Screening and Early

Diagnosis in Oncology

Başak Oyan-Uluç, MDYeditepe University Hospital

Department of Medical Oncology

Prevention

PrimaryElimination of

risk factor• Cessation of

smoking• Colonoscopy• Vaccination• Lifestyle

modifications

Onset of disease Clinical diagnosis

Asymptomatic Clinical courseHealthy

SecondaryEarly diagnosis

and treatment• Colonoscopy

• Mamography

• Pap smear

TertiaryReducing

complications (rehabilitation)

Cancer Screening

• Cancer screening: Early detection of asymptomatic or unrecognized disease by the application of inexpensive tests or examinations in a large number of people.

• Main objective: To reduce morbidity and mortality from a particular cancer among people screened.

• Screening procedure itself– Not diagnostic– Detects people with cancer risk – Positive or suspicious findings must be evaluated further to

determine diagnosis and appropriate treatment.

Screening vs. Diagnosis

Screening Diagnosis

Applied to asymptomatic groups

Applied to symptomatic individuals

Lower cost per test Higher cost, all necessary tests applied to identify disease

Lower yield per test Increased probability of case detection

Lower adverse consequences of error

Failure to identify true positive can delay treatment, worsen prognosis

Ideal screening program

Patient features• High impact: Morbidity,

mortality, economy• High incidance and high

prevelance• Predictable course and

biology • High prevelance of preclinic

phase• Effective treatment exists

Requirements of screening test

• Diagnosing disease at preclinical phase

• Acceptable sensitivity and specificy

• Acceptable to people• Simple anf cheap• Safe

Quality of primary or secondary prevention (Cheap, effective, safe)

Cervical Cancer-Pap Smear

1. Long preinvasive period

2. Increased morbidity and mortality in invasive period

3. Treatable if early diagnosis

4. PAP smear: Sensitive, low cost, easy to apply, safe

Benefits of Screening

• Improved prognosis for those with early-detected cancers

• Less radical treatment

• Reassurance for those with negative test results

• Reduction of treatment costs

• Although there are more than 100 different cancers, most of them lack proven screening interventions

• Cancers that have widely accepted screening interventions

• Breast• Cervical cancer• Colorectal• Prostate ?

• Hepatocellular cancer in patients with risk factor• Lung cancer in people with defined risk factors

Cancers suitable for screening

Breast Cancer Screening

• Most common cancer in females

• Average risk

• Increased risk– Prior thoracic RT (eg. Mantle)– Women who have a lifetime risk of >%20– Strong family history of genetic predisposition– LCIS/atypical hyperplasia– Prior history of breast cancer

Breast Cancer ScreeningAverage risk women

Widely accepted techniques for breast cancer screening includes:– Brest self-examination: Monthly after age 20

– Clinical breast examination: • Age 20-39: Every 3 years• Every year after age 40

– Mamography: Every 1-2 years after age 40-50• In Turkey (KETEM): Every 2 years after age 40

Mamography

Trial Age Decrease in mortality(%)

HIP 40-64 24Malmö 45-69 192-kanton, İsveç 40-74 32Edinburg 45-64 21Stockholm 40-64 26Kanada-1 40-49 -3Kanada-2 50-59 -2Gothenburg 39-59 16

All trials 39-74 24

CA Cancer J Clin 2003; 53:141

Mamography

• Microcalcifikcations Spicular mass lesion

0.4 cm komedo dkis 0.7 cm inv lob k

1993 1999

Controversial points

• Initiation of screening (age 40-49?)• Frequency (1 vs. 2 years)• Radiation dose• Side effects• Cost• High risk women

Age of initiation of screening

• 40-49 years – Controversial– Long term follow-up results shows benefit– Decrease in mortality : 15%– Gothenburg trial: Decrease in mortality 45%– Metaanalyses: Decrease in mortality 15%

Frequency of screening

• Decrease in distant metastases– Screening every year: 51%– Screening every 2 year: 22%

Michaelson ve ark. Radiology 1999; 212:551

Radyasyon Dozu

• ACS guidelines:“many women are concerned about the exposure to x-rays but the level of radiation used in modern mammograms does not significantly increase the risk for breast cancer”

• Mamography: Dose < 2 mGr (~ 1 mGr)

• Ages 40-90 years, mamography every year: Total 20-40 rad– Dose of radiation exposure during a flight between New

York and California : Equlas to 1 mamography

Radiation Risk in Breast Screening

• Risk of radiation induced cancer for screening is about 1 in 20,000 per visit

• ~170 cancers detected for every cancer induced• Mortality benefit of screening exceeds radiation

induced detriment by ~ 100:1

Risk of mamography

Similar risks• Traveling 4000 miles by air• Traveling 600 miles by car• 15 minutes of mountain climbing• Smoking 8 cigarettes

LIMITATIONS OF MAMMOGRAPHY

• As many as 5 – 15% of breast cancers are not detected mammographically

• A negative mammogram should not deter work-up of a clinically suspicious abnormality

