PREVENTABLE CAUSES OF CANCERS: REVISITING THE 1981 DOLL & PETO REPORT Gilbert S. Omenn, M. D. , Ph. D. David Schottenfeld Lecturer, 20 July, 2011 University of Michigan School of Public Health Based on collaboration of David Schottenfeld, Patricia Buffler, Steven Gruber, and Gil Omenn for EPID 704, UM Graduate Summer Program in Epidemiology, 26 -30 July, 2010
Honoring Dr. David Schottenfeld
Cancer y Epidemiolog The Newest, Up-to-Date Volume by David Schottenfeld 3
Cancer Incidence and Mortality, USA • The American Cancer Society estimates 1. 53 million new cases and 570, 000 deaths from cancers in 2011. • Women top 3: breast, lung, colon; overall mortality rate is down 12. 3% 1990 -2006 • Men top 3: prostate, lung, colon; overall mortality rate is down 21. 0% 1990 -2006 • Avoided 767, 000 cancer deaths over 16 yrs
The Crucial Influence of Heterogeneity • The need to speak of “cancers” in the plural: the illusion of “The War on Cancer” (1970) • The emergence of new signaling pathways, receptors, molecular targets, and m. RNA and protein expression patterns • The importance for research strategies on carcinogenic mechanisms, diagnosis, treatments, and preventive interventions • The ramifications of subpopulation analysis and pharmaco-genomics
Annual Age-Adjusted Cancer Incidence and Mortality Rates, 1975 -2006
Cancer Incidence Rates for Selected Cancers by Sex, 1975 -2006
Mortality Rates for Cancers and Heart Disease 1975 -2006
Total Number of Cancer Deaths Avoided, 1991 -2006
Cancer Prevention 1978 • I was a member of the National Cancer Institute Advisory Board (NCAB) and deputy science adviser in the White House Office of Science & Technology Policy. • NCAB pressed NCI to do more about prevention. Congress made representatives of federal regulatory agencies members of the NCAB. There was heightened attention to environmental hazards and to cancer prevention research.
The 1978 OSHA Hearings • Bridbord K, Decoufle P, Fraumeni JF Jr, Hoel DG, Hoover RN, Rall DP, Saffiotti U, Schneiderman MA, Upton AC. Estimates of the fraction of cancer in the United States related to occupational factors. Testimony presented to Occupational Safety and Health Administration hearings, 15 September, 1978. • Preceded by a press conference in April by Joseph Califano, HEW Secretary.
The OSHA Hearing Testimony • Extrapolating from reported RR’s for just 6 of the presumably thousands of occupational and environmental chemical exposures—asbestos, arsenic, benzene, chromium, nickel, petroleum products—the scientists estimated that 23 -38% of all cancers could be attributed to these six and proclaimed that future risks could be higher. • Media coverage was intense. • The Congressional Office of Technology Assessment enlisted British epidemiologists Sir Richard Doll and Richard Peto to make an independent assessment.
Summary of Doll & Peto, JNCI 1981
The Controversial Attribution for Occupational Cancer Risks • Doll & Peto attributed 4% (range 2 -8%) of total cancer deaths to occupational chemical causes. They attacked the much publicized “OSHA Hearing Report” from prominent U. S. scientists attributing 23 -38% of all cancer deaths to the six occupational carcinogens, with 13 -18% from asbestos alone, due to extreme assumptions about prevalence, duration, level of exposures and RRs. • Benzene is ubiquitous, but it is implicated only in leukemias. Others were arsenic, chromium, nickel, petroleum products.
A JNCI Request in 2009 • In 2009, the Journal of the NCI editor wrote to suggest a reprise, 30 years later, of the Doll & Peto analysis. • I turned to my colleagues David Schottenfeld, Patricia Buffler (UCB), and Steve Gruber. I hope you attended Pat Buffler’s David Schottenfeld Lecture last July. • We agreed to start by presenting a GSS course in July 2010, which was well-received and enjoyable. We are still working toward a manuscript.
