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Cancer detection


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Cancer detection

  2. 2. Top Ten Leading Cancer Site in Male 2000 - 2009 Lung 32.4 Prostate 14.8 Colon 13.6 Lymph Node 12.5 Liver 12.5 Rectal 11.4 Skin 11.2 Gastric 10.7 Larynx 8.2Thyroid Gland 7.2Nasopharynx 7 0 5 10 15 20 25 30 35
  3. 3. Ten Leading Cancer Sites by Gender Adjusted 2000 - 2009 119.9 Breast 24.1 Colorectal 23.3 Cervix 22.8 Ovary 21.2Head and Neck 20.7 Lung 18.8 Corpus Uteri 16.6 Prostate 16.5 Thyroid Gland 11.3 Lymph Node 0 20 40 60 80 100 120
  4. 4. Site 1975-1977 1984-1986 1996-2002 All sites 50 53 66 Breast (female) 75 79 89 Colon 51 59 65 Leukemia 35 42 49 Lung and bronchus 13 13 16 Melanoma 82 86 92 Non-Hodgkin lymphoma 48 53 63 Ovary 37 40 45 Pancreas 2 3 5 Prostate 69 76 100 Rectum 49 57 66 Urinary bladder 73 78 82*5-year relative survival rates based on follow up of patients through 2003.†Recent changes in classification of ovarian cancer have affected 1996-2002 survival rates.Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control andPopulation Sciences, National Cancer Institute, 2006.
  5. 5.  Disease incidence should be high Diagnosed at early stage but without any signs Early diagnosis and treatment should be more effective than late treatment Benefit of early treatment should be higher than the cost and harmfulness of screening
  6. 6.  Being a womanAge Genetic factors - mutations in BRCA1 or BRCA2;50-60% of women inheriting a BRCA1 mutationfrom either parent will have breast cancer by age 70 Family history of breast cancer (not related toBRCA mutations) Personal history of hyperplastic breast disease
  7. 7. Personal history of breast cancer Race: incidence is higher in Caucasian comparedwith African-American, Hispanic or Asian womenRadiation treatment: chest irradiation as a child/youngwoman can significantly increase risk of developingbreast cancerMenstrual history: early menarche (<12 yr) or latemenopause (>50yr) has some association with increasedrisk. Also nulliparous, or first childbirth at >30 yrs.
  8. 8.  Oral contraceptives - remains controversial Hormone replacement therapy - >5 years of therapy with combined estrogen and progesterone may increase risk Not breast feeding Diet and obesity; physical activity Smoking - still being investigated Alcohol - 2-5 drinks/day can increase risk x 1.5 over non-drinkers.
  9. 9. StudyAge Mortality reduction (%)HIP 40-64 24Malmö 45-69 19Sweeden 40-74 32Edinburgh 45-64 21Stockholm 40-64 26Canada-1 40-49 -3Canada-2 50-59 -2Gothenburgh 39-59 16All studies 39-74 24 CA Cancer J Clin 2003; 53:141-169
  10. 10.  All women starting at 40 years old should be screened with mammography
  11. 11.  EVERY YEAR
  12. 12.  Provide equivalent detection level compared with conventional mammography Offers a lower average dose of radiation Easier access to images and computer- assisted diagnosis Superior in pre and postmenopausal women with dense breast and women under the age of 50
  13. 13. Breast USIt is more subjective than mammography Could not detect microcalcifications Sonographic contrast is week betweentumor and adipous tissue Documentation is problematic Not useful for screening
  14. 14.  Expensive Higher sensitivity with lower spesificity Not safe for detection of microcalcification Useful for additional screening method for high risk women having mammography
  15. 15.  Highly sensitive but high false positive rate Useful for screening BRCA patients May be useful in staging known breast cancer May become an important screening modality
  16. 16.  Tc99m sestamibi scan (Miraluma) Tomosynthesis (variation of mammogram)
  17. 17.  Greatly increased risk RR>4.0  Inherited genetic mutations for breast cancer  ≥ 2 first degree relatives with breast cancer diagnosed at early age  Personal history of breast cancer  Age >65 (increasing risk with increasing age to 80)
  18. 18.  Mammographic screening should be start at 30 years of age (rarely before this age) Screening interval can be shorter (e.g. 6 mos) MRI can be added US can be added
  19. 19.  Yearly mammograms are recommended starting at age 40. A clinical breast exam should be part of a periodic health examination, about every 3 years for women in their 20s and 30s. Asymptomatic women aged 40 and older should continue to undergo a clinical breast exam, preferably annually*. Beginning in their early 20s, women should be told about the benefits and limitations of breast-self examination. Women should know how their breasts normally feel and report any breast changes promptly to their health care providers. Beginning at age 40 years, annual CBE should be performed prior to mammography
  20. 20.  incidence decreased >50%the past 30 years American Cancer Society estimates 11,270 new cases of cervical cancer in the United States in 2009, with 4,070 deaths from the disease
  21. 21.  should begin at21 years of age Screening done regardless of the age of onset of sexual intercourse
  22. 22.  Even at a high rate of infection with HPV in sexually active adolescents,invasive cervical cancer is very rare in women younger than 21 years old.
