Risk of CRC in Patients With Previous Negative Fecal Test
Risk of CRC in Patients With Previous Negative Fecal Test
Two consecutive screening rounds have been completed in a fecal test– based CRC pilot screening program in the Amsterdam region of The Netherlands. The first round was conducted in 2006. In this first round, 10,054 invitees were randomized to receive either a guaiac FOBT or a FIT. The second round used FIT only and was performed among 10,258 persons in 2008 (trial registration no. NTR1327). Ethical approval was provided by the Dutch Health Council (2005/03WBO, The Hague, The Netherlands). The study designs of the first and second rounds have been reported in detail elsewhere.15,19 A summary is given in the following text.
Asymptomatic persons aged 50 to 74 years and living in the catchment area of the pilot program were eligible for invitation to the screening program. Symptomatic persons were advised not to participate in the program but to contact their general physician. The catchment area comprised 3 postal code areas within the surroundings of Amsterdam.
A file containing all eligible persons based on birth date and postal code was extracted by the municipalities from the population database. A random sample of this file was invited through an invitation letter by postal mail. Invitations were coordinated by the regional Comprehensive Cancer Center Amsterdam, an organization that is also responsible for the logistics of the nationwide breast and cervical cancer screening programs in The Netherlands.
Persons with a positive test result in the first round were excluded from participation in the second round. In case of adenomas, these test-positive persons were enrolled in a surveillance program according to the Dutch guidelines.20 In case of CRC, they were referred to the departments of oncology and/or surgery of our hospital for treatment. Other individuals who no longer fulfilled eligibility criteria at the start of the second round did not receive an invitation for the second round. This concerned persons older than 74 years or persons who had moved out of the catchment area.
An invitation kit with the stool test was sent by postal mail. The invitation letter was signed by the principal investigator. In addition to the invitation letter, the kit also contained a detailed information brochure, a test instruction leaflet, and a postage-free return envelope. Participants could perform the test at home and return it by postal mail. A signed informed consent form had to be enclosed in the return envelope. A reminder letter was sent to nonresponders at 6 weeks and at 3 months.
Guaiac FOBT The guaiac FOBT used in the first round was the Hemoccult II (Beckman Coulter Inc, Fullerton, CA). No dietary instructions were given. Persons were instructed to collect 2 samples of 3 consecutive bowel movements. Cards were developed and read by 2 trained laboratory technicians. Cards were not rehydrated. A test result was considered positive if one or more of the 6 samples showed a blue discoloration.
FIT. The FIT that was used in both rounds was the OC-Sensor by Eiken (Tokyo, Japan). After arrival at the laboratory, tests were stored at 4°C and processed in batches by using an automated clinical analyzer (OC-Sensor Micro; Eiken). A single test was used on one occasion, and a hemoglobin value of 50 ngHb/mL was used as the threshold for test positivity.
All participants with a positive test result received a mailed invitation for a consultation at the screening center. During this consultation, the positive test result was explained and, in the absence of contraindications, a colonoscopy was advised. Contraindications for colonoscopy were imaging of the colon within the past 2 years (colonoscopy or computed tomographic colonography), a life expectancy of less than 5 years, or severe comorbidity. The cost of colonoscopy was covered by the participants' health insurance company.
Colonoscopies were scheduled within 2 weeks after the consultation and were performed by experienced endoscopists. All persons were routinely offered conscious sedation using intravenous midazolam 0.5 mg and/or fentanyl 0.01 mg. Polyethylene glycol solution (2 L; MoviPrep(r), Salix Pharmaceuticals, Morrisville, NC) combined with bisacodyl 10 mg orally was used for bowel preparation. During the procedures, a research assistant was present to record key performance indicators. Size, location, and type of treatment were recorded for all lesions. Lesion size was estimated by using a 7-mm open biopsy forceps. Location was considered distal if the lesion was located distal from the splenic flexure. Indigo carmine staining and/or scopolamine 20 mg were used on endoscopists' request only. All lesions were preferably removed endoscopically during the first procedure and reviewed histopathologically.
All biopsy specimens, polyps, and excision specimens were examined by one experienced pathologist. Histology, grade of dysplasia, and involvement of margins were reported for all lesions. An advanced adenoma was defined as any adenoma ≥10 mm or an adenoma with a villous component >20% or with high-grade dysplasia. Cancer was defined as CRC with invasion beyond the muscularis mucosa. Cancers were staged according to the 5th edition of the American Joint Committee on Cancer classification.21 Formerly used categories such as carcinoma in situ and intramucosal carcinoma were classified as high-grade dysplasia. Sessile serrated and traditional serrated lesions were classified as adenomas. Nonneoplastic lesions included hyperplastic polyps and inflammatory polyps.
