section name header

Info


A. Introduction

  1. Goal is to develop sensitive and specific screening tests
  2. These tests should be inexpensive, easily administered, and reduce mortality/morbidity
  3. For many neoplasms, there is controversy over screening
  4. The screening tests below are directed at asymptomatic, low risk patients
  5. Patients with a family history of specific cancers are automatically not low risk
  6. Tumor markers can provide some help for high risk patients, particularly with masses [13]
  7. Prostate specific antigen (PSA) is currently only routinely used screening marker [13]
  8. Patients with Involuntary Weight Loss [71]
    1. Usually warrants screening for cancer
    2. Standard laboratory blood testing (full chemistry, blood counts, sedimentation rate)
    3. Abdominal ultrasonography (computerized tomography may also be used)
  9. Screening in patients with <5 years life expectancy has no benefit [1]
  10. Hereditary Cancer Syndromes
    1. Higher penetrance and generally at younger age than spontaneous cancers
    2. Usually involve one or more genetic mutations
    3. Screening is typically done at younger age and with more frequent intervals
    4. Recommendations for screening for tumors in patients genetic cancer syndromes are generally not covered here
  11. Whole-body 19F-flurodeoxyglucose PET scanning has been used to detect occult disease
  12. Cholesterol lowering statins have no effect on cancer risk or incidence [17]

