Original Article
Depressive Symptoms Predict Head and Neck Cancer Survival: Examining Plausible Behavioral and Biological Pathways Lauren A. Zimmaro, MA1; Sandra E. Sephton, PhD1,2; Chelsea J. Siwik, BA1; Kala M. Phillips, MS1; Whitney N. Rebholz, PhD 3; Helena C. Kraemer, PhD4; Janine Giese-Davis, PhD5,6,7; Liz Wilson, BSN2,3; Jeffrey M. Bumpous, MD2,3; and Elizabeth D. Cash, PhD 1,2,3
BACKGROUND: Head and neck cancers are associated with high rates of depression, which may increase the risk for poorer immediate and long-term outcomes. Here it was hypothesized that greater depressive symptoms would predict earlier mortality, and behavioral (treatment interruption) and biological (treatment response) mediators were examined. METHODS: Patients (n 5 134) reported depressive symptomatology at treatment planning. Clinical data were reviewed at the 2-year follow-up. RESULTS: Greater depressive symptoms were associated with significantly shorter survival (hazard ratio, 0.868; 95% confidence interval [CI], 0.819-0.921; P < .001), higher rates of chemoradiation interruption (odds ratio, 0.865; 95% CI, 0.774-0.966; P 5 .010), and poorer treatment response (odds ratio, 0.879; 95% CI, 0.803-0.963; P 5 .005). The poorer treatment response partially explained the depression-survival relation. Other known prognostic indicators did not challenge these results. CONCLUSIONS: Depressive symptoms at the time of treatment planning predict overall 2-year mortality. Effects are partly influenced by the treatment response. Depression screening and intervention may be beneficial. Future studies should examine parallel biological pathways linking depression to cancer survival, including endocrine C 2018 American Cancer Society. disruption and inflammation. Cancer 2018;124:1053-60. V KEYWORDS: depression, head and neck cancer, residual tumor, survival.
INTRODUCTION Patients with head and neck cancer endorse a wide range of depressive symptomatology. They experience rates of clinical depression higher than those of the general population, and they have some of the highest rates among cancer patients.1 Depression has been shown to predict early mortality across a number of different cancers.2,3 A meta-analysis examining multiple cancer types found that depressed patients may have a 26% to 39% greater mortality risk than their nondepressed counterparts.4 The converse is also supported because decreasing depression levels predict improved survival among metastatic breast cancer patients.5 Burgeoning evidence supports the relation between depression and early mortality among patients with head and neck cancer as well. Studies examining mixed head and neck tumor sites have revealed depressive symptoms to be prognostic for 2- and 3-year overall survival.6,7 Depression has also been shown to predict 5-year overall survival for patients with advanced-stage oropharyngeal cancer.8 A recent epidemiological analysis using Surveillance, Epidemiology, and End Results data from 3466 patients with head and neck cancer demonstrated significantly elevated mortality rates for cancer patients diagnosed with depression.9 In contrast, 2 previous studies reported nonsignificant associations between depressed mood and survival in head and neck samples.10,11 However, the assessments may have been less sensitive12 or may not have provided valid or reliable assessments of depression in the samples.13 There are limited pathways by which psychosocial factors, including depression, may affect cancer survival. These include the receipt of treatment (adherence), biological pathways (eg, the tumor-host biology interaction),5 and aspects of preventative self-care such as diet, exercise, and smoking.2 Cancer patients with depression may face additional obstacles related to depressive symptoms, such as low motivation, which may manifest in behavioral difficulties in attending scheduled treatment appointments. Up to 70% of patients with head and neck cancer experience an interruption in treatment,14 and patients with head and neck cancer suffering from depression have triple the odds of noncompliance with medical treatment recommendations.15 Patients with laryngeal tumors who experienced a 5- to 30-day interruption in treatment had a 68% increased risk of mortality in comparison with patients with no unscheduled interruptions.16 Corresponding author: Elizabeth D. Cash, PhD, Department of Otolaryngology–Head and Neck Surgery and Communicative Disorders, University of Louisville School of Medicine, 529 South Jackson Street, 3rd Floor ENT Suite, Louisville, KY 40202;
