Therapeutics
Annual or biennial FOBT screening reduced colorectal cancer mortality, but not all-cause mortality, at 30 years
Shaukat A, Mongin SJ, Geisser MS, et al. Long-term mortality after screening for colorectal cancer. N Engl J Med. 2013;369:1106-14.
Clinical impact ratings: F ★★★★★★✩ g ★★★★★★✩ Question
*Information provided by author.
Does colorectal cancer screening using fecal occult blood testing (FOBT) reduce long-term all-cause and disease-specific mortality?
†See Glossary.
Methods
Sources of funding: Veterans Affairs Merit Review Award Program; National Institutes of Health; National Cancer Institute.
Design: Randomized controlled trial (Minnesota Colon Cancer Control Study). Allocation: {Concealed}*.† Blinding: Blinded† (adjudicators of colorectal cancer mortality during the first 15 y of the study). Follow-up period: 30 years. Setting: Minnesota and Wisconsin, USA. Participants: 46 551 healthy adults 50 to 80 years of age (mean age 62 y, 52% women). Intervention: Annual colorectal cancer screening using FOBT (n = 15 570), biennial screening using FOBT (n = 15 587), or usual care (n = 15 394). Screening was done from 1976 to 1982 and 1986 to 1992, and persons with a positive FOBT were invited for further diagnostic tests, including colonoscopy. Outcomes: Colorectal cancer mortality and all-cause mortality, based on data obtained from annual study follow-ups to 1999 and the US National Death Index from 1999 to 2008. Participant follow-up: 100% were included in the intentionto-treat analysis.
Main results At 30 years, 71% of participants had died. Annual or biennial screening with FOBT reduced colorectal cancer mortality, but not all-cause mortality, compared with usual care (Table). In subgroup analyses by sex, biennial screening reduced colorectal cancer mortality compared with usual care in men (relative risk [RR] 0.63, 95% CI 0.48 to 0.82) but not in women (RR 0.92, CI 0.72 to 1.18, P = 0.04 for interaction); annual screening reduced colorectal cancer mortality compared with usual care in both men and women (P = 0.30 for interaction). Screening effects for colorectal cancer mortality did not differ by age group.
Conclusion In healthy adults, annual or biennial screening with fecal occult blood testing reduced colorectal cancer mortality, but not all-cause mortality, at 30 years. Annual or biennial FOBT vs usual care in healthy adults‡ Outcomes
Cumulative event rates§ Annual Biennial Usual FOBT FOBT care
Colorectal cancer mortality
2%
—
—
2%
All-cause mortality
71%
—
—
71%
71%
At 30 y RRR (95% CI) NNT (CI)
3%
32% (18 to 44)
105 (76 to 186)
3%
22% (7 to 35)
152 (96 to 477)
71%
0% (−1 to 1)
Not significant
1% (−1 to 2)
Not significant
‡FOBT = fecal occult blood testing; other abbreviations defined in Glossary. RRR, NNT, and CI calculated from Kaplan-Meier–estimated relative risks and control event rates in article. §Based on Kaplan-Meier estimates.
JC2
© 2014 American College of Physicians
For correspondence: Dr. A. Shaukat, University of Minnesota, Minneapolis, MN, USA. E-mail [email protected]. ■
Commentary Guaiac-based FOBTs have well-established efficacy for colorectal cancer screening but are being replaced by immunologic FOBTs, which are more sensitive and specific than the guaiac-based test currently recommended (1). In some affluent countries, both types of FOBT are being replaced by colonoscopy (in the USA) (2) or sigmoidoscopy. We can learn useful lessons from the study by Shaukat and colleagues. Because there are no randomized trials of screening with immunologic tests, evidence for their effectiveness depends on strong studies of the guaiac-based test and the assumption that the immunologic test performs at least as well as the rehydrated (more sensitive) test used in this study. Although preventive trials have reported follow-up of 18 to 20 years, follow-up in the study by Shaukat and colleagues spans the full period of recommended screening—ages 50 to 75 years. Mortality reduction persisted long after randomized screening ended, probably because many patients remained in screening programs after the trial and because removal of adenomas is expected to have effects for a decade or more by preventing their progression to cancer. Effectiveness of annual screening with a guaiac-based test was comparable to flexible sigmoidoscopy, the other screening test supported by randomized trial evidence (3). Of note, age and sex influenced effectiveness, as other studies have shown for right- vs left-sided cancers, although not enough to change clinical policy. Reasons for these differences in biologic behavior are not yet well-understood. Although the 32% relative reduction in colorectal cancer deaths seems large, the absolute effect seems much smaller, with only about 6 deaths prevented per 1000 persons screened for 30 years, based on raw event rates. In addition, screening did not reduce total mortality. But even if the only effect of screening were a net reduction in deaths as observed for colorectal cancer, it would be such a small percentage of total deaths that it would be statistically undetectable. Does this damage the case for screening? I think not. Most people would value not dying of colorectal cancer— with a cancer diagnosis, major surgery, and possibly colostomy and chemotherapy along the way—regardless of whether they lived longer because of screening. Robert H. Fletcher, MD, MSc Harvard Medical School Boston, Massachusetts, USA References 1. Brenner H, Tao S. Eur J Cancer. 2013;49:3049-54. 2. Klabunde CN, Djenaba JA, King JB, White A, Plescia M; Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep. 2013;62:881-8. 3. Atkin WS, Edwards R, Kralj-Hans I, et al; UK Flexible Sigmoidoscopy Trial Investigators. Lancet. 2010;375:1624-33.