B. Breast Cancer (Ca) [12]

  1. Screening Overview
    1. Mammography is the best method for screening currently available
    2. Recommend mammography in women >50 years; consider based on risk in age 40-49 [37]
    3. Screening clinical breast exam detects some Ca missed on mammography
    4. Community based clinical breast exam has ~30% sensitivity
    5. Breast self-examination has not reduced overal mortality but increases breast biopsies
    6. Full-field digital mammography no better than standard methods
    7. Magnetic resonance imgaging (MRI) is more sensitive than mammography
    8. Contrast enhanced MRI should be used for screening in women with high familial breast cancer risk [26,86]
    9. Ultrasound + mammography detects an additional >5 cancers/1000 women but increases false positive rates by about 2 fold [31]
    10. Most patients still detected when symptoms occur rather than through screening [32]
    11. Screening reduces breast ca death 30-46% [90]
  2. Mammography Overview
    1. Reduces risk of death >20% for all age groups
    2. Clear reductions in death for >49 year old; strong trends for >39-49 year olds [26]
    3. Patients with mammography delays of >3 months have 12% lower 5 year survival [32]
    4. Delays of 3-6 months are associated with 7% lower 5 year survival [32]
    5. Unclear which clinical factors predict longer delays in initial diagnosis [33]
    6. Delay in diagnosis by 3 months or more was found NOT to affect survival in another study [34]
    7. Positive predictive value of abnormality on mammography is 3-5% [58]
    8. Use of hormone replacement therapy (HRT) increases risk of abnormal mammogram and overall risk of total and invasive breast Ca [72]
    9. Extensive (>75%) mammographic density associated with ~4.7X increased odds of breast Ca and had poorer detection on mammography [25]
    10. Digital and film mammography have similar accuracy overall, but digital is more accurate in women <50 years, with dense breasts, or premenopausal [89]
    11. Positive predictive value (PPV) of mammography is 22% in one study [31]
    12. Ultraound plus mammography detects >5 cancers/1000 women but reduces PPV to 11% [31]
    13. Mammography missed ~50% of DCIS which are detected on MRI [27]
  3. Mammography Recommendations [37,38,64,69]
    1. Low Risk Patients: Begin age 50 q 1-2years; unclear benefit prior to age 50
    2. Moderate Risk: screen at age 35 then at age 40, then q 1-3 years
    3. Unlikely benefit for low or average risk women age 40-49 years old [9,64]
    4. However, mamography in age <50 is not harmful so individual person should decide [37,69]
    5. Younger women have more fibrous breasts, reducing sensitivy of mammography
    6. Screening mammography improves early detection in women 66-79 years [45]
    7. There is benefit to continuing mammography >69 years, particularly in women with higher bone mineral density (thought to reflect estrogen effects)
    8. Cancer detection rates in women with first degree relative with breast Ca similar to those in women a decade earlier with no family history [58]
    9. Detection of breast Ca with mammographic screening associated with reduced risk of distant metastases compared with similar sized tumors discovered otherwise [81]
    10. Use of HRT reduces sensitivity of mamography [44] and increases abnormalities [72]
    11. Strongly recommend screening mammography, particularly in age >50 [64,69]
    12. Screening mammography is cost effective in women >65 years old without clinically significant comorbidity [2]
  4. Action based on Mammography Screening Results [75]
    1. Suspicious abnormalities or highly suggestive of malignancy: undergo biopsy
    2. Core needle or surgical biopsy may be performed
    3. Need additional imagining evaluation: undergo diagnostic mammography or ultrasonography
    4. Probably benign finding: low risk malignancy, can safely repeat in 6 months
  5. MRI can be used for breast imaging rather than mammography [27,83]
    1. Sensitivity (88%) is superior to mammography
    2. Specificity ~68%
    3. Characteristics independent of breast density, tumor type, menopausal status
    4. Does not obviate need for breast biopsy
    5. Detects ~2X as many DCIS as mammography (DCIS sensitivity ~92%) [27]
    6. MRI clearly indicated for screening women at high risk for breast cancer [12,36]
    7. MRI breast ca screening is cost effective in women with BRCA1/2 mutations [20]
  6. Breast Examination [41]
    1. Physician Exam: every 2-3 years begin age 20; every year begin age 40
    2. Patient Exam: each month begin early; 2 positions, 3 minutes per breast minimum
    3. Self breast exam has not been shown to reduce mortality [12,38]
    4. Indirect evidence suggests that clinical breast exam can reduce mortality
    5. Negative clinical breast exam associated with 50% reduced risk of breast Ca [41]
    6. Either fine-needle aspiration biopsy or ultrasonography for palpable breast abnormality [75]
    7. Diagnostic mammography does not help determine if palpable breast mass should be biopsied [75]
  7. Breast Implants [3]
    1. May reduce sensitivity of self-exam screening for breast cancer
    2. Appear to reduce sensitivity of screening mamography
    3. No effect on false positive rate or prognostic variables in breast cancer
  8. Recommend Baseline Screening during 40s then q1-2 years at age 50 [12]
    1. Considerable controversy exists at this time at which age to begin
    2. Younger women have more fibrous breasts and poorer sensitivity with mamography
    3. Current recommendations suggest yearly exam age 50; screening exam at ~45 years
    4. High risk patients have screening exam age 35-40 and rescreening ages 40-50
  9. Familial Breast Cancer [30,49,50]
    1. Mutatations in BRCA1 or BRCA2 cause autosomal dominant familial breast Ca
    2. Routine DNA screening for BRCA1/2 mutations is not indicated
    3. Recommend BRCA1/2 DNA test for women with the following:
    4. Ashkenazi Jewish women with any first degree relative with breast or ovarian Ca
    5. Two first-degree relatives with breast Ca, one age <50
    6. More than two 1st or 2nd degree relatives with breast Ca
    7. Both breast and ovarian Ca among 1st and 2nd degree relatives
    8. A first degree relative with bilateral breast Ca
    9. Two or more 1st or 2nd degree relatives with ovarian Ca
    10. A 1st or 2nd degree relative with ovarian Ca
    11. A male relative with breast Ca
    12. Monitoring BRCA1/2 carriers with MRI is clearly superior to mammography, ultrasound, and clinical breast examination [12,82]
    13. Women with BRCA1/2 mutations consider prophylactic mastectomy ± oopherectomy or use of anti-estrogenic agents such as tamoxifen, raloxifene [49,50]

C. Ovarian Ca [93]

  1. Decision to routinely screen patients currently depends only on family history
  2. No family history of Ovarian Ca
    1. Screening transvaginal ultrasound (TVUS) is not recommended in ANY women
    2. Screening CA-125 is not recommended in ANY women
    3. Combination of ultrasound AND CA-125 may be of some benefit but is experimental [93]
  3. Positive family history
    1. Routine screening not recommended
    2. May be done after counseling
    3. Generally, combination of TVUS and CA-125 is recommended
  4. Early screening for ovarian CA is recommended in patients with mutant BRCA1 or 2
  5. Familial Ovarian Cancer Syndrome: referral to Gyn-Onc specialist
  6. To date, no demonstrated decline in mortality from ovarian Ca with screening
  7. Serum proteomic patterns under development for screening general population for any stage early ovarian cancer [63]

