Social determinants of health in studies using PROMs to assess toxicities associated with immune checkpoint inhibitor treatment: a systematic review.

Introduction
Immunotherapy with immune check point inhibitors (ICIs) has become a standard systemic treatment for cancer and has been proven to improve survival across many different types of cancer [1, 2]. However, immunotherapy treatment can potentially cause a unique spectrum of severe and potentially life-threatening toxicities known as immune-related adverse events (irAEs) presenting as various symptoms across different organs and body systems [3–5]. This underlines the importance of early recognition of toxicity to initiate treatment and prevent harmful consequences [6, 7].
Increasingly more clinical trials assessing the efficacy of ICIs have also been reporting participants’ symptoms and irAEs. However, rather than focusing on individual patient outcomes, they report outcomes generically as the data are collected routinely [8, 9]. This lack of focus on individual characteristics and outcomes in addition to strict eligibility criteria that are implemented in the trials can decrease the representativeness of real-world experiences of clinicians and patients [10]. It is vital to increase our understanding of the real-life experience of patients’ symptoms and irAEs and their assessment to inform service development and improve patient outcomes [11]. These symptoms are self-reported through patient-reported outcome measures (PROMs) rather than by clinicians [12]. PROMs are usually validated questionnaires and promote collaboration between patients and clinicians in the treatment [13, 14]. Existing PROMs are not tailored to immune-related symptoms and toxicities from ICIs [15]. Given the extent of patients undergoing ICI immunotherapy treatment and the potential likelihood of experiencing toxicity and irAEs, it is important to understand and refine them, particularly with PROMs used in clinical practice [16].

Social determinants of health (SDOH) must be taken into consideration to ensure these new PROMs do not contribute to health inequity. SDOH are defined as conditions in which people are born, live, work, and age, and they play an important role in their health and quality of life [17, 18]. Existing literature provides abundant evidence that SDOH can exert an influence not only on cancer screening, diagnosis, and survival but also on the recognition and management of toxicities derived from ICI treatment [19–21]. These factors can contribute to variabilities in cancer burden among different populations, such as through unequal access to screening, clinical trial participation, and therapeutic interventions [22].
“Equity-relevant” data is important because their effective collection and reporting can enhance our understanding of health inequalities and promote action to address avoidable disparities in health as well as tailor drug treatment. Collecting SDOH can assist researchers with planning, conducting, and interpreting health research and guide them on targeting populations for clinical studies [23]. These data can also contribute to acquiring information about the generalizability of study findings and the impact of interventions on different populations [24].
SDOH are important to collect in both interventional and observational studies because they can significantly impact health outcomes and can confound the results of research. Addressing SDOH in interventional studies can provide insight into the short-term effects of ICI treatment, whereas observational studies provide insights into their longer-term effects. In addition, knowledge of SDOH is essential for achieving health equity and understanding why some individuals experience better health outcomes than others. On the other hand, if SDOH are not sufficiently considered in observational studies, they can also act as confounders in the relationship between treatment and outcomes, potentially resulting in biased or inaccurate results. For example, if a patient population with certain SDOH is more likely to be treated with a particular drug, and those same individuals also tend to have poorer health outcomes because of their SDOH, poor outcomes might be incorrectly attributed to the drug rather than the SDOH themselves. In this instance, SDOH collected from observational studies on a particular patient population will help guide and inform the treatment plan in order to increase its effectiveness and improve treatment outcomes.
The reason for our specific focus on the inclusion of SDOH indicators in studies that used PROMs to assess ICI toxicities is twofold. First, the development of ICI treatment has been a key advancement in immunotherapy in recent years and holds promise for further improving patient outcomes and shaping the future of cancer care [25]. Thus, increasing our understanding and optimising therapeutic outcomes in ICI cancer treatment is of utmost importance. Secondly, clinical outcomes in patients with cancer treated with ICIs can differ across subgroups of sex, age, and race and ethnicity [26–29]. Gender, ethnicity, and age are known to influence response to anticancer chemotherapeutic agents and immunotherapy in varying ways [30]. For example, Asian patients have longer overall survival rates [28] while Hispanic patients have lower response rates [29] as compared to white patients. Further factors that could influence a patient’s response to ICI treatment could also include aging phenomena such as immunosenescence [31, 32]. All of the above make collection of SDOH in this field extremely useful as they can elucidate the potential sources of patients’ varying treatment response to ICIs. However, patients’ physical, emotional, psychosocial well-being, and overall quality of life (QoL) [33, 34] also need to be considered to acquire a comprehensive picture of the influencing factors at play. PROMs provide a window into patient experience and outcomes (in terms of how patients feel and function), offering a fuller picture of health status, functional capacity, quality of life, and health care priorities. They can add invaluable information beyond what can be acquired from clinical indicators alone and thus could provide further insight into why and how treatment impact and side effects vary significantly between patients and populations. Routine PROM use has been shown to improve disease and treatment outcomes such as significantly fewer emergency room visits, greater improvement in health-related quality of life (HRQL), better ability to tolerate treatment, and a significant increase in overall survival rates [35, 36].
Reporting of SDOH within clinical trials is often poor. A review of clinical trials showed that only 25.2% of clinical trials reported race and performed sub-analyses [37]. Higher socioeconomic deprivation was associated with poorer overall survival, even after adjusting for insurance coverage and rural residency status [38]. However, socioeconomic status (SES) was only reported in 15% of randomised clinical trials [39]. Failure to record and account for these characteristics risks extending or exacerbating inequities by limiting the generalisability of the data.
Given the amount of evidence highlighting the importance of SDOH in cancer morbidity, mortality, and QoL, there is a clear unmet need to assess SDOH in all research studies, including those examining toxicities of immunotherapy treatment with the use of PROMs in people with cancer.
The purpose of this review is to describe the extent of inclusion of indicators of SDOH in studies using PROMs to assess toxicities associated with ICI treatment. Findings from this review will contribute to informing the design of future studies using PROMs for assessing irAEs in patients who undergo ICI treatment. The review will also help identify areas for improving methodological approaches to minimise bias and improve health equity when using PROMs for patients in these settings.