Adverse events

• False negative mamography and interval cancers

• False reassurance related to false negative mamography

• Overdiagnosis of tumors not causing mortality

• False positive mamography (recall rate %8-9) and unnecessary additionla tests and biopsy

• Anxiety

Cervical Cancer Screening

• Second most common cancer in females worldwide particularly in the underdeveloped regions

• The incidence has declined in many countries due to the improved standard of living throughout the world

Cervical Cancer Screening

• Pap test: Introduced in 1930s by Dr. Papanicolaou

• Screening should begin at age 21

Cervical Cytologic Screening Guidelines from the American College of Obstetricians and Gynecologists, 2009

Screening not discontinued in: •In-uterine DES exposure•Personal history of cervical cancer, CIN grade 2/3•Immune insuffiency (eg. HIV) •HPV DNA (+)

Colorectal Cancer Screening

• Causes morbidity and mortality in both men and women

• Second leading cause of death due to cancer

• The natural history of colon cancer with relatively long time from biologic onset to development of carcinoma makes it a good candidate for screening

Adenoma-carcinoma sequence

Risk groups for screening• Average risk

– Age ≥ 50 y– No inflammatoy bowel disease– No history of adenoma or colorectal cancer– Negative family history

• Increased risk– Personal history of

• Adenoma/sessile serrated polyp• Inflammatoy bowel disease• Colorectal cancer

– Positive family history

• High risk syndromes– Lynch syndrome/Hereditary nonpolyposis colorectal cancer (HNPCC)– Polyposis syndromes (familial adenomatous polyposis, Peutz-

Jeggers syndrome, Juvenile polyposis syndrome, hyperplastic polyposis syndrome)

Screening tests for colorectal cancerAverage risk

Starts at age 50

1. Colonoscopy every 10 years • preferred if available• For every 1% increase in complete colonoscopy rate, the hazard of

death decreased by 3%.

2. Annual FOBT+/-Flexible sigmoidoscopy every 5 years

Annual Fecal occult blood test (FOBT)• Testing of stool for occult blood to detect colorectal cancer at an early

stage• Variation is observed in estimates of the sensitivity but its lower cost and

increased specificity to detect right-isded colonic lesions make it a good screening test

Flexible sigmoidoscopy every 5 years • In contrast to FOBT, has a high sensitivity and specificity • Involves the use of a 60 cm flexible sigmoidoscope• Detects left sided lesions

Colorectal Cancer Screening Guidelines*

Prostate Cancer Screening

• Most commonly diagnosed cancer among men and is the second leading cause of male cancer deaths

• Two main screening modalities• Serum prostate specific antigen (PSA) • Digital rectal examination (DRE)

Prostate Cancer Screening• Benefit of screening is controversial

• Prostate cancer is common and potentially lethal; however, more patients die with, rather than from, the disease.

• Incidence: 1/6 Mortality: 1/30

• Screening detects more cases of organ-confined disease, but there is no proof that this detection saves lives.

• In more instances, prostate cancer is not the cause of elevated PSA level.

NEJM 2009; 360:1310NEJM 2009; 360:1320

Prostate Cancer Screening

• Localized treatment of prostate cancer is effective but is associated with complications than can include impotence and incontinence (~ 50%).

• It is likely that prostate cancer screening using the PSA level is beneficial in a subset of men; however, the characteristics of the subset have not been defined.

Prostate Cancer Screening

• Discuss benefit and harms of screening with the patient

• In men with a life expectancy of >10 years, start screening at age 40y with: – PSA – Digital rectal examination

• In last years, it is recommended to offer a baseline DRE and PSA at age 40 y.

Prostate Cancer Screening

• Serum PSA level• Allows earlier detection of prostate cancer• Normal PSA values are found in 1/3 of localized tumors

(false negative)• Often elevated in men with noncancerous conditions

such as benign prostatic hyperplasia (false positive)

Prostate Cancer Screening

• NCCN recommendation– DRE yearly starting at age 40– PSA yearly starting at age 40

Lung Cancer Screening

Target population:•Age: 55-74 years +•Smoked ≥ 30 pack/year +•Continue to smoke or have quitted smoking within 15 years

Screeninig method: Low dose thorax CT

%20 reduction in lung-cancer related mortality

Hepatocellular Carcinoma

Cirrhosis• Hepatitis B, C• Alcohol• Genetic hemocromatosis• Non-alcoholic

steatohepatitis• Autoimmune hepatitis• Primary biliary cirrhosis

No cirrhosis• Hepatitis B carrier• Non-alcoholic

steatohepatitis

Ultrasonography

Alpha-feto protein (AFP)

Every 6-12 months

Diagnosis rate: %92

False (+): %7.5

People not to be screened

• Life expectancy <5 years

• People who do not wish to undergo additional diagnostic tests or who do not want any treatment

Future of Screening

• Compliance: Encourage people to adhere the proven cancer screening modalities

• New and better methods: With the discovery of cancer susceptibility genes (e.g. BRCA-1 susceptibility gene for breast cancer) lifetime risk for an individual to develop a specific cancer could be estimated.

