Abstract
Introduction
Lung cancer is a leading cause of cancer-related mortality worldwide. Non–small cell lung cancer (NSCLC) represents approximately 84% of lung cancer cases with more than half in advanced stages at presentation.1,2 NSCLC patients have high rates of psychological symptoms, and many of their family caregivers experience significant distress.3-5
Epidermal growth factor receptor (EGFR) mutations facilitated drugs such as erlotinib, icotinib, and afatinib, which have been approved as first-line treatments for NSCLC with EGFR mutations.6,7 The EGFR mutation rate in East-Asian populations is relatively high.7,8 Several studies confirmed that EGFR-tyrosine kinase inhibitors (TKIs) could improve the quality of life (QOL) of patients.6,8-10 Nevertheless, despite improvements in cancer-related QOL, current treatments are associated with toxicities and proper management is necessary to further improve the QOL.11,12
Previous studies showed that patients with NSCLC and their caregivers are highly vulnerable to psychosocial morbidity and high levels of distress including depression, anxiety, and reduced QOL.3,13,14 Distress is a frequently reported adverse event, and early recognition and effective management of psychosocial morbidity can improve the QOL of patients and their caregivers,3,4,15-18 while preventing unnecessary disruption of cancer care. It has been shown that caregivers should be involved in the management of patients with advanced NSCLC.3-5,19 Some nonpharmacologic interventions were tried and showed promising results, such as biofeedback-assisted stress management, 20 psycho-oncologic interventions, 21 early palliative care, 22 and couple-based yoga, 23 among others. Nevertheless, the conclusions often suffer from low-quality trials, 21 and well-designed randomized controlled trials (RCTs) are necessary.
Despite the probable benefits of physical activity in cancer patients,24-26 a recent preliminary clinical investigation performed by our group in our patient population showed that <2% of 410 patients with incurable lung cancer and 8% of their caregivers engage in regular physical activity. Considering disability, social behavior, and economic costs associated with lung cancer, we advocate paying close attention to the development of nonpharmacological approaches that include education and mindfulness.
Therefore, we hypothesized that a psycho-oncologic wellness education (WE) could improve the QOL of patients and their caregivers. We designed a feasibility prospective pilot RCT study that encourages patients with NSCLC and their caregivers to join a WE group during icotinib treatment. This intervention, received on a voluntary basis, involves instruction on exercise, balanced diet and nutrition, pharmacological management, legal issues relevant to health, and mental health issues. In addition, particular attention is given to the individual’s treatment experiences, including thoughts, feelings, and physical sensations. The present study aimed to evaluate the participant recruitment, intervention provision, data collection, and the efficacy of the WE intervention on patients with advanced NSCLC treated with icotinib as first-line treatment and on their caregivers. The primary outcome was QOL after 8 weeks.
Methods
Study Design and Participants
This study was a prospective randomized 8-week WE intervention feasibility study of patients undergoing icotinib treatment, carried on from December 2016 to December 2017 at the Department of Medical Oncology of the Tianjin Cancer Hospital. The eligibility criteria were the following: (1) outpatients initiated icotinib hydrochloride as first-line treatment (125 mg tid [3 times a day]; Zhejiang Beta Pharma, Zhejiang, China); (2) Eastern Cooperative Oncology Group performance status 0 to 2; (3) >18 years of age; (4) histologically confirmed stage III-IV NSCLC (UICC/AJCC Staging Manual, 6th edition 27 ); and (5) confirmed activating mutation in EGFR, that is, exon 19 deletion or exon 21 L858R point mutation. 28 The exclusion criteria were the following: (1) poor therapeutic compliance during the initial observation period judged by the patient or the caretaker or (2) the patient/caretaker did not come to the hospital as scheduled to take obtain the drugs.
Ethical approval was obtained from the Research Ethics Committee of Tianjin Cancer Hospital. All participants and their families, who were interested in participating, signed a “permission to contact” form and were subsequently contacted by the research team to assess eligibility and obtain consent.