The Four Main Differences after 30 Years 1. Infectious causes—after launching The War on Cancer, there was disillusionment about tumor viruses; now we recognize dramatic roles of H. pylori, hepatitis B and C, HPV, EBV, HIV, KSHV= about 20% of cancers (globally) 2. Obesity and physical inactivity are growing problems 3. Increased radiation from medical imaging 4. Renewed publicity and perhaps uncertainty about consequences of occupational and environmental exposures
History of Efforts to Identify the Role of Infection in Cancer Etiology • Earliest efforts at beginning of the 20 th century focused on parasitic infections. • Turning point in 1911: Peyton Rous isolated virus from sarcoma in chicken (Rous sarcoma virus) • 2010: ~20% of all cancers caused by an infectious agent—higher in developing countries 18
Infectious Agents and Human Cancers • Viruses: – – – Epstein-Barr virus (EBV) HTLV-1 Hepatitis B Virus (HBV) Hepatitis C Virus (HCV) Human papilloma virus (HPV) Human herpes virus 8 (HHV-8) • Bacteria – Helicobacter pylori • Fungi – Aflatoxin B • Parasites – Schistosoma haematobium 19
Infection-related Cancers: Worldwide Estimates for 2002 (Parkin, IJC 2006) Agent Cancer HPV Cervix Ano-genital Oral Number % of all of cases cancers 492, 800 53, 880 5. 2 14, 500 HBV and HCV Liver Viruses Bacteria Helminths All agents 535, 000 Nasopharynx Hodgkin lymphoma EBV Burkitt's lymphoma Kaposi's sarcoma HIV / HHV-8 Non-Hodgkin's lymphoma HTLV-I ATL Stomach H. pylori Lymphoma Schistosomes Bladder Liver flukes Liver 78, 100 28, 600 6, 700 66, 200 36, 100 4. 9 1. 0 0. 9 3, 300 592, 000 11, 500 10, 600 2, 500 0. 03 1, 932, 800 17. 8 5. 5 0. 1 0. 02 20
Infection-related Cancers: Worldwide Estimates for 2002 (Parkin, IJC 2006) Developed countries Cancer Liver Developing countries Agent. Total % all attributable cancers cancers HBV, HCV 110, 400 Flukes 48, 000 1. 0 513, 100 0 475, 000 8. 2 2, 500 Cervix HPV 83, 400 1. 7 409, 400 7. 0 Stomach H. pylori 311, 200 192, 000 3. 8 619, 200 400, 000 6. 9 KS HIV/HHV 8 3, 700 0. 1 62, 500 1. 1 H. pylori 5, 600 NHL EBV HIV 151, 100 HTLV-I 5, 900 100 9, 300 0. 2 149, 200 550 6, 600 26, 800 0. 7 2, 790 Anogenital HPV 38, 000 22, 450 0. 4 58, 700 31, 430 0. 5 Nasopharynx EBV 7, 200 6, 500 0. 1 72, 600 71, 600 1. 2 Oral HPV 115, 500 5, 600 0. 1 210, 700 8, 800 0. 2 Hodgkin lymphoma EBV 28, 000 11, 500 0. 2 34, 300 17, 100 0. 3 Bladder Schistosomes 225, 200 0 0. 0 131, 000 10, 600 21 0. 2 All cancers All agents 5, 016, 000 389, 000 7. 7 5, 828, 000 1, 527, 000 26. 3
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IARC Overall Evaluation of Carcinogenicity (International Agency for Research on Cancer, WHO) Group 1: The exposure circumstance is carcinogenic to humans. • Sufficient evidence of carcinogenicity in humans. • Evidence less than sufficient in humans but sufficient in experimental animals and strong evidence that in exposed humans the agent acts through a relevant carcinogenic mechanism. Group 2 A: The exposure circumstance is probably carcinogenic to humans. • Limited evidence in humans but sufficient in experimental animals. • Inadequate evidence in humans but sufficient in experimental animals and strong evidence that in exposed humans the agent acts through a relevant carcinogenic mechanism. Group 2 B: The exposure circumstance is possibly carcinogenic to humans. • Limited evidence in humans and less than sufficient evidence in experimental animals. • Inadequate evidence in humans but limited evidence in experimental animals with supporting evidence from other relevant data. Group 3: The exposure circumstance is not classifiable as to its carcinogenicity to humans. • Evidence inadequate in humans and inadequate or limited in experimental animals. • Evidence inadequate in humans and sufficient in experimental animals but carcinogenic mechanism in animals does not operate in humans. Group 4: The exposure circumstance is probably not carcinogenic to humans. • Evidence suggesting lack of carcinogenicity in humans and in experimental animals. 23
Recent assessment of Epstein–Barr Virus (EBV) by IARC Monograph 100 B Working Group Cancers for which there is sufficient evidence in humans: u Nasopharyngeal carcinoma u Burkitt’s lymphoma u Immune-suppression-related non-Hodgkin lymphoma u Extranodal NK/T-cell lymphoma (nasal type) u Hodgkin lymphoma Other sites with limited evidence in humans: u Gastric Established mechanistic events: u Cell carcinoma* u Lympho-epithelioma-like carcinoma * proliferation u Inhibition of apoptosis u Genomic instability u Cell migration * Newly identified link between virus and cancer. 24 Bouvard V, et al. A review of human carcinogens-Part B: biological agents. Lancet Oncol. 2009; 10(4): 321 -2.