Materials and methods
The guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement were followed [16]. The systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42023457063).

Search strategy
A systematic search in collaboration with a library manager (PH) was conducted in MEDLINE, EMBASE, PsycINFO, The Cochrane Library, Web of Knowledge, and CINAHL for studies published between 2008 and 24th October 2024. Detailed methods have been previously described [40]. Briefly, similar keywords were used across databases adapting Boolean operators and MeSH terms. The search terms are related to “patient-reported outcomes measures”, “immunotherapy”, “immune checkpoint inhibitors”, and “toxicities”.

Eligibility criteria
Articles were eligible for inclusion if they (1) included adult patients with a diagnosis of any type of cancer, currently receiving or having received immunotherapy as a treatment (irrespective of other preceding treatments); (2) were primary research studies only and (3) included at least one PROM in the reporting of study outcomes; and (4) were reported in English.

Data extraction
Identification and screening of titles and abstracts as well as eligibility assessment were performed by two researchers (SC & SG) and were confirmed by two additional team members (PJ & JD). Any disagreements were discussed and resolved by all four.
Variables extracted from each of the included studies comprised authors, country/sites, study design/aim, patient characteristics, clinical assessment, PROMs, and outcome. SDOH and health equity data were extracted by applying the PROGRESS-Plus framework [41]. PROGRESS-Plus is the only formalised framework used to conceptualise dimensions of equity impacts [42] and is already being increasingly used by systematic reviewers [24, 42]. It can cover a wide range of health and non-health, upstream and downstream interventions, and how they affect health equity [41]. In addition, PROGRESS-Plus is proposed as the framework for the PRISMA Equity Extension and from both the Campbell and Cochrane Collaborations such as the Equity Methods Group and the Public Health and International Development Review Groups. Several published checklists could have been considered to review and consider issues of equity such as the Cochrane and Campbell Equity Checklist for Systematic Review Authors for protocol planning [43], or the PRISMA-Equity Checklist to report findings from equity-focused systematic reviews [44]. These frameworks, however, are not sufficiently comprehensive to capture various SDOH that could be implicated in different effects of interventions and treatment in diverse populations.
PROGRESS-Plus has and can be used to assess a variety of factors that are known to influence health status and personal characteristics associated with discrimination such as age, disability, and sexual orientation [42]. In addition, PROGRESS-Plus provides guidance on equity analyses and aims to ensure that equity will be explicitly considered when new intervention studies are designed and systematic reviews undertaken. PROGRESS-Plus includes 11 characteristics that stratify health opportunities and outcomes. “PROGRESS” refers to place of residence, race/ethnicity/culture/language, occupation, gender/sex, religion, education, SES, and social whereas “Plus” refers to personal characteristics associated with discrimination, features of relationships, and time-dependent relationships. In the present systematic review, individual SDOH features were included in the “Plus” part of the framework and considered age, disability, and sexual orientation. The assessment was performed independently by two researchers (SG & SC), and disagreements were resolved by a third team member (JD).