  23. 23.  Cervical cytology screening :21–29 years, every 2 years usingconventional or liquid-based cytology.30 years and older with three consecutive cervical cytology test results that are negative for CIN and malignancy may be screened every 3 years> 65 years old no testing.
  24. 24.  May require more frequent cytology screening  Women who are infected with human immunodeficiency virus (HIV)  Women who are immunosuppressed (such as those who have received renal transplants)  Women who were exposed to diethylstilbestrol in utero  Women previously treated for CIN 2, CIN 3, or cancer
  25. 25.  It has been demonstrated, however, that the rate of dysplasia decreases as the number of sequential negative Pap test results increases
  26. 26.  Formal cost-effective analysis of data from this national program showed that the most cost- effective strategy for cervical cancer screening is cytology testing no more often than every 3 years in women with prior normal screening test results
  27. 27.  May discontinue cytology screening withthree or more negative cytology test results in a row and no abnormal test results in the past 10 years.
  28. 28.  70 % of cervical cancer result from infection with HPV 16 and 18 90% of Genital wart are caused by 6 and 11
  29. 29. Organization/NationStart Vaccine Catch UpACIP 11-12 13-2 6American College of Ob-Gyn 9-26American Cancer Society 11-18 NoneWorld Health Organization 9-13
  30. 30.  Anal Pap smears  4000 cases of anal cancer in women in 2003 and in contrast to cervical cancer the rates are increasing
  31. 31.  55 – 74:> 30 pack years smoking history ceased smoking < 15 years > 50 years> 20 pack year smoking history one additional risk factor
  32. 32. % Stage I I-ELCAP 85 Mayo 69Turino 73Randomized Trials LSS 43Depiscan 38 DANTE 57 NELSON 64
  33. 33.  Many nodules that require follow-up Potential Psychological Impact Surgery for Benign Disease Lung Cancer Deaths in Screened Participants Interval Cancers (failure of screening) Potential Overdiagnosis Cases
  34. 34.  Prostate Lung Colo-rectal Ovarian Cancer Screening Trial Determine effects of screening in mortality among men and women aged 55 to 74 Completed in 2005
  35. 35. Randomized 154,900 Individuals Age 55-74 to CXR or Usual Care (4 years)Screening Adherence Was 86% Baseline and 79-84% Yearly – 11% Screening Done in Usual CareJAMA 2011; 306: 1865-1873
  36. 36. • Annual Screening with CXR (4 years) Did Not Reduce Lung Cancer Mortality Compared to Usual Care.• In Subset Analysis of NLST Eligible Participants, There Was No Mortality Reduction in the Chest X-ray Screened Arm.JAMA 2011; 306: 1865-1873
