BME 301 Lecture Twelve

Review of Lecture 11 Belmont Report Respect for persons Beneficence Justice Process of informed consent

Four Questions What are the major health problems worldwide? Who pays to solve problems in health care? How can technology solve health care problems? How are health care technologies managed?

Three Case Studies Prevention of infectious disease HIV/AIDS Early detection of cancer Cervical Cancer Ovarian Cancer Prostate Cancer Treatment of heart disease Atherosclerosis and heart attack Heart failure

Where do innovations come from? Technology Assessment: The Big Picture Start here How can we use science and technology to solve problems in health care? Advance to next unit Where do innovations come from? Technology Assessment: The Big Picture Patient Outcomes Biological plausibility Science Drives Engineering Clinical Trials Scientific Method Societal Outcomes Technical Feasibility Engineering design How do we test and refine innovations? Case studies Treatment of Heart Disease Early Detection of Cancer Prevention of Infectious Diseases Pre-cancer  cancer transformation The circulatory system Detection of Morphologic Changes Gene Chips – molecular changes Microorganisms Arteriosclerosis CABG PTCA Heart Failure LVAD Transplant Ovary Cervix Prostate Immunity Vaccines Outcomes Cost effectiveness Cost effectiveness HIV Outcomes Cost effectiveness

Outline The burden of cancer How does cancer develop? Why is early detection so important? Strategies for early detection Example cancers/technologies Cervical cancer Ovarian cancer Prostate cancer

The Burden of Cancer: U.S. 2nd leading cause of death in US 1 of every 4 deaths is from cancer 5-year survival rate for all cancers: 62% Annual costs for cancer: $172 billion $61 billion - direct medical costs $16 billion - lost productivity to illness $95 billion - lost productivity to premature death

U.S. Cancer Incidence & Mortality 2004 New cases of cancer: United States: 1,368,030 Texas: 84,530 Deaths due to cancer: United States: 563,700 www.cancer.org, Cancer Facts & Figures

US Mortality, 2001 No. of deaths % of all deaths Rank Cause of Death 1. Heart Diseases 700,142 29.0 2. Cancer 553,768 22.9 3. Cerebrovascular diseases 163,538 6.8 4. Chronic lower respiratory diseases 123,013 5.1 5. Accidents (Unintentional injuries) 101,537 4.2 6. Diabetes mellitus 71,372 3.0 7. Influenza and Pneumonia 62,034 2.6 8. Alzheimer’s disease 53,852 2.2 9. Nephritis 39,480 1.6 10. Septicemia 32,238 1.3 Cancer accounts for nearly one-quarter of deaths in the United States, exceeded only by heart disease. In 2001, there were 553,768 cancer deaths in the US. Source: US Mortality Public Use Data Tape 2001, National Center for Health Statistics, Centers for Disease Control and Prevention, 2003.

2004 Estimated US Cancer Cases* Men 699,560 Women 668,470 32% Breast 12% Lung & bronchus 11% Colon & rectum 6% Uterine corpus 4% Ovary 4% Non-Hodgkin lymphoma 4% Melanoma of skin 3% Thyroid 2% Pancreas 2% Urinary bladder 20% All Other Sites Prostate 33% Lung & bronchus 13% Colon & rectum 11% Urinary bladder 6% Melanoma of skin 4% Non-Hodgkin lymphoma 4% Kidney 3% Oral Cavity 3% Leukemia 3% Pancreas 2% All Other Sites 18% Now we will turn our attention to the number of new cancers anticipated in the US this year. It is estimated that 1.37 million new cases of cancer will be diagnosed in 2004. Cancers of the prostate and breast will be the most frequently diagnosed cancers in men and women, respectively, followed by lung and colorectal cancers both in men and in women. *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2004.

