IM 3B: ONCOLOGY TOBACCO-RELATED CANCERS/RISK:

PREVENTION AND EARLY DETECTION

SOURCE: 2017 PPT - Lung cancer - Smokers have 1 in 3 lifetime risks of
February 2017 - Bladder cancer dying prematurely from tobacco
- Laryngeal cancer related cancer
PREVENTION AND EARLY DETECTION - Pancreatic cancer - Number of cigarettes and level of
- Oropharyngeal cancer inhalation are correlated with lung
GOALS: - Gastric cancer cancer mortality
- To develop specific interventions to prevent cancer in those at risk - Esophageal cancer - Environmental tobacco causes lung
- To have more sensitive and specific screening for early detection of cancer - Renal cancer cancer in nonsmokers

CARCINOGENESIS: SMOKING CESSATION:

- A process, a continuum of discrete tissue and cellular changes overtime resulting in - Decrease 10-year lung cancer mortality by 30-50%
more aberrant physiologic process. - Save more lives than any other public health activity
- Cancer arises from interaction between genetics and environmental exposures
COMMIT:
- COMmunity Intervention Trial for smoking cessatin
- A 4 year program
- Demonstrated that:
- Light smoker (<25cigarette/day) were more likely to benefit from simple
cessation messages and cessation program.
- Quit rate:
- 30.6% in the intervention group
- 27.5% in the control group
- Unsuccesful in heavy smokers
- needs an intense broad based cessation programs like:
- counseling
- behavioral strategies
- pharmacologic adjunct such as:
- Nicotine replacement: gum, spray, lozenges and inhalers
- Bupropion
- Vareniciline
CANCER PREVENTION:
- The identification and manipulation of the genetic, biologic, and environmental
PHYSICAL ACTIVITY:
factors in the casual pathway of cancer
- Biologic - Associated with decreased risk of colon and breast cancer
- Environmental
- Social DIET MODIFICATION:
- Studies have conflicting results on effect of low fat, high fiber diet in the risk of
- Genetic
developing cancer
- Evidence does not currently establish anti carcinogenic value of vitamin, mineral or
EDUCATION AND HEALTHFUL HABITS:
- Smoking Cessation nutritional supplement in amounts greater than those provided by a balance diet
- Physical Activity
- Diet modification ENERGY BALANCE:
- Causality has not been established, but BMI >25kg/m2 appears to increase the risk
- Energy Balance
- Sun avoidance of cancer
- Obesity is associated with increased risk of colon, breast (female,
postmenopausal), endometrial, renal and esophageal cancers
- Observational studies:

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 - Relative risk of colon cancer is ind by 1.5-2 in obese men and 1.2-1.5 in obese CHEMOPREVENTION OF LUNG CANCER IN PATIENTS AT HIGH RISK:
women A. ATBC LUNG CANCER PREVENTION TRIAL:
- Obese postmenopausal women have 30-50% increased in RR of breast cancer - male smokers, with average 35.9 pack year
- age 50-69 at entry
SUN AVOIDANCE: - received alpha- tocopherol, beta carotene, and/or placebo in a randomizeded 2x2
- Reduction of sun exposure through protective clothing and changing pattern of factorial design
outdoor activities can reduce skin cancer risk - RESULTS:
- Sunscreens decrease risk of actinic keratosis (precursor of squamous cell skin - After median follow-up go 6.1 years
cancer) - Lung cancer incidence and mortality were statistically increased in those
receiving B-carotene
CANCER CHEMOPREVENTION: - Alpha-tocopherol has no effect on lung cancer mortality but had a higher
- Involves use of specific natural or synthetic chemical agents to reverse, suppress, incidence of hemorrhagic stroke
or prevent carcinogenesis before the development of invasive malignancy - No evidence suggested interaction between the 2 drugs
- Potential points are the genetic and epigenetic changes and growth regulatory - Patients receiving alpha-tocopherol had a higher incidence of hemorrhagic
pathways stroke

CARCINOGENESIS: B. CARET: THE B-CAROTENE AND RETINOL EFFICACY TRIAL:

INITIATION
- Initial changes
- Alteration can be inherited or acquired
through the action of physical,
infectious or chemical carcinogens
PROMOTION
- The initiated cell and its surrounding
tissue microenvironment progress
through carcinogenesis
- as influenced by promoters ex:
hormones, and androgens
- 17, 000 American smokers and workers with asbestos exposure
- Patients: Randomly assigned to receive B-carotene, retinol and/or placebo in a 2x2
factorial design
- Result: Demonstrated harm from B- carotene
- A lung cancer rate of 5 per 1000 subjects per year for those receiving placebo
- 6 per 1000 subjects for those receiving B- carotene

