Protocol for a prospective observational cohort study collecting data on demographics, symptoms and biomarkers in people with mesothelioma (ASSESS-meso)

Abstract

Introduction

Mesothelioma is a heterogeneous disease that can be challenging to monitor and prognosticate. ASSESS-meso is a multicentre, prospective, longitudinal observational cohort study of patients with mesothelioma. The primary aim is to describe different clinical phenotypes and investigate predictive and prognostic factors, including biomarkers from blood and pleural fluid. The secondary aim is to provide a resource for future trials and substudies.

Methods and analysis

We aim to recruit 700 patients with a histological, cytological or clinicopathological diagnosis of mesothelioma, at any anatomical site (pleural, peritoneal, pericardial, etc). Longitudinal data will be collected, including clinical information, radiological investigations, blood tests and patient-reported outcome measures for breathlessness, chest pain and sweats. Preplanned analyses will use Cox proportional hazards method to evaluate factors associated with survival, linear and logistic regression models to investigate associations with symptoms, and analysis of variance modelling to explore changes in symptoms over time.

Ethics and dissemination

Ethical approval has been granted by the Research Ethics Committee South West—Central Bristol (17-SW-0019) and Health Research Authority (IRAS ID 220360). A study steering committee has been established and results will be published OpenAccess in peer-reviewed journals.

Trial registration number

ISRCTN: 61861764.

STRENGTHS AND LIMITATIONS OF THIS STUDY

• ASSESS-meso is a pragmatic prospective observational cohort study, which allows collection of longitudinal data in a representative cohort of patients with mesothelioma for the first time.

• The high volume of demographic and disease characteristic data, alongside patient-reported outcome measures across multiple domains, will allow us to describe clinical phenotypes and factors associated with poor prognosis.

• Collection and storage of serial biological samples throughout the clinical journey provides an invaluable resource for further exploration into key unanswered research questions around diagnostic and treatment response biomarkers.

• The main limitation is that our study is observational, and therefore, analysis will be primarily descriptive with scope for regression analysis and hazards modelling.

Introduction

Mesothelioma is an aggressive asbestos-associated malignancy of the serosal surface that affects the pleura most commonly (malignant pleural mesothelioma, MPM).¹ Mesothelioma is usually incurable with a median survival of 8–14 months from diagnosis.^{2 3} For two decades, cisplatin and pemetrexed doublet was the standard of care for MPM, despite offering a median survival benefit of just 2.8 months, compared with single-agent cisplatin.⁴ Recently, addition of the vascular endothelial growth factor antibody bevacizumab to this regimen has been shown to extend survival to 18.8 months.⁵ Surgical resection approaches have failed to demonstrate significant improvement in survival^6–9 and are therefore no longer routinely offered, particularly in the UK setting. Pleurodesis via VATS or talc slurry and poudrage, and indwelling pleural catheters are useful for pleural fluid management.^{7 10}

However, the greatest breakthrough in MPM treatment came in early 2021 with the demonstration that combination ipilimumab (CTLA4 antagonist) and nivolumab (PD1 antagonist) enhanced overall survival compared with cisplatin/pemetrexed¹¹—a finding that is likely to change the standard of care in the front-line setting. Further novel therapies are under investigation, including oncolytic viruses, mesothelin-targeted agents and multimodal approaches.^12–14

The mesothelioma literature consists predominantly of clinical trials, reflecting the impressive efforts that have been channelled into finding effective treatments over the past decade.4 5 11 15 However, trial populations are often skewed towards patients with better performance status, younger age and fewer comorbidities, limiting generalisability to the wider mesothelioma population.¹⁶ In addition, most clinical trials require patients to have received or be willing to receive chemotherapy, which excludes a proportion of patients.¹⁷ There is a need to collect representative, longitudinal data in people with mesothelioma, to better understand the natural history of the disease and phenotype the highly variable disease pathways and prognosis.

