Developing a fit-for-purpose composite symptom score as a symptom burden endpoint for clinical trials in patients with malignant pleural mesothelioma

Our plain-English summary of Developing a fit-for-purpose composite symptom score as a symptom burden endpoint for clinical trials in patients with malignant pleural mesothelioma, by C.S. Cleeland, K.N. Keating, B. Cuffel, et al (Scientific Reports, 2024).

The study

• Authors: C.S. Cleeland, K.N. Keating, B. Cuffel, C. Elbi, J.M. Siegel, C. Gerlinger, T. Symonds, J.A. Sloan, A.C. Dueck, A. Bottomley, X.S. Wang, L.A. Williams, T.R. Mendoza
• Journal: Scientific Reports
• Published: 2024;14(1):14839
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

We developed a composite symptom score (CSS) representing disease-related symptom burden over time in patients with malignant pleural mesothelioma (MPM). Longitudinal data were collected from an open-label Phase IIB study in which 239 patients completed the validated MD Anderson Symptom Inventory for MPM (MDASI-MPM). A blinded, independent review committee of external patient-reported outcomes experts advised on MDASI-MPM symptoms to include in the CSS. Through iterative analyses of potential symptom-item combinations, 5 MPM symptoms (pain, fatigue, shortness of breath, muscle weakness, coughing) were selected. The CSS correlated strongly with the full MDASI-MPM symptom set (0.92-0.94) and the Lung Cancer Symptom Scale-Mesothelioma (0.79-0.87) at each co-administration of the scales. The CSS also had good sensitivity to worsening disease and global quality-of-life ratings. The MDASI-MPM CSS can be used as an outcome in MPM clinical trials, including in responder analyses and at the individual patient level. It is brief enough to administer frequently, including electronically, to better capture symptom trajectories during and after a trial and in clinical practice. As a single score, the CSS addresses multiplicity issues that can arise when several symptoms increase due to worsening disease. Our process can be adapted to produce a CSS for other advanced-cancer trials.

© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

In plain English

This study built and tested a short symptom score for clinical trials in patients with malignant pleural mesothelioma. It did not examine asbestos exposure. The authors used blinded, pooled questionnaire data from 239 of the 248 patients randomized in a Phase IIB drug trial. An outside expert committee chose five symptoms from the MD Anderson Symptom Inventory for mesothelioma: pain, fatigue, shortness of breath, muscle weakness and coughing. The score was internally consistent (Cronbach alphas 0.80 to 0.84) and stable on retesting in 82 patients (intraclass correlation 0.84). It correlated with the full inventory (0.92 to 0.94) and with the LCSS-Meso scale (0.79 to 0.87). In 50 patients, the mean score rose from 3.3 at baseline to 4.5 at safety follow-up on a 0 to 10 scale. A 1-point change was judged meaningful, and the committee suggested 2 points for regulatory use. Of 95 patients scored at both times, 47% worsened and 21% improved. The authors noted that disease progressed rapidly, that patients and site investigators were not blinded, and that litigation might have biased symptom reporting, which they could not check.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Development and psychometric testing of a composite symptom score, using blinded, pooled patient-reported data from a randomized, open-label Phase IIB clinical trial
• Who was studied: 239 of 248 randomized patients with malignant pleural mesothelioma in a multinational Phase IIB trial (anetumab ravtansine versus vinorelbine) at more than 60 sites. The patients had nonmissing questionnaire data and mainly stage III or IV epithelioid disease.
• Main results:
  • An independent review committee recommended a final score made of five symptoms: pain, fatigue, shortness of breath, muscle weakness and coughing.
  • Internal consistency: Cronbach alpha 0.82 (95% CI 0.78 to 0.86) at baseline, 0.84 at Cycle 3 Day 1, and 0.80 at the safety follow-up.
  • Test-retest reliability in 82 clinically stable patients: intraclass correlation 0.84 (95% CI 0.78 to 0.88).
  • The score correlated with the LCSS-Meso at 0.79 to 0.87 and with the full MDASI-MPM symptom items at 0.92 to 0.94 across timepoints.
  • Scores differed significantly between fully active (ECOG PS 0) and restricted active (ECOG PS 1) patients at the first three timepoints, up to Cycle 3 Day 1.
  • In the sensitivity analysis (n = 50), the mean score rose from 3.3 at baseline to 4.5 at safety follow-up on a 0 to 10 scale. The mean difference was 1.2 points (P = 0.001) and the effect size was 0.57.
  • A 1-point change was judged minimally important. The committee suggested a more conservative 2-point change for regulatory use.
  • Of 95 patients who completed the questionnaire at baseline and safety follow-up, 47% had symptom worsening and 21% had symptom improvement, using a 1-point threshold.
• The authors' conclusion: The authors concluded that they had developed a composite symptom score for the MDASI-MPM from qualitative and quantitative data. They stated that the approach could be used to build composite scores for other cancers and treatments.
• Limitations the authors state:
  • Disease progressed rapidly in the sample, which limited assessment of symptoms linked to disease improvement.
  • Data came mainly from stage III or IV epithelioid MPM. Use in earlier-stage disease would require recalibration.
  • Patients and trial site investigators were not blinded to treatment.
  • Litigation and settlements might bias patients toward inflating symptom reports. Litigation status was missing, so this could not be investigated.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Clinical Trial, Pleural Mesothelioma, Lung Cancer, Mesothelioma.

Related studies

• Modification of existing patient-reported outcome measures: qualitative development of the MD Anderson Symptom Inventory for malignant pleural mesothelioma (MDASI-MPM) — L.A. Williams, M.S. Whisenant, et al. (2018)
• A multicentre non-blinded randomised controlled trial to assess the impact of regular early specialist symptom control treatment on quality of life in malignant mesothelioma (RESPECT-MESO): study protocol for a randomised controlled trial — S. Gunatilake, F.J. Brims, et al. (2014)
• Content validity and electronic PRO (ePRO) usability of the Lung Cancer Symptom Scale-Mesothelioma (LCSS-Meso) in mesothelioma patients — H.L. Gelhorn, A.M. Skalicky, et al. (2018)
• A tailored, supportive care intervention using systematic assessment designed for people with inoperable lung cancer: a randomised controlled trial — P. Schofield, A. Ugalde, et al. (2013)
• Evaluation of the psychometric properties and minimally important difference of the MD Anderson Symptom Inventory for malignant pleural mesothelioma (MDASI-MPM) — T.R. Mendoza, L.A. Williams, et al. (2019)
• Symptom Burden and Unmet Needs in Malignant Pleural Mesothelioma: Exploratory Analyses From the RESPECT-Meso Study — S.N. Hoon, I. Lawrie, et al. (2021)

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