These guidelines have been withdrawn · These guidelines have been withdrawn MOH clinical practice guidelines are considered withdrawn five years after publication unless otherwise

These guidelines have been withdrawn MOH clinical practice guidelines are considered withdrawn five years after publication unless otherwise specified in individual guidelines. Users should keep in mind that evidence-based guidelines are only as current as the evidence that supports them and new evidence can supersede recommendations made in the guidelines.

CLINICAL PRACTICE GUIDELINES

Health Screening

NMRC National Medical Research Council

July 2003 Ministry of Health

MOH Clinical Practice Guidelines 6/2003

Levels of evidence and grades of recommendation

Levels of evidence Level Type of Evidence

Ia

Ib

IIa

IIb

III

IV

Evidence obtained from meta-analysis of randomised controlled trials.

Evidence obtained from at least one randomised controlled trial.

Evidence obtained from at least one well-designed controlled study without randomisation

Evidence obtained from at least one other type of well-designed quasi-experimental study.

Evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies and case studies.

Evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities.

Grades of recommendation Grade Recommendation

A (evidence levels Ia,

Ib)

B (evidence levels IIa,

IIb, III)

C (evidence level IV)

GPP (good practice

points)

Requires at least one randomised controlled trial as part of the body of literature of overall good quality and consistency addressing the specific recommendation.

Requires availability of well conducted clinical studies but no randomised clinical trials on the topic of recommendation.

Requires evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities. Indicates absence of directly applicable clinical studies of good quality.

Recommended best practice based on the clinical experience of the guideline development group.


Health Screening


Copyright © 2003 by Ministry of Health, Singapore Available on the MOH website: http://www.gov.sg/moh/pub/cpg/cpg.htm

Statement of Intent These guidelines are not intended to serve as a standard of medical care. Standards of medical care are determined on the basis of all clinical data available for an individual case and are subject to change as scientific knowledge advances and patterns of care evolve. The contents of this publication are guidelines to clinical practice, based on the best available evidence at the time of development. Adherence to these guidelines may not ensure a successful outcome in every case, nor should they be construed as including all proper methods of care or excluding other acceptable methods of care. Each physician is ultimately responsible for the management of his/her unique patient in the light of the clinical data presented by the patient and the diagnostic and treatment options available.

Foreword

Health screening aims to identify diseases in apparently well people through the application of tests, examinations or other procedures which can be easily applied. Screening must be based on evidence that it is associated with improved clinical outcomes. For mass screening, there should also be evidence of cost-effectiveness. While there is a general perception that screening will improve clinical outcomes, this may not be so. This is because no screening test is 100% sensitive and specific. False positive tests will inevitably generate anxiety and require further testing, with attached risks and costs, while false negatives may give the patients a false sense of security. Hence there is a need for recommendation on health screening based on a rigorous review of evidence. I would like to commend the Committee on Health Screening for their hard work and commitment in producing the guidelines on health screening. I hope that these guidelines will assist medical professionals in their clinical practice. PROFESSOR TAN CHORH CHUAN DIRECTOR OF MEDICAL SERVICES

Contents

Page Executive summary of recommendations 1

1 Introduction 19

2 Screening for blood cholesterol 23

3 Screening for hypertension 29

4 Screening for diabetes mellitus 35

5 Screening for obesity 41

6 Screening for lung cancer 45

7 Screening for hepatocellular carcinoma (HCC) 49

8 Screening for colorectal cancer 55

9 Screening for prostate cancer 67

10 Screening for breast cancer 75

11 Screening for cervical cancer 95

12 Screening for uterine cancer 101

13 Screening for ovarian cancer 105

14 Screening for tuberculosis 109

15 Screening for hepatitis B 119

16 Screening for renal diseases 123

17 Screening for osteoporosis 131

18 Screening for visual acuity for the elderly 143

19 Screening for sexually transmitted infection 145

20 Clinical audit 163

Summary chart 165

Self-assessment (MCQs) 169

Workgroup members 177

Acknowledgements 179

List of Endorsing Agencies 181

Executive summary of recommendations

Details of recommendations can be found in the main text at the pages indicated. Screening for blood cholesterol C In screening for cholesterol, the optimal test is a full lipid profile including LDL-cholesterol, fasting triglyceride and HDL cholesterol. (pg 25)

Grade C, Level IV

GPP If the results are optimal based on the current recommendations for Singapore, we recommend repeat screening at 3 yearly intervals. (pg 24)

GPP

B Screening should be carried out in all individuals above the age of 40 years on an opportunistic basis. (pg 24)

Grade B, Level IIb A All patients with pre-existing coronary heart disease, stroke or peripheral vascular disease should be screened irrespective of age. (pg 24)

Grade A, Level Ia A All patients with diabetes mellitus should be screened irrespective of age. (pg 24)

Grade A, Level Ib B All individuals with impaired fasting glycaemia or impaired glucose tolerance should be screened at any age. (pg 24)

Grade B, Level III B All individuals with a family history and/or clinical evidence of familial hyperlipidaemia should be screened after the age of 2 years. (pg 24)

Grade B, Level IIa GPP Earlier screening from age 30 should be considered for individuals with other risk factors for CHD e.g. smoking, hypertension, family history of premature CHD. (pg 24)

GPP

1

B Earlier screening from age 30 years should be considered for those of Indian ethnicity. (pg 24)

Grade B, Level III Screening for hypertension

C Blood pressure should be measured at least once every 2 years for adults aged 21 years and above with diastolic pressure below 85 mmHg and a systolic pressure below 130 mmHg (i.e. normal BP). (pg 30)

Grade C, Level IV A Measurements are recommended annually for persons with a diastolic blood pressure of 85-89 mmHg or systolic blood pressure of 130-139 mmHg (i.e. high normal BP). Persons with higher blood pressures or major coronary risk factor such as diabetes mellitus require more frequent measurement. (pg 30)

Grade A, Level Ib C Any person aged 21 years and above should have their blood pressure measured during any visit to a physician ("case finding"). (pg 31)

Grade C, Level IV A Sphygmomanometry is the recommended method for blood pressure measurement, and it should be performed in accordance with the recommended technique. (pg 31)

Grade A, Level Ia A Pregnant women should have their blood pressure checked routinely as part of the prenatal care. (pg 32)

Grade A, Level Ia A Routine counselling to promote physical activity and a healthy diet for the primary prevention of hypertension is recommended for all adults. (pg 31)

Grade A, Level Ia

Screening for diabetes mellitus C Screening of asymptomatic individuals at high risk for type 2 diabetes mellitus should be carried out on an opportunistic basis. (pg 35)

Grade C, Level IV

2

C Screening should begin at age 40 years, and be considered at an earlier age (e.g. 30 years) if risk factors for diabetes are present. (pg 35)

Grade C, Level IV

B Fasting plasma glucose (FPG) is the recommended test for screening in the clinical setting because it is easy to perform and convenient. Individuals with a FPG ≥ 7.0 mmol/L should have a repeat testing on a different day to confirm the diagnosis of diabetes. Individuals with FPG of 6.1-6.9 mmol/l on screening should undergo a 75g oral glucose tolerance test (OGTT) to determine precisely the degree of glucose intolerance. (pg 38)

Grade B, Level III B OGTT is also a suitable test for screening. (pg 38)

Grade B, Level III

C Individuals found to have normal glucose tolerance on screening and who do not have risk factors for developing diabetes should have repeat screening at 3 yearly intervals. For those with diabetes risk factors, repeat screening may be performed more frequently e.g. at annual interval.

(pg 39) Grade C, Level IV

B Those detected to have impaired fasting glycemia (IFG) or impaired glucose tolerance (IGT) should have repeated screening on an annual interval in view of the high rate of conversion to diabetes. (pg 39)

Grade B, Level III Screening for obesity B Body mass index (BMI) and waist circumference can be used to classify obesity and assess risk. (pg 41)

Grade B, Level III

C All individuals ≥18 years of age should be screened. (pg 42) Grade C, Level IV

GPP Screening should be done once a year for all individuals ≥ 18 years. (pg 42)

GPP

3

Screening for lung cancer A Neither chest X-ray nor sputum cytology is recommended for screening. (pg 46)

Grade A, Level Ib

C The screening efficacy of low-dose spiral CT is unknown at present. (pg 46)

Grade C, Level IV Screening for hepatocellular carcinoma (HCC) GPP There is no evidence to support population-based surveillance for HCC. However, HCC surveillance should be offered to patients with chronic hepatitis B infection, hepatitis C liver cirrhosis and liver cirrhosis from other etiologies. HCC surveillance should be performed periodically with alpha-fetoprotein 3 to 6 monthly and ultrasound of the liver at 6 to 12 monthly interval. There is no definite recommended age to start surveillance. However, it is noted that the local statistics showed that HCC detection starts to increase from the age of 30 years. (pg 52)

GPP

C Current accepted tests used for HCC surveillance include ultrasound of the hepato-biliary system and alpha feto-protein level. (pg 49)

Grade C, Level IV Screening for colorectal cancer A Asymptomatic individuals above the age of 50 years should undergo screening for colorectal cancer. This would include asymptomatic individuals with a family history limited to non-first degree relatives. The screening options would be faecal occult blood testing annually. (pg 62)

Grade A, Level Ia

B Alternatively, other methods that could be employed in this group include flexible sigmoidoscopy every 5 years; (pg 62)

Grade B, Level IIa

4

B or colonoscopy every 10 years. (pg 62) Grade B, Level IIb

(Those with a positive faecal occult blood test would undergo colonoscopy or when technically not possible, a barium enema.)

B In individuals with a history of colorectal cancer in a first degree relative aged 45 years or younger or with a family history of two or more affected first degree relatives, colonoscopy is recommended every 3 years performed 10 years prior to the youngest case in the family. (pg 62)

Grade B, Level IIa

B In individuals who have a history of colorectal cancer in a first degree relative over the age of 45 years, colonoscopy is recommended every 10 years. The age of commencing colonoscopy is 10 years prior to the youngest case in the family or age 50 years whichever is earlier. (pg 62)

Grade B, Level IIb

A In individuals with a personal past history of colorectal polyps, colonoscopy is recommended one year after polypectomy in the presence of high risk features (polyp > 1cm, multiple, villous architecture) or three years after polypectomy in the absence of high risk features (solitary, tubular architecture). (pg 62)

Grade A, Level Ib

B In individuals with a personal past history of colorectal cancer, colonoscopy is recommended one year after resection provided that total imaging of the bowel was achieved prior to surgery. (pg 62)

Grade B, Level IIa

B In individuals with a family history of familial adenomatous polyposis, flexible sigmoidoscopy is recommended annually from the onset of puberty. (pg 62)

Grade B, Level IIb Genetic counselling should be considered.

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B In individuals with a family history of Hereditary Non-polyposis Colorectal Cancer, colonoscopy is recommended every two years 10 years prior to the diagnosis of colorectal cancer in the youngest family member. (pg 62)

Grade B, Level IIb

Genetic counselling should be considered. B In individuals with left-sided ulcerative colitis, colonoscopy is recommended every 1-2 years from the 15th year after diagnosis. For individuals with pan-colitis, colonoscopy is recommended every 1-2 years from the 8th year after diagnosis. (pg 62)

Grade B, Level IIb

C Plasma CEA (carcinoembryonic antigen) levels are not recommended for use in the screening of asymptomatic, average risk individuals. (pg 61)

Grade C, Level IV Screening for prostate cancer A Population screening for prostate cancer should not be recommended at present among Asians. (pg 68)

Grade A, Level Ia GPP High-risk men, such as men above 50 years of age with a history of a first degree relative with prostate cancer at a young age (<60 years), should be offered screening. (pg 68)

GPP

B Combined use of prostate specific antigen (PSA) and digital rectal examination (DRE) has a higher detection rate for prostate cancer than either test alone. (pg 68)

Grade B, Level IIb

B Transrectal ultrasound (TRUS)-guided biopsy for raised PSA and/or abnormal DRE is recommended. (pg 69)

Grade B, Level IIb

6

Screening for breast cancer A All normal risk, asymptomatic women 50-64 years of age should be screened with mammography only, every 2 years. Ultrasound and breast examination are not routinely required. (pg 80)

Grade A, Level Ia A In Western nations, the evidence supports mammographic screening every 2 years for all normal risk women 65-75 years of age. However, for Singaporean women the much lower incidence of breast cancer in this age group suggests that screening mammography may be less beneficial. If individual screening is performed, it should be at two-yearly intervals. Ultrasound and breast examination are not routinely required. (pg 80)

Grade A, Level Ia

A Women with breast implants are recommended to have routine screening mammography once every 1-2 years, depending on their age. (pg 87)

Grade A, Level Ia A Normal risk, asymptomatic women under 40 years should not undergo breast screening with any imaging modality. (pg 81)

Grade A, Level Ib

A Clinical breast examination has been proven to confer no mortality benefit in a screening population. (pg 83)

Grade A, Level Ib

B Breast ultrasound and MRI can both detect cancers that are occult on mammography. However, they should not be used for routine breast screening outside of clinical trials. (pg 84)

Grade B, Level IIa

B Nuclear scintimammography shows promise as an adjunct technique for detection of breast cancer in limited circumstances, usually in conjunction with mammography. Its use for breast screening is unwarranted. (pg 85)

Grade B, Level III

7

C Women at normal risk aged 40-49 years should be encouraged to have annual screening mammography. Ultrasound and breast examination are not routinely required. (pg 81)

Grade C, Level IV C Women on conventional hormone replacement therapy have a very slightly increased risk of breast cancer. They should have regular screening mammography. Those aged 40-49 years should be screened annually, and those aged 50-65 years biannually, for up to 5 years after cessation of HRT. (pg 81)

Grade C, Level IV C Women who are at very high risk of breast cancer by virtue of being a BRCA gene carrier, or a very strong first-degree family history of breast cancer, should perform monthly breast self examination, 6-monthly clinical breast examination and ultrasound, and annual mammography. Screening should start as early as 5 years before the age of onset of breast cancer in the youngest family member. Breast magnetic resonance imaging should be considered, but only if cost is not problematic and the expertise and equipment for MRI-guided breast needle biopsy and localisation are available. (pg 82)

Grade C, Level IV C Thermography and Electrical Impedance Scanning must be regarded as investigational techniques. Their use for breast screening is not warranted. (pg 86)

Grade C, Level IV GPP Women with prior breast cancer should receive annual screening mammography of the remnant and contralateral breasts. At 5 years disease-free post-surgery, they may return to the standard screening interval for asymptomatic women of the same age. (pg 86)

