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Whitlock EP, Lin J, Liles E, et al. Screening for Colorectal Cancer: An Updated Systematic Review [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2008 Oct. (Evidence Syntheses, No. 65.1.)

Cover of Screening for Colorectal Cancer: An Updated Systematic Review

Screening for Colorectal Cancer: An Updated Systematic Review [Internet].

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Appendix B. Key Question 1 study details

There are four large trials examining long-term outcomes for a group of people randomized to FOBT screening (Hemoccult II) biennially (every 2 years), compared to a control group who received no screening. Two of the trials used nonrehydrated slides (Nottingham, Funen), and two used rehydrated slides (Minnesota, Goteborg). While the latter technique increased sensitivity, it also reduced specificity.

The Nottingham trial had a statistically significant CRC mortality reduction of 15 percent for the screening group, relative to the control group, at the end of the screening period (7.8 years).3 The CRC-related mortality rate difference between screening and control groups continued 3.9 years after the screening program had stopped (total followup of 11.7 years), with a statistically significant relative mortality reduction of 13 percent.132 It is notable that this mortality reduction was achieved using a higher threshold for test positives (4 of 6 squares) and employing a Hemoccult retesting strategy for some test-positives (see Appendix B Table 1). This approach differs from trials in which persons with one of six test squares was considered screen-positive (see Appendix B Table 1).

The Funen trial is the only trial that has continued its screening program over the entire followup period. Three reports from this trial published in 1996,4 2002,134 and 2004131 indicate a statistically significant relative mortality reduction for CRC-related deaths after five, seven, and nine rounds of screening (corresponding to 10, 13 and 17 years of followup). At 10-years followup this relative CRC-related mortality reduction was 21 percent, at 13 years the reduction was 18 percent, and at 17 years the reduction was 16 percent. When comparing the CRC mortality rates that include deaths related to CRC treatment, however, the relative CRC mortality reduction is no longer statistically significant at 13 and 17 years. It is not clear from the published methods what categories of death would have been considered treatment-related, as opposed to CRC-related, making this distinction difficult to interpret. While the individuals judging cause of death were blinded to group assignment, there is insufficient information to completely interpret the elimination of CRC mortality benefit due to analyzing deaths in this manner.

In the Goteborg trial, no statistically significant reduction in the relative risk of colorectal cancer mortality was found (RR 0.88; CI: 0.69,1.12) after 8.3 years of followup.326 After 15 years of followup, more than 13 years after the screening program stopped, a CRC-related mortality reduction of 16 percent was statistically significant (RR 0.84; CI 0.67,0.99).94 Given that the Goteborg trial enrolled only 60 to 64 year olds, held only two rounds of FOBT screening in total, and offered positive tests further workup without using colonoscopy, a 16 percent reduction in CRC deaths 13 years later is difficult to explain.

The Minnesota trial examined both annual and biennial screening. The biennial screening group did not have a statistically significant relative CRC mortality reduction, compared to the control group, after 13 years of followup (RR 0.94; CI: 0.68,1.31).5 This reduction did reach significance after 18 years of followup, which was 5 years after the screening program had stopped (RR 0.79; CI:0.62, 0.97).135 After 13 years of annual screening, the relative CRC-related mortality reduction was 33 percent. 5 This reduction remained constant after 18 years of followup (5 years after the screening program had ceased).135 It is unclear, however, whether the higher mortality impact of this study is due to annual screening or due to the use of rehydrated slides (yielding a 9.8 percent positivity rate, as compared to a 2.4 percent positivity rate for nonrehydrated). This could have led to a high proportion of patients receiving colonoscopy, and subsequent high rates of CRC and adenoma detection.

Table 1Key question 1 evidence table

StudySample DemographicsFOBT prep

FOBT development
Follow-up of positive FOBTCRC incidence (per 1000)CRC Cumulative mortality (per 1,000 persons)Relative Risk
Annual Screening
Minnesota (USA)
Mandel 19935
Sample size:
S: 15,570
C: 15,394
Proportion completing screening:
>1 screen: 90.2%
All rounds of screening: 46.2%
Ages: 50–80
Dietary and medication restrictions

Rehydrated
Definition of positive test : ≥1/6 positive squares
Follow-up of positive test:
1.

