Health-Related Quality of Life in Non-Small Cell Lung Cancer (NSCLC) Patients with Mutation of Epidermal Growth Factor Receptor (EGFR) in Indonesia

Seftika Sari¹^,2, Tri Murti Andayani³*, Dwi Endarti⁴, Kartika Widayati⁵

¹Doctoral Program in Pharmaceutical Science, Faculty of Pharmacy, Universitas Gadjah Mada,

Yogyakarta, Indonesia

²Sekolah Tinggi Ilmu Farmasi Riau, Pekanbaru, Indonesia

³Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Gadjah Mada University, Yogyakarta, Indonesia

⁴Department of Pharmaceutics, Faculty of Pharmacy, Gadjah Mada University, Yogyakarta, Indonesia

⁵Department of Internal Medicine, Division of Hematology and Medical Oncology, Faculty of Medicine Gadjah Mada University-Dr. Sardjito Hospital, Yogyakarta, Indonesia.

*Corresponding Author E-mail: trimutia@yahoo.com

ABSTRACT:

Background: Aside from being the main goal for therapy, Health-Related Quality of Life (HRQOL) also can also be used for pharmacoeconomic analysis or Health Technology Assessment (HTA). The Study on HRQOL employing the EQ-5D-5L questionnaire was still limited. It aims to calculate the HRQOL according to health status and to know the determinant factors which affect the NSCLC mutation EGFR patients' quality of life.

Methods and Material: A cross-sectional study was performed by interviewing with the patients using EQ 5D 5L questionnaire in RSUP Dr. Sardjito, Yogyakarta and RSUP Dr. Kariadi, Semarang, Indonesia

Patients’ health status was consisted of Progression Free / PF (no progression), Progressive Disease 1 / PD1 (experiencing progression before or when diagnosed NSCLC with mutation of EGFR), and Progressive Disease2/PD2 (experiencing progression after being diagnosed NCLC with mutation of EGFR)

Result: There were 74 patients identified, 29 patients had not experienced disease progression (PF), 21 patients experienced the progress before or altogether after being diagnosed with NSCLC EGFR mutation positive (PD1), and 24 patients experienced the progression of the disease after being diagnosed with NSCLC EGFR mutation positive (PD2). Common problems occurred such as pain and usual activities (75,7% and 60,8%.). The mean of the utility value (SD) on patients PF, PD1, and PD2 were 0,824 (0,164); 0,528 (0,489); 0,544 (0,339). The mean of EQ5D VAS on PF, PD1, and PD2 patients were 69,65 (9,904); 57,14 (16,09); 53,95 (11,12). Mann Whitney test and Kruskal-Wallis test showed that age, gender, and mutation type did not affect the patients' utility, yet according to descriptive statistic and Kruskal-Wallis test, it was shown that health status affects patients' HRQOL.

Conclusion: NSCL EGFR mutation brought negative impact on patients' HRQOL and patients' health status significantly affected HRQOL in NSCLC EGFR mutation-positive patients.

KEYWORDS: NSCLC EGFR mutation, EQ-5D-5L, HRQOL, Utility.

INTRODUCTION:

Non-Small Cell Lung Cancer is one of the types of lung cancer that mostly occurred, where patients with advanced stage experienced a mutation of epidermal growth factor receptors (EGFR). EGFR mutation can be found in 10-15% cases in western countries patients and up to 50% in Asian Patients^1,2. Here in Indonesia, the prevalence for lung cancer is increasing from year to year and is one of the ‘givers’ for the cancer incidences in men and the main cause of 21.8%³. There are several types of medication for NSCLC EGFR mutation, such as radiotherapy, platinum-based chemotherapy, and target therapy where target therapy acts as first-line therapy⁴. The abundance of variations obtained by patients might lead us to a point of right decision making for drug-choice. Aside from clinical effectiveness, we also should consider the effect in health-related quality of life, because life quality can be used as a standard of patients' wellness after the treatment^5,6.