2004 Estimated US Cancer Deaths* Men 290,890 Women 272,810 Lung & bronchus 32% Prostate 10% Colon & rectum 10% Pancreas 5% Leukemia 5% Non-Hodgkin 4% lymphoma Esophagus 4% Liver & intrahepatic 3% bile duct Urinary bladder 3% Kidney 3% All other sites 21% 25% Lung & bronchus 15% Breast 10% Colon & rectum 6% Ovary 6% Pancreas 4% Leukemia 3% Non-Hodgkin lymphoma 3% Uterine corpus 2% Multiple myeloma 2% Brain/ONS 24% All other sites Lung cancer is, by far, the most common fatal cancer in men (32%), followed by prostate (10%), and colon & rectum (10%). In women, lung (25%), breast (15%), and colon & rectum (10%) are the leading sites of cancer death. ONS=Other nervous system. Source: American Cancer Society, 2004.

Worldwide Causes of Death, 1996

Causes of Mortality, 1996

Worldwide Burden of Cancer Today: 11 million new cases every year 6.2 million deaths every year (12% of deaths) Can prevent 1/3 of these cases: Reduce tobacco use Implement existing screening techniques Healthy lifestyle and diet In 2020: 15 million new cases predicted in 2020 10 million deaths predicted in 2020 Increase due to ageing population Increase in smoking

Worldwide Burden of Cancer 23% of cancers in developing countries caused by infectious agents Hepatitis (liver) HPV (cervix) H. pylori (stomach) Vaccination could be key to preventing these cancers

1996 Estimated Worldwide Cancer Cases* Men Women 910 Breast 524 Cervix 431 Colon & rectum 379 Stomach 333 Lung & bronchus 192 Mouth 191 Ovary 172 Uterine corpus Lung & bronchus 988 Stomach 634 Colon & rectum 445 Prostate 400 Mouth 384 Liver 374 Esophagus 320 Urinary bladder 236 Now we will turn our attention to the number of new cancers anticipated in the US this year. It is estimated that 1.37 million new cases of cancer will be diagnosed in 2004. Cancers of the prostate and breast will be the most frequently diagnosed cancers in men and women, respectively, followed by lung and colorectal cancers both in men and in women.

What is Cancer? Characterized by uncontrolled growth & spread of abnormal cells Can be caused by: External factors: Tobacco, chemicals, radiation, infectious organisms Internal factors: Mutations, hormones, immune conditions

Squamous Epithelial Tissue

Precancer  Cancer Sequence

Histologic Images Normal Cervical Pre-Cancer

http://www.gcarlson.com/images/metastasis.jpg

Fig 7.33 – The Metastatic cascade Neoplasia

http://www. drugdevelopment-technology. com/projects/avastin/avastin2 http://www.drugdevelopment-technology.com/projects/avastin/avastin2.html

http://www.mdanderson.org/images/metastasesmodeljosh1.gif

Clinical Liver Metastases http://www.pathology.vcu.edu/education/pathogenesis/images/6d.b.jpg

What is Your Lifetime Cancer Risk?

Lifetime Probability of Developing Cancer, by Site, Men, US, 1998-2000 Risk All sites 1 in 2 Prostate 1 in 6 Lung & bronchus 1 in 13 Colon & rectum 1 in 17 Urinary bladder 1 in 29 Non-Hodgkin lymphoma 1 in 48 Melanoma 1 in 55 Leukemia 1 in 70 Oral cavity 1 in 72 Kidney 1 in 69 Stomach 1 in 81 The next four slides look at the lifetime probability of developing cancer and relative survival rates of cancer.   Presently, the risk of an American man developing cancer over his lifetime is one in two. The leading cancer sites are prostate, lung, and colon & rectum. Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 5.1 Statistical Research and Applications Branch, NCI, 2003. http://srab.cancer.gov/devcan

Lifetime Probability of Developing Cancer, by Site, Women, US, 1998-2000 Risk All sites 1 in 3 Breast 1 in 7 Lung & bronchus 1 in 17 Colon & rectum 1 in 18 Uterine corpus 1 in 38 Non-Hodgkin lymphoma 1 in 57 Ovary 1 in 59 Pancreas 1 in 83 Melanoma 1 in 82 Urinary bladder 1 in 91 Uterine cervix 1 in 128 Approximately one in three women in the United States will develop cancer over her lifetime. The leading sites are breast, lung, and colon & rectum. Source:DevCan: Probability of Developing or Dying of Cancer Software, Version 5.1 Statistical Research and Applications Branch, NCI, 2003. http://srab.cancer.gov/devcan

How Can You Reduce Your Cancer Risk?