[email protected] 1 Department of Psychological and Brain Sciences, University of Louisville, Louisville, Kentucky; 2James Graham Brown Cancer Center, Louisville, Kentucky; 3Department of Otolaryngology–Head and Neck Surgery and Communicative Disorders, University of Louisville School of Medicine, Louisville, Kentucky; 4Department of Psychiatry and Behavioral Sciences, Stanford University Medical Center, Stanford, California; 5Alberta Health Services Center Care (Holy Cross Site), Calgary, Alberta, Canada; 6Division of Psychosocial Oncology, Department of Oncology, Faculty of Medicine, University of Calgary, Alberta, Canada; 7Department of Psychology, University of Calgary, Calgary, Alberta, Canada
DOI: 10.1002/cncr.31109, Received: August 16, 2017; Revised: September 25, 2017; Accepted: October 10, 2017, Published online January 22, 2018 in Wiley Online Library (wileyonlinelibrary.com)
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Furthermore, patients with head and neck cancer who have moderate to severe pretreatment depression ratings exhibit lower rates of chemoradiation completion.17 The issue of radiotherapy and chemotherapy adherence is complicated by many factors, including patient education, difficult side effects, extended treatment times, and patient-provider relationships.18 Depressed patients’ greater difficulty in attending scheduled treatments is likely to result in worse treatment outcomes. Difficulty in coping with negative affect, which is common in depression, may lead to a higher propensity to engage in highrisk behaviors such as continued tobacco use after the cancer diagnosis, a poor diet, and poor sleep.19 Depression and survival may also be linked via biological pathways. Depression may accelerate cancer progression via endocrine and immune changes that result in tumor promotion.2,5,19 For example, autonomic sympathetic activation modulates gene expression in immune cells in the tumor microenvironment, and this results in the promotion of metastasis, inflammation, angiogenesis, and suppression of cellular immune responses that combat tumor progression.20 Research has begun to examine the mechanisms by which depression or depressive symptoms may be linked with survival outcomes.21-23 These studies support the notion that endocrine and inflammatory pathways may underlie the depression–cancer survival associations. In clinical settings, paying special attention to depressive symptoms may be warranted among patients with head and neck cancer because of elevated depressive symptom reports1 and potential downstream effects of depression on tumor progression.24 This highlights the need for more prospective research that will allow an examination of potential behavioral pathways (treatment adherence and other health-related behaviors) and biological pathways of the effects of depression in head and neck cancer. The current study explored 2 of these pathways with a longitudinal design that measured depressive symptoms at the outset of treatment and subsequently recorded the presence of treatment attendance interruptions, the treatment response, and the survival time. We used a measure of depressive symptoms that has demonstrated high sensitivity among patients with head and neck cancer12 and administered this measure early in the treatment planning phase. We hypothesized that patients who presented at treatment planning with greater depressive symptoms would experience significantly shorter overall cancer survival. To then elucidate 2 possible behavioral and biological pathways by which depression may influence cancer survival, we examined data from a cohort of 134 patients 1054
with head and neck cancer over an approximately 2-year period. For the behavioral pathway, we focused on the role of an interruption to scheduled treatment, and for the biological pathway, we tested the role of the tumor response to treatment in the depression-survival relation. MATERIALS AND METHODS Participants and Procedures
We reviewed all patients presenting to our institutional multidisciplinary head and neck cancer clinic from October 2012 to October 2013. This study received approval from our institutional review board with a waiver of informed consent. Patients completed depression assessments upon presentation to the multidisciplinary clinic for radiation and/or chemotherapy treatment planning. Patients had typically received notification of their biopsy-proven diagnosis 1 to 4 weeks before presentation, with some of the sample (39%) already having undergone surgical procedures to confirm the extent of the malignancy or for extirpation. Of the 244 patients referred to our clinic during the 1-year study period, 134 patients were included in the current analysis. The 110 remaining patients either did not return psychometric data (n 5 101) or were patients of the Veteran Affairs system or incarcerated (ie, they could not be included in the research; n 5 9). There were no differences in age, site, or stage of disease between the patients who were included and the patients who were not included in this data set. Measures Clinical variables