- Distinction between initiators and promoters are indistinct. Component of cigarette * ATBC and CARET results demonstrate the importance of testing chemoprevention
smoke are complete carcinogens hypothesis thoroughly before their widespread implementation as the results
contradict a number of observational studies
CHEMOPREVENTION
- Cancer can be prevented or controlled through interference with the factors that CHEMOPREVENTION OF COLON CANCER:
cause cancer initiation, promotion or progression - Trials use adenoma recurrence or disappearance as a surrogate endpoint for
- Compounds of interest in chemoprevention often have: colon cancer prevention
- antimutagenic - anti-inflammatory - Early trials suggest that NSAIDS such as piroxicam, sulindac, and aspirin, may
- antioxidant - anti proliferative or pro-apoptotic activity prevent adenoma formation or cause regression of adenomatous polyps
- or combination - Mechanism of action : unknown presumed they work through the COX pathway

CHEMOPREVENTION OF CANCERS OF UPPER AERODIGESTIVE TRACT: A. ASPIRIN:

HPV vaccine
- HPV infection, particularly HPV-16, increases the risk for cancers of the
oropharynx
- even in the absence of other risk factors such as smoking or alcohol use
- infection is believed to be largely sexually acquired
- The introduction of the HPV vaccine might eventually reduce oropharyngeal
cancer rates
- Physicians' Health Study and Womens Health Study
- Aspirin had no effect on colon cancer incidence in persons with no previous
history of colonic lesions
- Showed an approx. 18% relative risk reduction for colonic adenoma incidence in
persons with a previous history of adenomas after 1 years therapy
- Pooled findings from observational cohort studies do demonstrate a 22% and 28%
relative reduction in colorectal cancer and adenoma incidence, respectively
- Meta-analysis of four randomized controlled trials (albeit primarily designed to
examine aspirins effects on CV events)

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 - Aspirin at doses of at least 75 mg resulted in a 24% relative reduction in - Adjuvant Tamoxifen trials:
colorectal cancer incidence after 29 ears, with no clear increase in efficacy at - reduced the number of new breast cancer in the opposite breast by >1/3
higher doses. - In a randomized placebo-controlled prevention trial, involving >13,000 female at
high risk:
B. COX-2 INHIBITORS - Result: Tamoxifen decreases risk by 49% (from 43.4 to 22 per 1000
- Trials were initiated but an increased risk of CV events in those taking the COX-2 females),after a median follow-up of nearly 6 years
inhibitors was noted - IBIS-I: The international breast cancer intervention study and italian randomized
- These agents are not suitable for chemoprevention in the general population Tamoxifen Prevention Trial: similar findings
- Both studies showed that Tamoxifen also reduced bone fractures but with small
C. CALCIUM increase in risk of endometrial cancer, stroke, pulmonary emboli and deep vein
- Epidemiologic studies suggest that diets high in calcium lower colon cancer thrombosis
risk
- Calcium binds bile and fatty acids, which cause proliferation of colonic B. TAMOXIFEN AND RALOXIFENE
epithelium. - RALOXIFENE- another selective estrogen receptor modulator
- Calcium polyp prevention study: - Both tamoxifen and raloxifine have been approved by the US FDA for reduction of
- RCT breast cancer in women at high risk for the disease (1.66 % risk at 5 year based on
- Calcium supplementation decreased the absolute risk of adenomatous polyp the Gail Risk Model)
recurrence by 7% at 4 years
- 12% absolute risk reduction 5 years after cessation of treatment C. AROMATASE INHIBITOR
- Womens health initiative: - Aromatase inhibitors are even more effective than tamoxifen in adjuvant breast
- Combined use of calcium carbonate and vitamin D twice daily DID NOT reduce cancer therapy > they are more effective as chemoprevention
the incidence of invasive colorectal cancer compared with placebo after 7 years - Randomized, placebo-controlled trials of exemestane reported a 65% relative
reduction (from 5.5 to 1.9 per 1000 women) in the incidence of invasive breast
D. HORMONES cancer in women at elevated risk ( median follow-up of about 3 years)
- The womens health initiative demonstrated that post-menopausal women takin - Common adverse effects: arthralgia, hot flushes, fatigue, and insomnia
estrogen plus progestin have a 44% lower risk of colorectal cancer compared to
women taking placebo CHEMOPREVENTION OF PROSTATE CANCER:
- Other findings: - FINASTERIDE
- Modest increase in cardiovascular disease and - 5-alpha-reductase inhibitor
breast cancer risk associated with combined - inhibits conversion of testosterone to dihydrotestosterone (DHT), potent
estrogen and progestin therapy stimulator of prostate cell proliferation
- Positive effect on colon cancer is mitigated by the - THE PROSTATE CANCER PREVENTION TRIAL:
modest increase in CV and breast cancer risks - Randomly assigned men >55 years at average risk for prostate cancer to
finasteride or Placebo
E. STATINS - After 7 years prostate cancer incidence was 18.4 % with finasteride arm and
- A case control study suggest that statins decrease the incidence of colorectal 24.8 % with placebo arm ( statistically significant difference)
cancer - Finasteride group has more patients with tumor of Gleason Score of 7 and
- No RCTs higher compared to placebo group
- A meta-analysis of statins showed no protective effect - Long-term (10 or 15 years) follow- up didnt reveal any statistically significant
of statins on overall cancer incidence or death difference in in overall mortality between all men in the finasteride and placebo
arms
CHEMOPREVENTION OF BREAST CANCER: - DUTASTERIDE
A. TAMOXIFEN - REDUCE: Reduction by Dutasteride of Prostate Cancer Events trial
- In a randomized placebo-estrogen with partial estrogen agonists activity in some - 8200 men with an elevated PSA (2.510 ng/mL for men aged 50 60 years
tissues, such as endometrium and bone and 310 ng/mL for men aged 60 years or older) and negative prostate
- one of its action is to up regulate Transforming Growth Factor (TGF- ) biopsy on enrolment received daily 0.5 mg dutasteride or placebo
which decreases breast cell proliferation