D. Colorectal Ca (CRC) [4,5,7]

  1. All persons 50 years or older should be screened [4,7]
    1. Fecal Occult Blood Test (FOBT) is strongly recommended
    2. Fecal DNA testing is more sensitive and as specific as FOBT and may replace FOBT [6]
    3. Overall FOBT 10-14% sensitivity for colon cancer or high grade polyps
    4. Quantitative immunochemical FOBT appears superior to standard FOBT (see below) [92]
    5. Fecal DNA testing 14-40% sensitivity for colon cancer or high grade polyps
    6. Sigmoidoscopy has shown clear evidence for reducing mortality
    7. Colonoscopy is probably effective for reducing mortality, but data not clear
    8. People with one first degree relative with CRC have ~2X risk of CRC and should undergo colonoscopy at 40 years, or 10 years before age of youngest affective relative [88]
  2. FOBT
    1. Should be done with guaiac cards (3 samples) every 1-2 years beginning at age 50
    2. Sensitivity for colon cancer <20%, specificity ~95% [6]
    3. Single digital FOBT at primary care exam is not sufficient for screening for colon Ca [85]
    4. Reduces death from colon cancer 15-40% over 10-18 years [56]
    5. HemeSelect test is more sensitive than Hemoccult II test for stool occult blood
    6. Hemeoccult II Sensa had the highest sensitivity (slightly reduced specificity)
    7. Quantitative immunochemical FOBT appears superior to standard FOBT, with ~90% sensitivity/specificity for detection of CRC [92]
    8. Patients with abnormal FOBT should undergo colonoscopy
    9. Colonoscopy or sigmoidoscopy are better for screening for colon cancer than occult blood
  3. Screening Sigmoidoscopy [65]
    1. Every 5 years probably adequate
    2. Repeat sigmoidoscopy 3 years after initial negative exam lead to polyp or mass removal in ~14% of cases; therefore, repeat exams every 3-5 years recommended [73]
    3. Clearly reduces mortality from cancer of the rectum and distal colon [4,7]
    4. Proper screening techniques critical to effective prevention of metastatic disease [62]
    5. Combined with occult blood tests, is an effective method for screening for colon ca [54]
    6. Distal adenomas detected in 12.1% and distal cancers in 0.3% [65]
    7. Referrals for colonoscopy ~5% [65]
    8. Finding of even small (<6mm) adenomas should prompt colonoscopy
    9. Distal adenomas detected on sigmoidoscopy are a risk factor for more proximal lesions
    10. However, about 50% of patients without distal lesions have significant proximal lesions [52]
  4. Colonoscopy [18,21]
    1. The most accurate method for detecting colon cancer [14,53]
    2. More accurate than air contrast barium enema, CT colonography, sigmoidoscopy [14,51]
    3. Screening recommended after age 50 every 10 years [19,53]
    4. Not recomended ages 40-49 for "average risk" persons [35]
    5. Recommended at age 40 for persons with one first degree relative with CRC [88]
    6. increased risk 1.7X of detecting neoplasia in men versus women [21]
    7. Unclear if major benefit in persons with normal (negative) FOBT [18]
    8. Colonoscopy detects 2-2.5 fold more significant adenomas than sigmoidoscopy [15,51,52]
    9. Single colonoscopy at age 55 detects about 50% of total colon cancers early (compared with screening every 10 years with colonoscopy) [54]
    10. Patients in very high risk populations should be screened yearly
    11. Small adenomas found on sigmoidoscopy are a marker for more proximal lesions [51]
    12. Both flat and polypoid adenomas should be evaluated for neoplastic content [46]
    13. Nonpolypoid (flat and depressed) colorectal growths occur in >9% of veterans [95]
    14. Of these nonpolypoid growths, >8% contain in situ or submucosal invasive carcinoma [95]
    15. For individuals with high risk (at least 3 adenomas or any advanced adenoma) on initial testing, repeat colonoscopy at 3 years is recommended (6.6% risk of advanced adenoma on repeat) [42]
  5. Computed Tomographic Colonocoscopy (CTC) [28,94]
    1. Non-invasive virtual colonoscopy: high resolution CT scan and 3 dimensional reconstruction
    2. Early reports of similar sensitivity and specificity as optical colonoscopy [47]
    3. Multicenter study showed inferior sesntivitiy (39-55%) with similar specificity [39]
    4. In large prospective study, identified as many high risk (mainly >9mm) polyps as standard colonoscopy with reduced actual polypectomy and no perforations [26]
    5. Increasing use due to non-invasive nature of test
  6. Rectal Examination a Insensitive way to detect rectal masses
    1. Even with apparent hemorrhoids, more careful evaluation of colorectum is recommended
    2. Sigmoidoscopy + double contrast enema OR colonscopy is recommended
  7. DNA Testing
    1. About 10% of colon cancers are hereditary
    2. These cancers arise from mutations in DNA mismatch repair enzymes
    3. These patients typically have colon and endometrial cancer predispositions without polyps
    4. Syndrome is called Hereditary Nonpolyposis Colon Ca (HNPCC) or Lynch Syndrome
    5. Family members of patients with HNPCC should have DNA testing done
    6. Cancer screening programs have been developed for patients with HNPCC [24]
    7. Colonoscopy q1-2 years beginning age 20-30 (age 30 for MSH6 mutations), or 10 years younger than youngest relative diagnosed with syndrome [24]
    8. Endometrial sampling and transvaginal ultrasound of uterus and ovaries (age 30-35 years) and urinalysis with cytology (age ~30) also recommended [24]
  8. Recommendation [53,54]
    1. Best screening strategy for "average" risk persons is not clear
    2. Recommend an initial usual colonoscopy at age 50-55
    3. Consider CTC as an alternative initial screen (identifies mainly >9mm lesions)
    4. This is followed by occult blood + sigmoidoscopy every 5 years OR
    5. Colonoscopy every 10 years
    6. Critical that at least ONE method be employed in every patient

