The Impact of Pre-Existing Mental Health Disorders on the Diagnosis, Treatment and Survival among Lung Cancer Patients in the U.S. Military Health System

Abstract

Background

Higher cancer-related mortality has been observed among people with mental health disorders than in the general population. Both delay in diagnosis and inadequate treatment due to health care access have been found to explain the higher mortality. The U.S. Military Health System (MHS), in which all beneficiaries have equal access to health care, provides an ideal system to study this disparity where there are no or minimal barriers to health care access. This study assessed pre-existing mental health disorders and stage at diagnosis, receipt of cancer treatment and overall survival among non-small cell lung cancer (NSCLC) patients in the U.S. MHS.

Methods

The study used data from the linked database from the Department of Defense’s Central Cancer Registry and the MHS Data Repository (MDR). The study subjects included 5,054 patients with histologically confirmed primary NSCLC diagnosed between 1998 and 2007.

Results

Patients with a pre-existing mental disorder did not present with more advanced disease at diagnosis than those without. There were no significant differences in receiving cancer treatments between the two groups. However, patients with a mental health disorder had a higher mortality than those without (Adjusted Hazard ratio (HR) =1.11, 95% CI=1.03 to 1.20).

Conclusions

Poor survival in NSCLC in patients with a pre-existing mental health disorder is not necessarily associated with delay in diagnosis and/or inadequate cancer treatment.

Impact

This study contributes to the current understanding that health care access is not sufficient to explain the poor survival among NSCLC patients with pre-existing mental health disorder.

Introduction

There is mounting evidence of a higher all-cause mortality in people with mental illness than general population (1–9). When the causes of mortality were examined, it was found that except for suicide and other un-natural deaths, people with mental health disorders also experienced a higher mortality than general population, including cancer-related mortality (1, 9–14).

Mental health disorders may influence cancer outcomes through an array of socioeconomic, behavioral, and biological mechanisms. Socioeconomically, people with mental health disorders may be more likely to be unemployed, have lower education level, and live at or below the poverty level; these factors are associated with less access to healthcare, screening services, in-patient care and out-patient clinical visits, thereby resulting in delayed diagnosis (15–17), inadequate or less-aggressive treatments (16, 18, 19) and poorer survival (14–18, 20–25). Behaviorally, mental health disorders are commonly linked to unhealthy lifestyles such as smoking, alcohol and substance abuse, physical inactivity, poor nutrition and poor physical health, which contribute to cancer progression and mortality (10, 11, 14, 26, 27). It is also possible that biologically, mental illness could affect biochemical pathways, which include increased cell damaging processes and decreased cell protective or restorative processes (28), dysfunctional immune surveillance, accumulation of somatic mutations, and genome instability(29). These biological changes may also facilitate cancer progression.

Lung cancer is the leading cause of cancer-related death worldwide(30). Non-small cell lung cancer (NSCLC) comprises 85% to 90% of all lung cancers (30). Previous studies have found increased mortality among lung cancer patients with mental illness (1, 10, 11, 13, 14, 31, 32). However, it is not clear what factors may contribute to the increased mortality while it can be reasonably postulated that treatment and treatment adherence may differ between patients with and without a mental health disorder. One recent study showed no association between depression and the receipt of surgery, chemotherapy or radiation among military veterans with NSCLC (31). Another study that was restricted to advanced stage NSCLC veteran patients (stages III and IV) did not find an association between depression and receipt of chemotherapy (33). However, depression was reported to be associated with poor treatment adherence among advanced stage NSCLC patients (32). To the best of our knowledge, no studies have examined if mental health disorders overall or specific mental health disorders other than depression could affect stage at diagnosis, cancer treatment and survival among NSCLC patients.