GPP

GPP Despite evidence that it has no survival benefits, BSE is generally recommended as it is felt to improve women’s awareness of their own breasts and breast cancer. As the incidence of breast cancer is extremely low before the age of 30 years, BSE is only recommended from the age of 30 years for normal risk women. (pg 84)

GPP

8

GPP When encountered, women with free silicone or paraffin oil injections in their breasts should be clinically examined and counselled as to the futility of screening using any currently available test. MRI may be useful in highly selected cases where there is a strong suspicion of breast cancer. (pg 87)

GPP

Screening for cervical cancer

B Well-run population-based cervical cancer screening programme with good coverage reduces the incidence and mortality of cervical cancer. (pg 96)

Grade B, Level IIa B All women who have ever had sexual intercourse should have a Pap smear by the age of 25 years. (pg 96)

Grade B, Level III B Pap smear screening should be performed every 3 years. (pg 96)

Grade B, Level IIa B Screening can be discontinued at age 65 years if the smear taken at age 65 years was negative and the previous smears were negative. (pg 96)

Grade B, Level III

B HIV positive women should be screened earlier and more frequently, preferably annually. (pg 97)

Grade B, Level III Screening for uterine cancer B There is no indication that screening is warranted for women who are at average or increased risk* for endometrial cancer. (pg 102)

Grade B, Level IIb *Women may be regarded as being average risk, increased risk or high risk for endometrial cancer. C Hereditary Non-Polyposis Colorectal Cancer is a syndrome in which there is an inherited tendency to develop colorectal cancer. Women with or

9

at risk for hereditary non-polyposis colorectal cancer (HNPCC) are considered high risk and should be offered annual screening for endometrial cancer with endometrial biopsy by age 35 years. (pg 102)

Grade C, Level IV

Screening for ovarian cancer B Routine population screening for ovarian cancer by ultrasound, the measurement of tumour markers, or pelvic examination is not recommended. (pg 105)

Grade B, Level IIa

GPP There is insufficient evidence to recommend for or against the screening of asymptomatic women at increased risk of developing ovarian cancer. Experts suggest referral of these women to tertiary centres for multimodal screening. (pg 106)

GPP

Screening for tuberculosis A Tuberculin Skin Test (TST) screening for latent TB infection is recommended only for identifying candidates for treatment of latent TB infection (generally with isoniazid, INH). Therefore, it is recommended only in persons at high risk of breakdown to TB disease. (pg 113)

Grade A, Level Ib (Indiscriminate screening or erroneous selection of subjects could lead to the needless administration of INH and the unnecessary exposure of these subjects to the risk of drug-induced hepatitis which in some cases may be fatal.) B As a rule, mass chest X-ray screening for TB is not recommended. (pg 114)

Grade B, Level III Screening for hepatitis B A All pregnant women should be tested for HBsAg during the early antenatal visit. The test may be repeated in the third trimester if acute

10

hepatitis is suspected, an exposure to hepatitis has occurred or the woman practices a high-risk behaviour such as intravenous drug abuse. (pg 120)

Grade A, Level Ib A Serological screening for HBsAg and anti-HBs should be performed pre-vaccination for all except newborn. (pg 121)

Grade A, Level Ib A Persons who remain at risk of HBV infection such as health care workers and dialysis patients should be screened using HBsAg and anti-HBs and vaccinated against hepatitis B if the test is negative. Such individuals should then be tested for response to the vaccination. (pg 121)

Grade A, Level Ib B Screening high risk individuals like those with a family history of hepatitis B infection, liver cancer or those at high behavioural risk should be performed. They should be tested at baseline and whenever exposure is suspected. (pg 121)

Grade B, Level IIa C Routine screening for HBV infection in the general population is not recommended but recommendations for screening may be made based on cost-effectiveness analyses. Such analyses suggest that screening can be cost-effective in groups with an HBV marker prevalence >20%. (pg 121)

Grade C, Level IV Screening for renal diseases C A healthy asymptomatic individual may undergo opportunistic screening with urine dipstick examination. (pg 125)

Grade C, Level IV C Specific individuals at increased risk (e.g. age over 50 years, hypertension, smoking, diabetes and family history of renal disease) of chronic renal disease should undergo annual dipstick testing for proteinuria. (pg 125)

Grade C, Level IV

11

C Individuals at increased risk of developing chronic renal disease should undergo testing of serum creatinine in order to estimate the level of glomerular filtration rate. (pg 126)

Grade C, Level IV C Individuals with a positive dipstick proteinuria should have a spot urinary protein-creatinine ratio test to quantitate their proteinuria. (pg 125)

Grade C, Level IV Screening for osteoporosis C All individuals with prior fragility fractures during adulthood should be considered for BMD measurement and osteoporosis treatment. (pg 133)

Grade C, Level IV C Population screening using BMD is not recommended for postmenopausal women. A case-finding strategy is preferred, measuring BMD in individuals at highest risk for osteoporosis identified using clinical evaluation tools such as OSTA or NOF guidelines, and clinical risk factor evaluation. (pg 138)

Grade C, Level IV

C Women with osteoporosis, who are being monitored for progression or who are being treated, should have a follow-up bone density measurement, usually at an interval of at least one year. In women with osteopenia, a reasonable interval might be 1 to 2 years, while in those with normal BMD, a more reasonable interval may be 2 to 5 years. (pg 138)

Grade C, Level IV C Screening is not recommended for premenopausal women and men. BMD measurement should be considered in those at high risk for fracture. (pg 138)

Grade C, Level IV C BMD measurement should be considered in patients with high risk for steroid-associated fractures, who are initiating or already on long-term higher-dose corticosteroid therapy. (pg 138)

Grade C, Level IV

12

Screening for visual acuity for the elderly B The population to be screened includes any person 65 years and above, and the screening test involves using a Snellen chart to test each eye. (pg 143)

Grade B, Level III B Any person screened and found to have vision worse than 6/12 can be referred for assessment and treatment. (pg 144)

Grade B, Level III C The optimal frequency for screening is not known and is left to the discretion of the screener. (pg 144)

Grade C, Level IV C Besides visual acuity testing using the Snellen chart, there is insufficient evidence to recommend for or against routine screening with ophthalmoscopy by the primary care physician in asymptomatic elderly patient. (pg 144)

Grade C, Level IV Screening for other sexually transmitted infections Chlamydia trachomatis infection A Sexually active women with the following risk factors may be at higher risk of chlamydial infection and should be considered for screening: those aged 25 years and younger, who have a new sexual partner, who have partners with symptoms of an STI or who have had two or more partners in the past 12 months and lack the use of barrier contraception. (pg 147)

Grade A, Level Ib A Women undergoing termination of pregnancy with risk factors (as above) should be screened. (pg 147)

Grade A, Level Ib

B Pregnant women aged 25 years and younger and other pregnant women at higher risk for infection (i.e. women who have had two or more sexual partners in the past 12 months, or partners with symptoms of an STI) should be considered for screening. (pg 147)

Grade B, Level IIb

13

C Women undergoing instrumentation of the uterus should be considered for screening on an individual case basis because even in low prevalence groups, there may be a resultant risk of ascending infection. (pg 147)

Grade C, Level IV C Asymptomatic men with high-risk behaviour such as frequent partner change, lack of use of barrier protection or sex with prostitutes can be considered for screening. These patients should be referred to specialist centres for counselling, and investigation. (pg 148)

Grade C, Level IV A Screening can be performed using cultures or enzyme immunoassays (EIA) on endocervical swabs in women and urethral swabs in men. (pg 148)

Grade A, Level Ia A Nucleic acid amplification tests (NAAT) using polymerase chain reaction (PCR) or ligase chain reaction (LCR) can also be used in screening on endocervical or urethral swabs, and have the advantage of being used on non-invasive specimens such as urine. (pg 148)

Grade A, Level Ia C Serological tests based on genus-specific complement fixation test are not useful in the diagnosis of chlamydial genital infections, with the possible exception of lymphogranuloma venereum. (pg 149)

Grade C, Level IV GPP In men, a Gram-stained urethral smear taken 4 hours from the last void of urine showing presence of 5 or more leukocytes per high-power field indicates urethritis. This may be due to Chlamydia trachomatis or other organisms, as well as other factors that may not be sexually transmitted. These patients should be assessed by specialist centres for counselling and advice. (pg 148)

GPP

GPP The optimal frequency of screening is a matter of clinical discretion. Screening for chlamydia infection should be performed about 1 week after high-risk exposure or change of sex partner. (pg 149)

GPP

14

Syphilis C All women and men at increased risk for infection, including sex workers, persons who exchange sex for money or drugs, persons with other STIs (including HIV) and genital ulceration, and sexual contacts of persons with active syphilis should be screened. (pg 150)

Grade C, Level IV B Pregnant women should be screened at their first antenatal visit. (pg 151)

Grade B, Level III C Pregnant women at higher risk of infection (i.e. women who have partners with symptoms of an STI, or continue to engage in sexual activity with multiple partners, or a partner who has sex with multiple partners) should have screening repeated in the third trimester. (pg 151)

Grade C, Level IV C Screening for syphilis is performed using nontreponemal tests such as RPR or VDRL. Positive results should be confirmed with a specific test such as TPPA or TPHA. Both nontreponemal and treponemal tests can be combined for use in screening, although this would be more costly and labour-intensive. (pg 152)

Grade C, Level IV C Follow up serologic tests should be obtained to document declines in titres after treatment. They should be performed using the same test initially used to document infection (e.g. VDRL or RPR) to ensure compatibility. (pg 153)

Grade C, Level IV GPP The optimal frequency of screening is a matter of clinical discretion. Screening for syphilis should be performed 1 month after exposure, and repeated again after 3 months. (pg 152)

GPP

15

Gonorrhoea C Women at high risk of infection – including sex workers, women with a history of repeated episodes of gonorrhoea, and women with two or more sex partners in the previous year should be screened. (pg 154)

Grade C, Level IV GPP Homosexual men with frequent partner change or other high-risk behaviour (i.e. those who have sex with partners with symptoms of an STI, those who do not use barrier protection including unprotected receptive and insertive oral and anal intercourse) should be considered for screening. (pg 154)

GPP

C The ideal screening test is isolation of Neisseria gonorrhoeae by culture from the appropriate sites. (pg 154)

Grade C, Level IV GPP Sites to be sampled will be determined by the history of sexual contact – urethra, cervix, rectum or pharynx. (pg 155)

GPP

GPP The optimal frequency of screening is a matter of clinical discretion. Screening for gonorrhoea should be performed about 1 week after exposure. (pg 155)

GPP

Genital Herpes Simplex GPP Routine screening for genital herpes simplex virus (HSV) infection by viral culture, serology or other means is not recommended for asymptomatic men or women, including asymptomatic pregnant women. (pg 155)

GPP

HIV C Clinicians should assess risk factors for HIV infection in all persons by obtaining a careful sexual history and inquiring about drug use. (pg 156)

Grade C, Level IV

16

C Counselling and testing for HIV should be offered to all persons at increased risk of infection. These include those seeking treatment for STI; men who have sex with men; past or present injecting drug users; persons who exchange sex for drugs or money and their sex partners; persons whose past or present sex partners were HIV-infected, and persons who have had a blood transfusion or an organ transplant that had not previously been screened. (pg 156)

Grade C, Level IV GPP Pregnant women should be offered the test in the first trimester. (pg 157)

GPP

C Screening for HIV is performed using ELISA. A positive result requires 2 reactive ELISA tests and confirmation with the Western Blot (WB) assay, performed by experienced laboratories that receive regular external proficiency testing. (pg 157)

Grade C, Level IV C Persons who continue to exhibit high-risk behaviour should have screening tests on a regular basis. The frequency at which these individuals are screened is a matter of clinical discretion. Screening for HIV should be performed 6-monthly in a person who continues to exhibit high-risk behaviour. (pg 157)

Grade C, Level IV C Persons with recent high-risk behaviour should be screened at 1 month, 3 months and 6 months after the last high-risk exposure to rule out a possible initial false negative result. (pg 157)

Grade C, Level IV Genital Human Papillomavirus (HPV) infection C Women with a history of STI may be at increased risk for cervical cancer, which is linked to certain HPV types. However, the HPV types that frequently cause anogenital warts do not cause cancer. The Pap smear is a screening test for cervical carcinoma and not a screening test for STIs, and women who have external genital warts do not need to have Pap smears more frequently than women who do not have warts. (pg 158)

Grade C, Level IV

17

C Clinical examination with the unaided eye is the oldest diagnostic technique in detection of genital warts. However, subclinical genital HPV infection, a term used to refer to manifestations of infection in the absence of genital warts, may still exist. No screening tests for subclinical infection are available, and there are no recommendations for routine screening. (pg 158)

Grade C, Level IV

18

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1 Introduction 1.1 Guideline Objectives and Target Group

The health screening guidelines are intended to assist medical practitioners, especially those in the primary health care sector, advise their patients on the screening to be conducted for various diseases based on the patient’s age, gender and presence of risk factors.

These guidelines provide current evidence-based clinical practice recommendations on screening for a range of disease conditions found across various medical disciplines. The individuals for whom these guidelines are recommended are average-risk asymptomatic adults. High-risk individuals have also been identified.

1.2 Guideline Development

The health screening guidelines were developed by a workgroup appointed by the Ministry of Health. Its members comprised experts in their area of specialty. The workgroup formulated these guidelines by reviewing published international screening guidelines and current evidence available in the research literature, and taking into consideration the local population’s characteristics. Feedback from relevant professional organisations was also sought in the process.

1.3 Principles for Screening

Screening people who are apparently well in order to pick up asymptomatic disease can be beneficial to the individual if early treatment is available to improve the prognosis. It is beneficial to society at large if identification leads to primary prevention in protecting others from becoming affected. However, there are other considerations for screening. Wilson and Junger1 cited the following principles of screening for early disease detection: a) The condition sought should be an important health problem b) The natural history of the disease should be adequately

understood

1 Wilson MG, Junger G. Principles and practice of screening for disease. Public Health Paper 34. Geneva. WHO. 1968.

c) There should be a recognisable latent or early symptomatic stage d) There should be a suitable and acceptable screening test or

examination e) There should be an accepted treatment or useful intervention for

patients with the disease f) Facilities for diagnosis and treatment should be available g) There should be an agreed policy on whom to treat as patients h) The cost of case-finding (including diagnosis and treatment of

patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole

i) Case finding should be a continuing process and not a once and for all project.

Whether or not a screening policy results in improved health outcomes depends on a number of factors viz. the characteristics of the disease, the screening test, and the patient population.