  37. 37.  Incidence Rate of Lung Cancer: per 10,000 Person Years on Control Arm (Intervention)  Never Smoker: 2.5 (3.3)  Former Smoker: 18.7 (19.3)  Current Smoker: 71.4 (79.9)Tammemagi et al. JNCI 2011; 103: 1058-68
  38. 38. 40,000 Low-dose fast spiral CT PLCOSmokerFormer smoker30 pk yr RandomizedAge 55-74 CXR 10,000 0 1 2 ACRIN Years CP1066773-57
  39. 39.  August 2002 - April 2004 Enrollment  Three rounds of screening through September 2007 Followed for Events through December 31, 2009  Median F/U = 6.5 years; Max 7.4 years Adherence to Screening  95% on CT arm: 93% on CXR  Average annual rate of CT in CXR arm was 4.3%NEJM 2011 epub June 29
  40. 40. CT CXRAbnormal Screen 24.2% 6.9%False Positive 96.4% 94.5%Clinically Significant 7.5% 2.1%other abnormalitiesTotal Lung Cancers 1,060 941LC per 100,000 person - years 645 572NEJM 2011 epub June 29
  41. 41. Diagnostic F/U ofPositive Screen CT CXR• Imaging 58% 78%– PET 8% 8%• FNA 1.8% 3.5%• Bronchoscopy 3.8% 4.5%• Surgical: Mediastinoscopy, 4.0% 4.8% Thorascopy, or ThoracotomyNEJM 2011 epub June 29
  42. 42. CT CXRTotal Lung Cancers 1,060 941Screen-detected Lung Cancer 649 279Lung Cancer after Negative Screen 44 137Either Missed Screening or 367 525After Screening Phase NEJM 2011 epub June 29
  43. 43. • 20% Mortality Reduction from Lung Cancer• 6.7% All Cause Mortality Reduction• 320 Persons Needed to be Screened with LDCT to Prevent One DeathNEJM 2011 epub June 29
  44. 44.  Screening with LDCT is Recommended for High-Risk Individuals Meeting the NLST Criteria (2A) Also Recommend Screening for (2B) – Age >50 Years and ≥20 Pk Years and One Additional Risk Factor Other Than Second Hand accessed 11/8/2011
  45. 45. 15 q 251) Amos et al. Nature Genetics 2008; 40:616-22.2) Hung et al. Nature 2008; 452:633-37. 15 q 241) Thorgeirsson et al. Nature 2008; 452:638-42. (Associated with nicotine dependence, lung cancer and vascular disease)
  46. 46.  Airway epithelial cells  Gene expression profiling  Chromosomal aneusomy – FISH  Gene methylation Blood biomarkers  Serum proteins  Autoantibodies to tumor antigens  Gene expression profiles in PBMC Breath analysis of VOC Urine markers of carcinogens
  47. 47.  573 case/control study with match for age sex and smoking  Sensitivity 40%; Specificity 90%; Accuracy 88%  Detect some cancers 3-5 years in advance of symptoms Autoantibodies to 6 cancer antigens  P53; NY-ESO-1; CAGE; GBU4-5; Annexin 1 and SOX2 Murray et al Ann Oncol ePub Feb 2010 and ASCO posters 2010
  48. 48. New York Times
  49. 49.  1/3 of compounds detected by solid phase microextraction were hydrocarbons  Aromatic hydrocarbons  Alcohols  Aldehydes  Ketones  Esters  Sulfur compounds  Nitrogen containing compounds  Halogenated compoundsLigor M et al. Clin Chem Lab Med 2009; 47:550-60.