ROLE OF TUMOR MARKERS IN SCREENİNGi DIAGNOSIS AND

FOLLOW-UP

Tumor Markers

• Secreted by the tumor or secreted in response to tumor

• Also secreted by normal cells and found in low concentrations in serum

• Some increase in inflammatory disease, hepatic and renal disorders

Ideal tumor marker

• Detect small sized tumor while asymptomatic• Elevated only in malignancy• Can be used for screening and early diagnosis

• (-) test result in healthy people and patients with benign diseases (Specificity 100%)

• (+) test result in cancer patients(sensitivity 100%)

• NO IDEAL TUMOR MARKER EXISTS

Application of Tumor Markers in Clinical Practice

1. Screening

2. Diagnosis

3. Prognosis and tumor load

4. Evaluation of treatment response and follow-up

Also: Radioactive labelled markers to detect metastatic regions

Classification

1. Oncofetal proteins• CEA• AFP

2. Enzymes• PAP

• LDH• NSE• PLAP

3. Hormones• Calcitonin• B-HCG• Thyroglobulin

4. Antigens• CA15-3• Ca 19-9• CA125• B2-microglobulin

5. Others• 5-HIAA• VMA• Ferritin

Carcinoembryonic Antigen (CEA)

• Surface glycoprotein of fetal colon epithelium• Not detected in normal adult tissues• Normal level: <5 ng/ml in non-smoker• Higher levels in smokers• Elevation

• Liver, colorectal, breast, gastric,pancreas cancer• Liver diseases (cirrhosis, hepatitis)• Pancreatitis• Inflamatory bowel disease• Chronic renal failure• Chronic lung disease• Rectal polyps

CEA

• Clinical use:• Prognosis (colon cancer)• Response evaluation and follow-up (detection of

relapses)

• Not used for screening and early diagnosis

Human Chorionic Gonadotropin (HCG)

• Elevation in males and non pregnant females->Cancer

• Half life: 14-24 hour

• Elevation: • Gestational trophoblastic tm• Ovarian and testicular germ cell tm

Alpha-fetoprotein (AFP)

• Secreted from fetal yolk sac, liver, intestines

• Max. level.: Gestational 12-15. week• Not detected in healthy patients > age 1• Elevation

• Liver diseases• Hepatocellular carcinoma (HCC)• Testicular and ovarian germ cell tm• Teratocarcinoma

AFP

• Clinical use:• Screening of HCC in patients with chronic active

hepatitis, cirrhosis, hepatitis B antigen carriers (every 6 month)

– >350 ng/ml

• Diagnosis• Prognosis• Response evaluation and follow-up

CA 19-9

• Clinical use• Pancreas cancer• Gastric cancer• Colorectal: elevated in only 42%

• Used in follow-up

CA 125

• Used in – Screening of females with family history of hereditary

ovarian cancer syndrome – Differential diagnosis of ovarian masses – Evaluation of response and follow-up of ovarian cancer

• Elevation: • Ovarian cancer• Diseases involving peritoneum• Lung, breast, cervical, endometrium, pancreas cancer• Benign diseases: Endometriosis, pregnancy, PID,

leiomyoma uteri

Tumor Markers in Clinical PracticeCancer Tumor marker Clinical Use

Breast CEA, CA 15-3 4

GI (colorectal, gastric, pancreas) CEA

CA 19-9

3,4

4

Prostate PSA

PAP

1 (?), 3, 4

3, 4

Hepatocellular AFP

CEA

1-4

4

Ovarian CA125 3, 4

Testis (germ cell) AFP, B-HCG

LDH, PLAP (seminoma)

2-4

3, 4

Gesta trophoblastic tm B-HCG 2-4

Small cell lung cancer NSE 4

Thyroid Thyroglobulin

Calcitonin (medullary)

4

1, 2, 4

Neuroblastoma VMA, Catecholamines 1-4

Myeloma Immunoglobulins 2, 3

1. Screening 2. Diagnosis 3. Prognosis 4. Evaluation of treatment response and follow-up

Tumor markers used in Screening

• AFP: screening for HCC in chronic hepatitis related to hepatitis B or C

• PSA

• Calcitonin in familial medullary thyroid disease

• CA 125: Screening of females with a family history of hereditary ovarian cancer syndrome

Guidelines for ordering/interpreting tumor marker tests

• Never rely on the result of a single test

• Order every test from the same laboratory

• Consider half-life of the tumor marker when interpreting the result

• Consider how the tumor marker is removed or metabolized

• Consider presence of HAMA antibodies

Conclusion

• Tumor markers should not be used as a tool for screening except:

• AFP for HCC in high risk patients• PSA for prostate cancer• Calcitonin in familial medullary thyroid disease

• Tumor markers are mainly a tool for response evaluation and follow-up.

• Tumor markers are not specific in most of the cases. They are also increased in several benign conditions.

Guidelines for ordering/interpreting tumor marker tests

• Never rely on the result of a single test

• Order every test from the same laboratory

• Consider half-life of the tumor marker when interpreting the result

• Consider how the tumor marker is removed or metabolized