21 January 2014 | ACP Journal Club | Volume 160 • Number 2
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/929674/ by a Universite Laval Biblioteque User on 07/30/2017
Annual or biennial FOBT screening reduced colorectal cancer mortality, but not all-cause mortality, at 30 years
Shaukat A, Mongin SJ, Geisser MS, et al. Long-term mortality after screening for colorectal cancer. N Engl J Med. 2013;369:1106-14.
Clinical impact ratings: F ★★★★★★✩ g ★★★★★★✩ Question
*Information provided by author.
Does colorectal cancer screening using fecal occult blood testing (FOBT) reduce long-term all-cause and disease-specific mortality?
†See Glossary.
Methods
Sources of funding: Veterans Affairs Merit Review Award Program; National Institutes of Health; National Cancer Institute.
Design: Randomized controlled trial (Minnesota Colon Cancer Control Study). Allocation: {Concealed}*.† Blinding: Blinded† (adjudicators of colorectal cancer mortality during the first 15 y of the study). Follow-up period: 30 years. Setting: Minnesota and Wisconsin, USA. Participants: 46 551 healthy adults 50 to 80 years of age (mean age 62 y, 52% women). Intervention: Annual colorectal cancer screening using FOBT (n = 15 570), biennial screening using FOBT (n = 15 587), or usual care (n = 15 394). Screening was done from 1976 to 1982 and 1986 to 1992, and persons with a positive FOBT were invited for further diagnostic tests, including colonoscopy. Outcomes: Colorectal cancer mortality and all-cause mortality, based on data obtained from annual study follow-ups to 1999 and the US National Death Index from 1999 to 2008. Participant follow-up: 100% were included in the intentionto-treat analysis.
Main results At 30 years, 71% of participants had died. Annual or biennial screening with FOBT reduced colorectal cancer mortality, but not all-cause mortality, compared with usual care (Table). In subgroup analyses by sex, biennial screening reduced colorectal cancer mortality compared with usual care in men (relative risk [RR] 0.63, 95% CI 0.48 to 0.82) but not in women (RR 0.92, CI 0.72 to 1.18, P = 0.04 for interaction); annual screening reduced colorectal cancer mortality compared with usual care in both men and women (P = 0.30 for interaction). Screening effects for colorectal cancer mortality did not differ by age group.
Conclusion In healthy adults, annual or biennial screening with fecal occult blood testing reduced colorectal cancer mortality, but not all-cause mortality, at 30 years. Annual or biennial FOBT vs usual care in healthy adults‡ Outcomes
Cumulative event rates§ Annual Biennial Usual FOBT FOBT care
Colorectal cancer mortality
2%
—
—
2%
All-cause mortality
71%
—
—
71%
71%
At 30 y RRR (95% CI) NNT (CI)
3%
32% (18 to 44)
105 (76 to 186)
3%
22% (7 to 35)
152 (96 to 477)
71%
0% (−1 to 1)
Not significant
1% (−1 to 2)
Not significant
‡FOBT = fecal occult blood testing; other abbreviations defined in Glossary. RRR, NNT, and CI calculated from Kaplan-Meier–estimated relative risks and control event rates in article. §Based on Kaplan-Meier estimates.
JC2
© 2014 American College of Physicians
For correspondence: Dr. A. Shaukat, University of Minnesota, Minneapolis, MN, USA. E-mail [email protected]. ■
Commentary Guaiac-based FOBTs have well-established efficacy for colorectal cancer screening but are being replaced by immunologic FOBTs, which are more sensitive and specific than the guaiac-based test currently recommended (1). In some affluent countries, both types of FOBT are being replaced by colonoscopy (in the USA) (2) or sigmoidoscopy. We can learn useful lessons from the study by Shaukat and colleagues. Because there are no randomized trials of screening with immunologic tests, evidence for their effectiveness depends on strong studies of the guaiac-based test and the assumption that the immunologic test performs at least as well as the rehydrated (more sensitive) test used in this study. Although preventive trials have reported follow-up of 18 to 20 years, follow-up in the study by Shaukat and colleagues spans the full period of recommended screening—ages 50 to 75 years. Mortality reduction persisted long after randomized screening ended, probably because many patients remained in screening programs after the trial and because removal of adenomas is expected to have effects for a decade or more by preventing their progression to cancer. Effectiveness of annual screening with a guaiac-based test was comparable to flexible sigmoidoscopy, the other screening test supported by randomized trial evidence (3). Of note, age and sex influenced effectiveness, as other studies have shown for right- vs left-sided cancers, although not enough to change clinical policy. Reasons for these differences in biologic behavior are not yet well-understood. Although the 32% relative reduction in colorectal cancer deaths seems large, the absolute effect seems much smaller, with only about 6 deaths prevented per 1000 persons screened for 30 years, based on raw event rates. In addition, screening did not reduce total mortality. But even if the only effect of screening were a net reduction in deaths as observed for colorectal cancer, it would be such a small percentage of total deaths that it would be statistically undetectable. Does this damage the case for screening? I think not. Most people would value not dying of colorectal cancer— with a cancer diagnosis, major surgery, and possibly colostomy and chemotherapy along the way—regardless of whether they lived longer because of screening. Robert H. Fletcher, MD, MSc Harvard Medical School Boston, Massachusetts, USA References 1. Brenner H, Tao S. Eur J Cancer. 2013;49:3049-54. 2. Klabunde CN, Djenaba JA, King JB, White A, Plescia M; Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep. 2013;62:881-8. 3. Atkin WS, Edwards R, Kralj-Hans I, et al; UK Flexible Sigmoidoscopy Trial Investigators. Lancet. 2010;375:1624-33.
21 January 2014 | ACP Journal Club | Volume 160 • Number 2
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/929674/ by a Universite Laval Biblioteque User on 07/30/2017