In the general population, patients with mental health disorders may differ from those without access to medical care due to unemployment, lower education level, and/or poverty. This differential access to care may affect research results in the general population on cancer diagnosis, treatment and survival because lack of health insurance, limited access to wellness visits and underutilization of health care service may be related to delayed diagnosis, inadequate treatment and poor survival among patients (16, 17, 22, 23). Research in a health system that provides universal healthcare could reduce the potential effects of unequal access to care. The U.S. military health system (MHS) provides health care to military personnel, retirees, and their family members and all beneficiaries have equal access to health care regardless of military rank, education, or income. A study within the MHS could demonstrate whether mental health disorders increases the mortality of cancer when there are no or minimal barriers to health care access, thus suggesting potential effects of factors other than those related to health care access. In addition, compared to the general population, military personnel are at higher risk of developing mental health problems (34–36) such as post-traumatic stress disorder related to prior combat. Family members of military personnel are also at increased risk of mental stress due to mobile lifestyle and frequent family separations (37, 38). Therefore, it is important to assess whether mental health disorders are related to cancer outcomes in the MHS. To the best of our knowledge, there have been no epidemiological studies on pre-existing mental health disorders in relation to diagnosis, treatment and survival of cancer including lung cancer among beneficiaries in the MHS. In this study, we investigated whether pre-existing mental health disorders are associated with the stage at diagnosis, cancer treatment received, and survival among patients with NSCLC in the MHS.

Materials and Methods

Data Sources

This study was based on the MHS, which provides health care to active duty members, retirees, National Guard and Reserve members, and their dependents. The linked database from the Department of Defense (DoD)’s Central Cancer Registry (CCR) and the MHS Data Repository (MDR) was used in this study and described previously (39, 40). The CCR contains information on cancer patients diagnosed or treated at military treatment facilities (MTFs). The CCR Data include demographic variables, tumor characteristics, cancer diagnosis, treatment, recurrence and vital status. Cancer site and histology codes are based on the International Classification of Diseases for Oncology, third edition (ICD-O-3) (41). The CCR registry staff conduct lifetime follow-up on patients. Quality assurance was conducted following the guidelines established by the North America Association of Central Cancer Registries. The MDR contains administrative and medical care information that includes both inpatient and outpatient care provided at MTFs and civilian facilities paid for by the DoD. The MDR database includes information on clinical diagnoses of all medical conditions, which are coded using the International Classification of Disease, 9^th Revision (ICD-9), and diagnostic and treatment procedures, which are coded using ICD-9 or Current Procedural Terminology (CPT) codes. The data linkage project was approved by the Institutional Review Boards of the Walter Reed National Military Medical Center, TRICARE Management Activity, and the National Institutes of Health Office of Human Subjects Research.

Study subjects

The study subjects were patients diagnosed with histologically confirmed primary NSCLC between 1998 and 2007. NSCLC constitutes about 85% to 90% of all lung cancers (30). The cancer site and histology were classified using the topography (C34.0 to C34.3, C34.8, C34.9) and morphology codes (8050-8078, 8083, 8084, 8250-8260, 8480-8490, 8570-8574, 8140, 8211, 8230, 8231, 8323, 8550, 8551, 8576, 8010-8012, 8014-8031, 8035, 8310, and any other NSCLC codes between 8010 to 8576) of the International Classification of Diseases for Oncology, third edition (ICD-O-3)(41).

Mental health disorder Variables

Pre-existing mental health disorders were defined as diagnoses of mental health disorders during the 2-year period before NSCLC diagnosis (16, 18). Mental health disorder diagnoses were identified using ICD-9 or CPT codes in the MDR data. The following mental health disorder categories were identified using specific ICD-9 codes: any mental health disorder (codes 29, 30, 31); psychotic disorders (codes 295, 297, 298, 293.81, 293.82)(11, 16, 23, 25, 42–44); dementia and other organic psychosis (codes 290, 294)(11, 16); mood disorders (codes 296, 311, 300.4, 309.1, 309.0, 309.4, 301.1, 301.10, 301.12, 301.13)(7, 11, 16, 18, 23, 25, 42–45); substance abuse and dependence disorders (codes 291, 292, 303, 301, 305)(7, 11, 16, 25, 42, 44, 45); anxiety disorders (codes 300 except 300.4, 308.3, 309.81)(25, 42–44), and all other mental health disorders that falls between codes 29 to 31 but not included in any of the above categories.

Statistical Analyses

There were three outcomes in this study: cancer stage at diagnosis, receipt of cancer treatments and all-cause mortality. Cancer stage was defined in accordance of the American Joint Committee on Cancer (AJCC) staging system, the 7^th edition (46). Stage was further grouped into early stage (stages I and II)(47, 48), advanced stage (stages III and IV) (49) and unknown stage (missing information in the data). Cancer treatments (lung cancer specific surgery, chemotherapy and radiation therapy) were identified and consolidated from both CCR and MDR. Vital status was from the CCR data.