E. Lung Ca [16,57,77]

  1. Overall evidence is insufficient to recommend for or against screening asymptomatic persons for lung cancer with chest radiography or sputum cytology [77,78]
  2. Recent data indicate that spiral CT scan should be considered for patients at high risk for lung cancer and may lead to reduced mortality due to early detection [61,91]
  3. Computerized Tomography (CT) [16,57,61]
    1. Spiral CT scans are much more sensitive than X-Ray for detecting lung nodules
    2. Detection of earlier disease allows for apparently curative surgical resection [91]
    3. Spiral CT with 0.625mm slices can be obtained in seconds
    4. High rate of non-malignant lung nodules are detected using spiral CT
    5. Lesions <5mm on initial CT can be re-evaluated in 12 months without high risk [74]
    6. Further evaluation of only lesions that have grown to >5mm appears safe
    7. Positron emission tomography (PET) scans can distinguish benign from malignant lesions
    8. Low dose spiral CT combined with PET had excellent detection rates for stage I lung cancers (all were non-small cell) and led to surgical resection [74]
    9. Screening persons with at least a 20-pack year smoking history with spiral CT may be beneficial and should be considered [16]
    10. Unclear if standard CT scanning reduces overal mortality from lung Ca [29]
  4. Convential Radiography (X-Ray)
    1. Many studies have shown no mortality benefit of screening in male smokers
    2. Annual chest radiography has reduced morbidity and mortality in some studies
    3. Two of four randomized trials showed mortality reduction
    4. Lead time and length biases likely contribute to apparent mortality reduction
  5. Sputum cytology screening does not appear to benefit smokers
  6. In patients with abnormal chest radiograph, detection of volatile organic compounds (VOC) was associated with lung cancer (71.7% sensitivity, 66.7% specificity) [40]