  50. 50. Prostate Cancer Early DetectionGuidelines >50 years with at least a 10 year life expectancy should receive information regarding possible benefits and limitations of finding and treating prostate cancer early, and should be offered both the PSA blood test and digital rectal exam annually Men in high risk groups (African Americans, men with close family members---fathers, brothers, or sons---who have had prostate cancer diagnosed at a young age) should be informed of the benefits and limitations of testing and be offered testing starting at age 45
  51. 51. .Types of Tests Diagnostic Tests - Tests done because of an identified problem (disease is suspected) Screening Tests -Test done on people who have no symptoms of disease There is widespread agreement on the use of diagnostic tests for prostate cancer Screening for prostate cancer is much more controversial
  52. 52. .Changes in the PSA Era  Tyrol, Austria 42% mortality reduction  Olmstead County, Minnesota 22% mortality reduction  SEER Decreased mortality in white men  Department of Defense Increased early stage disease
  53. 53. . Prostate cancer death rates have fallen during the PSA era, but it is not clear this is primarily due to screening Other possible reasons for this decline:  Disease is found earlier because of  increased awareness  utilization of diagnostic PSA testing  Improved treatments
  54. 54. . False negative results False positive results Overdiagnosis
  55. 55. . False negative results – PSA and DRE “normal”, but cancer is present – May lead to false reassurance, delayed diagnosis Research has shown that no cut-off value of PSA is completely reliable to rule-out cancer – Prostate Cancer Prevention Trial end of study biopsies found cancer in some men with PSA less than 1.0 ng/ml
  56. 56. 4.0+ Screen 10,000 Men PSA 4+ 7.6% PSA 4+ 760 Positive biopsy 25% Cancer 190 High grade 19% High grade 36<4.0 PSA <4 9240 Cancer 1386 “Normal PSA” 92.4% High grade 208 Positive biopsy 15% High grade 15% PSA SEER, PCAW, Prostate Cancer Prevention Trial Data
  57. 57. . False negative results False positive results  PSA and/or DRE abnormal, but no cancer found  Can lead to worry, additional tests, and increased costs
  58. 58. . False negative results False positive results Overdiagnosis  Some (many?) cancers found by screening grow very slowly and will never cause problems
  59. 59. .New Findings in Screening Results from 2 major, long-term studies reported this year – their findings conflict  ERSPC (European Randomized Screening for Prostate Cancer)  PLCO (Prostate, Lung, Colon and Ovarian)
  60. 60.  Began in 1991 in seven European countries 162,000 men aged 55 to 69 randomized to screening vs usual care Median follow-up about nine years
  61. 61. Findings More cancers detected with screening  5990 cancers in screening group  4307 cancers in control group Fewer prostate cancer deaths in screening group  261 deaths in screening group  363 deaths in control group Conclusion: 20% lower prostate cancer deaths in screening group
  62. 62.  Multiple concerns/questions:  Minimal-to-no participation of men of African origin  Different screening and follow-up protocols  Different PSA levels and DRE usage  Variable treatment and outcomes (quality questions)  To prevent one prostate cancer death  1410 men screened  48 men treated (with attendant risks, side- effects, complications) Bottom line  Screening every 4 years, with PSA threshold of 3 ng/ml may decrease chance of prostate cancer death  Unclear how this correlates to current U.S. pattern of annual screening with different PSA “triggers” (2.5 – 4.0 ng/ml)  High level of overdiagnosis and overtreatment with this approach (although these numbers are likely to go down after longer follow up period)
  63. 63.  Began in 1993, ten U.S. Centers 73,000 men aged 55 to 74 randomized to screening annually vs routine follow-up Median follow-up about ten years
  64. 64. Findings At 7 years, screening found more cases of cancer  2,820 prostate cancers in annual screening group  2332 cases in “usual care” group More prostate cancer deaths in screening group  7 years: 50 deaths among annually screened compared with 44 in usual care group  10 years: 92 deaths in annually screened vs 82 in usual care Conclusion – No mortality benefit with screening  Prostate cancer deaths similar in both groups