Screening may be considered where there is a high prevalence of the disease with potential serious consequences, the disease condition has a natural history with a latent stage during which symptoms of disease are either not present or early; and when detected and managed, is beneficial in improving the likelihood of favourable health outcomes (viz. reduced disease-specific morbidity or mortality). The screening test should be acceptable to the public, simple, fairly readily applied, and valid. With regard to diagnosis, the condition must be treatable and treatment and care available for those who need it. Early treatment should improve the outcome compared to treating patients when they present with signs and symptoms of the disease.

There is also a need for screening on a continuing basis rather than single-occasion screening. Single-occasion screening is of limited value because only a small proportion, often those at least risk, is likely to be screened, and screening picks up those persons in the population who just happen at that particular time to have that condition being checked for. It therefore does not affect the future incidence of disease. Continuing examinations have greater advantage as they cover more of the population at risk including, by re-examination, persons presenting with new disease.

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1.4 Screening tests characteristics

Sensitivity and specificity are important characteristics of the validity of a screening test. The validity of a screening test is the ability of the test to separate those who have the disease condition from those who do not. The result of the screening test is confirmed by an acceptable diagnostic procedure (“gold standard”) which distinguishes between “true” or “false” results. Sensitivity is the ability of the test to correctly identify those who truly have the disease. It is the ratio, expressed as a percentage, of the number of individuals with the disease whose screening tests are positive to the total number of individuals with the disease. Specificity is the ability of the test to correctly identify those who do not have the disease. It is the ratio, expressed as a percentage, of the number of individuals without the disease whose screening tests are negative to the total number of individuals without the disease.

A highly sensitive test will have a low proportion of false negative results, that is, there will be few missed cases. Few screened people who have the disease will be told incorrectly that they are free of the disease and have a false sense of security. A highly specific test will have a low proportion of false-positive results, that is, there will be few screened people free of the disease who are incorrectly told that they have the condition. False-positives could generate anxiety and unnecessary additional tests which may have potential adverse effects and cost. Ultimately, the medical practitioner would have to weigh the benefits and disadvantages for screening an individual.

The positive predictive value (PPV) is the screening test’s ability to identify those who have the disease (true-positives) among all those whose screening tests are positive. PPV is affected by disease prevalence. For example, PPV increases with increasing prevalence of a disease in a high risk population. Reliability is the ability of the test when reproduced, to have the same result. A poorly reliable test is likely to have high interobserver variation (e.g. between different laboratories) or intraobserver variation (i.e. between the same observer).

21

1.5 Assessing the evidence

In assessing the evidence, different study designs were considered including randomised controlled trials, cohort studies, case-control studies and uncontrolled cohort studies. Recommendations to screen average and/or high risk individuals are influenced by multiple factors including scientific evidence of effectiveness, costs and policy concerns.

It is often considered that picking up diseases by screening will be economical for a community as a whole. To diagnose and treat all patients would however, also add considerably to the total screening cost. Hence, only prospective studies which determine if morbidity or mortality has been reduced and life improved when compared to a non-screened population can demonstrate the savings in cost to a community. However, there are often limitations to such studies including the difficulty in practice in randomising people into screened and control groups, ethical issues to conduct randomised trials when screening using a test is already regarded as normal practice, and significant losses over time in both the intervention and control groups during the study.

22

2 Screening for blood cholesterol 2.1 Introduction

The treatment of hyperlipidaemia to reduce the risk of coronary heart disease (CHD) is supported by a wealth of good clinical trial data. The benefits of treatment in those with high coronary risk have been clearly demonstrated1-4. The recently released Heart Protection Study has further shown that benefits of treatment are seen regardless of gender, age and baseline LDL cholesterol levels5. However, it is also true that knowledge of benefits do not necessarily translate into clinical practice6. This treatment gap is seen in both primary care as well as hospital-based practice. The National Health Survey in 19927 and 19988 had shown that substantial proportions of individuals with hyperlipidaemia are undiagnosed. Before treatment can be initiated, those with hyperlipidaemia must be identified and hence the need for guidelines on screening individuals in our population for hyperlipidaemia.

This guideline on cholesterol screening is closely patterned after the Clinical Practice Guidelines on Lipids which was released by the Ministry of Health in 20019 but with minor modifications based on further data being made available. In preparing these recommendations, we have also taken into consideration the Ministry of Health recommendations for screening for diabetes mellitus in asymptomatic subjects10 to facilitate better use of resources and identification of those at risk of dyslipidaemia.

23

2.2 Who should be tested The following individuals should be screened for blood cholesterol:

Individuals to be screened

Grade of recommendation, level of evidence

All individuals aged 40 years and above*. Grade B, Level IIb All patients with pre-existing CHD, cerebrovascular or peripheral artery disease irrespective of age1,3,5.

Grade A, Level Ia

All patients with diabetes mellitus irrespective of age5.

Grade A, Level Ib

All individuals with impaired fasting glycaemia or impaired glucose tolerance† irrespective of age11.

Grade B, Level III

All individuals with a family history and/or clinical evidence of familial hyperlipidaemia12,13 after the age of 2 years14.

Grade B, Level IIa

Earlier screening from age 30 years should be considered for individuals with other risk factors for CHD, e.g. smoking, hypertension, family history of premature CHD.

GPP

Earlier screening from age 30 years should be considered for those of Indian ethnicity15.

Grade B, Level III

* Based on the steep rise of prevalence of diabetes after the age of 40 years and that

96% of diabetic patients had elevated LDL cholesterol (LDL-C) at diagnosis in the National Health Survey 1998. As patients will be screened for diabetes every 3 years, the lipids should be screened concurrently.

† 91% of impaired glucose tolerance (IGT) patients had elevated LDL-C. It is also reasonable to screen lipids in individuals undergoing a general health screening.

GPP If the results are optimal based on the current recommendations for Singapore9, we recommend repeat screening at 3 yearly intervals.

GPP

24

2.3 What should be tested

C In screening for cholesterol, the optimal test is a full lipid profile including LDL cholesterol (LDL-C), fasting triglyceride (TG) and HDL cholesterol (HDL-C)9,16,17.

Grade C, Level IV Serum total cholesterol and HDL-C concentration can be measured at any time of the day in the non-fasting state. However, TG levels must be obtained after 10-12 hours of fasting. Total cholesterol (TC), HDL-C and TG are measured directly. LDL-C is usually calculated using the Friedwald formula18 which is as follows:

LDL-C (mmol/l) = TC – (HDL-C + {TG / 2.2})

This formula cannot be used if the TG is >4.5 mmol/l (400 mg/dl). Direct measurement of LDL-C is now available in certain laboratories in Singapore.

References 1. Randomised trial of cholesterol lowering in 4444 patients with coronary

heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9.

2. Prevention of cardiovascular events and death with pravastatin in patients

with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-57.

3. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on

coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996;335:1001-9.

4. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease

with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333:1301-7.

25

5. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22.

6. Pearson TA, Laurora I, Chu H, et al. The lipid treatment assessment

project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000; 160:459-67.

7. Tan CE, Emmanuel SC, Tan BY, et al. Prevalence of diabetes and ethnic

differences in cardiovascular risk factors. The 1992 Singapore National Health Survey. Diabetes Care 1999;22:241-7.

8. Cutter J, Tan BY, Chew SK. Levels of cardiovascular disease risk factors

in Singapore following a national intervention programme. Bull World Health Organ 2001;79:908-15.

9. Clinical Practice Guidelines. Lipids. Singapore: Ministry of Health;

2001. 10. Clinical Practice Guidelines. Diabetes Mellitus. Singapore: Ministry of

Health; 1999. 11. Ministry of Health. Epidemiology and Disease Control Department,

National Health Survey 1998, Singapore. 12. Kane JP, Malloy MJ, Ports TA, et al. Regression of coronary

atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. JAMA 1990;264:3007-12.

13. Tomochika Y, Okuda F, Tanaka N, et al. Improvement of atherosclerosis

and stiffness of the thoracic descending aorta with cholesterol-lowering therapies in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 1996;16:955-62.

14. Wray R, Neil H, Rees J. Screening for hyperlipidaemia in childhood.

Recommendations of the British Hyperlipidaemia Association. J R Coll Physicians Lond 1996;30:115-8.

15. Lee J, Heng D, Chia KS, et al. Risk factors and incident coronary heart

disease in Chinese, Malay and Asian Indian males: the Singapore Cardiovascular Cohort Study. Int J Epidemiol 2001;30:983-8.

26

16. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2486-97.

17. Wood D, De Backer G, Faergeman O, et al. Prevention of coronary heart

disease in clinical practice: recommendations of the Second Joint Task Force of European and other Societies on Coronary Prevention. Atherosclerosis 1998;140:199-270.

18. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the

concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502.

27

28

3 Screening for hypertension 3.1 Introduction

Hypertension is defined as a diastolic blood pressure of 90 mmHg or higher, or a systolic pressure of 140 mmHg or higher1,2. It is an important risk factor for coronary heart disease, congestive heart failure, stroke, ruptured aortic aneurysm, renal disease, and retinopathy. Milder forms of hypertension predict progression to more severe elevations and development of cardiovascular disease. In Singapore, ischemic and other heart disease is the second while cerebrovascular disease is the fourth leading cause of death, respectively. Together both accounted for nearly 36% of all deaths in 20012,3,10. The 1998 Singapore National Health Survey showed that the percentage of adults aged 30-69 years old with high blood pressure (defined as BP > 140/90 mmHg) had risen from 22.2% in 1992 to 27.3% in 19983. Only a third of the treated hypertensives reached the recommended target level. Among those who were found to have hypertension at the survey, 53% had not been previously diagnosed3. Fifty-four percent of patients suffering from acute myocardial infarction in Singapore had underlying hypertension (unpublished data, Myocardial Infarct Registry, National Heart Centre of Singapore). Coronary heart disease mortality begins to increase at systolic blood pressure above 110 mmHg and at diastolic pressure above 70 mmHg4. Successful efforts to lower blood pressure could thus have substantial impact on population morbidity and mortality. Hence, primary prevention, early detection and adequate treatment of hypertension are essential in order to prevent complications and death from the disease.

3.2 Definition

A person with blood pressure > 140/90 mmHg is considered hypertensive, while those with systolic blood pressure ranging from 130-139 mmHg or diastolic blood pressure 85-89 mmHg belong to the high normal range1,2,6.

Sphygmomanometry remains the most appropriate screening test for hypertension in the asymptomatic population. Although the apparatus is highly accurate when performed correctly, false-positive and false-negative results do occur in clinical practice. Self-measured (home)

29

blood pressure and ambulatory blood pressure monitoring may provide useful information in special circumstances such as “white-coat” or “resistant” hypertension, but there is insufficient evidence at present to warrant their routine use in screening5,7. Other non-mercury, non-invasive devices might be used provided that they are accurate and are periodically calibrated with the standard, mercury sphygmomanometer.

Sphygmomanometry should be performed in accordance with recommended technique5,6. Hypertension should not be diagnosed on the basis of a single measurement. Elevated readings should be confirmed on more than one reading at different visits1,6.

3.3 Effectiveness of Early Detection

There is a direct relationship between the magnitude of blood pressure elevation and the benefit of lowering pressure. Over the past three decades, many randomized clinical trials on hypertension have demonstrated benefits in morbidity and/or mortality in adult patients (>21 years of age) either for severe, moderate and even mild hypertension. The efficacy of treating hypertension is clear. An average diastolic blood pressure reduction of 5-6 mmHg in anyone with hypertension could reduce the incidence of coronary heart disease by 14% and the incidence of strokes by 42%. Treatment of hypertension is associated with multiple benefits, including reduced coronary heart disease and vascular deaths, but meta-analyses suggest it produces the largest reductions in cerebrovascular morbidity and mortality8,9.

3.4 Screening

The optimal interval for blood pressure screening has not been determined and is left to clinical discretion.

C Blood pressure should be measured at least once every 2 years for adults aged 21 years and above with diastolic pressure below 85 mmHg and a systolic pressure below 130 mmHg6,10 (i.e. normal BP).

Grade C, Level IV

A Measurements are recommended annually for persons with a diastolic blood pressure of 85-89 mmHg or systolic blood pressure of

30

130-139 mmHg (i.e. high normal BP). Persons with higher blood pressures or a major coronary risk factor such as diabetes mellitus require more frequent measurement6,10.

Grade A, Level Ib

C Any person aged 21 years and above should have their blood pressure measured during any visit to a physician (“case finding”)6, 10.

Grade C, Level IV

The Canadian Task Force on the Perodic Health Examination found insufficient evidence to recommend for or against routine blood pressure measurement in persons under 21 years of age11.

It is important for clinicians to minimize the potential harmful effects of under or over diagnosing hypertension. For example, if performed incorrectly, sphygmomanometry can produce misleading results, resulting in some hypertensive patients thereby escaping detection (false negatives) and some normotensive persons receiving inappropriate labeling and treatment (false positives). This will cause certain psychological, behavioral, and financial consequences. Treatment of hypertension may also have undesirable side effects, especially from drug therapy. A Sphygmomanometry is the recommended method for blood pressure measurement, and it should be performed in accordance with the recommended technique5, 6.

Grade A, Level Ia

In adults, blood pressure criteria for the diagnosis of hypertension are an average diastolic pressure of 90 mmHg or greater and/or an average systolic pressure of 140 mmHg or greater. Once confirmed, patients should receive appropriate counseling regarding physical activity, weight reduction, dietary sodium intake, and alcohol consumption. Antihypertensive drugs should be prescribed in accordance with recent guidelines.

A Routine counseling to promote physical activity and a healthy diet for the primary prevention of hypertension is recommended for all adults10.

Grade A, Level Ia

31

3.5 Other relevant information A Pregnant women should have their blood pressure checked routinely as part of prenatal care10.

Grade A, Level Ia Prospective cohort studies have shown that children with high normal blood pressure are more likely than their normal counterparts to have hypertension as adults12. There is no trial, however, to show that treating high blood pressure in childhood will result in reduced blood pressure in adulthood. Moreover in children, the criteria defining hypertension vary with age. There is insufficient evidence to recommend for or against routine, periodic blood pressure measurement to detect essential hypertension in this age group, although measurement of blood pressure during office consultation is recommended for children and adolescents in specific situations, e.g. children with recurrent urinary tract infections, with features of polycystic disease, Cushing’s syndrome or unequal peripheral pulses10, 12.