F. Prostate Ca [22]

  1. Digital Rectal Examination (yearly for men >50 years old)
    1. Originally considered gold standard
    2. Detects central cancers only, though most prostate malignancies are peripheral
    3. May not detect "curable" disease
  2. Prostate Specific Antigen (PSA) [60,66]
    1. PSA is a glycoprotein produced by both normal and abnormal prostate tissue
    2. PSA levels (secreted into blood) increase with mass of prostate tissue
    3. Thus, benign prostatic hyperplasia (BPH) has elevated levels
    4. BPH, prostatitis, and prostate cancer can all cause elevated PSA levels
    5. Levels >10ng/mL strongly suggest metastatic disease
    6. Levels <4ng/mL suggest benign disease or normal
    7. However, 15% of men with PSA <4.0ng/mL had biopsy proven prostate cancer; 15% of these had Gleason score 7 or higher [79]
    8. Levels >2.5ng/mL have been recommended for biopsy but this is controversial [10,11]
    9. Changes in PSA >0.75ng/mL/year is more specific for cancer than total PSA level
    10. Normal age specific PSA ranges have been derived for the 4-10ng/mL range
    11. Prostate cancers associated with lower levels of free (versus protein bound) PSA than are normal or BPH tissue
    12. Blacks and whites have slightly different reference range
    13. Use of bound/free PSA, PSA velocity, and PSA density are being investigated
  3. PSA and Other Screening Recommendations [60,66,68]
    1. American College of Physicians recommends offerring screening after discussion with patient
    2. American Cancer Society (ACS) and Urologists strongly recommend routine screening
    3. Consider routine screening in patients >50 years old with >10-15 year life expectancy [23]
    4. In general, discussion with patient should determine whether screening is done
    5. Trials are underway to determine clearly if screening reduces mortality but unclear [68]
    6. Preliminary estimates suggest that screening can reduce mortality
    7. For persons with PSA <4.0ng/mL and normal prostate exam, screen q1-2 years
    8. No consistent cutpoint of PSA with simultaneous high sensitivity and specificity [87]
    9. Screening every 2 years for "average" risk persons beginning age 40-45 is probably more effective than annual screening beginning age 50 [55]
    10. For persons with family hstory of prostate cancer, begin screening <40 years of age
    11. Isolated PSA increase should be confirmed >2 weeks later before biopsy due to variations in PSA [70]

G. Cervical And Vaginal Ca

  1. External Genitalia Examination
  2. Papanicalou (PAP) Smear and Pelvic Examination
    1. Yearly once sexually active
    2. May be every 2 years once three consecutive smears are normal
    3. For screening interval of 3 years, there is increased of cervical cancer of 3 per 100,000 persons [76]
    4. May be every 2-3 years once patients are not sexually active
    5. Sensitivity ~50% and specificity ~90% for cytologic abnormalities [48]
    6. Reduces risk of developing invasive cervical cancer >75%
    7. Pap smear is not beneficial and should not be done after hysterectomy for benign disease [80]
  3. Exposure to DES in utero
    1. More intensive screening recommended
    2. At least yearly PAP smears

H. Skin Ca

  1. Careful skin examination
  2. Referral to dermatologist for any suspicious lesions
  3. Attention to congenital nevi
  4. Avoid sun; use sunblocking agents
  5. Melanomas [84]
    1. Evaluate "ABCDE" for all pigmented lesions
    2. The folowing are associated with increased risk for melanoma:
    3. A=asymmetry
    4. B=border irregularity
    5. C=color variation
    6. D=diameter >6mm
    7. E=evolving (getting larger or other changes over time)

I. Cancer of the Oral Cavitary

  1. Risks are tobacco (especially pipes and cigars) and alcohol
  2. Oral cavity exam should be done q3 years through age 40, then yearly

J. Urinary Bladder Ca

  1. Urinalysis not generally recommended for routine screening of bladder cancer
  2. However, presence of microscopic hematuria confirmed on followup should prompt evaluation
  3. Evaluation of "clean catch" urine for cytology is recommended for hematuria
  4. Screening for abnormal urine cytology in high risk patients is recommended
    1. Smoking
    2. Renal Dysfunction, especially stones
    3. Aniline Dye exposures
    4. History of bladder-toxic chemotherapy including cyclophosphamide, ifosfamide
  5. Detection of Survivin [59]
    1. Survivin is found in ~80% of bladder cancers
    2. Survivin is not found in normal urogenital epithelial cells
    3. Western blot for survivin had 100% sensitivity and 95% specificity for bladder cancer
    4. Urine levels of survivin correlate somewhat with tumor load
    5. General screening with survivin is under evaluation