  65. 65.  Questions/concerns with study  44% of men had at least one PSA test prior to study  May have excluded more aggressive prevalent cancers  Selectively included men with prostate cancers not detected by PSA screening (bias against showing a screening effect)  Many men in the “usual care” group were screened during the course of the study  Initially powered for 20% contamination, later revised to 38%  PSA screening in control group : 40% first year; 52% by year 6  Less than half of those with a positive screen result had a biopsy  Insufficient African American participation (< 5%) to allow specific analysis of outcomes in this group Bottom line – no difference in death rates at 10 years between intensively screened and less-intensively screened men
  66. 66. New Findings in Treatment JAMA, September 2009
  67. 67. Study published September 2009 14,500 men aged 65 + with localized prostate cancer No active treatment for at least 6 mos following prostate cancer diagnosis At 10 years, 9% of men had died of prostate cancer  1017 men died of prostate cancer  5721 men died of other causes  7420 men still aliveApproximately 11% African Americans in study population, but authors did not report findings separately for this group
  68. 68. Summary PotentialBe PotentialHar nefits ms• PSA screening detects cancers • False positives are common. earlier. • Overdiagnosis and overtreatment• Treating PSA-detected cancers is a problem, but magnitude is may be more effective, but uncertain. this is uncertain. • Treatment-related side effects are• PSA may contribute to the fairly common. declining death rate but the extent is unclear Bottom line: Uncertainty about degree of benefits and magnitude of harms
  69. 69. Current ACS Screening Guidelines Men age 50 and over with at least a 10 year life expectancy should receive information regarding possible benefits and limitations of finding and treating prostate cancer early, and should be offered both the PSA blood test and digital rectal exam annually Men in high risk groups (African Americans, men with close family members---fathers, brothers, or sons---who have had prostate cancer diagnosed at a young age) should be informed of the benefits and limitations of testing and be offered testing starting at age 45
  70. 70.  50 years of age No history of adenoma or colon cancer No history of inflammatory bowel disease Negative family history
  71. 71.  Adenoma/sessile serrated polyp History of colorectal cancer Inflammatory bowel disease Positive family history
  72. 72.  Lynch Syndrome (hereditary nonpolyposis colorectal cancer) Polyposis syndrome  Classical familial adenomatouspolyposis  Attenuated Familial AdenomatousPolposis  MUTYH-Associated Polyposis  PeutzhJeghers Syndrome  Juvenile Polyposis Syndrome  Serrated Polyposis Syndrome
  73. 73. Sporadic (average risk) (65%–85%) Family history (10%–30%) Raresyndromes (<0.1%) Hereditary nonpolyposis colorectal cancer (HNPCC) (5%) Familial adenomatous polyposis (FAP) (1%) CENTERS FOR DISEASE CONTROL AND PREVENTION
  74. 74. Normal to Adenoma to Carcinoma Human colon carcinogenesisprogresses by the dysplasia/adenoma to carcinoma pathway
  75. 75.  Cancer Prevention  Removal of pre-cancerous polyps prevent cancer (unique aspect of colon cancer screening) Improved survival  Early detection markedly improves chances of long term survival
  76. 76.  Fecal Occult Blood Testing (FOBT)  Guaiac  Immunochemical Flexible Sigmoidoscopy (FSIG) FSIG + FOBT Colonoscopy Double Contrast Barium Enema (DCBE)
  77. 77.  American Cancer Society U. S. Multi-Society Task Force on Colorectal Cancer  American Gastroenterological Association  American College of Gastroenterology  American Society of Gastrointestinal Endoscopists American College of Radiology
  78. 78.  Two new tests recommended:  stool DNA (sDNA) and  computerized tomographic colonography (CTC) – sometimes referred to as virtual colonoscopy The guidelines establish a sensitivity threshold for recommended tests The guidelines delineate important quality- The full article can be accessed at: related factors for each form of testing
  79. 79. Tests That Detect Adenomatous Polyps and Cancer Flexible sigmoidoscopy (FSIG) every 5 years*, or Colonoscopy every 10 years, or Double contrast barium enema (DCBE) every 5 years*, or CT colonography (CTC) every 5 years*Tests That Primarily Detect Cancer Annual guaiac-based fecal occult blood test (gFOBT) with high test sensitivity for cancer *, ** or Annual fecal immunochemical test (FIT) with high test sensitivity for cancer*,** or Stool DNA test (sDNA), with high sensitivity for cancer*, interval uncertain * Colonoscopy should be done if test results are positive.** For gFOBT or FIT used as a screening test, the take-home multiple sample method should be used. gFOBT or FIT done during a digital rectal exam in the doctors office is not adequate for screening.
