Lung cancer symptom appraisal, help‐seeking and diagnosis – rapid systematic review of differences between patients with and without a smoking history

Lung cancer is the leading cause of cancer death in the world. A significant minority of lung cancer patients have never smoked (14% in the UK, and ranging from 10% to 25% worldwide). Current evidence suggests that never‐smokers encounter delays during the diagnostic pathway, yet it is unclear how their experiences and reasons for delayed diagnoses differ from those of current and former smokers. This rapid review assessed literature about patient experiences in relation to symptom awareness and appraisal, help‐seeking, and the lung cancer diagnostic pathway, comparing patients with and without a smoking history.


| INTRODUCTION
Lung cancer is the leading cause of cancer death in the world. 1 Patients who have never smoked represent approximately 14% of UK lung cancer cases, 2 while worldwide this varies from 10% to 25%. 3 To put this into perspective, when measured as a separate cancer, lung cancer in never-smokers is the seventh most prevalent cancer in the world 4 ; and the eighth most prevalent cause of cancer-related death in the UK; higher than cervical cancer, ovarian cancer, leukaemia, and lymphoma. 2,5 Low net-survival of lung cancer is often attributed to late-stage detection; treatment can offer encouraging prognosis when lung cancer is detected at an earlier stage. 6,7 However, the majority of patients are still diagnosed when their lung cancer has advanced to stage III/IV 6 where one-year net-survival is poorest. 8,9 There are a number of potential differences between lung cancer patients who have never smoked (hereafter referred to as 'neversmokers') and those who are currently or have previously smoked ('ever-smokers'). First, there are biologically distinct pathways towards lung cancer caused by tobacco smoking compared with other exposures or genes. Tobacco smoke damages the DNA in lung epithelial cells, leading to tumour development and progression. 10,11 In contrast, never-smokers' cancers are more likely to be caused by environmental substances (e.g. pollution), occupational substances (e.g. carcinogenic chemicals) or genetic predisposition. 12 These differences in aetiology contribute to different forms of cancer. Eversmokers have higher levels of squamous cell lung cancers that grow in the centre of the lungs (bronchi) compared to never smokers who are more likely to have adenocarcinomas that grow in the outer part of the lung. 13,14 This can mean that never-smokers are less likely to experience noticeable symptoms at an early stage of disease, which is likely to contribute to delays in diagnosis.
Second, never-smokers may assume that they are not at-risk of lung cancer and have an amplified tendency to attribute symptoms to other acute conditions. 15 For example, they are less likely to recognise breathlessness as a potential symptom of lung cancer compared to those with a smoking history. 16 This may be due to international public health efforts to reduce the burden of lung cancer, primarily targeted via anti-smoking educational campaigns. 17,18 This has resulted in widespread public awareness of the link between lung cancer and tobacco exposure, as well as stereotypical views of who is likely to get lung cancer, but potentially obscured the fact that never smokers can get lung cancer too.
Third, healthcare professionals in the diagnostic pathway may display a detection bias against pursuing a diagnosis of lung cancer in never-smokers until other diagnoses have been excluded. 19 Although never-smokers make up a significant proportion of lung cancer cases, not much is known about this population.
Responding to an urgent need for information about the experience of lung cancer patients who have never smoked, we designed the PEARL study (Patient Experience of symptoms, help-seeking And Risk factors in Lung cancer in never smokers). The first part of the study is this rapid review, synthesizing evidence relating to experiences of the pathway to diagnosis for patients with-and without a smoking history. This will inform a qualitative study that will aim to generate targeted recommendations to reduce delays in diagnosis of lung cancer in patients who have never smoked.
The Model of Pathways to Treatment (MPT) is a framework that can be used to understand intervals and structure research findings across the cancer patient pathway: including Symptom Appraisal, Help-seeking, Diagnosis and Pre-treatment (see Figure 2). 20 This framework promotes greater consistency (e.g. in terms of defining intervals) across early diagnosis research, allowing comparisons to be made with existing literature, as well as ensuring consideration of range of patient (e.g. comorbidities), healthcare system (e.g. access) and disease factors (e.g. tumour type).
The MPT 20 was used in this study to categorise the experiences of patients into chronological order using the intervals, with a particular focus on findings that may explain or contribute towards delays in the pathway to diagnosis for never-smokers.