HRQOL value can be used for pharmacoeconomic analysis or Health Technology Assessment (HTA); used for utility cost-analysis, where to obtain Quality Adjusted Life Years (QALYs) (result from utility-cost analysis) can be obtained by multiplying the life expectancy with HRQOL⁷. HRQOL can be measured by a specific questionnaire, and generic questionnaire⁸, in many countries, instrument EuroQol (EQ-5D) instrument is the mostly-used instrument to search for utility score. The utility can be converted from health status EQ-5D using score algorithm and country-specific score, and it ranged from 0 (death) to 1 (perfect wellness)^7,9.

EQ-5D questionnaire is consisted of EQ-5D descriptive system and EQ-5D visual analog scale (EQ-5D VAS), while EQ-5D 5L is the novel form of EQ-5D questionnaire. EQ-5D descriptive system can show health profile and balanced index, while Eq-5D VAS take notes from vertical analog and visual analog. The scale is ranged from 0 (worst health condition) to 100 (Best health condition) ¹⁰. Several studies related to HRQOL on NSCLC patients in many countries such as European countries, Canada, Australia, Turkey, UK, and Holland; they used cross-sectional methods for sample-taking ^1,11,12, yet there were fewer studies on NSCLC patient with EGFR mutation-positive. Here in Indonesia, a study about HRQOL on NSCLC EGFR mutation-positive patients with EQ-5D-5L questionnaire has not been performed yet. Therefore, scientists are eager to perform this study. This study aims to measure the utility of the health status in NSCLC EGFR mutation-positive patients in Indonesia, and to understand the factors that affect the patients' utility, so that we can obtain the primary data for Quality Adjusted Life Years (QALYs) measurement, and to produce cost-utility analysis (CUA) on pharmacoeconomic studies.

MATERIAL AND METHODS:

Subject:

This is a cross-sectional study, by performing an interview on 74 NSCLC EGFR mutation-positive patients that follow the treatment and medication in RSUP Dr. Sardjito, Yogyakarta and RSUP Dr. Kariadi, Semarang, Java, Indonesia on the period of September 2018 – February 2019. The inclusion criteria are patients above 18 years old, inpatient or outpatient patients. The exclusion criteria are the patients who did not want to be respondents. Patients who participated in this study were already given informed consent to declare the agreement in order to join the study.

Health Status:

Patients were grouped based on their health condition. Health status used in this study were Progression Free/PF (no disease progression), Progressive Disease 1/ PD1 (experiencing disease progression before and while diagnosed) and Progressive Disease 2/ PD2 (experiencing disease progression after diagnosed).

Data Collection and Analysis:

The patients’ data were obtained by interview with the patients and observe the medical record of the patients related to patients’ social-demographic and their health condition. Patients’ characteristics were categorized into groups: age, gender, mutation type, and health status.

HRQOL was measured with the Indonesian version of EQ-5D-5L ¹³. The utility score (EQ-5D index score) was measured with the Indonesian set ¹⁴. HRQOL such as patients' utility score, VAS, and health status were measured in a descriptive manner, while other determinant factors that affect utility were observed with different methods, such as Mann-Whitney for patients' characteristic (Age and gender), Kruskal Wallis for mutation type and patients' health status. Patients' age was categorized in above 59 and below 59 (>59 and <59), while for gender it differed in two (man and woman), mutation types such as exon 18,19, 20, 21, and wild type, while health statuses such as PF, PD1, and PD2.

