Endoscopic Surveillance for Esophageal Adenocarcinomas
Endoscopic Surveillance for Esophageal Adenocarcinomas
The underlying study population was all adult (≥18 y) members of Kaiser Permanente, Northern California (KPNC) during the years 1995–2009. KPNC is an integrated health care delivery system with approximately 3.3 million current members who are approximately representative of the age, sex, and ethnic distributions of the underlying regional population. Patients with Barrett's esophagus receive surveillance examinations through physician-directed recommendations.
Persons with Barrett's esophagus were identified using physician-assigned electronic diagnoses followed by manual confirmation using endoscopy and pathology records. Electronic diagnoses used the International Classification of Diseases, 9th revision code 530.2, which at KPNC is uniquely coded as Barrett's esophagitis, International Classification of Diseases, 9th revision code 530.85 (Barrett's esophagus), or the College of American Pathologists' Systematized Nomenclature of Human and Veterinary Medicine code 73330 (Barrett's esophagus). Manual physician review for confirmation required the presence of visible endoscopic changes consistent with Barrett's esophagus and the histologic presence of esophageal intestinal metaplasia. Patients were excluded if they had only gastric-type metaplasia of the esophagus, had columnar metaplasia without intestinal metaplasia, lacked endoscopic changes indicating Barrett's esophagus; or lacked an esophageal biopsy. Prior validation studies by our group showed that these combined methods (electronic coding, manual review, and pathology review) were accurate and highly reproducible.
The index date for cases was the cancer diagnosis date. The index date for controls was the corresponding date for their matched case.
Cases were adult KPNC members who were diagnosed with esophageal or gastroesophageal junction adenocarcinoma before September 2007; had a Barrett's esophagus diagnosis (as defined earlier) 6 months or more before their cancer diagnosis; and subsequently died of esophageal/gastroesophageal junction adenocarcinoma or its complications before December 31, 2009 (Appendix, Supplementary Table 1). Cancers were identified using the region's Surveillance, Epidemiology, and End Results (SEER) cancer registry; audits confirm the registry captures 99% or more of cancer diagnoses among KPNC members. Site and histology definitions used the International Classification of Disease for Oncology, 2nd edition, codes for esophageal carcinoma (C15.0–C15.9) and the gastroesophageal junction (C16.0); both locations were included to permit identification of all pertinent cancers.
Survival status was ascertained from mortality files that concatenate data from the SEER registry, membership files, death certificates, and the Social Security Death Index; cause of death was determined by manual record review.
Controls were KPNC members with a diagnosis of Barrett's esophagus (confirmed as described earlier) who did not die of esophageal or gastroesophageal junction adenocarcinoma through the end of the follow-up evaluation. Controls were matched to cases by age at Barrett's esophagus diagnosis, year of Barrett's esophagus diagnosis, medical center of Barrett's esophagus diagnosis, sex, and race (Table 1). For patients who lacked an exact diagnosis year match, we expanded the diagnosis year to within 1 or 2 years, and for patients without an exact race match, we modified the race category to white vs nonwhite. We did not exclude living patients with a cancer diagnosis from the control group so that we could include patients who may have benefited from surveillance. This matching scheme provided similar time periods and durations for surveillance opportunities between cases and controls.
A surveillance endoscopy was any esophagogastroduodenoscopy performed principally for cancer surveillance of a previously documented Barrett's esophagus, not for symptoms. A patient in surveillance was someone who had at least 1 surveillance endoscopy within the 3 years before the index date. We included as surveillance examinations those that diagnosed the index cancer, if the examination was performed only for surveillance and not for symptoms. A 3-year interval was selected a priori because it is the shortest recommended interval in guidelines for persons without dysplasia and, thus, the one most likely to be associated with a mortality benefit. Assignment of surveillance status used endoscopy reports, pathology requests, and outpatient visits; prior research by our group determined the surveillance status assignment was 97% reproducible between blinded reviewers.
After institutional review board approval, trained physicians, blinded to case status, abstracted medical records from the earliest date available to the index date. Double abstraction was performed to confirm surveillance status, Barrett's esophagus diagnosis, and cause of death.
A priori power calculations indicated that 34 cases (matched to up to 4 controls) would provide more than 99% power to detect a 40% difference in surveillance between cases vs controls (eg, 65% of controls in surveillance vs 25% of cases) and more than 80% power to detect a 30% difference. These proportions were considered conservative because prior studies suggested that few patients dying from esophageal adenocarcinoma (ie, cases) had received recent surveillance.
The relationship between case status and surveillance status was evaluated using conditional logistic regression. The main model adjusted for dysplasia status. Dysplasia status was defined as the most advanced level found before the 3-year surveillance period or, for persons with fewer than 3 years between their diagnosis and index dates, the dysplasia status from the first endoscopy (the first examination that diagnosed Barrett's esophagus, by definition, was not itself considered a surveillance examination). This definition was used because dysplasia before the 3-year surveillance window could influence both the likelihood of receiving surveillance in the 3-year surveillance window and the patient's cancer risk. In addition to adjusting for dysplasia status, sensitivity analyses were performed to determine whether excluding some patients with dysplasia (and their matched controls) influenced results. Analyses were performed using Stata version 10.1 (Stata Corporation, College Station, TX).