3.6 Summary

Periodic screening for hypertension is recommended for all adults aged 21 years or older. It is suggested that the interval for blood pressure screening should be at least once every two years for initial BP < 130/85 mmHg (i.e. normal BP), and annually if the diastolic blood pressure is 85-89 mmHg or systolic blood pressure is 130-139 mmHg (i.e. high normal BP) or if patient has major coronary risk factor such as diabetes mellitus. Currently, sphygmomanometry is the recommended method for blood pressure measurement, and it should be performed in accordance with the recommended technique. Other non-invasive, non-mercury devices might be used provided that the devices are accurate and are periodically calibrated with values obtained simultaneously from the mercury sphygmomanometer. Hypertension should not be diagnosed on the basis of a single abnormal blood pressure reading but an average of at least two abnormal readings at different visits. Once hypertension is confirmed on repeated sittings, patients should receive appropriate counseling (e.g. dietary salt intake, alcohol consumption, weight reduction, physical activity). Other cardiovascular risks should be vigorously

32

sought and appropriately managed if indicated. Drug therapy should be started using clinical judgement and currently available guidelines.

References 1. Singapore Hypertension Treatment Guidelines 2000. Ministry of Health,

Singapore. 2. The Guidelines Subcommittee of the World Health Organization –

International Society of Hypertension (WHO-ISH). Mild Hypertension Liaison Committee: 1999 WHO-ISH Guidelines for the Management of Hypertension. J. Hypertension 1999; 17:151-83.

3. Ministry of Health, Singapore. Epidemiology and Disease Control

Department. National Health Survey 1998 Report. 4. Neaton JD, Wentworth D. Serum cholesterol, blood pressure, cigarette

smoking, and death from coronary heart disease. Overall findings and differences by age for 316,099 white men. Multiple Risk Factor Intervention Trial Research Group. Arch Intern Med 1992; 152:56-64.

5. American Society of Hypertension. Recommendations for routine blood

pressure measurement by indirect cuff sphygmomanometry. Am J Hypertens 1995; 9:1-11.

6. Joint National Committee on Detection, Evaluation and Treatment of

High Blood Pressure. The sixth report of the Joint National Committee on Prevention, Detection and Treatment of High Blood Pressure (JNC VI). Arch Intern Med 1997; 157:2413-46.

7. Pickering TG, James GD, Boddie C, et al. How common is white coat

hypertension? JAMA 1988; 259:225-8. 8. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and

coronary heart disease. Part 2, short-term reductions in blood pressure: Overview of randomized drug trials in their epidemiological context. Lancet 1990; 335:827-38.

9. Hebert PR, Moser M, Mayer J, et al. Recent evidence on drug therapy of

mild to moderate hypertension and decreased risk of coronary heart disease . Arch Intern Med 1993; 153:578-81.

33

10. Summary of Policy Recommendations for Periodic Health Examination. Kansas City, Mo: American Academy of Family Physician; 1997.

11. Canadian Task Force on the Periodic Health Examination. Canadian

guide to clinical preventive health care. Ottawa:Canada Communication Group. 1994; 636-48, 944-51.

12. Gillman MW, Cook NR, Rosner B, et al. Identifying children at high

risk for the development of essential hypertension. Pediatrics 1993; 122:837-46.

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4 Screening for diabetes mellitus

4.1 Introduction Diabetes mellitus is a common and growing healthcare problem in Singapore, affecting 9.0% of the adult population according to the 1998 National Health Survey1. There is also epidemiological evidence that type 2 diabetes is appearing at a younger age, with diabetes being diagnosed in youths and even in children. In the 1998 health survey, the prevalence of diabetes was 0.8% in persons aged 18-29 years and 3.3% in persons aged 30-39 years, and rising to more than 10% in those 40 years and older.

Chronic hyperglycaemia is associated with damage and failure of various organs. Long-term complications of diabetes are the leading cause of blindness, renal failure and lower limb amputation. Individuals with undiagnosed diabetes are also at significantly higher risk for coronary heart disease, stroke and peripheral artery disease than the nondiabetic population. They also have a greater likelihood of having hypertension, hyperlipidaemia and obesity2.

Type 2 diabetes is often asymptomatic in its early stages, and can occur 4-6 years prior to clinical presentation3. The 1998 health survey found that 62% of Singaporeans found to have diabetes were previously unaware of the diagnosis. The purpose of screening is to identify asymptomatic individuals who are likely to have diabetes. Opportunistic screening for diabetes is appropriate under certain circumstances.

4.2 Who should be screened

C Screening of asymptomatic individuals at high risk for type 2 diabetes mellitus should be carried out on an opportunistic basis2,4,5.

Grade C, Level IV

C Screening should begin at age 40 years, and be considered at an earlier age (e.g. 30 years) if risk factors for diabetes are present.

Grade C, Level IV

35

This recommendation is based on the steep rise of diabetes prevalence in Singapore after age 40 years. B Risk factors for diabetes include: • Overweight/ obesity (body mass index ≥ 25 kg/m2)* • Hypertension (≥ 140/90 mmHg) • A first degree relative with diabetes mellitus • Previous gestational diabetes mellitus • Coronary artery disease • Polycystic ovary disease • Dyslipideamia (HDL cholesterol <1.0 mmol/l, and /or triglyceride

level ≥ 2.82 mmol/l) † • Previously identified impaired fasting glycaemia (IFG) or

impaired glucose tolerance (IGT). Grade B, Level III

* Based on prevalence of diabetes mellitus of ≥10% in those obese individuals aged

30-40 years (data from the 1992 National Health Survey). Note that the value has been lowered from BMI 27, the recommendation stated in the 1999 MOH Clinical Practice Guideline6

† New recommendation, not in the 1999 MOH Clinical Practice Guideline6

4.3 Screening test and effectiveness

Early diagnosis of diabetes and treatment can prevent or delay the progression of the major diabetic complications and reduce the burden of diabetes4,5.

Three recent large randomized clinical trials in subjects with impaired glucose tolerance7-9, had demonstrated that treatment with lifestyle intervention, metformin or acarbose, reduced the incidence of type 2 diabetes mellitus by 58%, 31% and 36% respectively, compared to those who were in the non-intervention groups. These studies showed that it should be possible to delay or prevent the development of type 2 diabetes and its related complications and suggest that more widespread screening to detect high risk individuals with prediabetes (IGT or IFG) may be justified.

36

Figure 1: Algorithm for screening for type 2 diabetes mellitus in asymptomatic individuals

No Yes

Repeat fasting plasma glucose

Fasting plasma glucose ≥ 7.0

mmol/l

Asymptomatic subject

No

Fasting plasma glucose ≥ 7.0

mmol/l

≤ 6.0 mmol/l

6.1-6.9 mmol/l

No

Fasting plasma glucose 6.1-6.9

mmol/l

Oral Glucose Tolerance Test (2-h post challenge)

Yes

Impaired fasting glycaemia

(repeat screen at 1 year )

Impaired glucose

tolerance (repeat screen at

1 year)

≥ 11.1 mmol/l

Diabetes Mellitus

Yes DIABETES MELLITUS

7.8 – 11.0 mmol/l

<7.8 mmol/l

No diabetes mellitus (repeat screen

at 3 years)

37

4.3.1 Fasting plasma glucose B Fasting plasma glucose (FPG) is the recommended test for screening in the clinical setting because it is easy to perform and convenient*10. Individuals with a FPG ≥ 7.0 mmol/L should have a repeat testing on a different day to confirm the diagnosis of diabetes10,11. Individuals with FPG of 6.1-6.9 mmol/l on screening should undergo a 75g oral glucose tolerance test (OGTT) to determine precisely the degree of glucose intolerance11.

Grade B, Level III

*Venous blood samples should be collected in appropriate tubes for plasma glucose measurement which should be performed by a laboratory reference method.

4.3.2 Oral glucose tolerance test (OGTT) B OGTT is also a suitable test for screening10,11.

Grade B, Level III A 2-hour plasma glucose value of ≥ 11.1 mmol/l on OGTT is a positive test for diabetes. Criteria for definition of IFG and IGT11 are shown in Table 1.

Table 1: Intermediate categories of glucose tolerance.

Fasting plasma

glucose (mmol/l)

2-hour plasma glucose during OGTT

(mmol/l)

Impaired Fasting Glycaemia (IFG)

6.1-6.9 <7.8

Impaired Glucose Tolerance (IGT)

<7.0 7.8-11.0And

And

Fingerprick capillary blood glucose testing measured by a glucose meter is better used for self-monitoring of blood glucose rather than as a screening tool, because of the imprecision of this method 12,13. The HbA1c test is currently not recommended for the screening of diabetes12,13.

38

4.4 Frequency of Screening

C Individuals found to have normal glucose tolerance on screening and who do not have risk factors for developing diabetes should have repeat screening at 3 yearly intervals13. The rationale for this interval is that there is little likelihood of an individual developing any complications of diabetes to a significant degree within 3 years of a negative screening test result. For those with other diabetes risk factors, repeat screening may be performed more frequently, e.g. at annual intervals13.

Grade C, Level IV

B Those detected to have IFG or IGT should have repeated screening at annual intervals in view of the high rate of conversion to diabetes14-

16. Grade B, Level III

References 1. Ministry of Health. Epidemiology and Disease Control Department,

National Health Survey 1998, Singapore.

2. Harris MI. Undiagnosed NIDDM: clinical and public health issues. Diabetes Care 1993; 16:642-52.

3. Harris MI, Klein R, Welborn TA, et al. Onset of NIDDM occurs at

least 4-7 yr before clinical diagnosis. Diabetes Care 1992; 15:815-9.

4. Pyorala K, Pedersen TR, Kjekshus J, et al. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 1997; 20:614-20.

5. The Diabetes Control and Complications Trial Research Group. The

effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977-86.

6. Clinical Practice Guidelines. Diabetes Mellitus. Singapore: Ministry

of Health; 1999.

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7. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Eng J Med 2002; 346:393-403.

8. Tuomilberto J and the Finnish Diabetes Prevention Study Group.

Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Eng J Med 2001;344:1343-50.

9. Chiasson J and the STOP-NIDDM Trial Research Group. Acarbose

for the prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002 ;359 : 2072-7.

10. The Expert Committee on the Diagnosis and Classification of

Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 20:1183-97.

11. Alberti, KGMM, Zimmet PZ. Definition, diagnosis and classification

of diabetes mellitus and its complications. Part 1: diagnosis of classification of diabetes mellitus. Provisional report of a WHO consultation. Diabetic Medicine 1998;15:539-53.

12. American Diabetes Association: Tests of glycemia in diabetes

(Position Statement). Diabetes Care 2003; 26: S106-8.

13. American Diabetes Association: Screening for type 2 diabetes (Technical Review). Diabetes Care 2000; 23: 1563-80.

14. Chou P, Li CL, Wu GS, et al. Progression to type 2 diabetes among

high-risk groups in Kin-Chen, Kinmen. Exploring the natural history of type 2 diabetes. Diabetes Care 1998; 21:1183-7.

15. Alberti KG. The clinical implications of impaired glucose tolerance.

Diabet Med 1996; 13:927-37.

16. Coutinho M, Gerstein HC, Wang Y, et al. The relationship between glucose and incident cardiovascular events. Diabetes Care 1999; 22:233-40.

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5 Screening for obesity 5.1 Introduction

Obesity and established cardiovascular risk factors such as hypertension, hyperlipidaemia, hyperglycaemia and coronary heart disease are positively associated1,2,3. The evidence for obesity as an independent predictor of cancer is less well established, although associations have been identified for cancers of the endometrium, ovaries, breast, prostate and colon4. Obesity is also associated with other medical problems such as gall bladder disease, sleep apnoea, osteoarthritis, reduced fertility, social stigmatization and discrimination. The 1998 National Health Survey of residents in Singapore aged 18-69 years found that overall 24.4% were overweight and 6.0% were obese5.


• Body mass index [BMI = (weight in kg)/(height in m)2] BMI is reliable and correlates well (r=0.7-0.8) with body fat content in adults6,7.

• Waist circumference is a reliable indicator of abdominal fat mass8.

B Body mass index (BMI) and waist circumference can be used to classify obesity and assess risk.

Grade B, Level III

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Table 2: NHLBI classification of overweight and obesity by BMI, waist circumference and associated disease risk

Disease risk relative to Normal weight and waist circumference*

BMI (kg/m2)

Obesity class

Men ≤102cm (≤40in) Women ≤88cm (≤35in)

>102cm (>40in)>88cm (>35in)

Underweight <18.5 - -

Normal † 18.5-24.9 - -

Overweight 25.0-29.9 Increased High

Obesity 30.0-34.9 I High Very High

35.0-39.9 II Very High Very High

Extreme Obesity

≥ 40.0 III Extremely High Extremely High

* Disease risk for type 2 diabetes, hypertension, and cardiovascular disease † Increased waist circumference can also be a marker for increased risk even in persons of normal weight Source: Reproduced with permission from the National Heart, Lung, and Blood Institute (NHLBI). The Practical Guide - Identification, Evaluation and Treatment of Overweight and Obesity in Adults (Oct 2000), National Institutes of Health. 5.3 Age and gender for screening

C All individuals 18 years of age or older should be screened1,2.

Grade C, Level IV 5.4 Frequency of screening

GPP Screening should be done once a year for all individuals 18 years or older.

GPP 5.5 Other relevant information

A reduction of Body Mass Index and/or waist circumference leads to a reduction in risk factors for cardiovascular disease1,2. Weight reduction measures include dietary restriction and an increase in physical activity. Adjunct behavioral modification like counseling may also be of benefit.

42

The initial goal of weight loss is to reduce body weight by 10% from the original. Weight loss should be about 0.5-1.0kg per week for a period of 6 months. Studies also suggest that weight loss and maintenance appear to be more successful in the long term with greater frequency of patient-physician contact.

References 1. National Institutes of Health, National Heart, Lung and Blood Institute.

Clinical Guidelines on the identification, evaluation, and treatment of overweight and obesity in adults- the evidence report. Obes Res 1998; 6:51S.

2. US Preventive Services Task Force. Screening for obesity. In: Guideline

for clinical preventive services. 2nd ed. Baltimore, Md.: Williams and Wilkins, 1994; 41.

3. World Health Organization. Obesity: Prevention and managing the global

epidemic. Report of a WHO consultation on obesity. WHO/NUT/NCD/98.1, Geneva 1998.

4. International Agency for Research in Cancer. Handbook for Cancer

Prevention Volume 6: Weight Control and Physical Activity 2002. IARC, WHO, Lyon.