| Research aims
To our knowledge, there has been no review of literature investigating the pre-diagnostic experiences of lung cancer patients who have never smoked. The current review aims to provide a narrative synthesis comparing the experiences of never-smokers and eversmokers. Additionally, the review will examine how any experiences unique to never-smokers may impact on, or introduce, delays in the pathway to diagnosis of lung cancer.
The research questions guiding this review were: � What are the symptom appraisal and help-seeking experiences of patients diagnosed with lung cancer, who have never smoked?
� How does this experience compare with the experience of patients with lung cancer who have smoked?
� How do the social and life histories of people prior to the development of lung cancer, particularly for never smokers, impact on their presentation and diagnosis? 2 | METHODS

| Rapid review
A rapid review methodology was chosen, as this is a systematic approach to synthesise current literature, which can provide a timely and conclusive answer in relation to the direction and strength of current evidence. 21 This will provide a foundation for the urgent subsequent planned work that will investigate experiences of the pathway to lung cancer diagnosis of patients who have never smoked.

| Eligibility criteria
Both qualitative and quantitative studies that met each of the inclusion criteria displayed in Table 1 were included in this review.
The review includes studies from any country/healthcare system, and studies that looked at actual as well as hypothetical symptom appraisal and help seeking. In terms of smoking history, we only selected studies that had samples that included both never-smokers and those with a smoking history, with a particular focus on differentiating the experiences of lung cancer patients by smoking status, or directly comparing experiences of never-smokers and eversmokers.
Studies were screened by abstract and full text for eligibility (see Table 1) by two reviewers (AS and SvO) independently; disagreements regarding final study selections were resolved by discussion.

| Quality appraisal
Two reviewers (AS and SvO) then assessed the methodological quality of the included studies independently using the Mixed Methods Appraisal Tool (MMAT), 24 which can concomitantly assess qualitative, quantitative and mixed-methods studies. Criteria assessed studies' methodological quality, analysis and interpretation of results using a simple 'Yes', 'No' or 'Can't tell' rating system. Differences were resolved by consensus with separate criteria for qualitative and quantitative studies. All evidence from studies that were included in the final analysis was treated equally.

| Data charting and analysis
The MPT 20 was used to categorise the experiences of patients into chronological order using the intervals. Data were extracted from articles that identified experiences unique to never-smokers or provided a direct comparison of experiences between smoking statuses, across any of the MPT intervals. This included: patient appraisal of lung cancer symptoms, interactions with healthcare professionals at any stage of the pathway, experiences of primary and secondary care, and experiences of stigmatisation. Data extraction prioritised any findings that may explain or contribute towards delays in the pathway to diagnosis for never-smokers.

Inclusion Exclusion
Qualitative/quantitative data Systematic/Scoping/Rapid review, editorials, books, dissertations and commentaries Published & peer-reviewed Full-text unavailable Due to the wide range of research designs included in the final analyses, and the rapid design of this review, a meta-analysis was not appropriate for data synthesis. Instead we carried out a narrative synthesis, a common alternative for the reporting of findings used in systematic reviews. 25 To limit the influence of reviewer bias, guidance outlined by the UK Economic and Social Research Council 26 was used throughout to direct data synthesis. Back-chaining of retrieved articles identified another 12 articles.

| RESULTS
After a full-text review of these 45 articles, 35 articles were excluded leaving seven quantitative studies and three qualitative studies.

| Study quality
All 10 studies passed the MMAT screening questions, and were taken through the full MMAT quality assessment (see Supporting Information for full MMAT results).
(2019) 31 included only a small proportion of never-smokers (5.7% of total sample). We were unable to examine non-response bias for three studies 29,31,32 as they did not report characteristics of nonresponders.

| Narrative synthesis
Once extracted, findings were categorised into the MPT intervals ( Figure 2) and themes were constructed. These themes are presented in this results section organised by MPT interval. factors and symptoms, which in turn may encourage earlier helpseeking amongst never-smokers.

| MPT help-seeking interval
Theme 2: Lack of evidence in relation to help-seeking amongst neversmokers/no clear evidence for differences.
Only one study reported on the help-seeking experiences of never-smokers. 27 No significant differences were found in the time from symptom onset to medical help-seeking behaviour between those with and without a smoking history. 27 No qualitative studies focused on help-seeking experiences of never smokers specifically.