Colonoscopy (if incomplete, DCBE)

2.

History and physical exam

3.

Routine lab tests

4.

X-rays of upper GI and chest

5.

EKG


Proportion of positive tests receiving colonoscopy
13 yrs: 80.9%
17 yrs: 83% (colonoscopy OR DCBE + FS)
S: 23 persons
C: 26 persons
13 yrs
S: 5.88
C: 8.83
0.67
(0.50–0.87)
Minnesota (USA)

Mandel 1999135
S: 32 person years
C: 39 person years
18 yrs (5 yrs after end of screening period)
S: 9.46
C: 14.09
0.67
(0.51–0.83)
Biennial Screening
Nottingham (UK)

Hardcastle 19963
S: 76,224
C: 76,079
Proportion completing screening:
>1 screen: 59.6%
All rounds of screening:
38.2%
Ages: 50–74
No dietary or medication restrictions

Nonrehydrated
Definition of positive initial test:
  • ≥5/6 positive squares OR
  • ≤4/6 positive squares followed by ≥1/12 positive squares on repeat FOBT (with dietary restrictions) OR
  • ≤4/6 positive squares followed by all negative squares on repeat FOBT (with dietary restrictions) followed 3 months later by ≥1/6 positive squares on repeat FOBT (with dietary restrictions)

Follow-up of positive test:
Colonoscopy
Proportion of positive tests receiving colonoscopy
7.8 yrs: 87% (c)
11.7 yrs: 73%
S: 1.49 person years
C: 1.44 person years
% of Dukes A:
S: 20%
C: 11%
p<0.001
7.8 yrs median
S: 0.60
C: 0.70
0.85
(0.74–0.98)
Nottingham (UK)

Scholefield 2002132
S: 1.51 person years
C: 1.53 person years
% of Dukes A:
NR
11.7 yrs (median)
(5 yrs after end of screening period)
S: 0.70
C: 0.81
0.87
(0.78–0.97)
Funen (Denmark)

Kronborg 19964
S: 30,762
C: 30,966
Proportion completing screening:
1996
>1 screen: 67.2%
All rounds of screening: 46.2%
2002
All rounds of screening: 35.9%
2004
All rounds of screening: 30.4%
Ages: 45–75
Dietary and medication restrictions

Nonrehydrated
Definition of positive test: ≥1/6 positive squares
Follow-up:
1.

Colonoscopy (if incomplete, DCBE)

2.

History and physical exam


Proportion of positive tests receiving colonoscopy
10 yrs: >85%
13 yrs: 94.1%
17 yrs: 93.2%
S: 1.71 person years
C: 1.72 person years
% of Dukes A:
S: 22%
C: 11%
p<0.01
10 yrs (5 screening rounds)
S: 0.65
C: 0.82
0.79
(0.65–0.96)
S: 0.73*
C: 0.89*
0.82*
(0.68–0.99)
Funen (Denmark)

Jorgenson 2002134
S: 1.84 person years
C: 1.81 person years
% of Dukes A: NR
13 yrs (7 screening rounds)
S: 0.72
C: 0.88
0.82
(0.69–0.97)
S: 0.83*
C: 0.97*
0.85 *
(0.73–1.00)
Funen (Denmark)

Kronborg 2004131, 134
S: 2.06 person years
C: 2.02 person years
% of Dukes A:
S: 18%
C: 11%
17 yrs (9 screening rounds)
S: 0.84
C: 1.00
0.84
(0.73–0.96)
S: 0.99*
C: 1.10*
0.89*
(0.78–1.01)
Minnesota (USA)

Mandel 19935
S: 15,587
C: 15,394
Proportion completing screening:
>1 screen: 89.9%

All rounds of screening:
59.7%

Ages: 50–80
Dietary and medication restrictions
Rehydrated
Definition of positive test: ≥1/6 positive squares
Follow-up of positive test:
1.

Colonoscopy (if incomplete, DCBE)

2.

History and physical exam

3.

Routine lab tests

4.

X-rays of upper GI and chest

5.