The patients were enrolled within 2 weeks after beginning TKI treatment if good compliance was observed. The authors were responsible for drug distribution and patient education at the hospital. The patients were approached for participation when they came to obtain the drugs.
The eligibility criteria of the main caregiver were the following: (1) at least 18 years of age; (2) spouse or adult child of the patient; (3) living with the patient; and (4) no apparent cognitive impairment.
All patients and their family caregivers were from the Tianjin Cancer Hospital. All participants signed an informed consent.
Randomization
The participants were randomized after the baseline evaluation. The participants were randomized and assigned 1:1 to the WE and control groups using sequential sealed envelopes prepared by an independent statistician using a computer-generated random number table.
Blinding
Due to the nature of the intervention, the participants could not be blinded. On the other hand, all assessors responsible to fill out the questionnaires with the participants were blinded to the grouping.
Data Collection
Sociodemographic data (eg, educational status and smoking history) were collected at baseline by questionnaire. Smoking was defined as smoking, irrespective of the amount of tobacco and frequency. Assessment of the QOL, psychological distress, and family relationships was performed at baseline (T0, week 0) and at the end of study (T1, week 8).
Outcomes
The primary outcomes were feasibility of participant recruitment, intervention provision, and data collection; and sample size needed to detect differences in the rates of unnecessary referral. Additional secondary outcomes included patient QOL and changes in the way of life and family relationships, anxiety, and depression.
Intervention
The intervention was composed of six 45-minute sessions of multidisciplinary components over 8 weeks. The intervention team was composed of 1 chief director physician, 1 deputy director physician, 2 graduate physicians, and 3 nurses. The sessions were offered on 3 different days each week, and the patients attended the session of their choice. The sessions included physical therapy, coping and communication strategies, mental health education, spirituality, social needs, knowledge about lung cancer, TKI treatment, nutrition, physical activity, symptoms, and pain management.
Patients were considered to have dropped out if they had low attendance rate (not due to a physical or health problem), or became physically unfit and unable to continue or finish final evaluation, withdrew consent, or died.
Participants Report Measures
The questionnaires used to assess patient QOL were the Functional Assessment of Cancer Therapy–Lung (FACT-L 29 ; validated Chinese version 30 ) and the Caregiver QOL Index–Cancer Scale (CQOLC 31 ; validated Chinese version 32 ). The FACT-L consists of 36 items grouped into 5 different categories: physical, social, emotional, and functional well-being, as well as the Lung Cancer Subscale 29 assessing the symptoms typical for lung cancer (validated in Chinese 33 ) and the Trial Outcome Index 34 (validated in Chinese 35 ). The CQOLC consists of 35 items on 5-point Likert-type scales to assess various domains of caregiver QOL and burden. A total score is obtained, as well as scores for subscales of burden, disruptiveness, adaptation, and financial concerns.
Psychological distress was measured using the Hospital Anxiety and Depression Scale (HADS) 36 that measures generalized anxiety and depression experienced during the past week with 2 subscales. A cutoff value of ≥8 was used to indicate at least mild distress on each subscale. In addition, a total HADS score (HADS-T) of ≥15 was used to indicate clinically significant distress.
Family relationships were evaluated using the relationship dimensions subscale of the Family Environment Scale (FES), 37 which is composed of 27 items (3 subscales) that measure cohesion, expressiveness, and conflict. High scores reflect better family relationships. Patients completed the FACT-L and HADS, and caregivers completed the CQOLC and FES–Chinese Version.
Statistical Analysis
The distribution of the continuous data was tested using the Kolmogorov-Smirnov test. Normally distributed continuous data were presented as mean ± standard deviation and analyzed using the Student’s t test. Nonnormally distributed data were presented as median (range) and analyzed using the Kruskal-Wallis test. Categorical data were presented as frequencies and analyzed using the χ2 test or the Fisher’s exact test, as appropriate. SAS 9.1 (SAS Institute, Cary, NY) was used for analysis. Two-sided P values <.05 were considered as statistically significant. As this was a feasibility study, statistical analyses were exploratory in nature. Thus, although hypothesis tests were performed, statistical significance was understood to be interpretable as a signal rather than a formal probability. Accordingly, no adjustment for multiple testing was performed. QOL, family relationships, anxiety, and depression were analyzed using the per-protocol set.