Monitoring mesothelioma is challenging, and the current gold standard of modified RECIST criteria applied to CT images is limited.¹⁸ Modified RECIST suffers from high intraobserver variability, poor correlation with volumetry and frequent mismatch with TNM staging.¹⁹ Alternative approaches to disease monitoring and evaluation of treatment responses are required. A blood or pleural fluid-based biomarker could provide this resource, as well as potentially contributing to characterisation of disease phenotypes and prognostication.

Finally, ASSESS-meso aims to provide a resource for future clinical trials and substudies. Randomised interventional trials will be embedded within ASSESS-meso, based on the Trials within Cohorts (TwiCs) methodology.²⁰ A highly pragmatic design, TwiCs replicate real-world clinical care, yielding generalisable effectiveness outcomes, with the additional benefit of efficient recruitment and reduced risk of attrition.

Methods and analysis

Study design and aims

ASSESS-meso is a multicentre, prospective, longitudinal observational cohort study of patients with mesothelioma. The primary aim is to describe varying clinical phenotypes, investigate the clinical and biochemical factors associated with survival and response to treatment, and collect serial biological samples in a representative patient cohort. A secondary aim is to provide a resource for future clinical trials (TwiCs) and substudies.

Participants

Patients with a diagnosis of mesothelioma, at any anatomical site, achieved through any investigative method, will be eligible.

To participate, participants must meet all of the following inclusion criteria:

• Histological, cytological, clinicopathological or clinicoradiological diagnosis of mesothelioma, confirmed by local or regional lung cancer or mesothelioma multidisciplinary team (MDT).

• Willing and able to comply with study follow-up assessments.

• Willing and able to provide written informed consent.

A person who meets any of the following criteria will be ineligible:

• Age <18 years old.

• Unable to give written informed consent.

• Declines ongoing hospital follow-up.

Setting and sites

Up to 20 recruiting sites will be selected across the UK. To be eligible, centres need to be at least a secondary care-level institution, caring for at least 10 patients with mesothelioma a year (either via respiratory, oncology, thoracic surgery or other specialities), and have access to discussion at a local or regional MDT. To date, the study is open at 15 hospitals (listed in online supplemental Appendix). Recruitment started on 4 July 2017. Potential study participants will be identified at MDT meetings, pleural clinics, oncology clinics and nurse-led clinics. Potential participants will be screened by a member of the ASSESS-meso team and those who are eligible will be invited to discuss the study at their subsequent clinic appointment.

Enrolment

Eligible participants will be provided with a participant information sheet (PIS) and given the opportunity to discuss the study with a member of the ASSESS-meso research team and ask questions. Patients will have as much time as required to consider participation; there is no time limit between date of diagnosis and study enrolment. If they decide to participate, written informed consent will be obtained. If a patient is enrolled during a telephone or virtual appointment, witnessed verbal consent will be obtained by two members of the research team.

Participants will be asked to provide additional consent for blood and pleural fluid samples to be stored (if available) anonymously. Consent will be sought to allow sharing of pseudoanonymised biological samples with other researchers for future ethically approved research studies. Participants will also be invited to consent to be screened for future trials (TwiCs), to undergo random selection for the same trials and for their data to be used as comparison data in those trials if they are not selected.²⁰

Withdrawal

Participants have the right to withdraw consent for their involvement in ASSESS-meso at any point. Withdrawal does not have to be justified and will not affect future or ongoing care. Participants can withdraw consent for all study involvement (in which case all data including biological samples will be destroyed), or from involvement with certain elements of the study (eg, further follow-up visits, the use of their existing recorded clinical data in future analyses, the storage and use of their biological samples).

Data collection

Electronic case report forms will be used to collect data at the initial baseline assessment and all subsequent follow-up visits. At each visit, assessment will occur across four main domains: clinical evaluation, patient-reported outcome measures (PROMs), biological samples and imaging (table 1). Study follow-up will occur when the participant attends for review as part of standard clinical care, at a minimum of 3 monthly. Data will be collected on a bespoke password-protected online database provided by REDCap (Vanderbilt University; Nashville, USA).

Table 1.