EKG


Proportion of positive tests receiving colonoscopy
13 yrs: 81.7%
17 yrs: 84% (colonoscopy OR DCBE + FS)
S: 23 person
C: 26 person
% of Dukes A:
S: 26.6%
C: 22.3%
13 yrs
NR (cum. incidence)
0.94
(0.68–1.31)
Minnesota (USA)

Mandel 1999135
S: 33 per 1,000 p
C: 39 per 1,000 p
18 yrs (5 years after end of screening period)
NR (cum. incidence)
0.79
(0.62–0.97)
Goteborg 1996 (Sweden)

Towler 1998326
S: 34,144
C: 34,164

1st screening: 63%
2nd screening: 60%

Ages: 60–64
Dietary and medication restrictions
Rehydrated (majority)
Definition of positive test: 1/6 positive
Follow up of positive test:
Proctoscopy
rectosigmoidoscopy
DCBE
Proportion of positive tests receiving full work-up
1st round: 85%
2nd round: 88%
NR 8.3 yrs (6 yrs after 2 screening rounds)
NR
0.88 (0.69–1.12)
Goteborg 2005 (Sweden)

Hewitson 200794
NR 15.5 yrs (13 years after 2 screening rounds)
NR
0.84 (0.67–0.99)
*

Includes deaths from CRC treatment

Table 2Relationship of findings in the distal and the proximal colon

StudyParticipantsPatient CharacteristicsOverall Prevalence of Proximal Neoplasia Prevalence of Proximal Neoplasia by FS Findings
Proximal AdenomaAdvanced Proximal AdenomaP-CRCPANNo LesionsDistal Polyps or Adenomas
SmallMediumLarge
O'Brien 2003330 5,291 FS
606 w/ ≥ 1 adenoma: (12%)
Age: 63.4 ± 0.6 yrs
% Ethnic Origin: NR
% Symptomatic: NR
% Female: 32
Avg. Risk Status: NR
SES: NR
# polyps: NR
34%
(186/550)
8% (41/550) 0.7% (4/550) NR NR Proximal Adenoma
550 w/ colonoscopy
Single Adenoma <6mm
27%
(23, 33%)
Single 6–10mm or multiple <11mm
36%
(29, 44%)
Adv. AD
45%
(38, 53%)
Advanced Proximal Adenoma
Single Adenomas <6mm
5%
(3, 9%)
Single 6–10mm or multiple <11mm
8%
(5, 13%)
Adv. AD
12%
(38, 53%)
Schoen 200654 64,658 FS
15,150 (23.4%) w/ any polyp or mass.
Age:
55–59yr: 30.2%
60–64yr: 31.7%
65–69yr: 24.7%
70–74yr: 13.4%
% Ethnic Origin:
%white: 91.5
% AA: 4.4
%Other: 4.0
% Symptomatic: NR
% Female: 39.6
Avg. Risk Status:
11.9% (1296) w/ first degree relative.
4.5% (487) missing fam history
SES:
College Grad: 34.3%
Post HS: 34.6%
HS or less: 30.8%
# polyps: NR
NRCan't calculate prevalence due to non-report of whole colon lesions distal in those with lesions greater than 10mmNRNR Advanced Proximal Adenoma
10,875 w/ CRC within 1 year <5mm polyp
Male
4.3%
(135/3155)
Female
2.3%
(53/2274)
5–9mm polyp
Male
4.2%
(91/2183)
Female
3.0%
(43/1426)
CRC
<5mm polyp
Male
0.3%
(8/3155)
Female
0.2%
(5/2274)
5–9mm polyp
Male
0.2%
(5/2183)
Female
0.2%
(3/1426)

PAN: Proximal Advanced Neoplasia: Advanced Proximal Adenoma + CRC

APA: Advanced Proximal Adenoma

Advanced Neoplasm: Any large adenoma ≥ 10mm and/or any size with villous histopathology and/or any size with severe dysplasia (including carcinoma); Diminutive Adenoma: ≤ 5mm (or per study)

Small Adenoma: 6–9mm (or per study)