In data analysis, we first presented the distributions of demographic, diagnostic, treatment and other variables by mental health disorder status. We then used multivariate logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (95% CI) of pre-existing mental health disorders (any and specific disorders) in relation to tumor stage at NSCLC diagnosis. ORs of mental health disorders were estimated for late stage vs. early stage and unknown stage vs. early stage, respectively. In regard to cancer treatment (yes or no) related to pre-existing mental health disorders, we used multivariate Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CI of. Time to treatment was used in the models and calculated as the interval between NSCLC diagnosis date and first cancer treatment date. Subjects who did not receive any cancer treatment before study end date were censored. For surgery, chemotherapy and radiation treatments, time to treatment was calculated as the interval between NSCLC diagnosis date and the date of receiving surgery, chemotherapy and radiation therapy, respectively. Considering recommended treatment guidelines (50, 51), receipt of surgery was assessed among stages I and II patients only and receipt of chemotherapy and radiation therapy was analyzed among stages III and IV patients only. In terms of cancer survival, we first analyzed overall survival by pre-existing mental health disorder status using Kaplan-Meir curve and log-rank test. Multivariate Cox proportional hazards models were then used to estimate HRs and 95% CI of mortality associated with pre-existing mental health disorders. Survival time was calculated as the interval from the date of diagnosis until death, date of last contact, or the study end date. Subjects who did not die during follow up were censored. Cox analysis was further stratified by tobacco use (never, former and current) and by comorbidity index group. Comorbidities were identified from the MDR data. A comorbid condition was considered to be present if at least one inpatient record or three outpatient records (52, 53) showed the diagnosis prior to the NSCLC diagnosis. The level of comorbidity was categorized according to the Charlson comorbidity index (54). The index score was further grouped into three groups with index score of 0, 1 and 2 or more, respectively. In all logistic and Cox regression analyses, the potential confounders, variables related to both mental health disorders and outcomes, were controlled in the models.

Results

A total of 5,054 NSCLC patients were identified from the data. Out of them, 1,858 had a history of pre-existing mental health disorder. The distributions of patient characteristics by mental health disorder are shown in Table 1. Compared to individuals without any mental health disorder, patients with a diagnosis of pre-existing mental health disorder were more likely to be in the age groups of 50–59 and 60–69 years old (P<0.001), female (P=0.007) and White (P<0.001). There was a higher percentage of Army beneficiaries with a mental health disorder than other military branches (P<0.001). Patients with a mental health disorder were more likely to be current smokers (P<0.001) and have more comorbidities than those without (P<0.001). Compared to those without mental health disorders, patients with a mental health disorder were more likely to have stage I, and less likely to have unknown information on tumor stage (P=0.002). They were more likely to be diagnosed with moderately differentiated, poorly differentiated and undifferentiated tumors (P=0.015), and with large cell histology (P<0.001) (Table 1). Differences between the two groups in cancer treatment, recurrence and marital status were not significant (Table 1).

Table 1.

Characteristics of non-small cell lung cancer patients by pre-existing mental health disorder status in the Military Health System (1998–2007)