Ethical Consideration:

This study had obtained the ethical agreement from Komite Etika Penelitian Medis dan Kesehatan (MHREC) Fakultas Kedokteran, Universitas Gajah Mada Indonesia with reference number KE/FK/0948/EC/2018 and Komite Etik Penelitian Kesehatan RSUP Dr. Kariadi with number 033/EC/KEPK-RSDK-2018

RESULT:

The mean of the patients' age is 59,35 years old (SD=11,91); all of them were advanced-stage patients (IIIB/IVA). The ratio of the patients was 52,4% women, 47,3% men. The most mutation found was exon 19 (45,94%), while the least mutation found were exon 18 and 20 (1,35%). Information about patients' health state, the amount of the patient with no progression (progression-free), and the post-diagnosed progression, and the pre-diagnosed and/or diagnosed progression were (39,2%;32,4%;28,4%) respectively as seen as in table 1.

Table 1. Patients Characteristic

Characteristic		n (74)	%
Age (year)	Mean ± SD	59,35 ± 11,91
Gender	Man	35	47,3
	Woman	39	52,7
Mutation	Exon 18	1	1,35
	Exon 19	34	45,95
	Exon 20 (T790M)	1	1,35
	Exon 21	20	27,03
Other	18	24,32
Health State	Progression Free	29	39,2
	Progressive Disease1	21	28
	Progressive Disease 2	24	32,4

The progression of the disease is a condition where the additional mutation, pleural effusion, brain metastasis, bone metastasis, and the increasing tumor lesions occurred.

Progression disease in this study was defined as the addition of the mutation, pleural effusion, brain metastasis, bone metastasis, and increased tumor lesion.

The health state, according to EQ-5D-5L descriptive system, shown that the pain/discomfort and imitation for daily activities were occurred (75,7% and 60,8%), while mostly occurred on the patients who were post-diagnosed (PD2). Depression and anxiety (56,76%) mostly occurred in patients who were pre-diagnosed or all together with the diagnosed (PD1), while for the progression-free patients, pain and discomfort also occurred. Least problem experienced was self-care (82,4%), as seen in table 2.

Table 2. Patient Response on EQ-5D-5L Descriptive System

Dimension		Health States
		PF		PD1		PD2
		n (29)	%	n (21)	%	n (24)	%	N (74)	%
Mobility	No Problem	23,00	79,30	10,00	47,60	10,00	41,70	43,00	58,10
Mobility	Problem	6,00	20,70	11,00	52,40	14,00	58,30	31,00	41,90
Self-Care	No Problem	28,00	97,60	14,00	66,70	19,00	79,20	61,00	82,40
	Problem	1,00	3,40	7,00	33,30	5,00	20,80	13,00	17,60
Usually Activities	No Problem	18,00	62,10	7,00	33,30	4,00	16,70	29,00	39,20
Usually Activities	Problem	11,00	37,90	14,00	66,70	20,00	83,30	45,00	60,80
Pain/Discomfort	No Problem	12,00	41,40	6,00	28,60	0	0	18,00	24,30
Pain/Discomfort	Problem	17,00	58,60	15,00	71,40	24,00	100,00	56,00	75,70
Anxiety/Depression	No Problem	17,00	58,60	6,00	28,60	9,00	37,50	32,00	43,24
Anxiety/Depression	Problem	12,00	41,40	15,00	71,40	15,00	62,50	42,00	56,76
PF	: Progressive Free
PD1	: Experiencing disease progression before and while diagnosed NSCLC
PD2	: Experiencing disease progression after diagnosed NSCLC

Table 3. Visualization of EQ 5D VAS and EQ 5DS Index Score classified by health status

	EQ-5D VAS score					EQ-5D index score
Health Status	Mean	SD	95% CI of mean		SE	Mean	SD	95% CI of mean		SE
			Lower	Upper				Lower	Upper
PF	69,65	9,904	65,88	73,42	1,84	0,824	0,164	0,761	0,887	0,03
PD1	57,14	16,09	49,81	64,46	3,51	0,528	0,489	0,305	0,751	0,11
PD2	53,95	11,12	49,25	58,65	2,27	0,544	0,339	0,401	0,687	0,06

EQ-5D = Euro Quality of Life five dimension; VAS = visual analogue scale; 95%CI = 95% confidence interval; SD = standard deviation; SE = standard error