Large Adenoma: ≥ 10mm

Adv AD: Advanced Adenoma: Advanced Neoplasm

Invasive Cancer: cell invades beyond muscularis mucosa

Table 3. Key question 1 excluded studies

Reference Reason for exclusion

  1. Anderson WF, Guyton KZ, Hiatt RA. et al. Colorectal cancer screening for persons at average risk. J Natl Cancer Inst. 2002;94(15):1126–1133. Excluded for study design. [PubMed: 12165637]
  2. Andreoni B, Crosta C, Lotti M. et al. Flexible sigmoidoscopy as a colorectal cancer screening test in the general population: recruitment phase results of a randomized controlled trial in Lombardia, Italy. Chir Ital. 2000;52(3):257–262. Does not report appropriate outcomes. [PubMed: 10932370]
  3. Atkin WS, Edwards R, Wardle J. et al. Design of a multicentre randomised trial to evaluate flexible sigmoidoscopy in colorectal cancer screening. J Med Screen. 2001;8(3):137–144. Does not report appropriate outcomes. [PubMed: 11678553]
  4. Banerjee S, Van Dam J. CT colonography for colon cancer screening. Gastrointest Endosc. 2006;63(1):121–133. Does not report appropriate outcomes. [PubMed: 16377329]
  5. Blue Cross Blue Shield Association. CT colonography (‘virtual colonoscopy’) for colon cancer screening. 2004. Chicago IL: Blue Cross Blue Shield Association (BCBS). Does not report appropriate outcomes.
  6. Blue Cross Blue Shield Association. Immunochemical versus guaiac fecal occult blood tests. 2004. Chicago IL: Blue Cross Blue Shield Association (BCBS). Does not report appropriate outcomes.
  7. Conlisk E. Colorectal cancer in North Carolina. Risk factors, screening behaviors, incidence, stage at diagnosis, and mortality. N C Med J. 2001;62(5):298–303. Excluded for study design. [PubMed: 11570330]
  8. Faivre J, Dancourt V, Lejeune C. et al. Reduction in colorectal cancer mortality by fecal occult blood screening in a French controlled study. Gastroenterology. 2004;126(7):1674–1680. Out of scope. [PubMed: 15188160]
  9. Gupta AK, Melton LJ III, Petersen GM. et al. Changing trends in the incidence, stage, survival, and screen-detection of colorectal cancer: a population-based study. Clinical Gastroenterology & Hepatology. 2005;3(2):150–158. Excluded for study design. [PubMed: 15704049]
  10. Hamashima C, Sobue T, Muramatsu Y. et al. Comparison of observed and expected numbers of detected cancers in the research center for cancer prevention and screening program. Jpn J Clin Oncol. 2006;36(5):301–308. Does not report appropriate outcomes. [PubMed: 16735372]
  11. Hoff G, Grotmol T, Bretthauer M et al. Flexible sigmoidoscopy screening: a randomised controlled study of the population in the south of Norway. The Norwegian colorectal cancer prevention study (NORCCAP). - Int J Cancer 2002; Issue Suppl 13:93, 2002. Does not report appropriate outcomes.
  12. Hoff G, Thiis-Evensen E, Grotmol T. et al. Do undesirable effects of screening affect all-cause mortality in flexible sigmoidoscopy programmes? Experience from the Telemark Polyp Study 1983-1996. Eur J Cancer Prev. 2001;10(2):131–137. Does not report appropriate outcomes. [PubMed: 11330453]
  13. Lewis PR, Dixon AJ, Newberry GL. Survival of patients with colorectal cancer detected by a community screening program. Med J Aust. 2000;172(10):516–518. Excluded population. [PubMed: 10901779]
  14. Malila N, Anttila A, Hakama M. Colorectal cancer screening in Finland: details of the national screening programme implemented in Autumn 2004. J Med Screen. 2005;12(1):28–32. Does not report appropriate outcomes. [PubMed: 15814016]
  15. McCallion K, Mitchell RM, Wilson RH. et al. Flexible sigmoidoscopy and the changing distribution of colorectal cancer: implications for screening. Gut. 2001;48(4):522–5. Does not report appropriate outcomes. [PMC free article: PMC1728246] [PubMed: 11247897]