Materials and Methods
Source Population and Data Sources
The underlying study population was all adult (≥18 y) members of Kaiser Permanente, Northern California (KPNC) during the years 1995–2009. KPNC is an integrated health care delivery system with approximately 3.3 million current members who are approximately representative of the age, sex, and ethnic distributions of the underlying regional population. Patients with Barrett's esophagus receive surveillance examinations through physician-directed recommendations.
Barrett's Esophagus
Persons with Barrett's esophagus were identified using physician-assigned electronic diagnoses followed by manual confirmation using endoscopy and pathology records. Electronic diagnoses used the International Classification of Diseases, 9th revision code 530.2, which at KPNC is uniquely coded as Barrett's esophagitis, International Classification of Diseases, 9th revision code 530.85 (Barrett's esophagus), or the College of American Pathologists' Systematized Nomenclature of Human and Veterinary Medicine code 73330 (Barrett's esophagus). Manual physician review for confirmation required the presence of visible endoscopic changes consistent with Barrett's esophagus and the histologic presence of esophageal intestinal metaplasia. Patients were excluded if they had only gastric-type metaplasia of the esophagus, had columnar metaplasia without intestinal metaplasia, lacked endoscopic changes indicating Barrett's esophagus; or lacked an esophageal biopsy. Prior validation studies by our group showed that these combined methods (electronic coding, manual review, and pathology review) were accurate and highly reproducible.
Index Date
The index date for cases was the cancer diagnosis date. The index date for controls was the corresponding date for their matched case.
Cases
Cases were adult KPNC members who were diagnosed with esophageal or gastroesophageal junction adenocarcinoma before September 2007; had a Barrett's esophagus diagnosis (as defined earlier) 6 months or more before their cancer diagnosis; and subsequently died of esophageal/gastroesophageal junction adenocarcinoma or its complications before December 31, 2009 (Appendix, Supplementary Table 1). Cancers were identified using the region's Surveillance, Epidemiology, and End Results (SEER) cancer registry; audits confirm the registry captures 99% or more of cancer diagnoses among KPNC members. Site and histology definitions used the International Classification of Disease for Oncology, 2nd edition, codes for esophageal carcinoma (C15.0–C15.9) and the gastroesophageal junction (C16.0); both locations were included to permit identification of all pertinent cancers.
Survival status was ascertained from mortality files that concatenate data from the SEER registry, membership files, death certificates, and the Social Security Death Index; cause of death was determined by manual record review.
Controls
Controls were KPNC members with a diagnosis of Barrett's esophagus (confirmed as described earlier) who did not die of esophageal or gastroesophageal junction adenocarcinoma through the end of the follow-up evaluation. Controls were matched to cases by age at Barrett's esophagus diagnosis, year of Barrett's esophagus diagnosis, medical center of Barrett's esophagus diagnosis, sex, and race (Table 1). For patients who lacked an exact diagnosis year match, we expanded the diagnosis year to within 1 or 2 years, and for patients without an exact race match, we modified the race category to white vs nonwhite. We did not exclude living patients with a cancer diagnosis from the control group so that we could include patients who may have benefited from surveillance. This matching scheme provided similar time periods and durations for surveillance opportunities between cases and controls.
Exposure Status: Surveillance
A surveillance endoscopy was any esophagogastroduodenoscopy performed principally for cancer surveillance of a previously documented Barrett's esophagus, not for symptoms. A patient in surveillance was someone who had at least 1 surveillance endoscopy within the 3 years before the index date. We included as surveillance examinations those that diagnosed the index cancer, if the examination was performed only for surveillance and not for symptoms. A 3-year interval was selected a priori because it is the shortest recommended interval in guidelines for persons without dysplasia and, thus, the one most likely to be associated with a mortality benefit. Assignment of surveillance status used endoscopy reports, pathology requests, and outpatient visits; prior research by our group determined the surveillance status assignment was 97% reproducible between blinded reviewers.
Data Collection
After institutional review board approval, trained physicians, blinded to case status, abstracted medical records from the earliest date available to the index date. Double abstraction was performed to confirm surveillance status, Barrett's esophagus diagnosis, and cause of death.
Power Calculations
A priori power calculations indicated that 34 cases (matched to up to 4 controls) would provide more than 99% power to detect a 40% difference in surveillance between cases vs controls (eg, 65% of controls in surveillance vs 25% of cases) and more than 80% power to detect a 30% difference. These proportions were considered conservative because prior studies suggested that few patients dying from esophageal adenocarcinoma (ie, cases) had received recent surveillance.
Statistical Methods
The relationship between case status and surveillance status was evaluated using conditional logistic regression. The main model adjusted for dysplasia status. Dysplasia status was defined as the most advanced level found before the 3-year surveillance period or, for persons with fewer than 3 years between their diagnosis and index dates, the dysplasia status from the first endoscopy (the first examination that diagnosed Barrett's esophagus, by definition, was not itself considered a surveillance examination). This definition was used because dysplasia before the 3-year surveillance window could influence both the likelihood of receiving surveillance in the 3-year surveillance window and the patient's cancer risk. In addition to adjusting for dysplasia status, sensitivity analyses were performed to determine whether excluding some patients with dysplasia (and their matched controls) influenced results. Analyses were performed using Stata version 10.1 (Stata Corporation, College Station, TX).
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