Variables	No Mental Health Disorder		Any Mental Health Disorder		P-Value
	Number (N)	Percentage (%)	Number (N)	Percentage (%)
Age					<0.001
<50	245	7.67	140	7.53
50–59	549	17.18	362	19.48
60–69	1181	36.95	756	40.69
70–79	920	28.79	483	26.00
80 and older	301	9.42	117	6.30
Sex					0.007
Male	2104	65.83	1153	62.06
Female	1092	34.17	705	37.94
Race					<0.001
White	2519	78.82	1526	82.13
Black	382	11.95	210	11.30
Asian	198	6.20	62	3.34
Other	79	2.47	47	2.53
Unknown or missing	18	0.56	13	0.70
Marital Status					0.148
Never Married	111	3.47	48	2.58
Married	2386	74.66	1389	74.76
Separated or Divorced	177	5.54	123	6.62
Widowed	396	12.39	237	12.76
Unknown or Missing	126	3.94	61	3.28
Sponsor Service Branch					<0.001
Army	1080	33.79	740	39.83
Navy	621	19.43	349	18.78
Air Force	1086	33.98	589	31.70
Marines	116	3.63	67	3.61
Coast Guard	24	0.75	12	0.65
Other, unknown or missing	269	8.42	101	5.44
Active Duty Status					0.204
No	3057	95.60	1795	96.61
Yes	107	3.35	51	2.74
Unknown or missing	32	1.00	12	0.65
Tobacco Use					<0.001
Never used	319	9.98	89	4.79
Previous use	1768	55.32	792	42.63
Current use	888	27.78	853	45.91
Unknown or missing	221	6.91	124	6.67
Comorbidity Index					<0.001
0	1616	50.56	504	27.13
1	611	19.12	448	24.11
2 or more	969	30.32	906	48.76
Tumor Stage					0.002
Stage I	1002	31.35	635	34.18
Stage II	270	8.45	161	8.67
Stage III	734	22.97	433	23.30
Stage IV	979	30.63	554	29.82
Unknown	211	6.60	75	4.04
Tumor Grade					0.015
Well Differentiated	271	8.48	135	7.27
Moderately Differentiated	689	21.56	437	23.52
Poorly Differentiated	1033	32.32	617	33.21
Undifferentiated	53	1.66	49	2.64
Unknown or missing	1150	35.98	620	33.37
Histology					<0.001
Squamous cell carcinoma	785	24.56	469	25.24
Adenocarcinoma	1437	44.96	811	43.65
Large cell carcinoma	349	1.09	150	8.07
Other	625	19.56	428	23.04
Surgery					0.845
No	1582	49.50	925	49.78
Yes	1614	50.50	933	50.22
Chemotherapy					0.706
No	1562	48.87	910	48.98
Yes	1610	50.38	930	50.05
Unknown	24	0.75	18	0.97
Radiation					0.269
No	1442	45.12	871	46.88
Yes	1740	54.44	975	52.48
Unknown	14	0.44	12	0.65
Recurrence					0.066
No	2647	82.82	1585	85.31
Yes	524	16.40	259	13.94
Unknown	25	0.78	14	0.75

Compared to those without a pre-existing mental health disorder, patients with any pre-existing mental health disorders were 42% less likely to be diagnosed with an unknown stage tumor (OR=0.58, 95% CI, 0.41 to 0.80) (Table 2). Further analysis showed that compared to patients without any pre-existing mental health disorders, the OR of unknown tumor stage was 0.66 (95% CI, 0.40 to 1.07) for those with one mental health disorder and 0.54 (95% CI, 0.37 to 0.79) for those with two or more mental health disorders (Table 2). The ORs were not significant in late tumor stage at diagnosis relative to early stage for patients with a mental health disorder compared to those without. In terms of specific mental health disorders, patients with substance abuse disorder were less likely to have an unknown tumor stage (OR=0.64, 95% CI=0.43 to 0.94) (Table 2). No significant ORs were observed between other specific mental health disorders and unknown tumor stage or late stage (Table 2).

Table 2.

The association between pre-existing mental health disorders and stage at diagnosis among non-small cell lung cancer patients in the Military Health System (1998–2007)

Mental Disorder Variables	Late Stage vs. Early Stage		Unknown Stage vs. Early Stage
	No. (Early/Late)	Adjusted OR (95% CI)*	No. (Early/Unknown)	Adjusted OR (95% CI)*
Any Mental Health Disorder
No	1272/1713	1.00 (ref)	1272/211	1.00 (ref)
Yes	796/987	0.95 (0.83 to 1.08)	796/75	0.58 (0.41 to 0.80)
Number of Mental Health Disorders
None	1272/1713	1.00 (ref)	1272/211	1.00 (ref)
One	553/731	1.00 (0.86 to 1.16)	553/47	0.66 (0.40 to 1.07)
Two or more	243/256	0.81 (0.66 to 1.00)	243/28	0.54 (0.37 to 0.79)
Psychotic Disorder
No	2046/2684	1.00 (ref)	2046/284	1.00 (ref)
Yes	22/16	0.60 (0.30 to 1.21)	22/2	0.75 (0.15 to 3.87)
Dementia
No	2034/2658	1.00 (ref)	2034/282	1.00 (ref)
Yes	34/42	0.98 (0.60 to 1.60)	34/4	0.96 (0.30 to 3.01)
Mood Disorder
No	1847/2442	1.00 (ref)	1847/257	1.00 (ref)
Yes	221/258	0.97 (0.77 to 1.21)	221/29	1.03 (0.60 to 1.78)
Substance Abuse Disorder
No	1515/2031	1.00 (ref)	1518/237	1.00 (ref)
Yes	550/669	0.90 (0.77 to 1.04)	550/49	0.64 (0.43 to 0.94)
Anxiety Disorder
No	1913/2524	1.00 (ref)	1913/263	1.00 (ref)
Yes	155/176	0.97 (0.75 to 1.26)	155/23	1.02 (0.56 to 1.86)
Other Mental Health Disorders
No	1928/2527	1.00 (ref)	1928/277	1.00 (ref)
Yes	140/173	1.03 (0.80 to 1.33)	140/9	0.51 (0.24 to 1.10)