K. Testicular Exam

  1. ~1% of all cancers in men are testicular; most common cancer in men ages 20-34
  2. Exam should be done yearly or biannually by a physician in young men
  3. Men should be taught testicular exam
  4. High risk in patients with cryptochidism, orchiopexy, testicular atrophy

L. Thyroid Exam

  1. Especially in patients with history of head/neck irradiation
  2. Exam every 3 years for patients under age 40, yearly therafter

M. Esophageal Ca [67]

  1. Most prevalent in smokers and heavy alcohol consumption
  2. Adenocarcinoma derives from Barrett Esophagus
  3. Chronic gastroesophageal reflux disease (GERD) is main risk factor
  4. Screening 50 year old men with GERD for Barrett esophagus is cost effective
  5. Screening patients with dysplasia and Barrett esophagus every 5 years is reasonable
  6. Screening patients without dysplasia and Barrett esophagus every 5 years is very costly

N. Annual New Ca Cases and Deaths

  1. Breast: >180,000
  2. Colon: >150,000
  3. Prostate: 150,000
  4. Lung: >180,000
  5. Melanoma: >40,000
  6. New cases and death rates have declined consistenly from 1973 to 2006
  7. Cancer deaths in USA 556,902 in 2003
  8. Increase in adolescent smoking may lead to a lung cancer epidemic, however