Hepatitis B Virus (HBV) • Hepatocellular carcinoma (HCC) – HCC is one of 10 leading types of cancers worldwide – Accounts for 10% of all deaths in endemic areas of China (20 -35/100, 000 in men) – HCC leading cause of cancer death in men in Taiwan – Males predominate; some areas as high as 4: 1 – Average in • Asia: 50 yrs • Africa: 40 • West: elderly – US: 300, 000 infected annually with HBV • 300 die of fulminant hepatitis • 30, 000 become chronically infected – 4000 die of cirrhosis – 1000 die of HCC 25
Hepatitis B Virus (HBV) (2) • Hepatocellular carcinoma (HCC) – HBV: DNA virus; replicates via RNA intermediate; can integrate randomly into the host chromosome – Loss of HBe. Ag (envelope antigen) associated with latency of infection. – HBs. Ag+ –transforms SV 40 rodent cells; may sensitize liver cells for environmental carcinogens (e. g. , aflatoxin) – Co-factors: • • • Aflatoxin-B Ethanol Elevated testosterone levels Cigarette smoking Oral contraceptives Hepatitis C virus 26
Recent assessment of Hepatitis B Virus (HBV) by IARC Monograph 100 B Working Group Cancers for which there is sufficient evidence in humans: u Hepatocellular Other sites with limited evidence in humans: u Cholangiocarcinoma* Established mechanistic events: u Inflammation u Non-Hodgkin carcinoma lymphoma* u Liver cirrhosis u Chronic hepatitis * Newly identified link between virus and cancer. 27 Bouvard V, et al. A review of human carcinogens-Part B: biological agents. Lancet Oncol. 2009; 10(4): 321 -2.
Recent assessment of Hepatitis C Virus (HCV) by IARC Monograph 100 B Working Group Cancers for which there is sufficient evidence in humans: u Hepatocellular carcinoma u Non-Hodgkin lymphoma* Other sites with limited evidence in humans: u Cholangiocarcinoma* Established mechanistic events: u Inflammation u Liver cirrhosis u Liver fibrosis * Newly identified link between virus and cancer. 28 Bouvard V, et al. A review of human carcinogens-Part B: biological agents. Lancet Oncol. 2009; 10(4): 321 -2.
HPV types reviewed by the IARC Working Group, Vol. 100 B (to be published) IARC Group HPV types Comments Alpha HPV types 1 16 Most potent HPV type, known to cause cancer at several sites 1 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 Sufficient evidence for cervical cancer 2 A 68 Limited evidence in humans and strong mechanistic evidence for cervical cancer 2 B 26, 53, 66, 67, 70, 73, 82 Limited evidence in humans for cervical cancer 2 B 30, 34, 69, 85, 97 Classified by phylogenetic analogy to HPV types with sufficient or limited evidence in humans 3 6, 11 Beta HPV types 2 B 5 and 8 3 Limited evidence for skin cancer in patients with epidermodysplasia verruciformis Other beta and gamma types Adapted from: Bouvard et al. , Lancet Oncol. Vol 10 April 2009 29
Helicobacter pylori - microbiology • Member of the genus Helicobacter (at least 20 species) • Gram-negative, spiral, curved, microaerophilic bacillus (on artificial media, could assume coccoid shape) 30
H. pylori in Peptic Ulcer Disease • H. pylori first described by Warren and Marshall in 1983 associated with chronic gastritis • H. pylori found in: – 95% of patients with duodenal ulcer – 80% of patients with gastric ulcer • Prospective studies: duodenal ulcers develop more frequently in persons infected with H. pylori than in uninfected persons • Rates of recurrence: – 60 -100% per year with anti-secretory therapy – Less than 15% with antibacterial treatment 31
Clinical manifestations • • Gastritis Peptic ulcer disease Gastric adenocarcinoma Gastric lymphoma 32
Epidemiology of H. pylori infection • Colonization of the stomach: – Developed countries: 30 -50% • US: 30 -40% (15% in 25 -yo; 60% in >70 yo in the late 1980 s) – Developing countries; 70 -90% – Prevalence varies by age, sex, geography, ethnicity, and socioeconomic status • Reservoir—humans; infection acquired early in life and persists throughout life • Transmission – ? ? ? 33
Recent Assessment of Helicobacter Pylori by IARC Monograph 100 B Working Group Cancers for which there is sufficient evidence in humans: u Non-cardia gastric carcinoma u Low-grade B-cell mucosa-associated lymphoid tissue (MALT) gastric lymphoma* Other sites with limited evidence in humans: u -- Established mechanistic events: u Inflammation u Oxidative stress u Altered cellular turn-over and gene expression u Methylation u Mutation * Newly identified link between virus and cancer. 34 Bouvard V, et al. A review of human carcinogens-Part B: biological agents. Lancet Oncol. 2009; 10(4): 321 -2.
