Impact of pre‐existing mental health disorders on the receipt of guideline recommended cancer treatments: A systematic review

Disparities in cancer outcomes for individuals with pre‐existing mental health disorders have already been identified, particularly for cancer screening and mortality. We aimed to systematically review the influence on the time from cancer diagnosis to cancer treatment, treatment adherence, and differences in receipt of guideline recommended cancer treatment.


| BACKGROUND
The burden of cancer is growing rapidly with the World Health Organization reporting 19 million new cancer cases and 9.9 million cancer deaths globally in 2020. 1 The management of co-existent diseases or health problems in people diagnosed with cancer is a major area of evaluation with mental health disorders increasingly recognized as being common in this population. 2 The prevalence of anxiety and/or depression is estimated to be between 20% and 25% amongst patients attending oncology clinics. 3 This is highly relevant in the light of evidence that disparities in access to and outcomes from cancer care have been identified in individuals with a pre-existing Mental Health Disorder (PMHD). 4 Previous research has demonstrated that cancer patients with these disorders are both less likely to undergo cancer screening and to have a higher risk of cancer mortality. 4,5 One meta-analysis found that women with schizophrenia are less likely to receive mammographic screening compared with those without. 5 A US study showed that patients with bipolar disorder, schizophrenia, or other psychotic disorder prior to a breast cancer diagnosis had higher all-cause mortality compared to those without. 6 Another US study found a higher risk for all-cause, cancer-related, and non-cancer-related mortality after 5 years for patients with pre-existing depression compared to those without. 7 In other words, individuals with PMHD have a lower life expectancy, especially those with severe PMHD.
It is known that good management of cancer care leads to a better outcome. However, a few studies including surveys of health professionals have found that the management of cancer care among individuals with PMHD is a challenge. For example, patients may experience diagnosis or treatment delays, have difficulties in adhering to or receipt of appropriate cancer treatment because of the symptoms of mental disorders. 8,9 Poorer adherence could lead to those individuals with PMHD not being allocated to recommended treatment pathways. Therefore, the important questions about the management of cancer in the context of PMHD are to what extent patients experience treatment delays or receive different/less effective treatment regimens compared to those without PMHD.
Such disparities are important to understand as they are likely to have an impact on mortality and morbidity from cancer. 10 Equally, they may also be amenable to intervention if major disparities are evident.
Although some studies have explored the potential impact of PMHD on receipt of guideline recommended cancer treatment, this has not yet been investigated systematically. Furthermore, the impact of PMHD on the timely receipt of treatment or on treatment adherence remains unknown. The purpose of this review is therefore to synthesize the influence of PMHD on the time from cancer diagnosis to treatment, cancer treatment adherence, and differences in receipt of guideline recommended cancer treatment.

| Search strategy and selection criteria
This systematic review aims to investigate the influence of PMHD on (1) the time from a cancer diagnosis to receiving treatment, (2) adherence to cancer treatment and (3) differences in receipt of guideline recommended cancer treatment. PMHD was defined as a mental health-related diagnosis that had occurred and been diagnosed prior to a cancer diagnosis. This study focused on the most commonly diagnosed mental health/psychiatric disorders including schizophrenia spectrum and other psychotic disorders, depressive disorders, anxiety disorders, obsessive-compulsive disorders, bipolar and related disorders, such as mania. 8 We also included trauma-and stressor-related disorders, dissociative disorders, feeding and eating disorders, substance-related and addictive disorders, and personality disorders. 11 However, mental health disorders caused by organic or neurological disorders, such as dementia and other cognitive disorders were excluded. The included and excluded mental disorders are listed in Table 1. All the mental health disorders in each study were determined using administrative health data which included outpatient or emergency department visits, hospital admissions, and physicians' notes (Table 2). (2) they did not include a comparison group; (3) the mental disorder was diagnosed at or after a cancer diagnosis; (4) the mental disorders were defined by self-report questionnaire, or (5) they were case studies, review articles, editorials, qualitative studies, abstracts only or conference proceedings.
The included studies were assessed for quality using the Newcastle-Ottawa Scale (NOS) which consists of eight items with three subscales. 13 The assessment of case-control studies includes case/control definition adequacy and representativeness, comparability of case and control, and ascertainment of exposure. The assessment of cohort studies includes representativeness of exposed/non-exposed cohorts, comparability of cohorts, and assessment of outcomes. The total maximum score is nine. A study scoring equal to or greater than seven is judged to demonstrate high quality and at a low risk of bias, and a study scoring equal to or less than four is low quality 14 and at a high risk of bias.
The studies included were initially selected by YHW and EAD with AA checking them and agreeing the excluded studies. YHW and EAD then extracted data from each study, assessed its quality, and discussed any disagreement with AA to reach a consensus. RS reviewed the findings from the perspective of clinical psychiatry. All authors critically reviewed the manuscript and approved the final version. Table 2 shows the data extracted for each study. Descriptors include year of publication, period of analysis, study country, data sources analyzed, information on study subjects (cancer types and number of patients), mental health disorders (types, definition of PMHD, and duration prior to a cancer diagnosis), study design (measured items and adjusted variables), and main findings. Table 3 shows the NOS assessment for each of the eight items and the total score for each study. We also listed the factors used to adjust analyses in each study in Table 4. These included patients' demographic characteristics (age at the cancer diagnosis, sex, socioeconomic status, race/ethnicity, and geography of residence), disease characteristics (cancer stage, cancer diagnosis method, tumor size, and comorbidity), health coverage, and health provider information.