References

  1. Walter LC and Covinsky KE. 2001. JAMA. 285(21):27
  2. Mandelblatt JM, Saha S, Teutsch S, et al. 2003. Ann Intern Med. 139(10):835 abstract
  3. Miglioretti DL, Rutter CM, Geller BM, et al. 2004. JAMA. 291(4):442 abstract
  4. Walsh JME and Terdiman JP. 2003. JAMA. 289(10):1288 abstract
  5. Walsh JME and Terdiman JP. 2003. JAMA. 289(10):1297 abstract
  6. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. 2004. NEJM. 351(26):2704 abstract
  7. US Preventive Services Task Force. 2002. Ann Intern Med.137(2):129 abstract
  8. Pignone M, Rich M, Teutsch SM, et al. 2002. Ann Intern Med. 137(2):132 abstract
  9. Miller AB, To T, Baines CJ, Wall C. 2002. Ann Intern Med. 137(5):305 abstract
  10. Punglia RS, D'Amico AV, Catalona WJ, et al. 2003. NEJM. 349(4):335 abstract
  11. Schroder FH and Kranse R. 2003. NEJM. 349(4):393 abstract
  12. Elmore JG, Armstrong K, Lehman CD, Fletcher SW. 2005. JAMA. 293(10):1245 abstract
  13. Perkins GL, Slater ED, Sanders GK, Prichard JG. 2003. Am Fam Phys. 68(6):1075 abstract
  14. Rockey DC, Paulson E, Niedzwiecki D, et al. 2005. Lancet. 365(9456):305 abstract
  15. Schoenfeld P, Cash B, Flood A, et al. 2005. NEJM. 352(20):2061 abstract
  16. Mulshine JL and Sullivan DC. 2005. NEJM. 352(26):2714 (Case Discussion) abstract
  17. Dale KM, Coleman CI, Henyan NN, et al. 2006. JAMA. 295(1):74 abstract
  18. Taylor WC. 2006. JAMA. 295(10):1161 (Case Discussion) abstract
  19. Singh H, Turner D, Xue L, et al. 2006. JAMA. 295(20):2366 abstract
  20. Plevritis SK, Kurian AW, Sigal BM, et al. 2006. JAMA. 295(20):2374 abstract
  21. Regula J, Rupinski M, Kraszewska E, et al. 2006. NEJM. 355(18):1863 abstract
  22. Frankel S, Smith GD, Donovan J, Neal D. 2003. Lancet. 361(9363):1122 abstract
  23. Harrington DW and Munekata MT. 2007. Ann Intern Med. 147(2):104 abstract
  24. Lindor NM, Petersen GM, Hadley DW, et al. 2006. JAMA. 296(12):1507 abstract
  25. Boyd NF, Guo H, Martin LJ, et al. 2007. NEJM. 356(3):227 abstract
  26. Moss SM, Cuckle H, Evans A, et al. 2006. Lancet. 368(9552):2053 abstract
  27. Kuhl CK, Schrading S, Bieling HB, et al. 2007. Lancet. 370(9586):465
  28. Virtual Colonoscopy. 2005. Med Let. 47(1202):13
  29. Bach PB, Jett JR, Pastorino U, et al. 2007. JAMA. 297(9):953 abstract
  30. BRCA Screening. 2007. Med Let. 49(1274):93 abstract
  31. Berg WA, Blume JD, Cormack JB, et al. 2008. JAMA. 299(18):2151 abstract
  32. Richards MA, Westcombe AM, Love SB, et al. 1999. Lancet. 353(9159):1119 abstract
  33. Ramirez AJ, Westcombe AM, Burgess CC, et al. 1999. Lancet. 353(9159):1127 abstract
  34. Sainsbury R, Johnston C, Haward B. 1999. Lancet. 353(9159):1132 abstract
  35. Imperiale TF, Wagner DR, Lin CY, et al. 2002. NEJM. 346(23):1781 abstract
  36. Warner E, Messersmith H, Causer P, et al. 2008. Ann Intern Med. 148(9):671 abstract
  37. Qaseem A, Snow V, Sherif K, et al. 2007. Ann Intern Med. 146(7):511 abstract
  38. UK Trial of Early Detection in Breast Cancer Group. 1999. Lancet. 353(9168):1909 abstract
  39. Cotton PB, Durkalski VL, Pineau BC, et al. 2004. JAMA. 291(14):1713 abstract
  40. Phillips M, Gleeson K, Hughes JMB, et al. 1999. Lancet. 353:1930 abstract
  41. Barton MB, Harris R, Fletcher SW. 1999. JAMA. 282(13):1270 abstract
  42. Laiyemo AO, Murphy G, Albert PS, et al. 2008. Ann Intern Med. 148(6):419 abstract
  43. Gertzsche PC and Olsen O. 2000. Lancet. 355(9198):129 abstract
  44. Kavanagh AM, Mitchell H, Giles GG. 2000. Lancet. 355(9200):270 abstract
  45. Smith-Bindman R, Kerlikowske K, Gebretsadik T, Newman J. 2000. Am J Med. 108(2):112 abstract
  46. Rembacken BJ, Fujii T, Cairns A, et al. 2000. Lancet. 355(9211):1211 abstract
  47. Pickhardt PJ, Choi JR, Hwang I, et al. 2003. NEJM. 349(23):2191 abstract