Proportion of Cancers Attributed to Different Factors Factor Tobacco Diet Infection: viral, bacterial, parasitic Reproductive factors and hormones Ionizing radiation Heredity Occupation Alcohol UV light Pollution Medicines Industrial products Food additives Best estimate (%) 33 30 18 7 6 5 3 3 1 <1 <1 Plausible Range (%) 25 - 40 20 - 60 10 - 25 5 - 10 4 -8 2 -8 2 -4 0. 5 - 1 <1 - 2 -2 - 1 35 Sources: Doll & Peto, 1981; 1996; Levine et al, 1989; Li et al. , 1991; Pisani et al. , 1997; Key et al. , 1997; Parkin et al. , 2006
Physical Activity/Inactivity • Metrics: energy expenditure, metabolic equivalent (METs) • Type, frequency, duration, intensity • Intensity: light, moderate, vigorous • 20 -30% lower CRC inc; 50% in most active • Study in Northern Calif, with PAF 13%: 4. 3 cases per 100, 000 preventable • EU: sedentary, PAFs 6 -10%
Physical activity • Breast: 20 -40%; greater in case-control than in cohort studies, and in pre-menopausal compared with post-meno. WCRF estimated PAF 17%. • Endometrial: 33% lower if intense activity • Total, Harvard: PAF sedentary 5%; combined BMI and physical inactivity 25 -33%
Obesity & Overweight (BMI) • Normal range BMI 18. 5 -14. 9 kg/m 2 • Prevalence of age-adjusted obesity = 33. 8%; OW + OB = 72% • Dysfunctional adipose tissue: insulin resistance, >IGF-1, decreased IGF-BPs; > sex-steroids, pro-inflammatory cytokines, metabolic syndrome • Renehan 2008/2010: 15 organ sites
Increased Cancer Risk with >BMI per 5 kg/m 2 Women: endometrial (RR 1. 59); gallbladder (1. 59); esophageal (1. 51); renal (1. 34); breast, thyroid, pancreas, colon, myeloma, non. Hodgkin lymphoma all 1. 07<RR<1. 15. Men: esophageal (1. 52), colon (1. 24), renal (1. 24), thyroid (1. 33), myeloma (1. 1), NHL 1. 06, leukemia (1. 08). PAF among never smokers 14% M, 20% F. PAFs 22 -56% for multiple individual sites.
Ionizing Radiation • If average person receives 100 mrem, then total annual dose = 22 million rem, which may be associated with 5500 cancer deaths or 1 -1. 4% of total cancer deaths, 50%+ from natural background sources (including radon). Per 100 Bq/m 3, RR 1. 16 for lung CA. • Parameters: type, intensity, duration, doserate, temporal period, mode of exposure.
Cancers Associated and Not Associated with Ionizing Radiation • IR increases incidence of thyroid, lung, liver, bone, and many other cancer sites. • IR does not increase rates of chronic lymphocytic leukemia, Hodgkin lymphoma, melanoma, or cancers of cervix, prostate, or testes. • 25 radioactive elements occur naturally in rocks, soil, and plants: Radon, radium, uranium, thorium, potassium. • Radon is submultiplicative with cigarette smoking for lung cancers. PAF nationally for radon = 5%.