IM 3B: Oncology -Prevention and early detection 3 of 6

 - Result: Statistically significant 23% relative risk reduction in the incidence of
biopsy-detected prostate cancer in the dutasteride arm at 4 years of
treatment (659 cases vs. 857 cases, respectively)
- Across years 1 through 4, there was no difference between the arms in
the number of tumors with a Gleason score 7 to 10
- During years 3 and 4, there was a statistically significant difference in
tumors with Gleason score of 8 to 10 in the dutasteride arm (12 tumors VS
1 tumors, respectively)
- FINASTERIDE AND DUTASTERIDE:
- The FDA has analyzed both trials
- The use of a 5--reductase inhibitor for prostate cancer
chemoprevention would result in one additional high- grade (Gleason score 8 to
10) prostate cancer for every three to four lower-grade (Gleason score <6)
tumors averted
- Could not conclusively dismiss a causative role for 5-- reductase inhibitors.
- These agents are therefore not FDA-approved for prostate cancer prevention
- VACCINE-HPV:
- Quadrivalent HPV vaccine (6,11,16,18) and bivalent (16,18) are available
- HPV types 16, 18 cause cervical and anal cancer
- HPV types 6, 11 cause genital papilloma
- For individuals not previously infected with these HPV strains, the vaccines
demonstrate high efficacy in preventing persistent strain specific HPV infections
- Vaccines ability to prevent cervical and anal cancer relied on surrogate outcome
measures
- Degree of durability of the immune response beyond 5 years is not currently
known
- Vaccines do not appear to impact pre-existing infections
- Efficacy appears to be markedly lower for populations that had previously been
exposed to vaccine-specific
HPV strains
- Recommendation in the United States for females and males age 926 years
SURGICAL PREVENTION
- Some organs in some individuals are at such high risk of developing cancer that
surgical removal of the organ at risk is recommended
- Severe cervical dysplasia are treated with conization and occasionally even
hysterectomy
- Familial polyposis or ulcerative colitis- colectomy is used to prevent colon cancer
- A larger (n = 639) retrospective cohort study reported a 9094% reduction in breast
cancer risk
- Post mastectomy breast cancerrelated deaths were reduced by 8194% for high-
risk women compared with sister controls and by 100% for moderate-risk women
when compared with expected rates.
B. PROPHYLACTIC OOPHORECTOMY:
- Employed for the prevention of ovarian and breast cancers among high-risk women
- A prospective cohort study evaluating the outcomes of BRCA mutation
- statistically significant reduced incidence of ovarian or primary peritoneal cancer
- 36% relative risk reduction, or a 4.5% absolute difference
- Studies of prophylactic oophorectomy for prevention of breast cancer in women
with genetic mutations
- Relative risk reduction of approximately 50%
- Greatest for women having the procedure at younger age
SCREENING
- a means of detecting disease early in asymptomatic individuals with the goal of
decreasing morbidity and mortality
- to be of value, it must detect disease earlier, and treatment of earlier disease must
yield a better outcome than treatment at the onset of symptoms
- Preferred endpoint: cause-specific mortality, rather than survival after diagnosis
- Done on asymptomatic, healthy persons, therefore should offer substantial
likelihood of benefit that outweighs harm
- Examinations, tests or procedures are usually not diagnostic of cancer but instead
indicate that a cancer may be present
- The diagnosis of cancer is made following a work-up that includes a biopsy and
pathologic confirmation
A. BREAST CANCER SCREENING:

A. PROPHYLACTIC BILATERAL MASTECTOMY:

- may be chosen for breast cancer prevention among women with genetic
predisposition to breast cancer
- Prospective series of 139 women with BRCA1 and BRCA2 mutations, 76 chose to
undergo prophylactic mastectomy and 63 chose close surveillance.
- Result: At 3 years, no cases of breast cancer had been diagnosed in those opting
for surgery, but eight patients in the surveillance group had developed breast
cancer.