Quality assessment
Quality assessment was performed with the use of the Mixed Methods Appraisal Tool (MMAT) [45]. The MMAT is a 21-item checklist, used to rate the quality of quantitative, qualitative, and mixed methods studies selected for review. Criteria relate to the appropriateness of methodology, data analysis techniques and data collection techniques, the representativeness of the sample, reliability of outcome data, and the researchers’ interpretation of research findings. Quality assessment was performed by two groups of two team members each (SC & JD and PJ & SG) for cross-checking. Discrepancies were resolved through discussion.

Results
The search resulted in 6912 articles. After title and abstract screening followed by full-text retrieval and application of the eligibility criteria, 43 papers were included in the review (see Fig. 1). The most common cancer type investigated was melanoma (n = 12) followed by lung cancer (n = 12). The remaining 19 studies assessed different cancer types. Most studies were randomised controlled trials (n = 20) with cohort studies second (n = 14). A smaller number of studies included cross-sectional studies/surveys (n = 6) and non-randomised interventional trials (n = 3) (see Table 1). A detailed table with the extracted data has been reported elsewhere [40].

Reporting of social determinants of health and PROGRESS-Plus characteristics
All studies (100%, 43/43) considered at least one PROGRESS-Plus factor in their studies using PROMs to assess toxicities in patients undergoing ICI treatment. The most frequently reported PROGRESS-Plus factors were residence and age (100%, 43/43) and gender (97.7%, 42/43). Race/ethnicity and education were included in 16 (37.2%) and 11 (25.6%) studies, respectively. Very few studies reported SES (11.6%, 5/43), occupation (9.3%, 4/43), and social capital (9.3%, 4/43), and none reported religion, disability, and sexual orientation (see Fig. 2).
In terms of study characteristics, the studies that captured the most factors (≥ 5) of PROGRESS-Plus were prospective cohort or cross-sectional study models. The majority of RCTs (n = 19) considered three or four PROGRESS-Plus factors in their methods and analyses (see Fig. 3).
Race/ethnicity was more likely to be reported by studies that were conducted in the USA (50%; 8/16) or across many different countries/worldwide (69%; 11/16). All five studies that reported socioeconomic status were conducted in the USA. Marital status, which was included as an indicator for social capital, was only reported by two Belgian studies and two US studies.
Regarding the number of PROGRESS-Plus characteristics considered by studies investigating irAEs in specific cancers, 16 studies reported race (see Online Resource 1). Of those, 31.3% (n = 5) were studies on melanoma and 50% (n = 8) on various cancers. Occupation was mentioned in a total of four studies, half of which were melanoma and half lung studies. Education was reported by 11 studies; four studies included patients with melanoma, four with various cancers, and three with lung cancer. Social capital, i.e. marital status, was reported only by two melanoma and one “other cancers” (head and neck) studies (see Online Resource 1).
Fourteen percent of the studies (6/43) collected additional PROGRESS-Plus factors such as SES (n = 2), social capital, i.e. marital status (n = 3), and occupation (n = 1) but did not present these data in their paper despite stating in their methods section that they had collected them. In addition, from what we could identify, only 5/43 studies had adjusted their analyses for confounding factors relating to SDOH. Two had adjusted their analyses for age only [46, 47], one for age and gender [48], one for gender and education [49], and one for patient demographics they had collected [50] (age, ethnicity, gender, SES, and social capital). Of these, two studies were on melanoma, two on lung cancer, and one on various cancers. Three were cross-section/observational studies and two were cohort studies. All were conducted in the USA except for one (cohort study) that was based in the Netherlands.

Quality assessment
Findings from the quality assessment using the MMAT instrument have previously been described [40]. Briefly, 30 studies out of 43 acquired an MMAT ≥ 70%, indicating a low risk of bias. The majority of the high-quality studies were non-randomised trials, RCTs, and mixed methods, whereas fewer than half of the descriptive studies achieved an MMAT score ≥ 70%. The main limitations identified in the included studies were small and non-representative samples, lack of detail relating to cancer type and/or treatment, and flaws in their methodology and design, as well as decrease in PROM completion levels over different timepoints.