  80. 80.  Evidence does not yet support any single test as “best” Uptake of screening remains disappointingly low Individuals differ in their preferences for one test or another Primary care physicians differ in their ability to offer, explain, or refer patients to all options equally Access is uneven geographically, and in terms of test charges and insurance coverage Uncertainty exists about performance of different screening methods with regard to benefits, harms, and costs (especially on programmatic basis)
  81. 81. Sensitivity of Take Home vs. In-Office FOBT Sensitivity FOBT method All Advanced Cancer (Hemoccult II) Lesions 3 card, take-home 23.9 % 43.9 % Single sample, in- office 4.9 % 9.5 %Collins et al, Annals of Int Med Jan 2005
  82. 82.  Rationale Fecal occult blood tests detect blood in the stool – which is intermittent and non-specific Colon cells are shed continuously Polyps and cancer cells contain abnormal DNA Stool DNA tests look for abnormal DNA from cells that are passed in the stool**All positive tests should be followed with colonoscopy
  83. 83.  Three versions of the previously marketed sDNA test have been evaluated  Version 1 (K-ras, APC, p53,BAT-26, DIA) was evaluated in the Imperiale trial  Version 1.1 (K-ras, APC, P53), PreGen-Plus is the currently marketed test  Version 2 (Vimentin only, or Vimentin + DIA) is currently under evaluation and is expected to enter the market in Fall 2008 Earlier and more recent tests were evaluated in smaller, mixed populations
  84. 84.  Testing evaluates stool for Study with One-Time Sensitivity for the presence of altered DNA Testing (v) Cancer in the adenoma-carcinoma Ahlquist, et al sequence 91% Gastro, 2000 (1) No dietary restrictions Imperiale, et al 51.6% NEJM, 2004 (1) No stool sampling (utilizes the entire stool) Syngal, et. al 63% Cancer, 2006 (1) Several studies suggesting Whitney, et al strong patient acceptance J Mol Diagn, 2004 (1.1) 70% Testing interval uncertain Chen, et al 46% JNCI, 2005 (2) Uncertainty about the meaning of false positives Itzkowitz, et al 88% DDW-AB, 2006 (2)
  85. 85. Limitations Misses some cancers Sensitivity for adenomas with current commercial version of test is low Technology (and test versions) are in transition Costs much more than other forms of stool testing (approximately $300 - $400 per test) Not covered by most insurers
  86. 86. Limitations (cont.) Appropriate re-screening interval is not known Not clear how to manage positive stool DNA test if colonoscopy is negative FDA issues Test availability
  87. 87. CTC Image Optical ColonoscopyCourtesy of Beth McFarland, MD
  88. 88. Rationale Allows detailed evaluation of the entire colon A number of studies have demonstrated a high level of sensitivity for cancer and large polyps Minimally invasive (rectal tube for air insufflation) No sedation required
  89. 89. Polyp Size CTC >10mm 6-9 mm Cancer performance Pooled 85-93% 70-86% 85.7% Sensitivity Pooled 97% 86-93% ---- SpecificityHalligan 2005, Mulhall 2005
  90. 90. Polyp Size >10mm >8mm >6mm CTC 92.2% 92.6% 85.7% Colonoscopy 88.2% 89.5% 90.0%Pickhardt et al, NEJM 2003
  91. 91. Most have limited clinical impact, but some areimportant:  Asymptomatic cancers outside of colon and rectum  Aortic aneurysms  Renal and gall bladder calculi
  92. 92. Limitations Requires full bowel prep (which most patients find to be the most distressing element of colonoscopy) Colonoscopy is required if abnormalities detected, sometimes necessitating a second bowel prep Steep learning curve for radiologists Limited availability to high quality exams in many parts of the country Most insurers do not currently cover CTC as
  93. 93. Limitations Extra-colonic findings can lead to additional testing (may have both positive and negative connotations) Questions regarding:  Significance of radiation exposure  Management of small polyps
  94. 94. U.S. Preventive Services Task Force, Ann Intern Med 2008