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Self examination - Women >20 years BSE is an option
Clinical - Women 20-39 years: perform every 3 years
examination - Women >40 years:Perform annually
- Women with >20% lifetime risk of breast cancer. Screen
with MRI + mammography annually
Magnetic - Women with 15-20% lifetime risk of breast cancer
Resonance
discuss option of MRI + mammography annually
Imaging (MRI)
- Women with <15% lifetime risk of breast cancer: do not
cream annually with MRI
- MAMMOGRAPHY:
- In most trials, breast cancer mortality rate is decreased by 2030%
- The U.K. Age Trial in women age 4049 year
- no statistically significant difference in breast cancer mortality for screened
women versus controls after about 11 years of follow up
- A metaanalysis of eight large randomized trials
- showed a 15% relative reduction in mortality from mammography screening
for women age 3949 years after 1120 years of followup
- High-risk individuals:
- For women with BRCA1 and BRCA2 mutations
- When to begin and the optimal frequency of screening have not been defined
- MRI screening may be more effective
- detecting breast cancer in women carrying BRCA1 and BRCA2 where
mammography is less sensitive, possibly because such CA occur in
younger women, in whom the test is known to be less sensitive
- No RCTs
B. CERVICAL CANCER SCREENING:
Pap test (cytology) - Women 21-29 years screen every 3 yeas
- Women 30-65 years. Acceptable approach to screen
with cytology every 3 years (see HPV rest below)
- Women <21 years: No screening
- Women >65 years: No screening following adequate
negative prior screening
- Women after total hysterectomy for noncancerous
causes: Do not screen
HPV test - Women 30-65 years. Preferred approach to screen
with HPV and cytology co-testing every 5 years (see
Pap test above)
- Women <30 years: Do not use HPV testing
- Women >65 years: No screening following adequate
negative prior screening
- Women after total hysterectomy for noncancerous
causes: Do not screen
IM 3B: Oncology -Prevention and early detection
C. COLORECTAL CANCER SCEENING:
Sigmoidoscopy Adults >50 years: Screen every 5 years
FOBT Adults >50 years: Screen every year
Colonoscopy Adults >50 years: Screen every 10 years
Fecal DNA testing Adults >50 years: Screen every year
Fecal immunochemical
Adults >50 years: Screen every year
testing
CT colonography Adults >50 years: Screen every 5 years
- FOBT
- A metaanalysis of four randomized controlled trials demonstrated a 15%
relative reduction in colorectal cancer mortality with FOBT
- The sensitivity for FOBT is increased if specimens are rehydrated before testing,
but at the cost of lower specificity
- The falsepositive rate for rehydrated FOBT is high
- 15% of persons tested have a positive test
- Only 210% of those with occult blood in the stool have cancer
- SIGMOIDOSCOPY:
- Two metaanalyses of five randomized controlled trials of sigmoidoscopy (i.e.,
the NORCCAP, SCORE, PLCO, Telemark, and U.K. trials)
- 18% relative reduction in colorectal cancer incidence
- 28% relative reduction in colorectal cancer mortality
- Population: 50 to 74 years
- Followup: 6 to 13 years.
- Diagnosis of adenomatous polyps by sigmoidoscopy should lead to evaluation
of the entire colon with colonoscopy
- Recommended interval: 5 years
- COLONOSCOPY:
- Onetime colonoscopy detects 25% more advanced lesions than onetime
FOBT with sigmoidoscopy
- Polyps >10 mm
- Villous adenomas
- Adenomatous polyps with highgrade dysplasia
- Invasive cancer
- Perforation rates are about 3/1000 for colonoscopy and 1/1000 for
sigmoidoscopy
- Observational studies suggest that efficacy of colonoscopy to decrease
colorectal cancer mortality is primarily limited to the left side of the colon
D. LUNG CANCER
- Low dose Computed Tomography CT scan
- Men and women, 55-74 yeats, with >30 pack-year smoking history, still smoking
or have quit within past 15 years. Discuss benefits, limitations, and potential
harms of screening; only perform screening in facilities with the right type of CT
scanner and with high expertise/specialists
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E. PROSTATE CANCER
- RCTs on impact of PSA screening on prostate cancer mortality
- The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening
Trial
- 77,000
- 55-74 years
- After 13 years of follow-up, no statistically significant difference in the number
of prostate cancer deaths were noted between annual PSA and usual care
- The European Randomized Study of Screening for Prostate Cancer
(ERSPC) PSA every 4 year or none
- 182,000 men wth a predefined core screwing group of men ages 55-69
years

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