Results
Enrollment
Figure 1 presents the patient flowchart. Between December 2016 and December 2017, 220 patients/caregivers were assessed for eligibility and 159 met the eligibility criteria and were randomized to the WE group (n = 80) and the control group (n = 79). At the end of the study period, 67 patients in the WE group and 71 in the control group could be analyzed and included in the per-protocol set.
Flow chart of the study.
Characteristics of the Patients
The baseline characteristics of the patients are shown in Table 1. There were no differences between the 2 groups for age, gender, marital status, Eastern Cooperative Oncology Group, brain metastases, initial cancer therapy, and smoking status (all P > .05).
Characteristics of the Patients.
Abbreviations: TKI, tyrosine kinase inhibitor; WE, wellness education; ECOG, Eastern Cooperative Oncology Group functional status; EGFR, epidermal growth factor receptor; HADS, Hospital Anxiety and Depression Scale cutoff scores (0-7 = normal, 8-10 = borderline abnormal [borderline case]; 11-21 = abnormal).
Characteristics of the Caregivers
The baseline characteristics of the caregivers are shown in Table 2. There were no differences between the 2 groups for age, gender, relationship to the patient, education, income, employment status, duration of caregiving, and private insurance (all P > .05).
Characteristics of the Caregivers.
Abbreviations: TKI, tyrosine kinase inhibitor; WE, wellness education; RMB, renminbi.
Outcomes
The main feasibility outcomes were recruitment and questionnaire completion rates. Feasibility targets were the following: (1) >70% study enrollment of eligible patients; (2) >90% of participants completing this study; and (3) <10% missing data. Preliminary effectiveness outcomes were assessed to inform a future larger scale RCT.
Table 3 shows the trial outcomes. Within the control group, the anxiety (from 10.4 to 7.6, P = .041) and depression (from 10.5 to 6.8, P = .034) subscales of the HADS were decreased. The adaptation score of the CQOLC was decreased (from 65.7 to 54.7, P = .018). Within the WE group, the WE intervention improved the emotional well-being (from 18.9 to 12.8, P = .037) and Trial Outcome Index (from 56.2 to 44.6, P = .021) scores of FACT-L, improved anxiety (from 10.4 to 6.1, P = .022) and depression (from 10.5 to 5.8, P = .039) subscales of HADS, lowered the burden (from 54.6 to 44.6, P = .039) and disruptiveness (from 79.7 to 57.0, P = .027) and adaptation score (from 63.6 to 46.4, P = .011) subscales of CQOLC, and improved the cohesion (from 5.6 ± 2.7 to 7.3 ± 1.8, P = .027) and conflict (from 4.5 ± 2.8 to 3.4 ± 1.9, P = .041) subscales of FES.
Study Endpoints.
Abbreviations: TKI, tyrosine kinase inhibitor; WE, wellness education; CI, confidence interval; FACT-L, Functional Assessment of Cancer Therapy–Lung; PWB, physical well-being; SWB, social well-being; EWB, emotional well-being; FWB, functional well-being; LCS, lung cancer subscale; TOI, Trial Outcome Index; HADS, Hospital Anxiety and Depression Scale; CQOLC, Caregiver QOL Index–Cancer Scale; FES-CV, Family relationship Chinese version of the Family Environment Scale.
Note: The significance of values in bold in table 3 are all P<0.05.
When comparing the 2 groups, the analyses showed that compared with the control group, the WE group had better scores at 8 weeks for the emotional well-being subscale of FACT-L (12.8 vs 15.6, P = .014), anxiety subscale of HADS (6.1 vs 6.7, P = .030), adaptation (66.0 vs 54.7, P = .037) and financial subscales of CQOLC (70.8 vs 69.8, P = .044), and the cohesion (7.3 ± 1.8 vs 5.7 ± 1.7, P = .021) and conflict (3.4 ± 1.9 vs 4.5 ± 1.7, P = .031) subscales of the FES.