Patient demographics, including age, sex, race, and alcohol and smoking history, were collected from intake forms. The American Joint Commission on Cancer staging at the time of presentation was determined with all available clinical, pathologic, and radiographic data. The viral status of oropharyngeal cases was determined from either human papillomavirus (tested by in situ hybridization) or p16 (immunohistochemistry) results. The tumor location was classified into 1 of 5 categories: oral, oropharyngeal, laryngeal, hypopharyngeal, or other (eg, neck disease/tumors of unknown origin, thyroid, or skin). Medical records were reviewed after all participants had completed treatment, and they yielded data on radiotherapy or combined treatment (radiotherapy plus chemotherapy), appointment attendance, the clinical response of the tumor to treatment, and 2-year survival outcomes. A treatment interruption was defined as a dichotomous indicator of 3 or more consecutive days without treatment. This allowed weekends to be Cancer
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considered as intentional gaps.14 Fourteen patients (10.5%) had at least 1 interruption of treatment according to this criterion. A dichotomous indicator of the treatment response was calculated. Patients were coded as poorly responsive if there was clinical or radiological evidence of the persistence of disease, tumor presence, or early recurrence observed 3 months after treatment. Otherwise, patients were coded as responsive to treatment. Overall survival was calculated from the date of study entry, which was also the date at which patients visited physicians to undertake planning for their cancer treatment (radiotherapy or combined chemoradiation). Depression
Depressive symptoms were measured at the time of study entry, before radiotherapy/chemotherapy treatment commenced, with the depression subscale of the Hospital Anxiety and Depression Scale (HADS).25 The HADS is a 14-item measure divided into 2 subscales (anxiety and depression). Total subscale scores range from 0 to 21. Scores 8 are indicative of clinically significant symptomatology. The HADS has previously been used with patients with head and neck cancer,26,27 and it has demonstrated the highest screening accuracy in comparison with other depression measures for patients with head and neck cancer.12 Statistical Analyses
Descriptive and summary statistics characterized clinical and demographic features. Before analyses, independent variables were centered,28 and all statistical assumptions were met. Primary hypothesis
The relation between depressive symptoms and overall survival was examined with a Cox proportional hazards model. Secondary hypothesis: possible mediators
Separate logistic regressions tested relations between depressive symptoms and treatment interruption and treatment response. Tests of mediation on the relation between depression and survival were then performed with the MacArthur approach,29 in which predictors were centered and interaction terms were included. To show that B mediates A on C, it must be shown that A, B, and C happen in that order, that A and B are correlated, and that B explains all (complete) or part (partial) of the association between A and C. In a linear model, that means that the main effect of B, the interaction between A and B, or both are statistically significant. Cox models were Cancer
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TABLE 1. Clinical and Demographic Characteristics (n 5 134) Characteristic Age at diagnosis, median/mean (SD), ya Male sex, No. (%) Race, No. (%) Non-Hispanic white African American Asian Pack-years, median/mean (SD)b Disease site, No. (%) Oral Oropharyngeal HPV-positive HPV-negative HPV status unknown Laryngeal Hypopharyngeal Other Summary stage, No. (%) I II III IV Recurrent Treatment received, No. (%) No data or observation only Surgery only Surgery plus radiation Radiation alone Radiation plus chemotherapy HADS depression score, median/mean (SD)c Above clinical cutoff (8), No. (%) Treatment interruption, No. (%) Total treatment interruption, median/mean (SD), dd Treatment response, No. (%)e Deaths at 2-y follow-up, No. (%) Overall survival at 2 y, median/mean (SD), df
Value 60.6/61.2 (13.0) 99 (73.9) 113 20 1 30.0/36.9
(84.3) (14.9) (0.7) (24.9)
19 (14.2) 20 (14.9) 8 (6.0) 7 (5.2) 22 (16.4) 4 (3.0) 54 (40.3) 21 10 22 50 31 6 5 18 44 61 5.0/5.9 45 14 3.5/7.6 25 39 589.5/496.4
(21.4) (9.7) (21.4) (48.5) (23.1) (4.5) (3.7) (13.4) (32.8) (45.5) (4.9) (33.6) (10.4) (12.4) (18.7) (29.1) (239.3)
Abbreviations: HADS, Hospital Anxiety and Depression Scale; HPV, human papillomavirus; SD, standard deviation. a The range was 22 to 87 y. b The range was 1.5 to 120 years. c The range was 0 to 20. d The range was 1 to 42 days. e Evidence of disease at completion. f The range was 11 to 730 days.