Tobacco Use in the US, 1900-2000 Per capita cigarette consumption Male lung cancer death rate The last set of slides describes at the prevalence of cancer risk factors, such as tobacco use and physical inactivity, and the prevalence of cancer screening, such as use of mammography.   Tobacco use is a major preventable cause of death, particularly from lung cancer. The year 2004 marks the anniversary of the release of the first Surgeon General’s report on Tobacco and Health, which initiated a decline of per capita cigarette smoking in the United States. As a result of the cigarette smoking epidemic, lung cancer death rates showed a steady increase through 1990, then began to decline. The lung cancer death rate among US women, who began regular cigarette smoking later than men, has continued to increase, but at a slower rate since the early 1990s. Female lung cancer death rate *Age-adjusted to 2000 US standard population. Source: Death rates: US Mortality Public Use Tapes, 1960-2000, US Mortality Volumes, 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2002. Cigarette consumption: US Department of Agriculture, 1900-2000.

Trends in Consumption of Five or More Recommended Vegetable and Fruit Servings for Cancer Prevention, Adults 18 and Older, US, 1994-2002 The American Cancer Society recommends that individuals eat five or more servings of vegetables and fruits a day for cancer prevention. Fruit and vegetable consumption may protect against cancers of the mouth and pharynx, esophagus, lung, stomach, and colon and rectum. However, there has been little improvement in consumption since the mid-1990s. Less than one in four adults was eating the recommended servings in 2002. Note: Data from participating states and the District of Columbia were aggregated to represent the United States. Source: Behavioral Risk Factor Surveillance System CD-ROM (1984-1995, 1996, 1998) and Public Use Data Tape (2000), National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, 1997, 1999, 2000, 2001.

The War on Cancer 1971 State of Union address: December 23, 1971 President Nixon requested $100 million for cancer research December 23, 1971 Nixon signed National Cancer Act into law "I hope in years ahead we will look back on this action today as the most significant action taken during my Administration."

Change in the US Death Rates* by Cause, 1950 & 2001 Rate Per 100,000 1950 2001 Compared to the rate in 1950, the cancer death rate was 0.2% higher in 2001, while rates for other major chronic diseases decreased during this period. Heart Diseases Cerebrovascular Diseases Pneumonia/ Influenza Cancer * Age-adjusted to 2000 US standard population. Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised. 2001 Mortality Data–NVSR-Death Final Data 2001–Volume 52, No. 3. http://www.cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_03.pdf

Cancer Death Rates*, for Men, US, 1930-2000 Rate Per 100,000 Lung Stomach Prostate Colon & rectum Most of the increase in cancer death rates for men prior to 1990 was attributable to lung cancer. However, since 1990, the age-adjusted lung cancer death rate in men has been decreasing. Stomach cancer mortality has decreased considerably since 1930. Death rates from prostate and colorectal cancers have also been declining. Pancreas Leukemia Liver *Age-adjusted to the 2000 US standard population. Source: US Mortality Public Use Data Tapes 1960-2000, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2003.

Cancer Death Rates*, for Women, US, 1930-2000 Rate Per 100,000 Lung Uterus Breast Currently, the lung cancer death rate in women is about two-and-a-half times what it was 25 years ago, and lung cancer is the most common cause of cancer death. In comparison, breast cancer death rates were virtually unchanged between 1930 and 1990, and have since decreased. The death rates for stomach and uterine cancers have decreased steadily since 1930; colorectal cancer death rates have been decreasing for over 50 years. Colon & rectum Stomach Ovary Pancreas *Age-adjusted to the 2000 US standard population. Source: US Mortality Public Use Data Tapes 1960-2000, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2003.

