.
	Cost per visit: See Supplementary material Table S4	-
Care needs	Four hours a week from a household employee. Cost per hour: €7.43	(84)

Table S20.

Financial proxies for time spent with family

	Minutes/ day (86)	Hours / year (86)	Financial proxies	Cost/ hour proxy (€)	References
Housework	53	322.63	Household employee	7.43	(87)
Eating	76	462.64	Daily menu in a restaurant	10.00	Assumption
Leisure	58	353.07	Spending on leisure of the Spanish population	0.08	(85)
Traveling	27	164.36	Spending on travel (leisure, recreation and vacation) of the Spanish population	0.03	(83)
TV	62	377.42	An inscription to a monthly television platform	0.07	(88)
Child care	56	340.89	Babysitter care	10.00	Assumption

Table S21.

Financial proxy for caregiver’s quality of life

Benefit	Financial proxies	References
Mental health	12 sessions of psychology per year. Cost per visit: €159.28	(6–19,25,26,89–92)
Physical health	24 sessions of physiotherapy per year. Cost per visit: €37.50	(81)
Social area	Average daily spending on leisure of the Spanish population: €1.81	(85)

Figure S1.

Care process in lung cancer

References: (5,93–96)