  16. McLeod R, with the Canadian Task Force on Preventive Health Care. Screening strategies for colorectal cancer: systematic review and recommendations. 2001. London, Ontario: Canadian Task Force on Preventive Health Care (CTFPHC). Precedes search period.
  17. Medical Services Advisory Committee. Faecal occult blood testing for population health screening. 2004. Canberra: Medical Services Advisory Committee (MSAC). Does not report appropriate outcomes.
  18. Nelson D. Colonoscopy and polypectomy. Hematology - Oncology Clinics of North America. 2002;16(4):867–74. Excluded for study design. [PubMed: 12418052]
  19. Newcomb PA, Norfleet RG, Storer BE. et al. Screening sigmoidoscopy and colorectal cancer mortality. J Natl Cancer Inst. 1992;84(20):1572–1575. Article covered by an included ser. [PubMed: 1404450]
  20. Niv Y. Screening the average risk population for colorectal cancer: the Israeli experience 1985-97. Colorectal Disease. 2003;5(4):358–361. Excluded for study relevance. [PubMed: 12814416]
  21. Rennert G. Fecal occult blood screening—trial evidence, practice and beyond. Recent Results Cancer Res. 2003;163:248–253. Excluded for study design. [PubMed: 12903859]
  22. Rex DK. Rationale for colonoscopy screening and estimated effectiveness in clinical practice. Gastrointestinal Endoscopy Clinics of North America. 2002;12(1):65–75. Excluded for study design. [PubMed: 11916162]
  23. Saito H, Soma Y, Koeda J. et al. Reduction in risk of mortality from colorectal cancer by fecal occult blood screening with immunochemical hemagglutination test. A case-control study. International Journal of Cancer. 1995;61(4):465–9. Precedes search period. [PubMed: 7759151]
  24. Saito H, Soma Y, Nakajima M. et al. A case-control study evaluating occult blood screening for colorectal cancer with hemoccult test and an immunochemical hemagglutination test. Oncol Rep. 2000;7(4):815–819. Excluded for study quality. [PubMed: 10854550]
  25. Sano Y, Fujii T, Oda Y. et al. A multicenter randomized controlled trial designed to evaluate follow-up surveillance strategies for colorectal cancer: the Japan Polyp Study. Digestive Endoscopy. 2004;16(4):376–378. Does not report appropriate outcomes.
  26. Scheitel SM, Ahlquist DA, Wollan PC. et al. Colorectal cancer screening: a community case-control study of proctosigmoidoscopy, barium enema radiography, and fecal occult blood test efficacy. Mayo Clinic Proceedings. 1999;74(12):1207–13. Precedes search period. [PubMed: 10593348]
  27. Segnan N, Senore C, Andreoni B. et al. Baseline findings of the Italian multicenter randomized controlled trial of “once-only sigmoidoscopy”—SCORE. J Natl Cancer Inst. 2002;94(23):1763–1772. Does not report appropriate outcomes. [PubMed: 12464648]
  28. Sharma VK, Vasudeva R, Howden CW. Colorectal cancer screening and surveillance practices by primary care physicians: results of a national survey. Am J Gastroenterol. 2000;95(6):1551–1556. Excluded for study relevance. [PubMed: 10894595]
  29. Steele RJ, Parker R, Patnick J. et al. A demonstration pilot trial for colorectal cancer screening in the United Kingdom: a new concept in the introduction of healthcare strategies. J Med Screen. 2001;8(4):197–202. Excluded for study relevance. [PubMed: 11743036]
  30. Walsh JM, Terdiman JP. Colorectal cancer screening: scientific review. JAMA. 2003;289(10):1288–96. Excluded for study design. [PubMed: 12633191]
  31. Zappa M, Castiglione G, Grazzini G. et al. “Does fecal occult blood testing really reduce mortality? A reanalysis of systematic review data.” by Moayyedi P and Achkar E. American Journal of Gastroenterology. 2006;101101(10)(10):2433. author reply 2433 –4. Excluded for study design. [PubMed: 17032207]
  32. Zheng S, Chen K, Liu X. et al. Cluster randomization trial of sequence mass screening for colorectal cancer. Diseases of the Colon & Rectum. 2003 461:51–58. Not applicable setting. [PubMed: 12544522]
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