Table 4. Patients’ Characteristic According to EQ 5D VAS and EQ 5D Index Score

EQ - SD VAS Score					EQ - SD Index Score
		Sig	Homogenity Of Variance	P. Value	Sig	Homogenity Of Variance	P. Value
Age ^a
	< 59 Year	0,875	0,442	0,201	0,000	0,290	0,884
	> 59 Year	0,198			0,000
Gender ^a
	Man	0,147	0,119	0,756	0,000	0,009	0,948
	Woman	0,028			0,000
Mutation type ^b
	Exon 19	0,161	0,16	0,512	0,000	0,095	0,421
	Exon 21	0,335			0,003
	Other	0,653			0,001
Health Status ^b
	PF	0,046	0,032	0,000	0,005	0,000	0,001
	PD1	0,817			0,001
	PD2	0,027			0,003
^a^b	^a: Mann – Whitney test
	^{b :}Kruskal – Wallis test

DISCUSSION:

Here in this study, Patients' quality life can be seen based on patients' health status and can be measured with the EQ-5D-5L questionnaire; yet from the study, we can obtain the result on patients' health condition, and it was shown that most common problems occurred in NSCLC EGFR mutation positive patients were pain/discomfort and limitation in usual activities. This result was similar to the study done in the UK, where pain/discomfort was the most occurred problems (20.8%)¹¹. Other studies performed in Europe, Canada, Australia, and Turkey also shown the similar result that pain/discomfort was the most occurred, followed by limitations in usually activities, while commonly occurred in progressive disease state for 76.9% and 64.4% each ¹¹. Pain/Discomfort can be connected with fatigue and depression, and yet they could be caused by NSCLC EGFR mutation positive itself, that could affect the daily activities ¹⁵. In order to ease the pain, the early palliative act can be performed on patient's management and complete pain management can be performed so that patients' quality of life and patients' life span can be elevated ¹⁶. Besides, a good communication between the doctors, pharmacists and patients, social support from family, those things could also help in patients’ quality of life and show a positive impact on health care ^17,18,19.

Least problem experienced on this study was self-care (82,4%); while the questionnaires were given to the patients, most of the participated patients did not show any disability and limitation on self-care, especially in PF patients. This result matched with Chouaid et al studies, where out of 206 NSCLC patients, there were 78% patients that did not experience problems on self-care. A similar result also found in other cancers such as cervix cancer where self-care was not a problem and limitation for the patients ^1,20.

Utility score that based on patients’ Health Status shown that patients with disease progression either post-diagnosed, pre-diagnosed, and while diagnosed NSCLC EGFR mutation-positive (PD1 and PD1) experienced a decline compared to those progression-free patients (PF).Similar studies with the similar result performed in Europe, Canada, Australia, and Turkey, while there were declining in utility and EQ-5D VAS with utility score of 0,58 versus 0,70; and EQ-5D VAS Score of 53,7 versus 66,6¹. Disease progression could affect patients’ HRQOL so that the health provider role is necessary in order to observe and ready for any progression. Besides, the right medication that could inhibit patients’ disease progression and limiting the symptoms occurred²¹.

Here, from Mann-Whitney and Kruskal Wallis test it was shown that age, Gender and mutation type did not have any correlations towards patients’ quality of life. This result was similar to studies done by Grutters et al and Trippoli et al, that age, Gender, and mutation type were not the factors that affect patients’ utility score. This can be seen in the statistic test performed that there were no significant result., Yet the studies done by Grutters et al and Trippoli et al, in a descriptive-statistic manner, health state could affect patients' quality of life, where the patients who had not experienced metastases yet had better quality of life compared to its vice with the result of 0,68 versus 0,53 and 0,76 versus 0,61^12,22,23. This result matched with the study where health state affects the patients’ life quality in a descriptive-statistic manner and Kruskal-Wallis test. On Kruskal-Wallis test, it was obtained a significance value of α < 0,005 where EQ-5D score index or EQ 5D VAS. The patient with the most affected health status was PD1 patients with a significance value of 0,001. In this study, patients with disease progression (PD1) experienced problems in five domains of EQ-5D-5L, especially in pain/discomfort, so that it could affect the declining on quality of life, compared to the progression-free patients. The finding is similar to the study performed by Doyle et al. 2008, stated that patients with o additional symptoms were declining to 0,557 caused by additional pain. Besides patients with PD1 also experiencing depression/anxiety (71,4%), while depression/anxiety can be triggered by several factors: such as the history of anxiety and trauma, disease and medication, and symptoms that patients experienced such as pain, insomnia, dyspnea, depression, and fatigue²⁴.