Discussion
In this systematic review, we found that all of the studies reported at least one SDOH, namely place of residence, age, and gender. However, consideration of other important SDOH such as race/ethnicity, SES, education, religion, occupation, social support, sexual orientation, and disability in these studies using PROMs to assess irAEs in patients with cancer was limited or non-existent. Interventional and randomised controlled trials reported a small number of SDOH, with none assessing five or more, whereas a number of cohort and cross-sectional studies included five or more PROGRESS-Plus factors. There were also a number of studies that collected additional SDOH—according to their methods sections—but results were not presented.
PROGRESS-Plus assessment highlighted a few key points and shortcomings in both non-reported and reported factors. For instance, while all studies reported place of residence, this was done by proxy through stating the location of the hospital/site/centre where the research took place. Sometimes this was as general as a country, and sometimes it was as specific as a city and/or hospital. As a result, there was no information on whether the place was rural, urban, etc., which can affect healthcare access [51–54], nor was the actual location of participants’ residence stated.
Race was reported by a minority of studies, and ethnicity even less so. Slightly over a third of the studies reported race/ethnicity information. Some reported ethnicity separately, e.g. ethnicity (Hispanic or Latino; non-Hispanic), and others only used a binary classification, e.g. white/non-white, Asian/non-Asian, or Hispanic/non-Hispanic. Culture and language were not described at all. Some studies conducted in non-English and English-speaking countries included fluency in a particular language as an inclusion criterion for participants, thus excluding any populations that did not speak the language well.
Regarding occupation, the four studies that reported it defined the category as being employed, unemployed, retired, or on sick leave. Gender was only reported as binary (male/female), not making allowances for other gender types. Personal characteristics associated with discrimination only included age but not disability or sexual orientation.
These findings highlight the need for more studies to not only include factors that have been completely omitted such as religion, disability, social capital, and sexual orientation but also to capture specifics of certain domains within the factors that have been reported that are very important when looking at health equity (e.g. type of disability, social capital, gender, religion). RCTs, in particular, could significantly improve their collection of characteristics that stratify health opportunities and outcomes in order to increase representativeness of the populations studied and to promote health equity. Such data may also provide important information regarding the efficacy/toxicity of particular treatments in particular populations based on patient characteristics.
Existing literature also emphasizes the need to include broader and more detailed SDOH in the wider field of cancer such as the impact of stress, lack of strong support networks, low SES (SES), and other social risk factors that have a significant impact on cancer outcomes [55]. This is vital as a large proportion of observed disparities in cancer outcomes between racial/ethnic groups are primarily reflecting interactions with disparities between SDOH and social risk factors [56, 57]. At the same time, it is also acknowledged that these data are still not systematically gathered in the clinical or clinical trial setting [56]. It is generally agreed that collecting such data would contribute to developing tailored support for patients with cancer during their cancer journey, as well as inform the design of future research aiming to assess the impact of specific social interventions on various cancer care outcomes [56]. Availability of these data would facilitate measuring and intervening upon SDOH at a systems level, which is a fundamental prerequisite for achieving cancer health equity [58].
SDOH such as disability, social capital, SES, culture, language, occupation, religion, and education were infrequently considered in the included studies, which suggests that significant biases may exist in the assessment of toxicities in patients undergoing immunotherapy using PROMs. Statistical analyses cannot be adjusted for confounders that are not included. Of note, authors did not adjust (or describe adjusting) for SDOH confounding variables even when they had collected and reported them. Only five of the 43 studies (11.6%) had adjusted their statistical analysis for one or more of the collected SDOH variables.
The current findings are very important, particularly in light of the abundant evidence on the potential impact of SDOH on cancer incidence, treatment, and outcomes [19–21]. If research studies do not collect and report SDOH, it is not possible to ensure representativeness of the sample population, which might lead to findings that apply only to particular and over-represented populations. This might also affect the effectiveness of the treatment and particular medicines, as they will have been tried on selected groups, which might be very different biologically, socially, and psychologically to the general population, especially underserved groups. Furthermore, lack of or insufficient consideration of SDOH in research studies will only contribute to perpetuating and increasing health disparities and bias. This is particularly pertinent to studies assessing toxicities of immunotherapy treatment with the use of PROMS in patients with cancer, as SDOH play a key role in the recognition and management of toxicities derived from ICIs [19–21].