Cancer Incidence Rates* for Men, US, 1975-2000 Rate Per 100,000 Prostate Lung Colon and rectum Prostate cancer incidence rates increased sharply from 1988 to 1992, after increasing steadily from 1975 to 1988. The short-lived surge in prostate cancer incidence most likely reflects the widespread introduction of the prostate-specific antigen (PSA) screening test in the late 1980s. Lung cancer incidence rates in men have declined in recent years, while rates for cancers of the colon & rectum have stabilized. Urinary bladder Non-Hodgkin lymphoma *Age-adjusted to the 2000 US standard population. Source: Surveillance, Epidemiology, and End Results Program, 1975-2000, Division of Cancer Control and Population Sciences, National Cancer Institute, 2003.

Cancer Incidence Rates* for Women, US, 1975-2000 Rate Per 100,000 Breast In women, the breast cancer incidence rate increased rapidly (approximately 4% per year) from 1980 to 1986 and then increased at a slower rate from 1986 through 2000. The apparent decrease in female breast cancer incidence in 2000 is likely due to delay in reporting. Lung cancer incidence rates have continued to increase, although the rate of increase has slowed since the early 1990s. Colorectal cancer incidence rates have leveled off since the mid 1990s. Incidence rates for uterine corpus cancer stabilized from 1998 to 2000, after a slight increase from 1988 to 1998. Ovarian cancer rates have decreased 0.7% per year from 1989 through 2000. Colon & rectum Lung Uterine corpus Ovary *Age-adjusted to the 1970 US standard population. Source: Surveillance, Epidemiology, and End Results Program, 1973-1998, Division of Cancer Control and Population Sciences, National Cancer Institute, 2001. *Age-adjusted to the 2000 US standard population. Source: Surveillance, Epidemiology, and End Results Program, 1975-2000, Division of Cancer Control and Population Sciences, National Cancer Institute, 2003.

Relative Survival* (%) during Three Time Periods by Cancer Site 1974-1976 1983-1985 1992-1999   All sites 50 52 63 Breast (female) 75 78 87 Colon & rectum 50 57 62 Leukemia 34 41 46 Lung & bronchus 12 14 15 Melanoma 80 85 90 Non-Hodgkin lymphoma 47 54 56 Ovary 37 41 53 Pancreas 3 3 4 Prostate 67 75 98 Urinary bladder 73 78 82 The survival rate for all cancers combined and for certain site-specific cancers have improved significantly since the 1970s, due, in part, to both earlier detection and advances in treatment. Survival rates markedly increased for cancers of the prostate, ovary, breast, colon & rectum, and for leukemia. With new treatment techniques and increased utilization of screening, there is hope for even greater improvements in the not-too-distant future. *5-year relative survival rates based on follow up of patients through 2000. Source: Surveillance, Epidemiology, and End Results Program, 1975-2000, Division of Cancer Control and Population Sciences, National Cancer Institute, 2003.

Mission: National Cancer Institute Eliminate suffering and death due to cancer by 2015 Budget Request 2004: $5,986,000

Importance of Early Detection Five Year Relative Survival Rates

Screening Use of simple tests in a healthy population Goal: Identify individuals who have disease, but do not yet have symptoms Should be undertaken only when: Effectiveness has been demonstrated Resources are sufficient to cover target group Facilities exist for confirming diagnoses Facilities exist for treatment and follow-up When disease prevalence is high enough to justify effort and costs of screening

Cancer Screening We routinely screen for 4 cancers: Female breast cancer Mammography Cervical cancer Pap smear Prostate cancer Serum PSA Digital rectal examination Colon and rectal cancer Fecal occult blood Flexible sigmoidoscopy, Colonoscopy