New Issue in Ionizing Radiation Exposures • As highlighted by the President’s Cancer Panel, exposure to ionizing radiation from medical imaging procedures—which are surely overutilized—is quite significant. • It is ironic that we have notably reduced exposures to fluoroscopy and other traditional radiology procedures, but seem to presume the new technologies safe. • Schottenfeld concluded average radiation dose from imaging has increased 6 -fold over 30 yrs, now 48% of total U. S. radiation exposure. CT rising from 0. 4% to 2% of all cancers (30, 000/yr).
What about Non-Ionizing Radiation: EMF and RF? • One of the most striking new technologies of the past 20 years is the global emergence of cell phones, with nearly one person on the planet: see Super. Course of Epidemiology/Global Health. • The phones are associated with electric and magnetic fields (EMF), as are cell towers and power lines. • The sum of hundreds of studies: no demonstrable cancer mechanism or increased risk, despite fears and occasional reports; latency question still open.
Ultraviolet/Solar Radiation • Doll & Peto attributed 90% of lip CA, 50% of melanomas, 80% of other skin cancers to UVR = 1 -2% of all cancer deaths. • Work-related: squamous; recreational: basal cell skin cancers (and melanomas). • >1 million SCC and BCC cases/yr in US, with 1000 -2000 deaths. • Definitely preventable by reducing exposures.
U. S. National Toxicology Program • This program, under the NIH/National Institute of Environmental Health Sciences, produces periodic reports from evidencebased reviews of chemicals judged to be human carcinogens. • 12 th Report on Human Carcinogens issued 10 May, 2010: www. ntp. niehs. nih. gov.
Evaluation of Evidence/Sources of Information • International Agency for Research on Cancer (IARC): Monograph Series (100 vols). Classification of groups: 1: sufficient evidence in humans 2 A: probably carcinogenic in humans---limited evidence in humans, sufficient in animals 2 B: possibly carcinogenic in humans 3: not classifiable as human carcinogen ---inadequate epidemiological data, absence of convincing evidence in animals and in vitro tests 4: definite evidence not carcinogenic
IARC Classes of Group 1 Carcinogens • • • Pharmaceuticals Biological Agents Metals, Arsenic, Dusts, Fibers Radiation Tobacco, Areca Nut, Alcohol, Coal Smoke, Salted Fish • Chemical Agents and Related Occupations IARC Monograph 100, Parts A-F, with summaries in Lancet Oncology (2009) and our CD
Pharmaceuticals (A) 5 Hormone Therapies: DES, post-menopausal estrogen/progesterone, oral contraceptives, tamoxifen 8 Genotoxic alkylating agents (cancer chemo) 2 Immunosuppressives (transplants, auto-immune) 2 Phenacetin and mixtures (pain medication) 1 Etoposide and combo (cancer chemo) 1 Aristolochic (plant cpd) (weight loss med) 1 Methoxsalen-UV light (psoriasis therapy)
Biological Agents (B) Covered above Viruses: EBV, HCV, KSHV, HIV-1, HPV-16/18, HTLV-1 Bacteria: Helicobacter pylori Parasites: Chlorchis, Opisthorchis, Schistosoma Estimated >20 percent of all cancers (Zur Hausen, 2006)
Metals, Dusts, Fibers (C) • • Arsenic Beryllium Cadmium, Chromium, Nickel Asbestos (all types), erionite Silica dust Leather, wood dusts Controversy over formaldehyde
Radiation (D) • Alpha- and beta-particle emitters: Radon-222, radium-224, 226, 228; thorium-232; plutonium-239; phosphorus-32, Sr-90, I-131 • X- or gamma-radiation: primarily medical; 6 -fold >dosage from imaging past 30 years • Solar (SCC, BCC of skin; melanoma on rise) • UV-emitting tanning devices • RF and EMF (non-ionizing radiation): very unlikely
Tobacco (E-1) • Tobacco dominates all environmental risks--70% of lung cancers; increased risks of many sites • Tobacco plus alcohol: dominates oral cavity and head & neck cancers • Second-hand smokeless tobacco: definite carcinogens • Numerous specific chemicals carcinogenic • Contribution to preventable cancers secure
Alcohol Ingestion (E-2) • Estimated 2 billion people worldwide are regular consumers of alcoholic beverages. • Dose-related increased cancer risk at multiple sites: oral cavity, pharynx, larynx, esophagus, colorectum, liver, female breast (possibly pancreas); presumed to be mediated by acetaldehyde and modified (risk increased) by ALDH 2*2 inactive enzyme/gene allele.