Discussion
Patients with advanced NSCLC suffer from distress. Approaches have been tried to manage distress,20-23 but there is a lack of well-designed trials. 21 Therefore, this study aimed to examine the effects of a WE intervention on QOL of patients with stages IIIB-IV NSCLC treated with icotinib and on their caregivers. The results showed that WE interventions in patients and caregivers with stages ⅢB-IV NSCLC treated with icotinib are feasible and could improve the QOL of the patients and their relationship with their caregiver.
NSCLC is a difficult experience for a patient and for his or her family. Facing the threat of death and dealing with treatments can strain the family’s coping abilities, placing the members into considerable burden, even despair. Psychological stress cannot only be considered a psychological impairment, but also a threat to the whole family relationship. Previous findings indicated that depression might be fostered by age and the level of education; older and less educated people are prone to a higher risk of depression. 38
Few reports have examined how the experience of cancer diagnosis and treatment affects family caregivers in patients with NSCLC in China. The present study suggests benefits of a WE intervention in patients and their caregivers, including improvements in QOL and psychological well-being. Caregivers face experiences that are different from those faced by patients, and thus different strategies could be beneficial. Indeed, through qualitative analyses of the participants’ verbatim, the WE intervention was well received by the patients and caregivers, and showed positive effects on family relationships, even though not all scores were strong enough for statistical significance. Second, the intervention had positive effects on some parameters of QOL, suggesting that it could be used in combination with other means to improve the overall QOL of the patients. Nevertheless, QOL scores were improved, but lung symptom scores were not, indicating that this approach could be complementary to medical interventions improving QOL.
The WE approach used here is a kind of psycho-oncologic intervention that is based on the voluntary participation of the patients and their caregivers. For the purpose of the study, the participants were required to attend 6 sessions over 8 weeks, but the participants had the choice to attend the session that fitted with their schedule. Such flexibility could increase the adherence of the participants to the intervention. Indeed, 84% of the patients/caregivers completed the entire study as per protocol. Compared with the control group, the WE group had better scores at 8 weeks for the emotional well-being subscale of FACT-L, anxiety subscale of HADS, adaptation and financial subscales of CQOLC, and the cohesion and conflict subscales of the FES. Although preliminary, the results were consistent with the general effect of psycho-oncologic interventions on the QOL of cancer patients and their caregivers. Indeed, as reviewed by Faller et al 21 and by Northouse et al, 39 the general trend of psycho-oncologic interventions is to improve the QOL of the patients and their caregivers, but the previous studies have to be taken with caution considering the wide variability in quality. In this article, a RCT was designed. Unfortunately, blinding was not possible for the participants, and some bias could be responsible for the observed differences.
Study Limitations
The study has some limitations. First, because the participants volunteered, the sample may have been subjected to some selection bias in that these patients may have been more motivated to participate in research activities than other persons. Therefore, the entire target population may have been misrepresented. Second, the follow-up was short, as the authors were only responsible for drug distribution for the first few months (patients could later receive free medication from charity if the drug was effective, and they no longer went to the hospital). Another study limitation is that only an immediate follow-up time point was used. Third, the participants might be physically healthier and therefore more willing to participate in the present study. Fourth, though the participants were randomized, blinding was impossible. Finally, participants in the control group formally requesting psycho-oncologic consultation or detected to be with clinically significant distress could not be denied any intervention. Additional multicenter study is necessary to determine the real effectiveness of the WE approach.
Conclusion
In conclusion, WE interventions in patients and caregivers with stages ⅢB-IV NSCLC treated with icotinib are feasible and could improve the QOL of the patients and their relationship with their caregiver.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Funds of China (Grant No. 81503622). The grant supporter has no roles in study design, data collection and analysis, or manuscript preparation.