^*Adjusted for age, sex, race, marital status, sponsor service branch, active duty status, tobacco use, comorbidity index, tumor grade, and histology. Specific mental disorders were also mutually adjusted.

OR=Odds Ratio; CI=Confidence Interval

There were no significant differences in receiving any cancer treatment between the groups by mental health disorder status (Table 3). However, subjects with dementia were less likely to receive treatment than subjects without (HR=0.74, 95% CI=0.57 to 0.97) (Table 3). No association was observed between other specific mental health disorders and receipt of any cancer treatment (Table 3). Further analyses on receipt of surgery (stages I and II patients only), chemotherapy (stages III and IV patients only) and radiation therapy (stages III and IV patients only) did not reveal differences between patients with and without mental health disorders (Table 4).

Table 3.

The association between pre-existing mental health disorders and receipt of cancer treatment among non-small cell lung cancer patients in the Military Health System (1998–2007)

Mental Disorder Variables	No. (No Treatment/Any Treatment)	Adjusted HR (95% CI)*
Any Mental Health Disorder
No	270 /2910	1.00 (ref)
Yes	166 /1686	1.00 (0.94 to 1.07)
Number of Mental Health Disorders
None	270/2910	1.00 (ref)
One	122/1206	0.99 (0.93 to 1.07)
Two or more	44/480	1.03 (0.93 to 1.14)
Psychotic Disorder
No	430/4562	1.00 (ref)
Yes	6/34	0.99 (0.70 to 1.39)
Dementia
No	412/4540	1.00 (ref)
Yes	24/56	0.74 (0.57 to 0.97)
Mood Disorder
No	393/4132	1.00 (ref)
Yes	43/464	1.02 (0.91 to 1.13)
Substance Abuse Disorder
No	319/3448	1.00 (ref)
Yes	117/1148	0.99 (0.92 to 1.06)
Anxiety Disorder
No	410/4270	1.00 (ref)
Yes	26/326	1.03 (0.91 to 1.17)
Other Mental Health Disorders
No	415/4298	1.00 (ref)
Yes	21/298	1.07 (0.95 to 1.21)

^*Adjusted for age, sex, race, marital status, sponsor service branch, active duty status, tobacco use, comorbidity index, tumor stage, grade, histology, and recurrence. Specific mental disorders were also mutually adjusted.

HR=Hazard Ratio; CI=Confidence Interval

Table 4.

The association between pre-existing mental health disorders and receipt of surgery, chemotherapy and radiation treatments among non-small cell lung cancer patients in the Military Health System (1998–2007)

