Table 1. Protocol of the Target Trial to Study Adjuvant Fluorouracil-Based Chemotherapy in Stage II Colorectal Cancer and Emulation Procedure Using the SEER-Medicare Database.

Protocol Component	Description of Target Trial	Description of Emulation Using SEER-Medicare Data
Eligibility criteria	Histologic diagnosis of stage II colorectal cancer (node negative) between 2008 and 2012 Aged into Medicare and was continuously enrolled in Parts A and B and not enrolled in an HMO for 12 mo before diagnosis Evidence of complete resection of colon or rectal cancer No history of cancer except nonmelanoma skin cancer No prior chemotherapy	Same as target trial
Treatment strategiesa	Initiate any dose of fluorouracil as first line treatment up to 3 mo after postsurgery hospital discharge No chemotherapy initiated within 3 mo of postsurgery hospital discharge	Same as target trial
Assignment procedures	Participants were randomized to a treatment strategy at baseline and were aware of the assigned strategy	Randomization was assumed conditional on baseline covariates: year, sex, race/ethnicity, marital status, region of the United States, metropolitan county, median household income in census tract, percentage of households under poverty line in census tract, time between diagnosis and surgery, prolonged hospitalization after surgery, preoperative radiotherapy, cancer type (colon, rectum, or both), tumor grade, and in the year before surgery, anemia, abdominal distention, abnormal weight loss, asthenia, change in bowel movements, constipation, diarrhea, irritable bowel syndrome, No. of emergency department visits, colonoscopy, and abdominal or pelvic CT scan
Follow-up	For each eligible person, follow-up started when the person was assigned to a treatment strategy at postsurgery discharge from the hospital and ended at the earliest of death, loss of insurance eligibility, December 31, 2013, or 60 mo	Same as target trial
Outcome	Death certified by a physician, reported to Medicare, and confirmed by the National Death Index	Same as target trial
Causal contrast	Intention-to-treat effect; per-protocol effect	Per-protocol effect
Analysis plan	Intention-to-treat analysis; per-protocol analysis: inverse probability weighted pooled logistic regression model with censoring at deviation from protocol. Weights estimated as a function of baseline and postbaseline covariates: anemia, abdominal distention, abnormal weight loss, asthenia, change in bowel movements, constipation, diarrhea, irritable bowel syndrome, No. of emergency department visits, colonoscopy, and abdominal or pelvic CT scan	Same as target trial, except the per-protocol analysis was conducted in an expanded data set that included 2 replicates (1 per treatment strategy) of each eligible individual

Abbreviations: CT, computed tomography; HMO, health maintenance organization; SEER, Surveillance, Epidemiology, and End Results.

^aUnder both strategies, the decision to discontinue fluorouracil at any time or start additional therapies after 3 months was left to the patient and physician’s discretion.