5. Ministry of Health. Epidemiology and Disease Control Department,

National Health Survey 1998, Singapore. 6. Deurenberg P, Weststrate JA, Seidell JC. Body mass index as a measure

of body fatness: age- and sex-specific formulas. Br J Nutr 1991; 65:105. 7. Gray DS, Fujioka K. Use of relative weight and body mass index for

determination of adiposity. J Clin Epidemiol 1991; 44:545. 8. Lemieux S, Prud’homme D, Bouchard C, et al. A single threshold value

of waist girth identifies normal-weight and overweight subjects with excess visceral adipose tissue. Am J Clin Nutr 1996; 64:685.

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44

6 Screening for lung cancer 6.1 Introduction

Routine screening for asymptomatic early lung cancer is not recommended for any subset of individuals at present. Previous studies of screening high-risk individuals using chest X-ray and/or sputum cytology have not confirmed a survival benefit1.

Anecdotal reports of favourable survival outcomes associated with resection of early lung cancers discovered serendipitously have raised the possibility, however, that more sensitive technologies than chest X-ray or sputum cytology could be capable of detecting lung cancers at a sufficiently early stage to confer a survival benefit. The advent of low-dose spiral computed tomography (CT) is relevant here, since two-thirds of CT-detected lung cancers in asymptomatic patients are early stage2, consistent with a 3- to 10-fold greater sensitivity of CT over chest X-ray3, 4. Whether the detection of such so-called early stage lung cancers translate into improved outcomes, i.e. reduced mortality, has not been demonstrated and is the subject of ongoing controlled trials. At present, however, there are no controlled clinical trial data available upon which to base any assessment of its efficacy or cost-effectiveness as a screening tool5.

Given the current state of ignorance regarding the screening utility or otherwise of low-dose spiral CT, it is imperative that at-risk individuals are not misled into believing that any such screening initiatives will necessarily reduce their odds of dying from lung cancer. In this context it is essential that patients be informed that the only proven strategy for reducing the probability of lung cancer mortality is smoking cessation6.

Not withstanding this important caveat regarding possible abuses involving the misleading promotion of low-dose spiral CT as a screening tool for lung cancer, and given a mandate upon providers to openly inform clients as to the lack of proven screening efficacy of the latter intervention, individuals who perceive themselves to be at heightened risk for lung cancer (and who are supported in that perception by their doctor) may wish to undertake a low-dose spiral CT examination, having been fully informed beforehand as to all costs and potential risks of such a procedure7.

45

6.2 Definition

There is no general recommendation to screen any subset of asymptomatic individuals for lung cancer at present. Individuals who are perceived to be at low risk, e.g. non-smoking males with no other risk factors, should be actively discouraged from undertaking routine lung cancer screening.


A Neither chest X-ray nor sputum cytology is recommended for screening1.

Grade A, Level Ib C The screening efficacy of low-dose spiral CT is unknown at present.

Grade C, Level IV 6.4 Age and gender for screening

No subset of individuals is recommended to undergo routine screening3.

6.5 Frequency of screening

Since no screening technology is of proven value, no optimal frequency of screening is established3.

6.6 Other relevant information

At-risk individuals who seek low-dose spiral CT examination outside of a clinical trial setting, having been fully informed of the aforementioned limitations and risks, should be referred for such examination via their primary care physician or specialist. Testing should only occur in a multidisciplinary setting3.

6.7 Summary

There is no proven evidence for the efficacy of lung screening at present. Emphasis should remain on smoking cessation, and such counselling should be mandatory prior to undertaking any potential

46

screening intervention. The screening utility of low-dose spiral CT is unknown at present and is currently being studied in ongoing trials.

References

1. Marcus PM, Bergstralh EJ, Fagerstrom R, et al. Lung cancer mortality in

the Mayo Lung Project: impact of extended follow-up. J Natl Cancer Inst 2000; 92:1308-16.

2. Aberle DR, Gamsu G, Henschke Cl, et al. Screening for lung cancer with

helical CT: Society of Thoracic Oncology consensus statement. J Thorac Imaging 2001; 16:65-8.

3. Henschke Cl, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action Project: overall design and findings from baseline screen. Lancet 1999; 354:99-105.

4. Sone S, Takashima S, Li F, et al. Mass screening for lung cancer with mobile spiral CT scanner. Lancet 1998; 351: 1242-5.

5. Heffner JF, Silveshi G. CT Screening for Lung Cancer – Is Smaller Better? Am J Respir Crit Care Med 2002; 165:433-4.

6. Sobue T, Moriyama N, Kaneko M, et al. Screening for lung cancer with low-dose helical computed tomography: anti-lung cancer association project. J Clin Oncol 2002; 20:911-20.

7. Smith RA, Cokkinides V, von Eschenbach AC, et al. American Cancer Society. Guidelines for the early detection of cancer. CA Cancer J Clin 2002; 52: 8-22.

47

48

7 Screening for hepatocellular carcinoma (HCC) 7.1 Introduction

Hepatocellular carcinoma (HCC) is one of the common cancers seen locally. It is the fourth most common cancer among Singaporean males. The male to female ratio is 4:11. The main risk factors for development of HCC include chronic hepatitis B infection and liver cirrhosis secondary to chronic liver inflammation from various etiologies (hepatitis C, alcohol and other chronic liver disease). In Singapore, the age-standardized rate of HCC has declined slightly from 1970 to 19951. However, the incidence is still considerably higher than the western population with Singapore ranked fourth to Japan, Shanghai and Hong Kong1.

7.2 Definition

The recommendations here are for HCC and not for other primary (cholangiocarcinoma, hepatoblastoma, etc) or secondary malignancy involving the liver.

7.3 Tests for hepatocellular carcinoma (HCC) surveillance

C Current accepted tests used for HCC surveillance include ultrasound of the hepato-biliary system and alpha feto-protein (∝FP) level.

Grade C, Level IV

7.3.1 Serum ∝FP levels

∝FP is secreted by hepatoma cells as well as regenerating hepatocytes. A rise in the serum ∝FP level in the absence of significant liver inflammation suggest HCC development. The negative predictive value of ∝FP is 99% but its positive predictive value ranges from 9% to 30% only2,3. ∝FP levels rising in a stepwise manner strongly suggests the presence of HCC and a person with persistent mildly elevated ∝FP (<200 ng/ml) is at higher risk of HCC development compared to those with a single elevated level2.

49

∝FP can be elevated in patients with inflammation of the liver. The levels may exceed thousands. Hence, ∝FP should never be used alone to establish diagnose HCC.

7.3.2 Ultrasonography of the liver

This, together with ∝FP, are the commonest tests used in the surveillance of HCC in at-risk population. The sensitivity of ultrasound for small HCC (<5 cm diameter) ranges from 68% to 87% and a false positive rate of 28% to 82%3-7. Regenerating nodules in a patient with cirrhosis is the leading cause of false-positive ultrasound. Upon detection of a nodule in the liver, the patient should be referred to a referral center for further evaluation. The combination, however, of ∝FP and ultrasound is superior to either test alone for HCC surveillance8.

7.3.3 Others

i) Liver function test. Although liver function test is usually performed in patients with chronic hepatitis B and C to detect flares and decompensation, it is not an investigation performed for HCC surveillance because the liver function test can be normal in early HCC. However, if there is a decrease in serum albumin associated with a rise in the serum alkaline phosphatase, this is suggestive of a space-occupying lesion and warrants further investigations9. ii) des-γ-carboxy prothrombin10

iii) Lens culinaris agglutinin a-reactive profiles of ∝FP10. These are under evaluation and await further data for their accuracy. They are currently not available in Singapore.

7.4 The evidence for HCC surveillance

To date, there is no data to support surveillance of HCC in the general population. However, longitudinal prospective studies have shown that patients with chronic hepatitis B infection and liver cirrhosis from

50

other etiologies are at higher risk of developing HCC. It is in this population of at-risk individuals that HCC surveillance can be offered. The aim of these surveillance programmes is to detect small (<5 cm diameter) HCC which are more amenable to therapy with reports of long-term tumour-free survival11,12. Four population-based screening studies have been published on hepatitis B carriers2,13-15. Using ∝FP as a screening method, small HCC were detected in 37% to 59% of persons with HCC. Although there is evidence that long-term survival can occur in some patients with resected small HCC, there is currently no data available comparing survival outcome in chronic hepatitis B infected persons who are surveyed for HCC versus no HCC surveillance8. It is also important to note that the high false positive rates of both ∝FP and ultrasound may result in expensive and higher risk procedures like angiographic studies and liver biopsy. Despite the lack of definite evidence for benefit in survival8, most hepatologists do surveillance based on the expectations and affordability of their patients. The risk factors for development of HCC in chronic HBV infected individuals are male gender, older age group (>45 years), family history of HCC, presence of liver cirrhosis and co-infection with hepatitis C16-20. While it is logical to target this group of individuals for HCC surveillance, it is known that HCC can also develop in young, asymptomatic, non-cirrhotic chronic HBV infected persons with normal alanine transaminase. These younger individuals, many without liver cirrhosis, showed a distinct survival advantage when the HCC was detected and treated early2. In view of this, the optimal age to initiate HCC surveillance is currently not defined. However, it is noted that local cancer statistics showed that HCC detection increases after 30 years of age. Surveillance of a large population of chronic HBV infected individuals need huge resources, which may not be feasible. Cirrhotic patients have a higher risk of HCC but also a higher chance of being unsuitable for liver resection21,22. Some patients at risk of HCC development may not benefit from the HCC surveillance program. It is important for the physician to discuss with the patient the aims, cost and expected benefits from HCC surveillance before initiating the program for the particular patient.

51

7.5 Summary

GPP There is no evidence to support population-based surveillance for HCC. However, HCC surveillance should be offered to patients with chronic hepatitis B infection, hepatitis C liver cirrhosis and liver cirrhosis from other etiologies. HCC surveillance should be performed periodically with alpha-fetoprotein 3 to 6 monthly and ultrasound of the liver at 6 to 12 monthly interval. There is no definite recommended age to start surveillance8. However, it is noted that the local statistics showed that HCC detection starts to increase from the age of 30 years.

GPP

References 1. KS Chia, A Seow, HP Lee, et al. Cancer incidence in Singapore 1993-

1997. Singapore Cancer Registry report no. 5: 82-3. 2. McMahon BJ, Bulkow Lharpster A, Snowball M, et al. Screening for

hepatocellular carcinoma in Alaska Natives infected with chronic hepatitis B: a 16-year population-based study. Hepatology 2000; 32:842-6.

3. Sherman M, Peltekian KM, Lee C. Screening for hepatocellular

carcinoma in chronic carriers of hepatitis B virus: incidence and prevalence of hepatocellular carcinoma in a North American urban population. Hepatology 1995; 22:432-7.

4. Sheu JC, Sung JL, Chen DS, et al. Early detection of hepatocellular

carcinoma by real-time ultrasonography. Cancer 1985; 56:660-6. 5. Colombo M, de Franchis R, Del Ninno, et al. Hepatocellular

carcinoma in Italian patients with cirrhosis. N Engl J Med 1991; 325:675-80.

6. Tanaka S, Kitamura T, Nakanishi K, et al. Effectiveness of periodic

checkup by ultrasonography for the early diagnosis of hepatocellular carcinoma. Cancer 1990; 66:2210-4.

52

7. Yuen MF, Cheng CC, Lauder IJ, et al. Early detection of hepatocellular carcinoma increases the chance of treatment: Hong Kong experience. Hepatology 2000; 31: 330-5.

8. Lok ASF, McMahon BJ. Chronic Hepatitis B. Hepatology 2001;

34:1225-41. 9. Teo EK, Fock KM. Hepatocellular Carcinoma: An Asian Perspective.

Dig Dis 2001; 19:263-8. 10. Shimauchi Y, Tanaka M, Kurumatsu R, et al. A simultaneous

monitoring of Lens culinaris agglutinin. A reactive alpha-fetoprotein and des-gamma-carboxy prothrombinas an early diagnosis of hepatocellular carcinoma in the follow-up of cirrhotic patients. Oncol Rep 2000; 7:249-56.

11. Dusheiko GM, Hobbs KEF, Dick R, et al. Treatment of small

hepatocellular carcinomas. Lancet 1992; 340:285-8. 12. Gazelle GS, Goldberg SN, Solbiati L, et al. Tumour ablation with

radio-frequency energy. Radiology 2000; 217:633-46. 13. Tang ZY, Yang BH, Zhou ZD. Primary prevention of hepatocellular

carcinoma. J Gastroenterol Hepatol 1995; 10:683-90. 14. Lee CS, Sheu JC, Wang M, et al. Long-term outcome after surgery for

asymptomatic small hepatocellular carcinoma. Br J Surg 1996; 83:330-3.

15. Mima S, Sekiya C, Kanagawa H, et al. Mass screening for

hepatocellular carcinoma: experience in Hokkaido, Japan. J Gastroenterol Hepatol 1994; 9:361-5.

16. Beasley RP. Hepatitis B virus. The major etiology of hepatocellular

carcinoma. Cancer 1988; 61:1942-56. 17. McMahon BJ. Hepatocellular carcinoma in viral hepatitis. In: Wilson

RA. Ed. Viral Hepatitis. New York: Marcel Dekker 1997; 315-30. 18. McMahon BJ, Holck P, Bulkow L, et al. Serologic and clinical

outcomes of 1536 Alaska natives chronically infected with hepatitis B virus. Ann Int Med 2001; 135:759-68.

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19. Fattovich G, Giustina G, Schalm SW, et al. Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis. Hepatology 1995; 21:77-82.

20. Liaw YF, Lin DY, Chen TJ, et al. Natural course after the

development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Liver 1989; 9:235-41.

21. Ebara M, Ohto M, Shinagawa T. Natural history of minute

hepatocellular carcinoma smaller than 3 centimeters complicating cirrhosis. Gastroenterology 1986; 90:289-98.

22. Sherman M. Hepatocellular carcinoma. Gastroenterologist 1995; 3:55-

6.

54

8 Screening for colorectal cancer 8.1 Introduction

Colorectal cancer has emerged as the cancer with the highest incidence in Singapore1. Individuals face a moderate to high risk of developing colorectal cancer which is comparable to developed countries. Despite improvement in surgical technique and the development of adjuvant therapy, mortality from colorectal cancer has not declined appreciably. One of the major reasons for this is the advanced stage of disease at the time of presentation2. This is in contrast to the five-year survival rate of approximately 90% for localized colon cancer2. Further, it has been demonstrated that most colorectal cancers develop from adenomas. Endoscopic removal of adenomas result in a reduced colorectal cancer risk3. The long pre-malignant period of this adenoma-carcinoma sequence makes it ideal to screen for colorectal cancer.