In this analysis, we evaluated the accuracy of FIT in second-round participants who had also participated in the first round. This means that only data from second-round participants with a negative test result in the first round were included. The accuracy results in this group were compared with the accuracy estimates for the FIT and for the guaiac FOBT obtained in all first-round screening participants. Primary outcome measures were the positivity rate, the positive predictive value (PPV) for CRC, and the PPV for advanced adenomas and CRC combined (hereafter referred to as advanced neoplasia).
The positivity rate was calculated as the number of positive test results relative to the number of tests returned. The PPV was calculated as the number of persons with the finding of interest relative to the number of persons with a positive test result and a complete colonoscopy. In case of multiple lesions in the same patient, colonoscopy results were classified according to the most advanced lesion per patient.
The group of first-round participants was subdivided into those allocated to guaiac FOBT (the first-round guaiac FOBT group) and those allocated to FIT (the first-round FIT group). The group of second-round participants was subdivided into those with a previous negative guaiac FOBT result (the FITafter- guaiac FOBT group) and those with a previous negative FIT result (FIT-after-FIT group).
Group differences in positivity rate and in PPV were tested for statistical significance using the χ test statistic and expressed as relative risks with corresponding 95% confidence intervals. We hypothesized that the positivity rate and the PPV for CRC and for advanced neoplasia would be lower in second-round participants compared with first-round participants. Because the FIT has a higher sensitivity for CRC than for advanced adenomas, we expected this decrease to be most pronounced for CRC. Differences between male and female subjects in positivity rate and PPV were evaluated using the χ test statistic in FIT users of both rounds.
A secondary outcome measure was the interval cancer rate, which was defined as the proportion of cancers diagnosed in first-round participants (both guaiac FOBT and FIT) outside the screening protocol but within the screening interval. Interval cancers were identified through cross-linkage of the screening pilot database with the Dutch cancer registry. Of all identified cancer cases, location (proximal or distal), date of diagnosis, and cancer stage at diagnosis according to the 5th edition of the American Joint Committee on Cancer classification were retrieved from the cancer registry. Descriptive statistics were used to analyze the interval cancers and the χ test statistic was used to analyze differences in the distribution of cancer stage and cancer location between screen-detected cancers of the first and the second round and interval cancers. Data were analyzed using the statistical software SPSS 18.0 (SPPS Inc, Chicago, IL).
Subjects and Methods
Two consecutive screening rounds have been completed in a fecal test– based CRC pilot screening program in the Amsterdam region of The Netherlands. The first round was conducted in 2006. In this first round, 10,054 invitees were randomized to receive either a guaiac FOBT or a FIT. The second round used FIT only and was performed among 10,258 persons in 2008 (trial registration no. NTR1327). Ethical approval was provided by the Dutch Health Council (2005/03WBO, The Hague, The Netherlands). The study designs of the first and second rounds have been reported in detail elsewhere.15,19 A summary is given in the following text.
Population and Design
Asymptomatic persons aged 50 to 74 years and living in the catchment area of the pilot program were eligible for invitation to the screening program. Symptomatic persons were advised not to participate in the program but to contact their general physician. The catchment area comprised 3 postal code areas within the surroundings of Amsterdam.
A file containing all eligible persons based on birth date and postal code was extracted by the municipalities from the population database. A random sample of this file was invited through an invitation letter by postal mail. Invitations were coordinated by the regional Comprehensive Cancer Center Amsterdam, an organization that is also responsible for the logistics of the nationwide breast and cervical cancer screening programs in The Netherlands.
Persons with a positive test result in the first round were excluded from participation in the second round. In case of adenomas, these test-positive persons were enrolled in a surveillance program according to the Dutch guidelines.20 In case of CRC, they were referred to the departments of oncology and/or surgery of our hospital for treatment. Other individuals who no longer fulfilled eligibility criteria at the start of the second round did not receive an invitation for the second round. This concerned persons older than 74 years or persons who had moved out of the catchment area.
Invitation Procedure
An invitation kit with the stool test was sent by postal mail. The invitation letter was signed by the principal investigator. In addition to the invitation letter, the kit also contained a detailed information brochure, a test instruction leaflet, and a postage-free return envelope. Participants could perform the test at home and return it by postal mail. A signed informed consent form had to be enclosed in the return envelope. A reminder letter was sent to nonresponders at 6 weeks and at 3 months.
Stool Tests
Guaiac FOBT The guaiac FOBT used in the first round was the Hemoccult II (Beckman Coulter Inc, Fullerton, CA). No dietary instructions were given. Persons were instructed to collect 2 samples of 3 consecutive bowel movements. Cards were developed and read by 2 trained laboratory technicians. Cards were not rehydrated. A test result was considered positive if one or more of the 6 samples showed a blue discoloration.