Mental Health Disorder Variables	Surgery (Stages I and II)		Chemotherapy (Stages III and IV)		Radiation (Stages III and IV)
	No. (Surgery/No Surgery)	Adjusted HR (95% CI)*	No. (Chemo/No Chemo)	Adjusted HR (95% CI)*	No. (Radiation/No Radiation)	Adjusted HR (95% CI)*
Any Mental Health Disorder
No	176/1096	1.00 (ref)	603/1102	1.00 (ref)	512/1191	1.00 (ref)
Yes	127/669	1.01 (0.91 to 1.12)	350/629	1.01 (0.91 to 1.12)	323/658	1.00 (0.93 to 1.11)
Number of Mental Health Disorders
None	176/1096	1.00 (ref)	603/1102	1.00 (ref)	512/1191	1.00 (ref)
One	86/467	1.03 (0.92 to 1.16)	254/473	1.04 (0.93 to 1.17)	239/488	0.98 (0.87 to 1.09)
Two or more	41/202	0.96 (0.82 to 1.13)	96/156	0.92 (0.78 to 1.10)	84/170	1.08 (0.91 to 1.28)
Psychotic Disorder
No	297 /1749	1.00 (ref)	943/1725	1.00 (ref)	829/1839	1.00 (ref)
Yes	6/16	0.84 (0.51 to 1.40)	10/6	1.93 (0.86 to 4.33)	6/10	1.25 (0.66 to 2.35)
Dementia
No	290/1744	1.00 (ref)	923/1719	1.00 (ref)	814/1828	1.00 (ref)
Yes	13/21	0.65 (0.42 to 1.00)	30/12	1.89 (1.07 to 3.35)	21/21	1.12 (0.72 to 1.74)
Mood Disorder
No	260/1587	1.00 (ref)	862/1567	1.00 (ref)	746/1684	1.00 (ref)
Yes	43/178	0.88 (0.74 to 1.05)	91/164	0.97 (0.81 to 1.16)	89/165	0.94 (0.79 to 1.13)
Substance Abuse Disorder
No	223/1295	1.00 (ref)	718/1301	1.00 (ref)	613/1403	1.00 (ref)
Yes	80/470	1.02 (0.81 to 1.15)	235/430	0.98 (0.87 to 1.10)	222/446	0.95 (0.85 to 1.07)
Anxiety Disorder
No	278/1635	1.00 (ref)	886/1626	1.00 (ref)	776/1734	1.00 (ref)
Yes	25/130	1.09 (0.89 to 1.33)	67/105	1.01 (0.82 to 1.26)	59/115	1.08 (0.87 to 1.33)
Other Mental Health Disorders
No	286/1642	1.00 (ref)	901/1613	1.00 (ref)	784/1729	1.00 (ref)
Yes	17/123	1.13 (0.93 to 1.38)	52/118	0.98 (0.81 to 1.19)	51/120	1.09 (0.90 to 1.32)

^*Adjusted for age, sex, race, marital status, sponsor service branch, active duty status, tobacco use, comorbidity index, tumor stage, grade, histology, and recurrence. Specific mental disorders were also mutually adjusted.

HR=Hazard Ratio; CI=Confidence Interval

Kaplan-Meier survival curves showed better survival for patients without any mental health disorder than patients with a diagnosis of a mental health disorder (Supplemental Figure 1) (Log Rank P=0.048). In the multivariate Cox regression model adjusting for confounders, pre-existing mental health disorder remained an independent risk factor for mortality (HR=1.11, 95% CI=1.03 to 1.20) (Table 5). Furthermore, the HR was 1.08 for those with one mental health disorder (95% CI, 1.00 to 1.17) and increased to 1.22 (95% CI, 1.08 to 1.37) for those with two or more mental health disorders. When data was analyzed on a specific mental health disorder, the increased mortality was observed for dementia (HR=1.43, 95% CI=1.10 to 1.86) and anxiety disorder (HR=1.20, 95% CI-1.03 to 1.39) (Table 5).

Table 5.

The association between pre-existing mental health disorders and mortality among non-small cell lung cancer patients in the Military Health System (1998–2007)

Mental Health Disorder Variables	No. (Alive/Dead)	Adjusted HR (95% CI)*
Any Mental Health Disorder
No	953/2243	1.00 (ref)
Yes	597/1261	1.11 (1.03 to 1.20)
Number of Mental Health Disorders
None	953/2243	1.00 (ref)
One	423/908	1.08 (1.00 to 1.17)
Two or more	174/353	1.22 (1.08 to 1.37)
Psychotic disorder
No	1542/3472	1.00 (ref)
Yes	8/32	1.18 (0.83 to 1.69)
Dementia
No	1531/3443	1.00 (ref)
Yes	19/61	1.43 (1.10 to 1.86)
Mood Disorder
No	1387/3159	1.00 (ref)
Yes	163/345	1.03 (0.91 to 1.17)
Substance Abuse Disorder
No	1135/2651	1.00 (ref)
Yes	415/853	1.03 (0.95 to 1.12)
Anxiety Disorder
No	1436/3264	1.00 (ref)
Yes	114/240	1.20 (1.03 to 1.39)
Other Mental Health Disorders
No	1436/3296	1.00 (ref)
Yes	114/208	1.04 (0.90 to 1.20)

^*Adjusted for age, sex, race, sponsor service branch, active duty status, tobacco use, comorbidity index, tumor stage, grade, histology, recurrence, surgery, chemotherapy, and radiation treatments. Specific mental disorders were also mutually adjusted.