8.2 Definition

8.2.1 Average-risk individuals The lifetime probability of an individual developing colorectal cancer is approximately 5%4. The risk rises with age, occurring sporadically among younger individuals and rising sharply after the age of 501

years. For average-risk individuals, screening should begin at the age of 50 years. This would include asymptomatic individuals and individuals who have a family history of colorectal cancer limited to non-first degree relatives and no other risk factors5-7. 8.2.2 High-risk individuals Patients at high risk for colorectal cancer include those who have one or more first-degree relatives with colorectal cancer8 or a personal history of colorectal neoplasia9. Patients with prior endometrial, ovarian or breast cancer and those who have had pelvic radiation may have a slightly higher than average risk of colorectal cancer10.

55

8.2.3 Very high-risk individuals Patients at very high risk for developing colorectal cancer are those with a hereditary or genetic predisposition for colorectal cancer, that is, a family history of familial adenomatous polyposis, other hereditary gastrointestinal polyposis syndromes or hereditary non-polyposis colorectal cancer11-14. Also at a high-risk are patients with a long history of extensive inflammatory bowel disease15, 16.

8.3 Screening tools and effectiveness

Screening tools currently available in current practice include • Annual faecal occult blood test • Flexible sigmoidoscopy • Double-contrast barium enema • Colonoscopy

8.4 Faecal Occult Blood Tests (FOBT)

In this screening strategy, FOBT when positive is followed up by colonoscopy or when technically not possible, a barium enema. Three groups of tests are available: the guaiac test, immunochemical tests and heme-porphyrin tests. The stool guaiac test works on the principle of the pseudo-peroxidase activity of either heme in its free form or bound to its apoprotein (as haemoglobin, myoglobin and certain cytochromes). The test does not turn positive with degradation products of heme which lack peroxidase activity. As the reaction is not specific for blood, dietary peroxidase from plant or animal origin will produce a positive test result. Drugs with reducing properties such as vitamin C will produce a false negative result. Dietary restrictions (red meat, horseradish, turnips) are necessary to reduce false-positive results, although the need for dietary restriction has been recently questioned17. The test does not localize the site of bleeding and may also test positive in the presence of upper gastrointestinal ulcer-inducing drugs like aspirin and NSAIDS. Other drugs such as colchicine and oxidizing agents such as iodine and reserpine may give false positive results.

In contrast, the immunochemical tests are the most chemically selective and specific for human haemoglobin and some of its early degradation forms. Non-human haemoglobin does not produce a false

56

positive result. Drugs related to gastrointestinal bleeding may result in a positive test. Technologies used in these tests include enzyme-linked immunosorbent assays (ELISA), radial immunodiffusion, reverse passive haemagglutination and latex haemagglutination. Test kits using these technologies are available.

The heme-porphyrin tests are specific for di-carboxylic porphyrins and detect intact heme in any form and its porphyrin degradation products. Fluorescent spectrometry is required and permits quantification. This had not been used in population screening because of the laborious testing process.

Test positivity is dependent on the site of the bleeding. Gastric and proximal small bowel bleeding would result in greater heme degradation products as opposed to distal colonic bleeding as there is more time for degradation to occur. This allows for greater specificity. However, there is a degree of overlap between blood loss in the normal gastrointestinal tract (estimated to be up to 1.5 ml per day) and patients with colorectal neoplasia. This mitigates against test accuracy and accounts for false positives observed.

The amount of bleeding is dependent on site of bleeding and size of the tumor. Proximal cancers bleed the most while adenomas bleed less than cancers. Adenomas of less than 1 cm are unlikely to bleed. The amount of bleeding varies resulting in the need to obtain multiple samples over several days. It has been shown that greater than three tests does not increase the sensitivity significantly18,19.

The Hemoccult II stool guaiac test is perhaps the most widely studied FOBT. The crude sensitivity in individuals screened with guaiac FOBT (Hemoccult II) is estimated to be in the region of 50% to 75% and as high as 90% for hydrated Hemoccult II5-7. These results are based on individuals who are known to have colorectal cancers. The test when applied in a population setting is affected by compliance and other factors19. The predictive values for cancers and adenomas in the Nottingham5 and Funen6 trials were 53% and 59% respectively. The results include a 2-year follow-up for interval or “screen-missed” cancers detected after the initial screening tests. These trials including one from Minnesota7 have also shown a significant reduction of mortality from colorectal cancer following FOBT screening of between 15% to 30%.

57

There has been no randomized, controlled population trials using an immunochemical test. In Japan, a reverse passive haemagglutination test (Hem-sp) was used in population screening from 1992 following the passage of the Law of the Aged. The Japanese Ministry of Health and Welfare targeted 2.5 million asymptomatic individuals aged 40 years and above for screening. Data was available for 1.1 million individuals in a survey20. 76,323 (7.1%) tested positive. 70.1% underwent further evaluation and 2,017 (0.2%) were found to have a colorectal cancer, of these 56% were early cancers. These results are comparable to the guaiac FOBT trials. Compared to the Nottingham trial which has the highest FOBT positivity of the five randomised trials (2.7 per 1,000 screened with rehydrated slides and 0.9 per 1,000 with unhydrated slides)5, the immunochemical test gave a cancer detection rate of 1.9 per 1,000 screened. The rates are similar using the “intention-to-screen” principle, taking into account compliance. It would appear that with the immunochemical test, although more sensitive than the guaiac test in detecting occult blood, the specificity for cancer is only modestly better. Polyp detection rate is relatively higher for the immunochemical tests21. Polypectomy and subsequent surveillance may result in a reduction in the incidence of colorectal cancer3.

8.5 Sigmoidoscopy

The rationale of using flexible sigmoidoscopy for screening lies in the fact that up to two-thirds of the colorectal cancer are within the reach of this procedure. Its secondary function in screening is the detection of index polyps that will necessitate a subsequent colonoscopy. Approximately 30% of cancers proximal to the splenic flexure have an index lesion situated distally22. In countries such as the US and UK, this procedure can be performed effectively and safely by trained nurse practitioners23. Early trials on sigmoidoscopy involved the rigid scope and were non-randomised case controlled trials. In a pooled analysis of 14 studies using flexible sigmoidoscopy for screening about 11,000 individuals, 30 cancers were detected and 24 of these were localized24. While empirically, flexible sigmoidoscopy screening should reduce mortality from colorectal cancer, its true effectiveness is still not clear until the results of the MRC sponsored trial and the NCI trial involving 148,000 individuals over 50 years of age are known in 2006 and 2008 respectively.

58

As an alternative screening option, asymptomatic individuals above the age of 50 years could undergo flexible sigmoidoscopy once every 5 years10,25-28. For individuals with a family history of familial adenomatous polyposis, flexible sigmoidoscopy is recommended annually from the onset of puberty10,28.

8.6 Double Contrast Barium Enema (DCBE)

There has been no trials using DCBE for population screening. The benefits have been extrapolated from studies using endoscopy. DCBE has a lower risk of perforation than colonoscopy but still requires bowel preparation for accurate diagnosis of small lesions like polyps. The American Society of Radiologists standard stipulates that the enema must be of a quality to detect 90% of the colorectal cancer and 80% of the polyps greater than 1 cm in diameter29. Even with good bowel preparation, DCBE is known to miss small polyps. This is less likely with colonoscopy. There is also a need to perform a colonoscopy if the DCBE is positive for confirmation and biopsy. As a tool in population screening, its role is still unknown.

8.7 Colonoscopy

While colonoscopy is the “gold-standard” in screening for colorectal cancer and has a widely accepted role in screening for high-risk individuals, its use in population screening in an average risk setting is still largely unknown. Two large studies have demonstrated that colonoscopy will detect a substantial portion of asymptomatic colorectal cancers and high risk polyps30, 31. A case control study has found that patients with a diagnosis of colorectal cancer were less likely to have had previous colonoscopy. The odds ratios for disease incidence were 0.47 for colon cancer and 0.61 for rectal cancer. For mortality, the odds ratio was also lower in patients with previous colonoscopy (0.43)32. It requires bowel preparation and inconvenience that will reduce compliance if used as a screening tool. Its major concerns are the costs involved and associated complication including death.

Perforation and bleeding after polypectomy are the major complications observed. In the Minnesota trial7, 12,246 colonoscopies were done with 4 perforations and 11 haemorrhages (rate of 12 per 10,000). In a screening trial from Goteborg33, 2,298

59

endoscopies (mainly flexible sigmoidoscopy) and DCBE were performed with a complication rate reported as 30 per 10,000. In the Nottingham trial5, 1,774 colonoscopies were done with 7 complications, 6 requiring surgery giving a rate of 39 per 10,000. In the Japanese series 20 of 53,536 examinations, 248 complications were reported (rate of 46 per 10,000). Twelve deaths were reported. Whilst colonoscopy is a relatively safe procedure, it is not devoid of complications. Asymptomatic individuals above the age of 50 years can undergo colonoscopy once every 10 years as a screening option10, 25-27. For individuals with a history of a colorectal cancer in a first degree relative over the age of 45 years, colonoscopy, every 10 years is recommended. For an individual with a family history of colorectal cancer aged 45 years or younger or a family history of 2 or more affected first degree relatives, colonoscopy every 3 years performed 10 years prior to the youngest case in the family is recommended10,26-

28. For individuals with a personal past history of colorectal polyps, colonoscopy is recommended one year after polypectomy in the presence of high risk features (polyp > 1 cm, multiple, villous architecture) or three years after polypectomy in the absence of high risk features10,28. For individuals with a personal past history of colorectal cancer, colonoscopy is recommended one year after resection provided that total imaging of the bowel was achieved prior to surgery7,35. For individuals with a family history of hereditary non-polyposis colorectal cancer, colonoscopy is recommended every 2 years commencing 10 years prior to the age of diagnosis of colorectal cancer in the youngest family member10,28. For individuals with left sided ulcerative colitis, colonoscopy is recommended every 1-2 years from the 15th year of diagnosis. For individuals with pan-colitis colonoscopy is recommended every 1-2 years from the 8th year of diagnosis20.

60

8.8 Comment on the use of carcinoembryonic antigen (CEA) for screening

The determination of plasma CEA levels has been used to detect early asymptomatic recurrence of colorectal cancer34. However, its use in the screening of asymptomatic, average-risk patients is difficult to justify. It can be elevated in other malignant conditions, benign conditions such as ulcerative colitis and liver cirrhosis and among smokers. The low specificity and sensitivity of the plasma CEA in the diagnosis of colorectal cancer makes it a poor screening tool35.

8.9 Summary

Colorectal cancer is the most common cancer in Singapore according to incidence. Screening for colorectal cancer should be performed after risk stratification. There is good evidence that screening for colorectal cancer will lead to reduction of mortality from the disease in all risk groups.

8.10 Screening guidelines

Based on the forgoing discussion and review of international practice parameters and guidelines10,25,26,27, the following recommendations are made for the screening of colorectal cancer (see Table 3).

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TABLE 3 : Recommendations for the Screening of Colorectal Cancer

RISK GROUP SCREENING TOOL ONSET (Age, years)

FREQUENCY

LEVEL OF EVIDENCE

GRADE OF RECOMMENDATION

A. Average risk Asymptomatic or family history limited to non-first degree relatives (screening tool alternatives in order of supporting evidence)

Faecal occult blood testing Flexible sigmoidoscopy Colonoscopy Barium Enema

50

50

50

50

Annually

Every 5 years

Every 10 years

Every 5 to 10 years

Ia

IIa

IIb

IV

A

B

B

C B. High Risk 1. Colorectal cancer in first

degree relative age 45 years or younger or two or more first degree relatives

2. Colorectal cancer in first degree relative

over the age of 45 years

3. Personal history of colorectal polyps 4. Personal history of colorectal malignancy 5. Personal history of ovarian or endometrial

cancer

Colonoscopy Colonoscopy Colonoscopy Colonoscopy Colonoscopy

10 years prior to youngest case in the family or age 45 years, whichever is earlier 10 years prior to youngest case in family or age 50 years, whichever is earlier One year after polypectomy in the presence of high risk features (>1cm, multiple, villous architecture) three years after polypectomy (solitary, tubular architecture) One year after resection One year after resection

Every 3 years

Every 10 years

IIa

IIb

Ib

IIa

IV

B

B

A

B

C

C. Very High-Risk 1. Family history of familial adenomatous

polyposis

2. Family history of hereditary non-polyposis colorectal cancer

3. Inflammatory bowel disease

a. left-sided colitis b. pan-colitis

Flexible sigmoidoscopy; consider genetic counselling and testing Colonoscopy; consider genetic counselling and testing Colonoscopy Colonoscopy

12 to 14 years (from puberty) From 10 years prior to the diagnosis in the youngest family member From 15th year of diagnosis onwards From 8th year of diagnosis onwards

Annually

Every 2 years

Every 1-2 years

Every 1-2 years

IIb

IIb

IIb

IIb

B

B

B

B

62

References 1. Chia KS, Seow A. Lee HP, et al. Cancer incidence in Singapore 1993-

1997. Singapore Cancer Registry Report No. 5 : 2000. 2. Ries LA, Miller BA, Hankey BF, et al. eds. SEER cancer statistics review

1973-1991: tables and graphs. Bethesda National Cancer Institute, 1994. 3. Winawer SJ, Zauber AG, O’Brien MJ, et al. Randomized comparison of

surveillance intervals after colonoscopic removal of newly diagnosed ademonatous polyps. N Engl J Med 1993; 328: 901-6.

4. Parker SL, Tong T, Bolden S, et al. Cancer statistics 1996. CA Cancer J

Clinic 1996; 46:5-27. 5. Hardcastle JD, Chamberlain JO, Robinson MH, et al. Randomized

controlled trial of faecal occult-blood screening for colorectal cancer. Lancet 1996; 348:1472-7.

6. Kronborg O, Fenger C, Olsen J et al. Randomized study of screening for

colorectal cancer with faecal occult blood for colorectal cancer. Lancet 1996; 348:1467-71.

7. Mandel JS, Bond JH, Church TR, et al. Reducing mortality from

colorectal cancer by screening for faecal occult blood. Minnesota colon cancer control study. N Eng J Med 1993; 328:1365-71.

8. Fuchs C S, Giovannuci EL, Colditz GA, et al. A prospective study of

amily history and risk of colorectal cancer. N Engl J Med 1994; 331:1669 – 74.