FIT. The FIT that was used in both rounds was the OC-Sensor by Eiken (Tokyo, Japan). After arrival at the laboratory, tests were stored at 4°C and processed in batches by using an automated clinical analyzer (OC-Sensor Micro; Eiken). A single test was used on one occasion, and a hemoglobin value of 50 ngHb/mL was used as the threshold for test positivity.
Colonoscopy
All participants with a positive test result received a mailed invitation for a consultation at the screening center. During this consultation, the positive test result was explained and, in the absence of contraindications, a colonoscopy was advised. Contraindications for colonoscopy were imaging of the colon within the past 2 years (colonoscopy or computed tomographic colonography), a life expectancy of less than 5 years, or severe comorbidity. The cost of colonoscopy was covered by the participants' health insurance company.
Colonoscopies were scheduled within 2 weeks after the consultation and were performed by experienced endoscopists. All persons were routinely offered conscious sedation using intravenous midazolam 0.5 mg and/or fentanyl 0.01 mg. Polyethylene glycol solution (2 L; MoviPrep(r), Salix Pharmaceuticals, Morrisville, NC) combined with bisacodyl 10 mg orally was used for bowel preparation. During the procedures, a research assistant was present to record key performance indicators. Size, location, and type of treatment were recorded for all lesions. Lesion size was estimated by using a 7-mm open biopsy forceps. Location was considered distal if the lesion was located distal from the splenic flexure. Indigo carmine staining and/or scopolamine 20 mg were used on endoscopists' request only. All lesions were preferably removed endoscopically during the first procedure and reviewed histopathologically.
Pathology
All biopsy specimens, polyps, and excision specimens were examined by one experienced pathologist. Histology, grade of dysplasia, and involvement of margins were reported for all lesions. An advanced adenoma was defined as any adenoma ≥10 mm or an adenoma with a villous component >20% or with high-grade dysplasia. Cancer was defined as CRC with invasion beyond the muscularis mucosa. Cancers were staged according to the 5th edition of the American Joint Committee on Cancer classification.21 Formerly used categories such as carcinoma in situ and intramucosal carcinoma were classified as high-grade dysplasia. Sessile serrated and traditional serrated lesions were classified as adenomas. Nonneoplastic lesions included hyperplastic polyps and inflammatory polyps.
Data Analysis
In this analysis, we evaluated the accuracy of FIT in second-round participants who had also participated in the first round. This means that only data from second-round participants with a negative test result in the first round were included. The accuracy results in this group were compared with the accuracy estimates for the FIT and for the guaiac FOBT obtained in all first-round screening participants. Primary outcome measures were the positivity rate, the positive predictive value (PPV) for CRC, and the PPV for advanced adenomas and CRC combined (hereafter referred to as advanced neoplasia).
The positivity rate was calculated as the number of positive test results relative to the number of tests returned. The PPV was calculated as the number of persons with the finding of interest relative to the number of persons with a positive test result and a complete colonoscopy. In case of multiple lesions in the same patient, colonoscopy results were classified according to the most advanced lesion per patient.
The group of first-round participants was subdivided into those allocated to guaiac FOBT (the first-round guaiac FOBT group) and those allocated to FIT (the first-round FIT group). The group of second-round participants was subdivided into those with a previous negative guaiac FOBT result (the FITafter- guaiac FOBT group) and those with a previous negative FIT result (FIT-after-FIT group).
Group differences in positivity rate and in PPV were tested for statistical significance using the χ test statistic and expressed as relative risks with corresponding 95% confidence intervals. We hypothesized that the positivity rate and the PPV for CRC and for advanced neoplasia would be lower in second-round participants compared with first-round participants. Because the FIT has a higher sensitivity for CRC than for advanced adenomas, we expected this decrease to be most pronounced for CRC. Differences between male and female subjects in positivity rate and PPV were evaluated using the χ test statistic in FIT users of both rounds.
A secondary outcome measure was the interval cancer rate, which was defined as the proportion of cancers diagnosed in first-round participants (both guaiac FOBT and FIT) outside the screening protocol but within the screening interval. Interval cancers were identified through cross-linkage of the screening pilot database with the Dutch cancer registry. Of all identified cancer cases, location (proximal or distal), date of diagnosis, and cancer stage at diagnosis according to the 5th edition of the American Joint Committee on Cancer classification were retrieved from the cancer registry. Descriptive statistics were used to analyze the interval cancers and the χ test statistic was used to analyze differences in the distribution of cancer stage and cancer location between screen-detected cancers of the first and the second round and interval cancers. Data were analyzed using the statistical software SPSS 18.0 (SPPS Inc, Chicago, IL).
