Hine 1984.

Study characteristics
Patient sampling	Country UK Study design Prospective Setting Hospital Dates of data collection N/R Population (n) 663 Inclusion criteria Radical surgery for colorectal cancer Exclusion criteria SCC anus, tumours in the appendix. 6 were lost to clinical follow‐up and 5 others were removed from the trial. Removal followed the development of unassociated conditions such as alcoholic cirrhosis which interfered with the interpretation of a significant CEA rise (3 patients) and in 2 patients the onset of psychiatric illness made the use of cancer chemotherapy inadvisable Participants Included (n) 626
Patient characteristics and setting	Age range 59 Smoking status Unknown Site of primary tumour 290 rectum, 373 colon Stage of primary tumour A in 38, B in 377 and C in 248 Perioperative investigations done to ensure no residual disease Not specified Chemotherapy/radiotherapy? Patients with at least 2 progressively rising CEA values of > 35 ngml‐1 but no other definite evidence of recurrent malignancy were randomised in a prospective trial of cytotoxic therapy Recurrences (n) 171 Site of recurrences N/R
Index tests	CEA Timing At each follow‐up visit CEA Technique CEA was measured in the unextracted serum by a double antibody radio‐immunoassay as developed by Egan et al. (1972) and adapted by Laurence et al. (1972). The inter‐ and intra‐assay variation of the method was found to be < 10%. An upper limit of 15 µg/L will include 99% of a normal population and in the present study a level of > 20 µg/L was regarded as abnormal CEA threshold 20 µg/L Definition of positive 1 elevated value Which CEA value (s) used? All
Target condition and reference standard(s)	Follow‐up schedule 3‐monthly for for first 2 postoperative years, then 6 ‐ 12‐monthly depending on the surgeon. Full clinical examination including sigmoidoscopy was performed Reference standard recurrence was primarily made on the basis of symptoms and signs of disease confirmed by other investigations when indicated (e.g. liver scan, bone scan, biopsy). Thorough clinical examination including sigmoidoscopy. If this indicated recurrent malignancy, confirmatory investigations were ordered and management was initiated appropriate to the results. When clinical examination failed to reveal malignancy, the subsequent course of events depended on the degree of elevation of the CEA. If the level was >20ngml‐1 but <35ngml‐ 1, the test was repeated at monthly intervals until it fell below 20ngml‐1 or rose above 35ngml‐1. All patients with levels >35ngml‐1 and no clinical evidence of recurrence had a further CEA estimation, full blood count, erythrocyte sedimentation rate, liver function tests, barium enema, chest X‐ray and isotope and/or ultrasound liver scan, together with bone scan and colonoscopy where indicated. If recurrence was diagnosed from the results of these investigations then appropriate management was instituted.
Flow and timing	Timing of CEA vs reference standard (days) Raised CEAs were recalled to clinic within 2 months of the date of the first sample for clinical exam and sigmoidoscopoy. If no recurrence found intensified frequency of testing whilst in the 20 ‐ 35 range. If > 35 but no signs of recurrence, then chemotherapy
Comparative
Notes
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Unclear
Did the study avoid inappropriate exclusions?	Yes
		Low	Low
DOMAIN 2: Index Test All CEA thresholds
If a threshold was used, was it pre‐specified?	Yes
Is the same method and instrument used for all CEA measurements?	Yes
Is there an estimation of reproducibility of the method, for example the % coefficient of variation at specific concentrations?	Yes
Is there an indication of method accuracy, for example, is there evidence of participation in an external quality assessment and proficiency testing scheme?	Unclear
		Low	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Unclear
Were the reference standard results interpreted without knowledge of the results of the index tests?	No
		Unclear	Low
DOMAIN 4: Flow and Timing
Did all patients receive the same reference standard?	No
Were all patients included in the analysis?	Yes
Was the index test repeated prior to the reference standard?	No
Was the the timing between index test(s) and reference standard ascertainable?	No
Did all patients receive a reference standard?	Unclear
		Unclear