HR = Hazard Ratio; CI=Confidence Interval

The analysis stratified by tobacco use or comorbidity index is shown in Table 6. Significantly increased mortality associated with mental health disorders was observed among current tobacco users (HR=1.18, 95%CI, 1.04 to 1.33), but not among previous users (HR=1.01, 95% CI, 0.91 to 1.13) or never users (HR=1.29, 95% CI, 0.89 to 1.88). The higher mortality associated with mental health disorders was also observed among patients who did not have comorbidity (HR=1.15, 95%CI, 1.01 to 1.31) and those with low comorbidity index (HR=1.18, 95% CI, 1.01 to 1.39), but not among those with high comorbidity index (HR=1.07, 95% CI, 0.95 to 1.20) (Table 6). However, in these stratified analyses, the 95% CIs were overlapped.

Table 6.

Stratified analysis of pre-existing mental health disorders and mortality among non-small cell lung cancer patients in the Military Health System (1998–2007)

Stratified Variables	Any Mental Health Disorder	No. (Alive/Dead)	Adjusted HR (95% CI)*
Tobacco Use
Never used	No	160/159	1.00 (ref)
	Yes	38/51	1.29 (0.89 to 1.88)
Previous use	No	519/1249	1.00 (ref)
	Yes	274/518	1.01 (0.91 to 1.13)
Current use	No	212/676	1.00 (ref)
	Yes	254/599	1.18 (1.04 to 1.33)
Comorbidity Index Group
0	No	485/1131	1.00 (ref)
	Yes	175/329	1.15 (1.01 to 1.31)
1	No	187/424	1.00 (ref)
	Yes	136/312	1.18 (1.01 to 1.39)
2 or more	No	281/688	1.00 (ref)
	Yes	286/620	1.07 (0.95 to 1.20)

^*Adjusted for age, sex, race, sponsor service branch, active duty status, tobacco use, comorbidity index, tumor stage, grade, histology, recurrence, surgery, chemotherapy, and radiation except for the stratified variable itself

HR = Hazard Ratio; CI=Confidence Interval

Discussion

Our results showed that in MHS, a system providing universal care to all beneficiaries, compared to NSCLC patients without any mental health disorder, patients with a diagnosis of mental health disorder did not present with more advanced disease at diagnosis and were less likely to have unknown information on staging. There were no differences in receipt of cancer treatment between those with and without mental health disorders. However, patients with pre-cancer mental health disorders experienced higher mortality than those without.

Higher mortality of cancer among people with mental health disorders has been reported. Kisely et al. (10) studied all cause-mortality of 135,442 cancer patients, including lung cancer patients, from 1988 to 2007 using Western Australian Cancer Registry and national morbidity data systems and reported increased mortality rates for major cancers in psychiatric patients as compared to sex- and age-matched general population. The rate ratio for lung cancer was 1.24 (95% CI=1.11 to 1.40). Two other studies in the same area observed similar excess lung cancer mortality in people with psychiatric illnesses (1, 11). In another study based on the linked data from death certificates and the mental health system in Ohio, Musuuza et al. (14) reported higher standardized mortality rates (SMRs) of lung cancer among people with mental illness than the general population, with SMRs ranging from 3 to 5 times higher stratified by race and gender, respectively (14). With respect to specific mental health disorders, a French study observed a more than 2-fold increase in the mortality of lung cancer among men with schizophrenia compared to the general population (13). Two other cohort studies identified psychological stress (12) and schizophrenia (21) as significant may exist for the observed associations in these studies. A recent study in veterans reported increased mortality among lung cancer patients with pre-existing depression (31) and depression was associated with poor survival in a small Mexican study (32). It is not clear what underlying factors might be for the observed associations in these studies.