  48. Nanda K, McCrory DC, Myers ER, et al. 2000. Ann Intern Med. 132(10):810 abstract
  49. US Preventive Services Task Force. 2005. Ann Intern Med. 143(5):355 abstract
  50. Nelson HD, Huffman LH, Fu R, Harris EL. 2005. Ann Intern Med. 143(5):362 abstract
  51. Lieberman DA, Weiss DG, Bond JH, et al. 2000. NEJM. 343(3):162 abstract
  52. Imperiale TF, Wagner DR, Lin CY, et al. 2000. NEJM. 343(3):169 abstract
  53. Sonnenberg A, Delco F, Inadomi JM. 2000. Ann Intern Med. 133(8):573 abstract
  54. Frazier AL, Colditz GA, Fuchs CS, Kuntz KM. 2000. JAMA. 284(15):1954 abstract
  55. Ross KS, Carter HB, Pearson JD, Guess HA. 2000. JAMA. 284(11):1399 abstract
  56. Mandel JS, Church TR, Bond JH, et al. 2000. NEJM. 343(22):1603 abstract
  57. Wallace J. 2003. Ann Intern Med. 139(6):499 abstract
  58. Kerlikowske K, Carney PA, Geller B, et al. 2000. Ann Intern Med. 133(11):855 abstract
  59. Smith SD, Wheller MA, Plescia J, et al. 2001. JAMA. 285(3):324 abstract
  60. Barry MJ. 2001. NEJM. 344(18):1373 abstract
  61. Screening for Lung Cancer. 2001. Med Let. 43(1109):61 abstract
  62. Ashley OS, Nadel M, Ransohoff DF. 2001. Am J Med. 111(8):643 abstract
  63. Petricoin EF, Ardekani AAM, Hitt BA, et al. 2002. Lancet. 359(9305):573
  64. Nystrom L, Andersson I, Bjurstam N, et al. 2002. Lancet. 359(9310):909 abstract
  65. UK Flexible Sigmoidoscopy Screening Trial Investigators. 2002. Lancet. 359(9314):1291 abstract
  66. Harris R and Lohr KN. 2002. Ann Intern Med. 137(11):915
  67. Inadomi JM, Sampliner R, Lagergren J, et al. 2003. Ann Intern Med. 138(3):176 abstract
  68. US Preventive Services Task Force. 2002. Ann Intern Med. 137(11):915 abstract
  69. Fletcher SW and Elmore JG. 2003. NEJM. 348(17):1672 abstract
  70. Eastham JA, Riedel E, Scardino PT, et al. 2003. JAMA. 289(20):2695 abstract
  71. Hernandez JL, Riancho JA, Matorras P, Gonzalez-Macias J. 2003. Am J Med. 114(8):631 abstract
  72. Chlebowski ST, Hendrix SL, Langer RD, et al. 2003. JAMA. 289(24):3243 abstract
  73. Schoen RE, Pinsky PF, Weissfeld JL, et al. 2003. JAMA. 290(1):41 abstract
  74. Pastorino U, Bellomi M, Landoni C, et al. 2003. Lancet. 362(9382):593
  75. Kerlikowske K, Smith-Bindman R, Ljung BM, Grady D. 2003. Ann Int Med. 139(4):274 abstract
  76. Sawaya GF, McConnell KJ, Kulasingam SL, et al. 2003. 349(16):1501 abstract
  77. US Preventive Services Task Force. 2004. Ann Intern Med. 140(9):738 abstract
  78. Humphrey LL, Teutsch S, Johnson M. 2004. Ann Intern Med. 140(9):740 abstract
  79. Thompson IM, Pauler DK, Goodman PJ, et al. 2004. NEJM. 350(22):2239 abstract
  80. Sirovich BE and Welch HG. 2004. JAMA. 291(24):2990 abstract
  81. Joensuu H, Lehtimaki T, Holli K, et al. 2004. JAMA. 292(9):1064 abstract
  82. Warner E, Plewes DB, Hill KA, et al. 2004. JAMA. 292(11):1317 abstract
  83. Bluemke DA, Gatsonis CA, Chen MH, et al. 2004. JAMA. 292(22):2735 abstract
  84. Abbasi NR, Shaw HM, Rigel DS, et al. 2004. JAMA. 292(22):2771 abstract
  85. Collins JF, Lieberman DA, Durbin TE, et al. 2005. Ann Intern Med. 142(2):81 abstract
  86. MARIBS Study Group. 2005. Lancet. 365:1769 abstract
  87. Thompson IM, Ankerst DP, Chi C, et al. 2005. JAMA. 294(1):66 abstract
  88. Eisen GM and Weinberg DS. 2005. Ann Intern Med. 143(3):190 abstract
  89. Pisano ED, Gatsonis C, Hendrick E, et al. 2005. NEJM. 353(17):1773 abstract
  90. Berry DA, Cronin KA, Plevritis SK, et al. 2005. NEJM. 353(17):1784 abstract
  91. International Earloy Lunch Cancer Action Program Investigators. 2006. NEJM. 355(17):1763 abstract
  92. Levi Z, Rozen P, Hazazi R, et al. 2007. Ann Intern Med. 146(4):244 abstract
  93. Testing for Ovarian Cancer. 2007. Med Let. 49(1264):53
  94. Kim DH, Pickhardt PJ, Taylor AJ, et al. 2007. NEJM. 357(14):1403 abstract
  95. Soetikno RM, Kaltenbach T, Rouse RV, et al. 2008. JAMA. 299(9):1027 abstract