Screening Guidelines for the Early Detection of Breast Cancer, American Cancer Society 2003 Yearly mammograms are recommended starting at age 40 and continuing for as long as a woman is in good health. A clinical breast exam should be part of a periodic health exam, about every three years for women in their 20s and 30s, and every year for women 40 and older. Women should know how their breast normally feel and report any breast changes promptly to their health care providers. Breast self-exam is an option for women starting in their 20s. Women at increased risk (e.g., family history, genetic tendency, past breast cancer) should talk with their doctors about the benefits and limitations of starting mammography screening earlier, having additional tests (i.e., breast ultrasound and MRI), or having more frequent exams. The American Cancer Society states that women aged 40 and older should have an annual mammogram and clinical breast exam (CBE) as part of a periodic health exam. Women should know how their breasts normally feel and report any changes to their health care provider. A breast self-examination (BSE) is an option for women starting in their 20s.

Mammogram Prevalence (%), by Educational Attainment and Health Insurance Status, Women 40 and Older, US, 1991-2002 All women 40 and older Women with less than a high school education Women with no health insurance The prevalence of women reporting a recent mammogram increased almost 25% from 50% in 1991 to 62% in 2000. During this time, mammogram utilization varied considerably by educational attainment. The prevalence of women with less than a high school education reporting a recent mammogram was approximately 10 percentage points lower than the prevalence for all women. Even more striking is that the prevalence for women with no health insurance is approximately 20 percentage points lower than the prevalence for all women. * A mammogram within the past year. Note: Data from participating states and the District of Columbia were aggregated to represent the United States. Source: Behavior Risk Factor Surveillance System CD-ROM (1984-1995, 1996-1997, 1998, 1999) and Public Use Data Tape (2000, 2002), National Centers for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention 1997, 1999, 2000, 2000, 2001,2003.

Screening Guidelines for the Early Detection of Colorectal Cancer, American Cancer Society 2003 Beginning at age 50, men and women should follow one of the following examination schedules: A fecal occult blood test (FOBT) every year A flexible sigmoidoscopy (FSIG) every five years Annual fecal occult blood test and flexible sigmoidoscopy every five years* A double-contrast barium enema every five years A colonoscopy every ten years *Combined testing is preferred over either annual FOBT, or FSIG every 5 years alone. People who are at moderate or high risk for colorectal cancer should talk with a doctor about a different testing schedule The American Cancer Society recommends that beginning at age 50, men and women should receive a fecal occult blood test (FOBT) every year, or a flexible sigmoidoscopy (FSIG) every five years, or an annual FOBT and FSIG every five years (preferred to either method alone), or a double-contrast barium enema every five years, or a colonoscopy every ten years.

Trends in Recent* Fecal Occult Blood Test Prevalence (%), by Educational Attainment and Health Insurance Status, Adults 50 Years and Older, US, 1997-2002 Despite an increase in FOBT use among both men and women from 1999 to 2002, prevalence remains low. Adults with less than a high school education are less likely to report a recent FOBT. Even more striking is that the prevalence for adults with no health insurance is approximately 10 percentage points lower than the prevalence for all adults. *A fecal occult blood test within the past year. Note: Data from participating states and the District of Columbia were aggregated to represent the United States. Source: Behavioral Risk Factor Surveillance System CD-ROM (1996-1997, 1999) and Public Use Data Tape (2001, 2002), National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention and Prevention, 1999, 2000, 2002, 2003.

Trends in Recent* Flexible Sigmoidoscopy Prevalence (%), by Educational Attainment and Health Insurance Status, Adults 50 Years and Older, US, 1997-2002 Similar to the fecal occult blood test, the prevalence of flexible sigmoidoscopy (FSIG) or colonoscopy within the past five years, while low, increased from 1999 to 2002. Adults with less than a high school education were less likely to report FSIG or colonoscopy than all adults. Even more striking is that the prevalence for adults with no health insurance is approximately 15 percentage points lower than the prevalence for all adults. In addition to continuing efforts to increase breast and cervical cancer screening, heightened awareness and enhanced cancer control measures are greatly needed to improve the use of early detection methods for colorectal cancer. *A flexible sigmoidoscopy or colonoscopy within the past five years. Note: Data from participating states and the District of Columbia were aggregated to represent the United States. Source: Behavioral Risk Factor Surveillance System CD-ROM (1996-1997, 1999) and Public Use Data Tape (2001, 2002), National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention and Prevention, 1999, 2000, 2002, 2003.