9. Cali RL, Pitsch RM, Thorson AG, et al. Cumulative incidence of

metachronous colorectal cancer. Dis Colon Rectum 1993; 36:388-93. 10. Winawer SJ, Fletcher RN, Miller L, et al. Colorectal cancer screening:

Clinical guidelines and rationale. Gastroenterglogy 1997; 112:594-642. 11. Jang YS, Steinhasem RM, Heimam TM. Colorectal cancer in familial

adenomatous polyposis. Dis colon Rectum 1997; 40:312-6. 12. Haggitt RC, Reid BJ. Hereditary gastrointestinal polyposis syndromes.

Am J Sung Pathol 1986; 10:871-7.

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13. Lovett E. Family studies in cancer of the colon and rectum. Br J Surg

1976; 630:13-8. 14. Lynch HT, Watson P, Smyrk TC, et al. Colon cancer genetics. Cancer

1992; 70:1300-12. 15. Bauer WM, Lashner BA. Inflammatory bowel disease and intestinal

cancer. Practical Gastroentrol 1998; 22:20-7. 16. Ekbom A, Helmick C, Zack M, et al. Ulcerative colitis and colorectal

cancer. A population based study. N Engl J Med 1990; 323:1228-33. 17. Rozen P, Knaai J, Samuel Z. Eliminating the need for dietary restrictions

when using a sensitive guaiac fecal occult blood test. Dig Dis Sci 1999;44:756-60.

18. Macrae FA, St John DJB. Relationship between patterns of bleeding and

Hemoccult sensitivity in patients with colorectal cancers or adenomas. Gastroenterology 1982; 82:89-898.

19. Hardcastle JD, Chamberlain J, Sheffield J, et al. Randomised controlled

trial of faecal occult blood screening for colorectal cancer. Results of the first 107349 subjects. Lancet 1989;27:1160-4.

20. Committee for a nationwide totaling of mass screening for

gastrointestinal cancers. J Gastroenterol Man Surv 1995; 33:200-18. 21. St John DJ, Young GP, Alexeyeff MA, et al. Evaluation of new occult

blood tests for detection of colorectal neoplasia. Gastroenterology, 1993;104:1661-8.

22. Selby JV. Targeting colonoscopy. Gastroenterology 1994; 106:1702-5. 23. Wallace MB, Ho KY, Trnka Y, et al. Comparison of nurse

practitioners/physician assistants to gastroenterologists in performing flexible sigmoidoscopy 1998; 114:A698.

24. Selby JV. Clinical trials in screening sigmoidoscopy. Cn: Colorectal

Cancer. Winawer SJ (ed). Raven Press 1985. New York 291-301. 25. American Cancer Society. Cancer Facts and figures, 1996. American

Cancer Society Publication no. 5008-96. 1996.

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26. Preventive health care, 2001 update: colorectal cancer screening. CMA J

2001 24; 165:206-8. 27. United States Preventive Services Task Force. Screening for colorectal

cancer. US Preventive Service Task Force report 1996. 28. The Standards Committee. Practice Parameters for the detection of

colorectal Neoplasms. The American Society of Colon and Rectal Surgeons. 2002.

29. Reston VA. Colon cancer diagnosis in an era of cost containment.

Council of the American College of Radiology, Reston, Virginia 1990. 30. Imperiale TF, Wagner DR, Lin CY, et al. Risk of advanced proximal

neoplasms in asymptomatic adults according to distal colorectal findings. N Eng J Med 2000; 343:169-74.

31. Lieberman DA, Weiss DG, Bond JH, et al. Use of colonoscopy to screen

asymptomatic adults for colorectal cancer. N Eng J Med 2000; 343:162-8. 32. Müller AD, Sonnenberg A. Protection by endoscopy against death from

colorectal cancer. A case-control study among veterans. Arch Intern Med 1995; 155:1741-8.

33. Kewenter J, Brevirge H, Haglund E, et al. Screening, rescreening and

follow-up in a prospective randomized study for detection of colorectal cancer by faecal occult blood testing. Scand J Gastroenterol 1994; 29:468-73.

34. Filella X, Molina R, Bedini JLA. Clinical usefulness of CRA as tumor

marker in patients with colorectal cancer. J Nucl Med Allied Sci 1990; 34:107-10.

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9 Screening for prostate cancer 9.1 Introduction

Adenocarcinoma of the prostate is the sixth most common cancer among men in Singapore with an incidence of 13 per 100,000 per year1. Autopsy studies have shown that approximately 30% of men over the age of 50 years have histologic evidence of prostate cancer2. Many men will die, however, from competing medical hazards and not prostate cancer. Prostate cancer is often a slowly progressive disease, and as a consequence, men with newly diagnosed disease often face difficult choices regarding appropriate treatment. Treatment options include watchful waiting, radical prostatectomy, radiotherapy, and hormonal therapy. Cure of prostate cancer is only possible when the disease is localised to the prostate. Current data supports the concept that Prostate Specific Antigen (PSA) screening results in early diagnosis and stage migration. The percentage of incurable prostate cancers has also greatly decreased, and the death rates from prostate cancer declined by nearly 5% per year since 19933. Recent publications from the National Cancer Institute have attributed this decline, at least in part, to PSA screening. However, other factors may also have contributed to this decline. From the economic standpoint, the financial costs of treating advanced prostate cancer are greater than those of treating early disease. Most of the tumours diagnosed in the PSA-era are not insignificant tumours by traditional grade and Gleason criteria. Multiple studies including the Surveillance, Epidemiology and End Results (SEER) Program have shown that moderately differentiated or Gleason sum 5-7 tumours pre-dominate in the PSA-era. Most of the available data are from Western populations and Asians are known to have lower incidences of prostate cancer3-6.

9.2 Who to screen Screening with PSA has the potential of diagnosing organ-confined prostate cancer. Early detection with PSA should not be refused to any man who is aware of the potential risks and benefits.

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In America, where prostate cancer is the most common cancer amongst men, the American Cancer Society and the American Urological Association recommend that men aged 50 years and older with at least 10 years life expectancy should be offered prostate cancer screening each year7. In Asia, the incidence of prostate cancer is much lower. Furthermore, scientific evidence to demonstrate a decrease in cancer-specific mortality from screening is lacking. The results of several large randomized studies on prostate cancer screening are also not ready. A Therefore, at present, population screening for prostate cancer is not recommended among Asians.

Grade A, Level Ia GPP High-risk men, such as men above 50 years of age with a history of a first degree relative with prostate cancer at a young age (<60 years), should be offered screening.

GPP


Screening for prostate cancer involves the following: • Digital rectal examination (DRE)

Digital rectal examination provides a rapid clinical assessment for the presence of any suspicious prostatic nodule. The rationale for including DRE stems from the fact that 10-25% of cancers have a normal PSA (<4 ng/ml)8. B Combined use of DRE and PSA has a higher detection rate for prostate cancer than either test alone8.

Grade B, Level IIb While the DRE is a rapid examination, it demands the involvement of an experienced investigator and is unpleasant for the man being screened.

• Prostate Specific Antigen (PSA) blood test

B The introduction of PSA testing has been instrumental to the dissemination of wide-spread prostate cancer screening. It is the

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single test with the highest positive predictive value for cancer. A PSA cut-off point of 4 ng/ml detects 75% of prostate cancers9.

Grade B, Level IIb

The simplicity of the test makes it very attractive for most men despite its low specificity and imperfect sensitivity. Approximately 15% of prostate cancers are detected between 3 and 4 ng/ml, have extracapsular extension and therefore are probably not curable10. However, lowering the PSA cut-off too much will decrease its specificity. Efforts to enhance specificity include the use of free PSA and free-to-total PSA ratio. A concept of combining a decreased PSA cut-off (to 2.5 ng/ml) with a low free-to-total PSA ratio (<0.20) could improve both sensitivity and specificity11,12. The value of using age-specific ranges of PSA to enhance the diagnosis of prostate cancer has been controversial and there is, at present, no established age-specific ranges in Asians.

• Transrectal ultrasound-guided biopsy (TRUS biopsy) Transrectal ultrasound (TRUS) was developed 20 years ago to detect prostate cancer.

B Several studies have shown that most hypoechoic lesions found on TRUS are not cancers and 50% of non-palpable cancer more than 1 cm are not visualized on TRUS13,14.

Grade B, Level IIb

The investigation is time-consuming and also less attractive for men as a screening procedure. The place of TRUS at present, is in guiding systematic core biopsies of the prostate. Prostate biopsies can be performed with little pain under local anaesthesia and with a serious complication rate of far less than 1%. B TRUS-guided biopsy is currently recommended for patients with abnormal PSA results and/or suspicious DRE8.

Grade B, Level IIb

Current biopsy strategies include obtaining more than six biopsies in most patients, focusing biopsies laterally, taking

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additional transitional zone biopsies in very large glands, and adjusting number of cores by taking prostate volume and patient’s age into consideration15. In patients with elevated PSA, a second biopsy found cancer in up to 34% of men after an initial negative biopsy16.


The optimal screening interval has yet to be determined. So far, investigators have studied intervals ranging from 6 months to 4 years. Lower PSA levels may be followed by a longer screening interval. A PSA level below 1 ng/ml seems to imply little risk for disease progression within 2-4 years13.


Data from several ongoing randomized trials of screening for prostate cancer are expected to be available in the near future. Regional mass screening cohort studies are being conducted in the Austrian state of Tyrol, where volunteers exposed to PSA testing are followed over time17. The European Randomized Study of Screening for Prostate Cancer (ERSPC) is conducted in 7 European countries18. The Prostate, Lung, Colorectal and Ovary (PLCO) cancer screening trial is in progress in the US; participants are recruited from 10 centres across the country19. Meanwhile, the first analysis of the Laval University Prostate Cancer Detection Program (LUPCDP) Canadian trial compared prostate cancer mortality in screened and unscreened men between 1988 and 199620. It indicated that the screening intervention could well lead to a reduction of cause-specific mortality that is larger and faster than expected. The outcome of the ERSPC, PLCO and Canadian trials will help in the modeling and recommendation of the screening policies, and in the ultimate decision for nation-wide introduction of cost-effective screening programs.

9.6 Summary

Despite the fact that population-based screening for prostate cancer has yet to be definitively proven or disproved to affect the disease-specific mortality, this summary explores changes in the PSA-era data

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from areas where screening has been prevalent to support the working hypothesis that disease-specific mortality can be decreased. It must be kept in mind that uncertainty exists regarding the reasons for the current declining mortality, from screening itself to aggressive treatment of disease identified in the PSA-era. Without direct evidence of decreased prostate cancer mortality from well conducted randomized population screening trials, it then becomes a personal choice for asymptomatic individuals to undergo testing for prostate cancer perhaps to lower the risk of dying from metastatic prostate cancer. This benefit has to be balanced against the burden of morbidity from testing and over treatment of some individuals.

References 1. Chia KS, A Seow, Lee HP, et al. Cancer incidence in Singapore 1993-

1997. Singapore Cancer Registry Report No. 5, 2000. 2. Scardino PT. Early detection of Prostate Cancer. Urol Clin N Amer 1989;

16:635. 3. Hankey BF, Feuer EJ, Clegg LX, et al. Cancer surveillance series:

Interpreting trends in prostate cancer - Part I: Evidence of the effects of screening in recent prostate cancer incidence, mortality and survival rates. J Natl Cancer Inst. 1999; 91:1017-24.

4. Stephenson RA. Population-based prostate cancer trends in the PSA era:

data from the Surveillance, Epidemiology, and End Results (SEER) program. Monographs in Urology 1998; 3.

5. Farkas A, Schenider D, Perotti M, et al. National trends in the

epidemiology of prostate cancer, 1973 to 1994: Evidence for the effectiveness of prostate-specific antigen screening. Urology 1998; 52:444.

6. McNeal JE, Redwine EA, Freiha FS, et al. Zonal distribution of prostateic

adenocarcinoma. Correlation with histological pattern and direction of spread. Am J Surg Pathol 1998; 12:897.

7. Smith RA, Cokkinides V, von Eschenbach AC, et al. American Cancer

Society guidelines for the early detection of cancer. CA Cancer Journal for Clinicians 2002; 52:8-22.

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8. Catalona WJ, Richie JP, Ahmann FR, et al. Comparison of digital rectal

examination versus prostate-specific antigen in the early detection of prostate cancer: Results from a multi-centre clinical trial of 6630 men. J Urol 1994; 151:1283-90.

9. Labrie F, Dupont A, Suburu R, et al. Serum prostate-specific antigen as

pre-screening test for prostate cancer. J Urol 1992; 147:846-52. 10. Lodding P, Aus G, Bergdahl S, et al. Characteristics of screening detected

prostate cancer in men 50-66 years old with 3 to 4 ng/ml Prostate Specific Antigen. Urology 1998; 159:899-903.

11. Lilja H, Stenman UH. Successful separation between benign prostatic

hyperplasia and prostate cancer by measurement of free and complexed PSA. Cancer Treat Res. 1996; 88:93-101.

12. Catalona WJ, Ramos CG, Carvahal GF, et al. Lowering PSA cutoffs to

enhance detection of curable prostate cancer. Urology 2000; 55:791-5. 13. Gustaffsson O, Norming U, Almgard LE, et al. Diagnostic methods in the

detection of prostate cancer: a study of randomly selected population of 2,400 men. J Urol. 1992; 148:1827-31.

14. Carter HB, Hamper UM, Sheth S, et al. Evaluation of transrectal

ultrasound in the diagnosis of prostate cancer. J Urol 1989; 142:1008-10. 15. Djavan B, Zlotta AR, Ekane S, et al. Is one set of sextant biopsies enough

to rule out prostate cancer? Influence of transition and total volumes on prostate cancer yield. Eur Urol 2000; 38:218-24.

16. Djavan B, Zlotta AR, Remzi M, et al. Optimal predictors of prostate

cancer on repeat biopsy: a prospective study of 1,051 men. J Urol 2000; 163:1144-8; discussion 1148-9.

17. Bartsch G, Horninger W, Klocker H, et al. Tyrol Prostate Cancer

Screening Group. Prostate cancer mortality after introduction of prostate-specific antigen mass screening in the Federal State of Tyrol, Austria. Urology 2001 Sep; 58:417-24.

18. De Koning HJ, Auvinen A, Berenguer Sanchez A, et al. Large scale

randomized prostate cancer screening trials: program performances in the

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European Randomised Study of Screening for Prostate Cancer (ERSPC). Int J Cancer 2002; 97:237-44.

19. Miller AB, Yurgalevitsch S, Weissfield JL. Prostate Lung Colorectal and

Ovarian Cancer Screening trial Project Team. Death review process in the PLCO Cancer Screening Trial. Control Clin Trials 2000; 21:400S-6S.

20. Labrie F, Candas B, Dupont A, et al. Screening decreases prostate cancer

death: first analysis of the 1988 Quebec prospective randomized controlled trial. Prostate 1999; 38:83-91.

