Development of a core outcome set for trials of chemoradiotherapy for anal squamous cell carcinoma

UoM administered thesis: Phd


Introduction: Six phase III randomised trials established the effectiveness of chemoradiotherapy as primary treatment for squamous cell carcinoma of the anus (SCCA) and over the last 30 years survival has progressively improved. However, variations in trial outcome reporting have limited between-study comparisons and hindered evidence synthesis, and despite considerable treatment-related morbidity no trial has comprehensively quantified late toxicity or quality of life. This thesis proposed to address these issues through the development of a core outcomes set (COS) “an agreed, standardised set of outcomes to be measured and reported, as a minimum, in all trials in a particular health area�. The project involved three phases described in subsequent chapters (i) outcome long-list generation through systematic review and semi-structured patient interviews; (ii) Delphi survey and (iii) face-to-face consensus meeting. Chapter 3 & 4: Systematic review (published in Colorectal Disease) identified 1243 outcomes from 101 trials and observational studies of chemoradiotherapy for SCCA. No outcome was reported in all trials and over half of outcomes were reported in less than five percent of studies. In 54% of studies no definition was provided. Reported outcomes were predominantly in the survival and disease activity domains; life impact and toxicity outcomes were reported infrequently. No core set of outcomes could be identified from the existing literature. Semi-structured interviews with 19 patients identified 56 outcomes including eight not identified in the systematic review. Thematic analysis identified how outcomes impact the lives of patients, including a novel description of symptom clusters in SCCA. Chapter 5: The long-list of outcomes generated from chapter 3 and 4 was used to populate a Delphi questionnaire. One hundred and forty-nine participants from 11 countries (patients 55; HCPs 94) completed both rounds of the Delphi. Twenty-three HCPs and 13 patients from four countries participated in the face to face consensus meeting where after discussion and anonymous voting the final COS of 19 outcomes was agreed. These were treatment response, local failure, regional failure, distant failure, disease progression, salvage surgery, overall survival, cancer-specific survival, disease-free survival, metastasis-free survival, progression-free survival, anal incontinence, faecal urgency, pelvic fistula, stoma, skin loss, physical function, sexual function, and health-related QoL (accepted for publication in Lancet Gastroenterology and Hepatology). Chapter 6: Three secondary methodological research questions were addressed. Systematic review of outcome domains in cancer COS informed the domain framework for the CORMAC project and contributed to the development of the outcome taxonomy recommended by COMET. Comparison of outcomes included in COS for site-specific cancers to those included in COS for cancer in general identified no emergent COS for cancer in general. A novel study using a simulated Delphi and think-aloud process demonstrated patients had good understanding of histograms in this context. Discussion: The findings in Chapter 3 and 4 demonstrate the lack of existing consensus on optimal trial outcomes in SCCA and that outcomes prioritized by patients are under-represented in existing studies. A core outcome set for trials of chemoradiotherapy for SCCA has been agreed through a methodologically rigorous and transparent consensus process involving key stakeholders. The steps required for implementation including agreement of recommend definitions and measurement instruments for outcomes in the COS are described.


Original languageEnglish
Awarding Institution
Award date1 Aug 2019