Areca Nut/Betel Quid, Coal Smoke, Salted Fish (E-3) • Betel quid contains areca nut, betel leaf, catechu, slaked lime, +/- tobacco; 600 million people chew betel quid in SE Asia. Highly addictive. • Household fuel/coal for cooking and heating, mostly in lower income countries • Salt-preserved fish---highly associated with nasopharyngeal CA in Hong Kong/China; mechanism uncertain
Occupations and Occupational Chemical Exposures (F) • Bladder carcinogens: aromatic amines/dye industry • Lung carcinogens: combustion products, bischloromethylether (chemical intermediate), painting; Ni, Cr, Asbestos • Leukemogens: benzene, HCHO, rubber industry • Liver carcinogens: vinyl chloride, aflatoxins, dioxins (mechanism), healthcare (HBV/HCV)
Reducing Exposures • Generally requires public health regulatory actions and enforcement • Often a balancing act between direct (medical therapies) or indirect benefits and risks • July 24, 2010, example of the challenges of regulation: NY Times story of drinking water contamination from high-pressure deep fracturing of rock to release natural gas
Successful Removal of Exposures Hemangiosarcoma of the liver due to vinyl chloride monomer Small-cell CA of the lung due to bis-chloromethylether CA of the urinary bladder due to aromatic amine dyes Search for more hazards; use precautionary, preventive strategy; harmonize TSCA with European REACH scheme.
2010 President’s Cancer Panel Report on Environmental Cancer Risks • Impact of environmental factors on cancer risk. The Panel considered industrial, occupational, and agricultural exposures as well as exposures related to medical practice, military activities, modern lifestyles, and natural sources. • Key regulatory, political, industrial, and cultural barriers to understanding and reducing environmental and occupational carcinogenic exposures were identified.
Highlights of the PCP Report • Recognize vulnerability of children and agricultural workers. • Conduct research on exposures and effects from mixtures, new technologies, and green chemistry. • Focus on military installations and nearby populations. • Note high cumulative radiation exposures from medical imaging and nuclear medicine. • Take personal action to reduce exposures.
NEJM Editorial by Christiani • Accepted Panel’s estimate of 19% of all cancers in U. S. due to environmental and occupational chemical exposures • Specifically named bisphenol A in plastic bottles, bags, and toys; 2 -methylnaphthalene contaminant in cereal packaging; and long-time known carcinogens benzene, asbestos, and formaldehyde. • 300 industrial chemicals detected in cord-blood • Says PARs for most cancers from environmental factors are “as high as 85 to 95%”.
Cumulative Meta-analysis of Risk of Breast Cancer and Exposure to DDE: initial (Wolff et al. , 1993) and five subsequent reports (IARC, 2000)
Poor Control of Risks • Aggressive promotion of tobacco globally • Excessive utilization of medical imaging and nuclear medicine • Slow utilization of vaccines against cancer-causing viruses: HPV and HBV; lack of vaccines against HCV, H. pylori, HIV • Poor compliance with advice to have 5 or more portions of fruits and vegetables daily • Fresh policy in Quebec to incentivize mining and export of asbestos, especially to Third World, despite international criticism.
Asbestos • Occupational exposures from mining of asbestos in Canada, Russia, Australia, and other major countries and from extensive use in construction and other occupations, especially in lower-income countries • Expose published this year by International Consortium for Investigative Journalism and Center for Public Integrity (www. publicintegrity. org) • Controversy in Quebec over government subsidies for continued mining and claims that certain kinds of asbestos are less hazardous.