constructed to include entry depressive symptoms, postentry treatment interruption or treatment response, and the interaction between the two. Secondary hypothesis: possible proxies
Spearman rank correlations were used to assess the contributions of traditional prognostic indicators, including the cancer stage, site of disease, age at diagnosis, sex, race, marital status, and tobacco history in pack-years. Those that correlated with both depression and survival were considered possible proxies according to the MacArthur definition.30 When this occurred, Cox models were constructed to include the entry depressive symptoms, the possible entry proxy, and the interaction between the two. 1055
Original Article TABLE 2. Associations Between Depressive Symptoms, 2-Year Overall Survival, and Potential Behavioral and Biological Mediators
Secondary hypothesis: possible mediators
Survival Analysis: Depressive Symptoms Predictor
B
df
P
Hazard Ratio
95% CI
Depression
–0.141
1
.060). The stage was classified as early (summary stages I and II), advanced (summary stages III and IV), or recurrent to meet analytic assumptions. The Cox proportional hazards model was rerun with depressive symptoms, summary stage, and their interaction entered to test whether the finding of poorer survival among those with higher depressive symptoms would remain. Depressive symptoms remained a significant predictor of overall survival. DISCUSSION Depressive symptoms before chemoradiation treatment predict shortened survival among patients with head and neck cancer. Our findings are consistent with recent studies showing that depression predicts early mortality among patients with head and neck cancer.6-9 Although we found that depressive symptoms were associated with increased treatment disruption, we did not find evidence that this mediated survival, likely because of the low percentage of patients with treatment disruption. However, Cancer
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Figure 1. To aid the understanding of the statistically significant interaction between depressive symptoms and treatment response (ie, for descriptive and not statistical purposes), patients were split into 6 groups according to their depressive symptom scores (none, mild/moderate, or above the clinical cutoff) and the response of their tumor to radiation/combined treatment (complete response or poor response). Kaplan-Meier curves depict all-cause mortality for each of these groups. Depressive symptoms were measured at the treatment planning visit with the Hospital Anxiety and Depression Scale. The scores were 0 for no symptoms, 1 to 7 for mild to moderate symptoms, and 8 for clinically significant symptoms. The response to treatment was assessed after the completion of radiotherapy or combined treatment, and it was categorized as complete (no evidence of disease) or poor (some evidence of disease present). No deaths occurred among patients who reported no depressive symptoms. Thus, the 2 survival curves for these patients (no depression plus a complete response and no depression plus a poor treatment response) overlap.
we documented 1 plausible mediating pathway of the depression-survival relation via the response of the tumor to treatment. Our data demonstrated that patients with greater depressive symptoms were significantly more likely to experience interruptions in treatment attendance despite the low number of patients who experienced such interruptions (ie, 14 of 134). However, in our study, treatment interruptions could not be shown to mediate the relation between depression and overall survival. Responses to individual items on the HADS suggested that although patients scored highest on the item “I feel as if I am slowed down,” it may be that the levels of this symptom were not high enough to significantly interfere with attendance at scheduled treatment appointments. Alternatively, because of the low number of patients with treatment interruptions and their various antecedents, the ability to detect effects on survival was likely underpowered. Thus, future research with larger sample numbers of events should continue to explore the hypothesis that treatment interruptions may be related to both depression and medical outcomes. Cancer
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Importantly, several findings were observed when we tested the biological pathway. First, depressive symptoms were significantly related to treatment response. To our knowledge, this is the first study to test the impact of depression on head and neck tumor responses to treatment. Second, when depression and treatment response were entered simultaneously into the survival model, depressive symptoms remained a significant prognostic factor that was partially mediated by treatment response. Thus, it is possible that biological processes can partially explain the effect of depression on treatment response. In our sample, only 4 of the patients who experienced a treatment interruption demonstrated a poor treatment response (ie, clinical or radiographic evidence of disease after treatment completion). The correlation between treatment interruption and treatment response was also small (Spearman r 5 0.281). This suggests that these 2 variables may be independent and supports the notion that depressive symptoms may adversely affect host defenses even for the compliant patient. In light of the impact on overall cancer mortality demonstrated by this study and previous studies, the mechanisms of 1057