| MPT diagnosis interval
Theme 3: Delayed diagnosis amongst never-smoker patients/What is driving diagnostic delays amongst never-smoker patients?
One quantitative paper assessed the differences in disease stage at diagnosis between never smokers and those with a smoking history. 35 Never-smokers were more likely to be diagnosed at a later stage, however, from the data collected it is impossible to identify whether this can be attributed to delays at the appraisal, helpseeking or diagnostic intervals. 35 Theme 4: HCP detection bias may contribute to late diagnosis of never-smokers.
The strong association between smoking and lung cancer was suggested to be a cause of clinical bias, 33

| MPT pre-treatment interval
Theme 5: Never-smokers report lower satisfaction with the care they receive.
The current literature does not report any statistically significant differences in anxiety, worry and health environment perceptions between ever and never-smokers. 31 However, Weiss et al. measured satisfaction with care and found that never-smokers rated their satisfaction lower than ever smokers. 32 There is also evidence that the association between feelings of personal responsibility and depressive symptoms, satisfaction with healthcare and psychological needs were significantly higher for never smokers than ever smokers. 30 The authors suggest that this may be due to never smokers attributing their cancer to personal traits (e.g. character flaws) or external factors (e.g. a partner who smokes), which makes them more likely to experience poor psychological outcomes.

| DISCUSSION
The findings of this review highlight that evidence about differences between lung cancer patients who have never smoked and patients with a smoking history is concentrated in the appraisal and diagnostic intervals, and that evidence in relation to help-seeking and GP referral is lacking (see Figure 2).
The unequivocal causal link between tobacco use and lung cancer risk, and resulting tobacco-centric/exclusive models of risk and referral have had a number of unintended consequences for patient, HCP and system behaviour resulting in delayed diagnosis. These include underestimated perceived lung cancer risk and misattribution of symptoms among never-smokers, and HCPs being less likely to consider lung cancer in never-smokers due to detection bias. Indeed, while longitudinal data suggest current smokers adopt riskminimising beliefs as a strategy to resolve cognitive dissonance, 37 there is evidence of a general tendency to underestimate one's relative risk of lung cancer (when compared with others) among former and never smokers too. 38 Furthermore, we found a small amount of evidence that suggests that never smokers experience lower satisfactions with healthcare, which is related to feelings of personal responsibility and may also relate to comparisons with other non-smoking-related cancers, where prognosis is better.

| Strengths and limitations
An effective rapid review must strike a balance between 'accelerating' its methods whilst maintaining rigour. This was applied in the current review to identify when and how never-smokers are most at risk of delayed diagnosis. Although rapid, this review utilised PRISMA guidelines to ensure a systematic process was followed. 22 Furthermore, the utilisation of a theoretical framework (MPT) provided structure to allow clear comparison of outcomes of the different studies included in this review. 20

| Implications
The findings of this study provide a number of implications for theory, research, and practice:

| Research
This review highlights a paucity of evidence in relation to the experiences of never-smokers during the appraisal, help-seeking and diagnosis intervals, and evidence differentiating the patient experiences of those with different types of lung cancers. This is particularly the case for those cancers more likely to occur in never-smokers (adenocarcinomas or mesotheliomas) and that may lead to different symptom experiences/profile of symptoms. Future research should focus its efforts in three areas: (1) Explore drivers of symptom awareness, symptom appraisal and propensity to act in HCPs and never-smokers in response to (potential) lung cancer symptoms.
(2) Development and testing of interventions based on findings of the above.

| Practice
We suggest that patients with known lung cancer risk factors such as exposure to industrial and environmental hazards (e.g. second-hand smoke) should have this information collected by, and flagged on, electronic health records, in order to prompt HCPs to consider lung cancer risk in consultations. Decision aids (e.g. in the UK; NICE guideline for referral of suspected cancer 41 and QCancer risk calculator 42 ) include little or no information about non-smoking risks (although NICE guidance includes asbestos exposure). These tools could be refined to consider the common risks for never-smokers. In addition, an increased awareness amongst HCPs that, albeit rarely, lung cancer can occur in people who do not have any of the known risk factors (e.g. due to genetic mutations) will help ensure that these patients are referred for further tests once more common potential explanations for their symptoms have been ruled out.

| Public health
This review suggests that from a public health perspective, public awareness of lesser-known lung cancer risk factors (e.g. radon exposure) needs to be improved, as well as awareness that people without these risk factors can still get lung cancer. For instance, in a population-based survey Simon et al. 43 identified that the majority of the UK population could only identify one risk factor for lung cancer, the most commonly reported factor by a large margin being smoking. affect patient outcomes. These findings highlight that clinical tools and public health campaigns need to strike a balance between explaining the dangers of smoking, and raising awareness of lung cancer in never-smokers, in order to promote appropriate helpseeking and referral of never-smokers. Improved understanding of the clinical utility of non-smoking risk factors of lung cancer, as well exploration of symptom awareness, appraisal and help-seeking of people who have never smoked, are important next steps in improving lung cancer outcomes for never-smokers.