The weakness in this study was that the small sample size that might affect the generalization. Advanced study with more sample sized is necessary, with other generic questionnaire and the specific questionnaire. This study gives important information for the next study, that can be used as economical evaluation related to the patients’ cost and utility. Utility score can be used to look for Quality Adjusted Life Years (QALYs) and could be useful for modeling-studies that related to cost-effectiveness ²³.

CONCLUSION:

This study confirmed that NSCL EGFR mutation positive brought a negative effect on HRQOL and patients' health state significantly affected HRQOL on NSCLC EGFR mutation patients.

CONFLICT OF INTEREST:

The author declares that there is no conflict of interest.

ACKNOWLEDGEMENT:

The author wish to thank all patients who participated in this study.

REFERENCES:

1. Chouaid C, Agulnik J, Goker E, Herder GJM, Lester JF, Vansteenkiste J, et al. Health-Related Quality of Life and Utility in Patients with Advanced Non–Small-Cell Lung Cancer: A Prospective Cross-Sectional Patient Survey in a Real-World Setting. J Thorac Oncol. 2013 Aug;8(8):997–1003.

2. Shi Y, Li J, Zhang S, Wang M, Yang S, Li N, et al. Molecular Epidemiology of EGFR Mutations in Asian Patients with Advanced Non-Small-Cell Lung Cancer of Adenocarcinoma Histology – Mainland China Subset Analysis of the PIONEER study. Chai KX, editor. PLOS ONE. 2015 Nov 23;10(11):e0143515.

3. World Health Organization. Cancer Country Profiles [Internet]. 2014. Available from: www.who.int/cancer/country-profiles/idnen.pdf

4. Ettinger DS, Govindan R, Martins R. NCCN Guidelines Index Table of Contents Discussion. 2017;200.

5. Greenberg D, Earle C, Fang C-H, Eldar-Lissai A, Neumann PJ. When is Cancer Care Cost-Effective? A Systematic Overview of Cost–Utility Analyses in Oncology. JNCI J Natl Cancer Inst. 2010 Jan 20;102(2):82–8.

6. Gangane N, Khairkar P, Hurtig A-K, Sebastián MS. Quality of Life Determinants in Breast Cancer Patients in Central Rural India. Asian Pac J Cancer Prev [Internet]. 2017 Dec [cited 2019 Mar 15]; (12). Available from: http://journal.waocp.org/article_53174.html

7. Drummond F, Torrance GW. Methods for the economic evaluation of health care programmes. Oxford University Press; 2005.

8. Teckle P, Peacock S, McTaggart-Cowan H, van der Hoek K, Chia S, Melosky B, et al. The ability of cancer-specific and generic preference-based instruments to discriminate across clinical and self-reported measures of cancer severities. Health Qual Life Outcomes. 2011;9(1):106.

9. Kementerian kesehatan Republik Indonesia. Buku panduan penilaian teknologi kesehatan. Komite Penilaian Teknologi Kesehatan; 2017.

10. Oemar M, Janssen B. User guide: basic information on how to use EQ-5D-5L instrument. EuroQol Group. 2013;

11. Doyle S, Lloyd A, Walker M. Health state utility scores in advanced non-small cell lung cancer. Lung Cancer. 2008 Dec;62(3):374–80.