Overcoming Past Exposures: Aims and Populations for Chemoprevention • Primary prevention: general population of healthy individuals, including subgroups with notable “risk factors” (“high-risk”) • Secondary prevention: individuals screened, with pre-malignant lesions at particular sites • Tertiary prevention: cancer patients, to prevent complications or second primaries after (presumed) cure of initial cancer
Beta-Carotene Trials • Alpha-Tocopherol, Beta-Carotene Trial (ATBC) • Beta-Carotene & Retinol Efficacy Trial (CARET) • Physicians Health Study (Aspirin/Beta-Carotene) • Women’s Health Study (Beta-Carotene/ASA/vit E) • Skin, colon, other cancer endpoints (Dartmouth trials) • Retinoic acid, beta-carotene, &13 -cis retinoic acid trials, head & neck, aerodigestive (M. D. Anderson) • Surrogate/intermediate endpoint trials: sputum, bronchial biopsy (Tyler, Texas; France) • Vitamins and minerals supplementation (Linxian trials)
Beta-Carotene and Retinol Efficacy Trial (CARET) in U. S. • 14, 254 heavy smokers (current/former, male & female) • 4060 men exposed occupationally to asbestos • Beta-carotene 30 mg/day + retinyl palmitate 25, 000 IU/day • Endpoint: designed for 110, 000 person-years to detect a 23% reduction in lung cancer incidence • Secondary endpoints: total and cardiovascular mortality • Many ancillary studies/publications
ATBC & CARET Surprises Stimulated Productive Laboratory Studies of Beta-Carotene • In oxidizing environments epoxides and ketones of beta-carotene are formed, which increased adduct formation (Ba. P + rat liver + DNA) • Beta-carotene (with TPA) increased DNA synthesis, ODC levels, and proliferation of BALB/c 3 T 3 cells • Beta-carotene with cigarette smoke increased c-jun/cfos and AP-1 and decreased RAR-beta in ferrets • Beta-carotene increased CYP 1 A 1/2, 3 A, 2 B 1, 2 A in rat lung
Take any new reports of disease-preventing vitamins with a grain of salt. When this is all sorted out, it could turn out that we will all have to take 50 or 60 different nutrients to get a real benefit. “That’s a possibility, ” says Goodman, of the Hutchinson Cancer Research Center. “It’s called broccoli. ” --Ross PE. Spinach in a pill. Forbes, November 4, 1996; 354 -355
Asbestos Exposure and Lung Cancer Risk in CARET • CARET had 4060 asbestos-exposed male workers from 8 trades in civilian and naval shipyards and 14, 254 men and women with heavy smoking histories. • In designing the trial and estimating its power, we noted that models that showed long-term lung CA risk increased with 4 th power of the years since first exposure.
Results in CARET The lung cancer incidence rate in the asbestosexposed/smoker cohort was 5. 9 per 1000 person -yrs, lower than the 7. 1 per 1000 p-y in the heavy smokers (statistically significant). Smoking history was greater in the smokers cohort, but these results strongly suggest that World War II and subsequent exposures were not in the same ballpark as Selikoff’s insulators. Neither the rate nor the RR has risen with longer follow-up.
SELECT: Selenium + Vitamin E Prostate Cancer Chemoprevention Trial • Based on suggestive epidemiological and skin cancer chemoprevention trial results, the NCI launched this study of 35, 533 men with PSA <4 ng/ml and normal digital exam. • The trial was halted due to no prospect of benefit and early evidence of increased prostate cancer incidence: RR 1. 13 for E, 1. 04 for Se, 1. 05 for both vs placebos (JAMA, 2009). • Follow-up results confirmed excess prostate cancer incidence (JAMA 2011).
“The clinical trials ought to be seen as representing a triumph of the scientific process rather than a failure of therapy. We now know that beta carotene supplements are not an effective means of lowering the risk of cancer…No one should discount the importance of epidemiologic studies of diet and chronic disease. Persons who eat a relatively large quantity of vegetables, fruits, and grains have a profoundly lower risk of death, particularly from cardiovascular disease and cancer. ” --Greenberg ER, Sporn MB. Editorial. NEJM, May 2, 1996.
Challenges of Reports of Clusters of Cancer Cases • “The best way of preventing cancer is to go into one of those places where there is a hot spot on the cancer maps and do a study--because it always disappears when you do”. --NCI epidemiologist Robert Hoover Quoted by R. Peto (Banbury, 1981, p. 654)
Proportion of Cancers Attributed to Different Factors Factor Tobacco Diet including obesity & inactivity Infection: viral, bacterial, parasitic Reproductive factors and hormones Ionizing radiation, especially imaging Heredity Occupation--reaffirmed Alcohol UV light Pollution Medicines Industrial products Food additives Best estimate (%) 33 30 18 7 6 5 3 3 1 <1 <1 Plausible Range (%) 25 - 40 20 - 60 10 - 25 5 - 10 4 -8 2 -8 2 -4 0. 5 - 1 <1 - 2 -2 - 1 79 Sources: Doll & Peto, 1981; 1996; Levine et al, 1989; Li et al. , 1991; Pisani et al. , 1997; Key et al. , 1997; Parkin et al. , 2006; our group
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