One of the possible factors related to the poor survival of cancer patients with mental illness may be socioeconomic disadvantages, which may limit their access to health care and services, resulting in delayed diagnosis or later cancer stage at diagnosis (15–17, 22), insufficient treatment(16, 18, 23), and therefore poor survival(15, 16, 18, 23). In lung cancer, however, there are few studies examining these possible factors. Sullivan et al. (31) found no association between depression and receipt of surgery, chemotherapy or radiation in a veteran population. Another study restricted to advanced stage veteran patients did not find an association between depression and receipt of chemotherapy (33). The authors concluded that other factors not included in their analysis may have contributed to the poor survival among patients with depression. Nevertheless, in other cancers, multiple large-scale studies have demonstrated that patients with mental health disorders tended to present with later stage tumors and were less likely to receive cancer treatments (16, 18, 23). In a study in Taiwan, Chang et al. (23)found that oral cancer patients with mental illness were less likely to undergo surgery with or without adjuvant therapy than those without mental illness. In the study by Kisely et al. (10), psychiatric patients had a higher proportion of cancer with metastases than the general population. They were also less likely to receive surgery of colorectal, breast and cervical cancers; radiotherapy for breast, colorectal and uterine cancers; and chemotherapy sessions (10). A SEER-Medicare based study (16) found that old colon cancer patients with pre-existing mental health disorders were more likely to be diagnosed at an unknown stage and less likely to have received any treatment (surgery, chemotherapy or radiation therapy) and less likely to receive chemotherapy (stage III patients), suggesting that individuals with mental health disorders may not be able to complete the diagnostic procedures for cancer staging and treatments, likely due to psychosocial and economic barriers to medical care(16).

In contrast to the above previous studies that found patients with mental health disorders were more likely to be diagnosed at an advanced stage or unknown stage and less likely to receive recommended treatment, our study showed that there was no difference in the stage at diagnosis between patients with mental health disorders and those without. Similarly, patients with mental health disorders were less likely to have unknown information on tumor stage. Regarding cancer treatment, with the exception of dementia patients who received less treatment which was largely driven by less surgery, there was no overall difference between those with and without a mental health disorder. The lower likelihood of having unknown stage and the absence of differences in receiving cancer treatments may be attributed to a high accessibility to health care for beneficiaries in MHS, in which there are no or minimum cost barriers to laboratory tests, radiology workup, and cancer prevention and surveillance services (55). Moreover, in early 2000, the MHS launched the initiative of integration behavioral health services into primary care services (56), which have facilitated the care and follow up of beneficiaries with mental health disorders in the system. The integration of mental healthcare into primary care services in MHS may have reduced the treatment disparity generally found in the general population. Consistent with our results, two studies in the Veteran Affairs (VA) system, a system providing care to all beneficiaries, did not observe an association between depression and treatment. A recent study in the VA system also did not find differences in the stage at diagnosis or delay in care for colorectal, urothelial, and head and neck cancer between patients with and without mental health problems(57). The authors concluded that mental health is not a barrier to cancer staging or treatment in the VA system that integrated mental health care and routine health care(57).

While cancer diagnosis and treatment related to health care access and socioeconomic barrier might not account for the survival disadvantage among those with mental health disorder in MHS, unhealthy lifestyles and poor physical health commonly found in patients with mental health disorder may affect survival indirectly(10, 11, 14, 26, 27). In our study population, there were higher percentages of tobacco users and higher percentages of people with comorbidities in the mental health disorder group. However, the decrease in survival among patients with mental health disorders was still observed after adjusting for tobacco use and comorbidity in survival analysis in our study. In addition, we stratified the survival analysis by tobacco use and comorbidity, and the results remained similar between the subgroups, suggesting the effects of factors other than smoking and comorbidity. The second factor is that patients with mental illness may be more likely to commit suicide, which contributes to overall mortality. However, the rate of suicide might not be high enough to account for the difference in survival. Another factor may be the time interval between treatments and treatment frequency. This difference between patients with and without mental health disorders warrants future study. This study only evaluated receipt of treatment, but adherence to treatment recommendations may differ between patients with vs. without mental health disorders, which may contribute to the overall survival difference. Finally, mental health disorders may affect interactions and communications between patients and their providers and patient-provider communications has been shown to influence clinical outcomes in lung cancer patients (21, 58, 59)

Our study was based on the existing cancer registry and medical claims data and thus there are limitations due to the use of such data for research, such as lack of detailed information and inaccurate records found in secondary data sources. Also, the numbers in specific mental health disorder groups were small and thus further research with a larger number of patients is warranted.

In conclusion, our study suggests that health care access and socioeconomic barriers commonly found to be responsible for the poor survival in the studies conducted within the general population may not explain the worse survival among patients with mental health disorders. There may be other factors at play and additional research is warranted to further examine the increased mortality of lung cancer among patients with mental health disorders.