12. Grutters JPC, Joore MA, Wiegman EM, Langendijk JA, de Ruysscher D, Hochstenbag M, et al. Health-related quality of life in patients surviving non-small cell lung cancer. Thorax. 2010 Oct 1;65(10):903–7.

13. Euro Qol Group. EQ-5D-5L [Internet]. Available from: http://www.euroqol.org/eq-5d-products/eq-5d-5l.html.

14. Purba FD, Hunfeld JAM, Iskandarsyah A, Fitriana TS, Sadarjoen SS, Ramos-Goñi JM, et al. The Indonesian EQ-5D-5L Value Set. PharmacoEconomics. 2017 Nov;35(11):1153–65.

15. Laird BJA, Scott AC, Colvin LA, McKeon A-L, Murray GD, Fearon KCH, et al. Pain, Depression, and Fatigue as a Symptom Cluster in Advanced Cancer. J Pain Symptom Manage. 2011 Jul;42(1):1–11.

16. Temel JS, Gallagher ER, Jackson VA, Blinderman CD, Billings JA. Early Palliative Care for Patients with Metastatic Non–Small-Cell Lung Cancer. N Engl J Med. 2010;10.

17. Nazik E, Nazik H, Ozdemir F, Soydan S. Social Support and Quality of Life in Turkish Patients with Gynecologic Cancer. Asian Pac J Cancer Prev. 2014 Apr 1;15(7):3081–6.

18. Zhao Z-M, Pan X-F, Lv S-H, Xie Y, Zhang S-K, Qiao Y-L, et al. Quality of life in women with cervical precursor lesions and cancer: a prospective, 6-month, hospital-based study in China. Chin J Cancer [Internet]. 2014 Apr 4 [cited 2019 Feb 26]; Available from: http://www.cjcsysu.cn/abstract_AOP.asp?fr=doi&id=13-139

19. Maheswari P, Somasundaram I (2016). Health Related Quality of Life Measurement in Asthma and Chronic Obstructive Pulmonary Disease. Research Journal of Pharmacy and Tecnology, 9(5): 518-520

20. Endarti D, Riewpaiboon A, Thavorncharoensap M, Praditsitthikorn N, Hutubessy R, Kristina SA. Evaluation of Health-Related Quality of Life among Patients with Cervical Cancer in Indonesia. Asian Pac J Cancer Prev. 2015 Apr 29;16(8):3345–50.

21. Walker MS, Wong W, Ravelo A, Miller PJE, Schwartzberg LS. Effectiveness outcomes and health related quality of life impact of disease progression in patients with advanced nonsquamous NSCLC treated in real-world community oncology settings: results from a prospective medical record registry study. Health Qual Life Outcomes [Internet]. 2017 Dec [cited 2019 Feb 26];15(1). Available from: http://hqlo.biomedcentral.com/articles/10.1186/s12955-017-0735-4

22. Trippoli S, Vaiani M, Lucioni C, Messori A. Quality of Life and Utility in Patients with Non-Small Cell Lung Cancer: PharmacoEconomics. 2001;19(8):855–63.

23. Oizumi S, Kobayashi K, Inoue A, Maemondo M, Sugawara S, Yoshizawa H, et al. Quality of Life with Gefitinib in Patients with EGFR-Mutated Non-Small Cell Lung Cancer: Quality of Life Analysis of North East Japan Study Group 002 Trial. The Oncologist. 2012 Jun 1;17(6):863–70.

24. Traeger L, Greer JA, Fernandez-Robles C, Temel JS, Pirl WF. Evidence-Based Treatment of Anxiety in Patients With Cancer. J Clin Oncol. 2012 Apr 10;30(11):1197–205.

Received on 18.07.2019 Modified on 20.08.2019

Research J. Pharm. and Tech. 2020; 13(1):443-447.

DOI: 10.5958/0974-360X.2020.00086.4