Schedule of investigations and assessments

Investigation	Baseline assessment	Follow-up assessments
Clinical review
Patient demographics	✓	n/a
Disease characteristics	✓	n/a
Patient comorbidities	✓	n/a
Medication history	✓	✓
Oncological treatment history	✓	✓
Pleural intervention history	✓	✓
Patient-reported outcome measures
VAS (breathlessness, chest pain, sweats)	✓	✓
Quality of life assessment	✓	✓
Pain (BPI)	✓	✓
Anxiety and depression (HADS)	✓	✓
Biological samples
Blood	✓	✓
Pleural fluid	✓ (if available)	✓ (if available)
Pleural biopsy retrieval	✓ (if available)	n/a
Blood and pleural fluid for storage	✓ (if available)	✓ (if available)
Imaging
CXR	✓	✓*
TUS	✓*	✓*
CT scan	✓	✓*
Assessment of eligibility for any current trials	✓	✓

*If clinically indicated.

BPI, brief pain inventory; CXR, chest X-ray; HADS, Hospital Anxiety and Depression Score; n/a, not available; TUS, thoracic ultrasound scan; VAS, Visual Analogue Scale.

Clinical evaluation

Baseline demographics, comorbidities, performance status and medication history will be recorded for all patients. Disease characteristics will also be collected (histology, stage, mode of diagnosis), as will any oncological treatments received and pleural intervention history. Involvement of specialist teams, including palliative care or specific palliative interventions (eg, cordotomy) will also be recorded.

Patient reported outcome measures

PROMs for quality of life (QoL) and symptom severity (breathlessness, pain, sweats, anxiety and depression) will be completed at each study visit. Validated tools will include the EuroQol 5 Dimensions 5 Level health questionnaire (EQ-5D-5L),²¹ the EORTC Quality of Life Questionnaire Core Questionnaire PALliative Cancer (QLQ-C15-PAL),²² the Brief Pain Inventory,^{23 24} and the Hospital Anxiety and Depression Score (HADS).²⁵

Symptom scores for breathlessness, chest pain and sweats will be evaluated by using 10 cm Visual Analogue Scale (VAS). VAS is a validated tool for assessing breathlessness and chest pain in malignant pleural disease and is acceptable to patients.^{26 27}

Biological samples

Baseline blood tests will include full blood count, urea and electrolytes, liver function tests, C reactive protein, lactate dehydrogenase (LDH), total protein, glucose and serum mesothelin. If appropriate, pleural fluid will be obtained and sent for protein, LDH, glucose, mesothelin and cytology. With consent, the research team will retrieve the biopsy on which the diagnosis of mesothelioma was made and, if there is sufficient tissue, sample(s) will be obtained and stored for research purposes.

The same blood tests will be taken at each follow-up visit. In addition, blood samples will be taken, processed and stored. If the participant has an indwelling pleural catheter in situ, drainage diaries will be reviewed at each follow-up visit, and a sample of pleural fluid obtained and stored.

Imaging

Thoracic ultrasound, chest X-ray (CXR) will be performed at baseline. The presence of non-expandable lung will be recorded. Diagnostic CT thorax will have been performed prior to the baseline assessment during initial clinical investigation, and the results of this will be recorded. At follow-up visits, imaging will be undertaken at the discretion of the clinician, as clinically indicated. All clinically indicated radiological investigations will be recorded for ASSESS-meso. It is anticipated that most participants will have a CXR at every clinic appointment and a CT scan every 6 months.

Screening for TwiCs

If a TwiC is underway, participants will be screened for eligibility at each study visit. Eligible participants will be randomly selected to participate, and those who are selected will be provided with a PIS for the trial. Having had the chance to discuss the trial with a member of the team, participants selected for the TwiC will be asked to provide consent to enrol in the trial. Eligible participants who are not selected for the TwiC will provide control data from within ASSESS-meso. Participants in ASSESS-meso who are enrolled in, have completed or are providing control data for a TwiC will undergo adverse event monitoring at each ASSESS-meso visit to ensure ongoing safety monitoring for participants and to allow collection of data on late complications.