How do we judge efficacy of a screening test? Sensitivity/Specificity Positive/Negative Predictive Value

Screening for Diabetes Questionnaire Se=72-78% Sp=50-51% Capillary Blood Glucose >140 mg/dL Se=56-65% Sp=95-96% >120 mg/dL Se=75-84% Sp=86-90%

Sensitivity & Specificity Probability that given DISEASE, patient tests POSITIVE Ability to correctly detect disease 100% - False Negative Rate Specificity Probability that given NO DISEASE, patient tests NEGATIVE Ability to avoid calling normal things disease 100% - False Positive Rate

Possible Test Results Test Positive Test Negative Disease Present TP FN # with Disease = TP+FN Disease Absent FP TN #without Disease = FP+TN # Test Pos = TP+FP # Test Neg = FN+TN Total Tested = TP+FN+FP+TN Se = TP/(# with disease) = TP/(TP+FN) Sp = TN/(# without disease) = TN/(TN+FP)

Amniocentesis Example Procedure to detect abnormal fetal chromosomes Efficacy: 1,000 40-year-old women given the test 28 children born with chromosomal abnormalities 32 amniocentesis test were positive, and of those 25 were truly positive Calculate: Sensitivity & Specificity

What Information Do You Want? As a patient: What Information Do You Want?

Predictive Value Positive Predictive Value Negative Predictive Value Probability that given a POSITIVE test result, you have DISEASE Ranges from 0-100% Negative Predictive Value Probability that given a NEGATIVE test result, you do NOT HAVE DISEASE Depends on the prevalence of the disease

Possible Test Results Test Positive Test Negative Disease Present TP FN # with Disease = TP+FN Disease Absent FP TN #without Disease = FP+TN # Test Pos = TP+FP # Test Neg = FN+TN Total Tested = TP+FN+FP+TN PPV = TP/(# Test Pos) = TP/(TP+FP) NPV = TN/(# Test Neg) = TN/(FN+TN)

Amniocentesis Example Procedure to detect abnormal fetal chromosomes Efficacy: 1,000 40-year-old women given the test 28 children born with chromosomal abnormalities 32 amniocentesis test were positive, and of those 25 were truly positive Calculate: Positive & Negative Predictive Value

Dependence on Prevalence Prevalence – is a disease common or rare? p = (# with disease)/total # p = (TP+FN)/(TP+FP+TN+FN) Does our test accuracy depend on p? Se/Sp do not depend on prevalence PPV/NPV are highly dependent on prevalence PPV = pSe/[pSe + (1-p)(1-Sp)] NPV = (1-p)Sp/[(1-p)Sp + p(1-Se)]

Is it Hard to Screen for Rare Disease? Amniocentesis: Procedure to detect abnormal fetal chromosomes Efficacy: 1,000 40-year-old women given the test 28 children born with chromosomal abnormalities 32 amniocentesis test were positive, and of those 25 were truly positive Calculate: Prevalence of chromosomal abnormalities

Is it Hard to Screen for Rare Disease? Amniocentesis: Usually offered to women > 35 yo Efficacy: 1,000 20-year-old women given the test Prevalence of chromosomal abnormalities is expected to be 2.8/1000 Calculate: Sensitivity & Specificity Positive & Negative Predictive Value Suppose a 20 yo woman has a positive test. What is the likelihood that the fetus has a chromosomal abnormality?

Summary of Lecture 12 The burden of cancer How does cancer develop? Contrasts between developed/developing world How does cancer develop? Cell transformation  Angiogenesis  Motility  Microinvasion  Embolism  Extravasation Why is early detection so important? Treat before cancer develops  Prevention Accuracy of screening/detection tests Se, Sp, PPV, NPV

Assignments Due Next Time HW5 WA7