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depression deserve further elucidation and are especially relevant to cancer control. One plausible mediator of depression, immune disruption, has garnered substantial research attention in the health care context. Depression is associated with systemic inflammation31,32 and higher levels of the proinflammatory cytokines interleukin 6, interleukin 1, and C-reactive protein.33,34 The relation between depression and hypothalamic-pituitary-adrenal axis dysregulation has also been well established35; depression has been associated with hypersecretion of the hormone cortisol,36 a blunted cortisol awakening response,37,38 and flattened diurnal cortisol profiles.32 In the cancer context, chronic inflammation has been established as a contributor to cancer progression,39,40 and flattened diurnal cortisol profiles have predicted shortened survival in examinations across a number of cancer types.23,41-43 Taken together, these biological processes likely decrease the host’s ability to fight tumors effectively and potentially impede the response to medical treatment. These biological pathways may run parallel to the effects of depression and warrant further attention because depression remained a significant and independent predictor of survival in our study. Our study underlines several important clinical implications. First, although the cancer stage at the time of diagnosis was associated with depressive symptoms and overall survival, depression appeared to be as important a predictor of survival as traditional clinical prognostic indicators. Among early-stage, late-stage, and recurrent disease cases, higher levels of depressive symptoms consistently predicted earlier mortality. Similar findings were observed by Lazure et al6 and Kim et al,7 who adjusted for clinical factors (including the stage) and found depression to be related to disease-free and overall oropharyngeal cancer survival. Similar research evaluating the effects of treatment interruption also has not demonstrated effects of the patient’s age, sex, or race, primary tumor site, or summary stage on treatment outcomes.44 Thus, an important point remains: depressive symptoms may be as powerful as the clinical features that health care professionals typically use as prognostic indicators for patients with head and neck cancer. This finding strengthens the importance of screening for depressive symptoms in all patients with head and neck cancer, particularly during the cancer treatment planning phase. Second, 67.2% of the participants in this study endorsed depressive symptoms at or below a score of 8 on the HADS depression subscale, the identified cutoff for clinically significant symptomatology. This emphasizes the importance of capturing or attending to subclinical 1058
symptoms of depression in patients with head and neck cancer because they may significantly influence overall survival. Our data are similar to those of other head and neck cancer samples in which the majority of patients also endorsed subclinical depressive symptomatology.6,8,10 Thus, our data highlight the importance of screening for depression among all patients with head and neck cancer. This information may then be used to facilitate discussions with patients and expedite the development of targeted behavioral interventions by psycho-oncologists or behavioral oncology specialists. Lastly, our study may serve to inform future research regarding depression treatment and medical outcomes. Although some evidence indicates that psychological interventions may be associated with improved cancer treatment outcomes,5,45 no studies to our knowledge have investigated the potential for a depression intervention to specifically affect medical treatment outcomes among patients with head and neck cancer. The need for advancements in psychosocial care with the potential to affect cancer survivorship has recently been highlighted46 because evidence-based psychosocial treatments have high potential to complement biomedical treatment efficacy.47 Several limitations exist in the current study. First, not all patients in this sample could be considered completely treatment-naive because some had already undergone a surgical procedure before presentation for definitive radiation or combined therapy treatment planning. Second, only a few patients experienced treatment interruptions directly related to psychosocial factors. Some suggest that treatment interruptions less than or equal to 5 days do not detectably influence outcomes.14,48 Direct toxic effects of radiation therapy were also not specifically examined; thus, their role in unscheduled treatment interruptions is unknown. Third, pathological or radiological confirmation of the disease status after the completion of treatment was also not readily available for some of the cases. We also did not have complete information on causes of death available. Head and neck cancer morbidity is often associated with disease burden (eg, refractory or advancing tumors, aspiration, and carotid infiltration). However, competing causes cannot be ruled out. These are important to consider because they may account for up to one-third of deaths in some head and neck cancer samples.49 Although this study was more than sufficiently powered to detect effects of depressive symptoms on overall survival, replication in a sample with a more substantial number of plausible mediating events (eg, treatment interruptions) would be useful in clarifying Cancer
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nuanced relations between depressive symptoms and medical and biological factors. Overall, patients with head and neck cancer experiencing greater depressive symptoms demonstrate poorer overall survival as well as a greater risk for treatment interruptions and poorer therapeutic responses. The treatment response may partly mediate the relation between depression and survival. These findings highlight the need for a careful assessment of depressive symptoms among patients with head and neck cancer preparing to undergo treatment, which may help to identify patients who may be at risk for an incomplete therapeutic response and poorer long-term outcomes. FUNDING SUPPORT A portion of this work was supported by a grant from the National Cancer Institute (grant R25 CA134283-06).
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
AUTHOR CONTRIBUTIONS Lauren A. Zimmaro: Data collection, analysis, and interpretation and manuscript preparation. Sandra E. Sephton: Study design, data interpretation, and manuscript preparation. Chelsea J. Siwik: Data interpretation and manuscript preparation. Kala M. Phillips: Data interpretation and manuscript preparation. Whitney N. Rebholz: Data collection, data interpretation, and manuscript preparation. Helena C. Kraemer: Data interpretation and manuscript preparation. Janine Giese-Davis: Data interpretation and manuscript preparation. Liz Wilson: Study design and data collection. Jeffrey M. Bumpous: Study concept and design and manuscript preparation. Elizabeth D. Cash: Study concept and design; data collection, analysis, and interpretation; and manuscript preparation.
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