The present review has several methodological strengths. It was conducted and reported in accordance with the guidelines of the PRISMA statement and registered with PROSPERO. Screening of titles and abstracts, eligibility, and quality assessment were shared between two groups of two reviewers confirming accuracy and consistency. The use of PROGRESS-Plus adds to the strengths of this review as it is the only formalised framework used to conceptualise dimensions of equity impacts [42] and endorsed by the Campbell and Cochrane Collaborations. The use of PROGRESS-Plus for reporting equity considerations has also been supported by various studies to improve reporting of equity-relevant data not only for systematic reviews [59] but also for clinical trials [60] and observational studies [61]. However, it is acknowledged that despite available guidance, evaluations of current practices indicate that adequate reporting standards are still not sufficient [62]. This further highlights the need for clear, consensus-based guidance on the type and the way to collect and report equity-relevant information that would improve standards [24].
Our inclusion of randomised controlled trials but also other study designs has resulted in a more comprehensive evaluation of the extent to which SDOH have been collected in recent research. As a result, our findings provide important evidence that suboptimal data reporting across PROGRESS-Plus is not confined to randomised trials but also to observational and other interventional studies and support the imperative for ongoing efforts to improve collection of health-equity data across research studies.
There are limitations to our review. The heterogeneity of studies in terms of design, definitions, and measurement of clinical factors and outcomes needs to be considered when it comes to our findings. While heterogeneity can lead to less interpretable and useful results, we have tried to address this issue, for example, by categorising the studies into specific cancer types and designs but also assessing them individually based on their characteristics in an attempt to decrease the likelihood of bias.
In addition, while PROGRESS-Plus is the only recognised SDOH framework to date [59], it does have certain limitations. Firstly, it includes crude definitions of SDOH. For instance, some terms and definitions are used interchangeably, e.g. the terms race/ethnicity/culture or language are used as a measurement of race or ethnicity despite them being very different concepts. Race is a social construct that refers to physical traits, such as skin colour or hair texture, which characterise people with shared ancestry [63]. Ethnicity, in contrast, is a social construct that refers to shared cultural characteristics, such as language, religion, ancestry, practices, and beliefs [63]. Similarly, the terms gender and sex are used in most studies interchangeably, despite them having very different definitions. The first refers to socially constructed concepts such as behaviour, whereas the latter refers to biological and physiological characteristics [64]. Secondly, the framework does not allow us to examine how the data were collected, for example, whether they were self-reported or assessed with the use of an objective or validated measure. Thus, the quality and reliability of these data cannot be ensured, which emphasises the need for standardisation of terms and definitions across studies. Standardisation can improve the quality of the data, which can contribute to the identification and subsequently minimisation of disparities or biases. Thirdly, PROGRESS-Plus assesses a variety of factors, some of which remain stable over time, such as race or ethnicity, and some having the potential for change, such as marital status, occupation, education, or SES.
The lack of adjustment for SDOH confounders in the statistical analyses of the included studies is a further limitation. We are not able to be certain that this would be appropriate or feasible for the studies because they might not have had sufficient power or data for these adjustments. Thus, the findings that hardly any studies did so should be considered with this limitation in mind. Despite these limitations, the present systematic review provides profound insight into the collection and reporting of social determinants of health in studies that use PROMS to assess toxicities of immunotherapy in cancer patients.

Conclusion
This review demonstrated that researchers studying PROMs to assess irAEs in cancer care currently collect a limited range of equity-relevant data. The inclusion of more granular data about social determinants of health within data collection and evaluation would enhance our understanding and ways of addressing health inequities. These data will inform guidelines to improve routine practices as well as contribute to decreasing disparities. Ensuring enrolment of patients from different backgrounds will improve the diversity of clinical trial participants, ensuring sufficient representation of underserved populations and will further improve our understanding of the pathogenesis and enhance the management of cancer and its treatment. As we design the next trials investigating irAEs, or indeed investigating any aspect of cancer care, we must ensure more SDOH are included, analysed, and reported sufficiently and appropriately.

Supplementary Information
Below is the link to the electronic supplementary material.