| RESULTS
We identified 7011 studies from our initial databases searches.
Following application of our inclusion and exclusion criteria, 45 studies (35 studies and 10 additional studies identified by using the snowball method) were included for full text review. Of these, 16 studies were excluded because of (1) a definition of PMHD by selfreport questionnaire, (2) without a comparison group, or (3) a diagnosis of mental health disorder at or after a cancer diagnosis.

| Time from cancer diagnosis to cancer treatments
Three studies, all from the US 15 The third study compared the time duration from a bladder cancer diagnosis to radical cystectomy between individuals with severe PMHD including bipolar disorder, schizophrenia, or other psychotic disorders (n = 726) to those without. 15 It found that the mean time to radical cystectomy was significantly lower for bladder cancer patients with severe PMHD compared to those without (1.5 vs. 3.9 months, p < 0.001). 15

| Cancer treatment adherence
Two studies from Denmark were concerned with adherence to cancer treatment. 19

| Differences in receipt of guideline recommended cancer treatments
Our review identified a total of 25 studies that focused on the treatment of nine main cancer types: breast, prostate, colon, rectum, NSCLC, bladder, head/neck, esophageal and pancreatic cancers (Table 2).

T A B L E 3 NOS scale.
Author   -323 63.2%, p = 0.0024) and less often received chemotherapy (40% vs. 88.7%, p < 0.0001), and guideline recommended cancer treatment (61.8% vs. 79.1%, p = 0.0004), compared with those women without schizophrenia. 16 However, there was no significant difference on radiation therapy (56.2% vs. 75.9%, p = 0.078), hormone therapy (84.2% vs. 90.6%, p = 0.20) and anti-HER2 therapy (50% vs. 81.5%, p = 0.35) between the two groups in that study. 16 Furthermore, one US study showed that women with a pre-existing diagnosis of depression were less likely to receive treatment with curative intent (59.7% vs. 66.2%, p < 0.05). 25 The study from Finland demonstrated that 48% of women without PMHD had received radiotherapy, in contrast to 38% of those with a history of non-affective psychosis, 43% of those with substance use disorder, and 43% of those with a history of mood disorder (p < 0.001). 17 However, one study from Germany showed that women with PMHD tended to receive a mastectomy (OR = 1.43, 95% CI = 0.79-2.60) rather than a breast conserving surgery (OR = 0.70, 95% CI = 0.42-1.17) but the odds were not significant after controlling for age, education, cancer stage, health condition, and health insurance. 18

| Prostate cancer
Two studies from the US focused on men with prostate cancer and reported consistent findings. Men defined as having a pre-existing diagnosis of depression (p < 0.006) or severe PMHD including bipolar disorder, schizophrenia, and other psychotic disorder were less likely to undergo either surgery or radiation therapy with curative intent. 38,39 Men with severe PMHD were less likely to receive surgery (OR = 0.66, 95% CI = 0.49-0.89) and radiation therapy with hormone therapy (OR = 0.81, 95% CI = 0.67-0.98). 38

| Colon and rectal cancers
The three studies evaluating the impact of PMHD in patients diagnosed with colon cancer all found an impact on the likelihood of receiving a guideline recommended therapy. 28 By contrast, the results from studies of rectal cancer were inconsistent. 28,40 One study from Denmark found no difference in the type of treatment received for patients with PMHD and those without (OR = 0.72, 95% CI = 0.46-1.11). 28  One study from Japan demonstrated that patients with colorectal or gastric cancers and pre-existing schizophrenia were less likely to receive invasive treatment (surgical or endoscopic treatment) (OR = 0.77, 95% CI = 0.69-0.85). 41

| Non-small cell lung cancer
The five studies of patients with NSCLC found inconsistent results. 30

| CONCLUSION
This study reveals evidence of a clear disparity in the receipt of guideline recommended cancer treatment for individuals with PMHD across different cancer types. To reduce the disparity and improve the outcomes of cancer care for patients with PMHD, a personcentered approach involving multidisciplinary professionals should be provided.

AUTHOR CONTRIBUTIONS
The studies included in this systematic review were initially selected