Telephone or virtual follow-up

Participants who are unable to attend regular in-person follow-up appointments may undergo telephone or virtual follow-up. Telephone and virtual appointments will be undertaken by a research nurse or any member of the research team. Assessments will include a clinical evaluation and review of pleural fluid drainage diaries. Any recent blood test results or imaging relevant to the current follow-up assessment will be imported and recorded. QoL questionnaires (EQ-5D-5L QoL) and symptom VAS scores will be sent via post or email for completion by the participant in their own time.

Cessation of follow-up and death

Follow-up assessments will cease if the participant dies or withdraws from the study. Mortality data will be cross-checked with National Health Service (NHS) Digital. A mortality form will be completed for each deceased patient.

Sample size

The sample size necessary to detect a difference in survival between different patient groups is 266 participants per group (532 in total). A recruitment target of 700 allows for approximately 20% withdrawal from the study, incomplete data and lost to follow-up. This calculation is based on the survival outcomes from previous chemotherapy trials in mesothelioma, in which chemotherapy increased 1-year survival from 38% to 50%.⁴ A cohort of this size will provide 80% power (alpha 0.05) to detect a similar difference in 1-year survival, based on an individual patient characteristics (split at the median) or treatment received (binary yes/no).

Statistical analysis

The aim of ASSESS-meso is to describe phenotypes of disease and explore factors associated with prognosis. Descriptive statistics will be used to summarise characteristics. Factors associated with survival will use adjusted and non-adjusted Cox proportional hazards model. Multiple linear regression will be used to compare continuous outcomes and logistic regression used to compare dichotomous outcomes. We will use random effects models or robust estimates to allow for clustering between centres. Outcomes with repeat measurements will be analysed using regression modelling with adjustment for baseline values.

The sensitivity, specificity, negative predictive value and positive predictive value for predicting disease progression will be assessed at established cut-off levels for serum and pleural fluid biomarkers, cytokines, immune profile, receptor status and epigenetic markers. Receiver operator characteristic curves will be drawn. The gold standard for disease progression will be confirmation of progressive disease made at the regional mesothelioma MDT meeting.

End of trial

The study will end when the final participant (n=700) has been followed up for 12 months (or until death), or until the study has run for 10 years. An interim analysis is planned to be undertaken when recruitment reaches 25% of target to evaluate recruitment efforts and the demographicsand disease features of the cohort.

Ethics and dissemination

This study is run in accordance with the International Conference on Harmonisation Good Clinical Practice. All participants provided written informed consent or witnessed verbal informed consent. The research sponsor is North Bristol NHS Trust, who will oversee annual monitoring of sites. A study steering committee (SSC) has been formed to review study progress and review emerging data. All proposed substudies, amendments to the study protocol and publications generated through ASSESS-meso are reviewed for approval by the SSC. The study has been approved by the Research Ethics Committee South West—Central Bristol (17-SW-0019) and Health Research Authority (IRAS ID 220360). Results will be published in peer-reviewed OpenAccess journals.

Patient and public involvement

The SSC includes a patient/participant representative, who were involved in the study and study protocol design. They contribute to reviews of study progress and emerging data.

Discussion

Mesothelioma continues to have a poor prognosis, with few tools for predicting survival or monitoring response to disease. ASSESS-meso is a pragmatic observational study that has been designed to address the need for longitudinal data from a representative cohort. By describing the variety of clinical phenotypes, it will provide insight into different disease pathways and outcomes. The repository of serial biological samples will provide a resource for exploring unanswered questions about blood and pleural biomarkers of diagnosis,²⁸ prognostication^29–34 and treatment response.^{35 36} Biological samples will also enable investigation into the pathological, immunological and genetic processes involved in disease evolution and progression. Finally, ASSESS-meso will provide a resource for future clinical trials and substudies, providing high generalisability and external validity due to its pragmatic inclusion criteria.

Ethics statements

Patient consent for publication

Not applicable.