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10 Screening for breast cancer 10.1 Introduction

Breast cancer is now the most common cancer in women in Singapore, and, according to the Singapore Cancer Registry1, the age-adjusted incidence over the last 30 years has approximately doubled, from 20 per 100,000 in 1968-72 to 46.1 per 100,000 in 1993-97, a rise of about 3-4% per annum. It should be noted that Australia has also seen a rise in age-adjusted breast cancer incidence from 70 cases per 100,000 in 1983 to 98 cases per 100,000 in 1996, an average annual rise of 3.4%2.

Breast screening may be sporadic (or opportunistic), where an individual woman chooses to have intermittent screening mammography at her discretion, or mass (or population-based screening), where women are systematically invited to have screening mammography at predetermined intervals.

Until recently, Singapore’s breast screening was entirely sporadic in nature. That is, the quality of mammographic screening was variable, an unknown number of cancers was missed, screening practice was unregulated and unaudited, screening was expensive for the individual woman, with a high proportion of negative surgical procedures, and there was no measurable beneficial outcome.

10.2 Key concepts in breast screening

10.2.1 Odds of significant disease

Significant disease in the context of breast cancer screening is the detection of either non-invasive in situ carcinoma, or invasive cancer. The prior probability of significant breast disease is greatly influenced by the clinical scenario:

• In a symptomatic woman presenting with a breast lump, there is

perhaps a 1:20 (5%) chance that the woman will turn out to have a malignancy. This statistic is fairly typical in symptomatic breast clinics in Singapore [National University Hospital Breast Clinic data, unpublished].

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• In an asymptomatic woman who is a BRCA gene carrier, any

single screening visit has about 0.5-1% per year cumulative chance of detecting cancer. This is derived from the estimated lifetime risk of breast cancer in such gene carriers of 50% to 75%3,4.

• Risk increases with age; in Singapore, an asymptomatic, normal

risk 30-year old woman has a 19 in 100,000 chance of developing breast cancer each year (0.019%), while one who is 50-55 years old has an annual risk of 185 in 100,000 (0.185%), which is almost 10 times higher5. More than 99.9% of normal risk, asymptomatic women screened by mammography or any other test will NOT have breast cancer.

10.2.2 Imperfection of mammography

Well-performed mammography in a formal screening program has a fairly high sensitivity for breast cancer, but is not very specific. In Singapore, a recall rate of 8% and a needle biopsy rate of 1% has been shown to be effective for detection of breast cancer in 0.5% of screened women6. The cancer detection rate does not significantly increase when recall rates exceed about 5%7. Recall rates much higher than this are typical in sporadic screening, and result in large numbers of unnecessary additional tests. It is established that reading screening mammograms with just a single radiologist can miss up to 30% of breast cancers8. Some radiologists miss as few as 3% of cancers on their own9, but they are highly experienced in screening and are in the minority. In general, adding a second reader increases the cancer detection rate over a single reader substantially10,11. Nevertheless, it is recognised that the interval cancer rate (cancers that appear between routine screening episodes) will be about 10% of all the cancers detected, typically at a level of about 10 per 10,000 screens at 2 years12-15; only about one-third of these will be detectable on retrospective review16. Therefore, about 7% of breast cancers cannot be detected by screening mammography, even in retrospect. It should be noted that routine screening mammography should be distinguished from diagnostic mammography, which is targeted at analysing a specific abnormality such as a palpable mass, or screen-detected microcalcifications.

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10.2.3 Sojourn time and screening interval

The time between the development of frankly malignant cellular behaviour to the point of detectability with a screening test is called the sojourn time. The time between screens must be appropriate for the tumour and the age of the client. The potential benefits of increased screening frequency must also be balanced by considerations of the attendant increases in cost, radiation exposure, and risk of false positive recalls. For breast screening, this optimal screening interval has empirically been determined through analysis of breast screening trial data17 to be: • 1 year for women aged 40 to 49, and • 2 years for women aged 50 to 70

10.2.4 Mass versus Individual screening

The goal of breast screening on a mass, or population basis is to produce a shift in cancer detection towards pre-invasive cancers, and to eventually reduce the mortality from breast cancer for the female population.

There is only one breast screening test that has been shown to do this, and that is well-performed, dual-read X-ray mammography. No other test (including poorly performed mammography) has been shown to have the same results. In general, mass breast screening is performed through structured, accredited and audited formal programmes where women are systematically invited to participate, usually at a reduced cost.

On an individual, or sporadic screening basis, the goal of the woman is to exclude cancer as best as possible. In general, this is an elective procedure and the entire cost of the process is borne by the woman. In this situation, it is common practice to perform breast ultrasound and clinical breast examination. This practice is not proven to reduce patient mortality, even though it occasionally reveals a mammographically occult tumour.

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10.3 Detailed recommendations

10.3.1 Screening with X-ray mammography

X-ray mammography has been subjected to randomised controlled trials (RCTs) and much controversy. It is the most well-studied yet most commonly misunderstood screening test which is in widespread use today. The Swedish Two-County trial of mammographic screening is a landmark study. There is long-term mortality data from this trial17, showing a persistent and significant 29% reduction in breast cancer mortality in the group invited to screening.

Garne et al. reported the mortality results from the Malmö breast screening trial18, showing that between 1977 and 1992, breast carcinoma mortality decreased in Malmö by 43% compared with 12% in the rest of Sweden (P < 0.001).

In 1996, Larsson and colleagues19 reviewed 5 of the Swedish screening RCTs and calculated the estimated reduction of breast cancer related mortality to be 24%. Nyström et al.20 reviewed overall and breast cancer-related mortality of four of the Swedish RCTs on breast screening, with similar results.

It is notable that there has been a statistically significant reduction in breast cancer mortality in some countries since 1990 despite an increase in incidence21,22. However, it is unclear if this decline is due to better treatment or to breast screening, or a combination of the two.

The accepted view that mass screening mammography reduced the breast cancer mortality was disputed recently by Gøtzsche and Olsen23,24, who concluded that all but two of the mammography screening trials were significantly flawed and their results could not be considered valid. In the two trials they deemed to be adequately randomised (the Canadian trial and the Malmö trial), they found no effect of screening on breast-cancer or total mortality, despite the conflicting mortality data published in 199718 which showed a significant reduction in mortality for women in Malmö who underwent screening.

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This conclusion has been rebutted strongly by several international experts. Most recently, Nystrom et al. have reviewed the Swedish trials in detail, with particular attention to the randomization methodology, including previously unpublished data25. They concluded that the Swedish trials did not show significant bias, and they reconfirmed a relative risk reduction on mortality of 24% for women who started screening at 50 and older.

For women under 50, the evidence for mortality reduction from breast screening is less clear-cut. Only one trial, from Gothenberg in Sweden, has shown a statistically significant survival benefit for women screened under the age of 50. This randomised controlled trial specifically enrolled women aged 39-49 to mammographic screening every 18 months. There was a 44% reduction in mortality (P<0.05) from breast cancer in the study group compared to the control group26. By contrast, the Canadian National Breast Screening Study showed improved detection but no survival benefit deriving from screening in this age group27.

Using subgroup analysis, the Two-County trial data has been calculated to show an overall reduction in breast cancer mortality of 13% for women aged 40-49 years at randomisation28. Pooled trial data suggests a survival benefit for women screened under the age of 5029. Pooled analysis of women enrolled from 40-49 years in four of the Swedish screening trials showed a 23% reduction in the breast cancer mortality30.

The potential survival benefit of breast screening has been calculated to be much higher for younger than for older women, with a high screening frequency resulting in more lifetime gained31. However, the cost of saving years of life in this age group would be at least twice as much for each cancer detected as for women from 50–69 years.

For Singaporean women aged 45-49, the breast cancer incidence of 166 per 100,0005 is very similar to the rate in the same age cohort in Australia [1992-1996, 187.5/100,000]32, Canada [1992, 170/100,000]21, and the USA [1992-1996, 198.6/100,000]33. Furthermore, the Singapore Breast Screening Project has confirmed that the mammographic cancer detection rate for local women is the same as is seen in Western programmes5.

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There is great variation in recommendations for mammographic screening for women aged 40-49. Guidelines from expert panels on breast screening for normal risk women in this age group vary from annual mammography at one extreme (US, American Cancer Society 34) to no mammography at all at the other (New Zealand, Royal New Zealand College of General Practitioners 35). The use of pooled subgroup analysis does not have the same weight of evidence as a meta-analysis of RCTs specifically investigating this subgroup. Therefore, recommendations for Singapore are based on a balance between the US guidelines and the relatively high incidence of breast cancer for Singaporean women in this age group, while taking into account the weaker evidence, higher costs and higher false positive rate of detecting breast cancer in this age group using screening mammography. 10.3.2 Mammography for normal risk, asymptomatic women Based on this discussion and review, a number of recommendations can be made about screening mammography. • Asymptomatic women 50-64 years

A All normal risk, asymptomatic women 50-64 years of age should be screened with mammography only, every two years. Ultrasound and breast examination are not routinely required.

Grade A, Level Ia • Asymptomatic women >65 years

A In Western nations, the evidence supports mammographic screening every 2 years for all normal risk women 65-75 years of age. However, for Singaporean women the much lower incidence of breast cancer in this age group suggests that screening mammography may be less beneficial. If individual screening is performed, it should be at two-yearly intervals. Ultrasound and breast examination are not routinely required.

Grade A, Level Ia

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• Asymptomatic women 40-49 years

C Women at normal risk aged 40-49 should be encouraged to have annual screening mammography. Ultrasound and breast examination are not routinely required.

Grade C, Level IV

• Asymptomatic women <40 years

There is no evidence that women under the age of 40 with no risk factors for developing breast cancer will derive any mortality benefit from screening mammography or any other imaging test, even if they occasionally detect an early breast cancer. A Normal risk, asymptomatic women under 40 should not undergo breast screening with any imaging modality.

Grade A, Level Ib

• Women on hormone replacement therapy

It is now accepted that there is a small but definite increase in risk of breast cancer with increasing use of hormone replacement therapy (HRT), resulting in a net increase in breast cancer of 0.2% at 5 years, 0.6% at 10 years and 1.2% at 15 years of continuous HRT. This very small absolute increase in risk appears to disappear within 5 years of ceasing HRT36. There is no evidence that this slight increase in breast cancer increases patient mortality.

It is reasonable to perform screening mammography regularly for these women. There is no evidence that mammography is significantly less effective in these women, though HRT does increase the amount and degree of mammographic glandular density. No RCT of screening mammography in these women has been performed, and there is no consensus about the ideal screening interval. However, there is definitely no evidence that these women should have more frequent screening than women of the same age who do not receive HRT.

C Women on conventional HRT have a very slightly increased risk of breast cancer. They should have regular screening mammography. Those aged 40-49 should be screened annually,

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and those aged 50-65 biannually, for up to 5 years after cessation of HRT.

Grade C, Level IV 10.3.3 Women at increased risk of breast cancer

• BRCA gene carriers & strong family history

These women, and women with very strong first-degree family histories of breast and/or ovarian cancer have a 5-10 times increased risk of breast cancer (0.5-1% per year) than women without these risk factors. In addition, they frequently have their cancers diagnosed before the age of 40. In most respects, they fall outside the normal guidelines for routine breast screening.

There have been no RCTs of screening in these women, mainly for logistic reasons. Only one prospective non-randomised study has been reported to date, comparing the use of mammography, ultrasound (US) and clinical breast examination (CBE) to magnetic resonance imaging (MRI)37. While breast MRI was shown to be more sensitive and specific for early cancer detection, the cost of detection for each cancer is very high, and there is currently no evidence that this confers any mortality benefit.

Breast self-examination (BSE) has been shown to be of no value in reducing mortality from breast cancer in a very large scale randomised trial38. Its use should be recognised as being of value mainly in increasing an individual woman’s awareness of the normal feel of her own breasts at various times in the menstrual cycle.

From these considerations, any recommendations for this group of women are based on best practice and limited published data.

C Women who are at very high risk of breast cancer by virtue of being a BRCA gene carrier, or a very strong first-degree family history of breast cancer, should perform monthly BSE, 6-monthly CBE and US, and annual mammography. Screening should start as early as 5 years before the age of onset of breast cancer in the youngest family member. Breast MRI should be considered, but

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only if cost is not problematic and the expertise and equipment for MRI-guided breast needle biopsy and localisation are available.

Grade C, Level IV

10.4 Screening with other tests

The paradox of mammography is that while it is excellent at detecting very early breast cancer, sometimes large palpable tumours are simply not visible, particularly in dense breast tissue. This has led to recommendations that screening include CBE, BSE, US, scintimammography, breast MRI, and other tests as an adjunct to mammographic screening. US, MRI and scintimammography have all been subjected to small clinical studies, but none of these have been RCTs or had mortality used as an outcome measure. These tests are discussed in detail below. 10.4.1 Clinical breast examination (CBE)

The New York Health Insurance Plan trial39 and the Canadian National Breast Screening trials27,40 included clinical breast examination (CBE) in their studies. Both failed to show any benefit from clinical breast examination. A CBE has been proven to confer no mortality benefit in a screening population.

Grade A, Level Ib

10.4.2 Breast self-examination (BSE)

Breast self-examination (BSE) has been studied in a high quality large-scale RCT as a screening test for breast cancer in Chinese women38. This trial showed no mortality benefit from BSE when used for screening. Nevertheless, its widespread availability, low cost, continuous nature and lack of proven harm argue for its continued use largely because it is felt to improve women’s awareness of their own breasts and breast cancer in general. In Singapore, the breast cancer incidence starts to rise significantly only for women over the age of 30. It can be argued that routine BSE for Singapore women should start after 30 if it is to be used at all.

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GPP Despite evidence that it has no survival benefits, BSE is generally recommended as it is felt to improve women’s awareness of their own breasts and breast cancer. As the incidence of breast cancer is extremely low before the age of 30, BSE is only recommended from the age of 30 for normal risk women.

GPP 10.4.3 Breast ultrasound (US) and breast magnetic resonance imaging (MRI)

The addition of routine US does appear to increase the detection of cancers in women with mammographically dense breasts slightly at the cost of a high proportion of negative diagnostic biopsies41. However, there is no evidence that this application of US reduces breast cancer mortality.

It has been argued that if US can detect additional cancers, then it should be routinely used for screening, particularly if the patient is paying herself. However, it is difficult to know where to stop. For example, MRI is proven to be more sensitive and specific for invasive breast malignancy than either ultrasound or mammography42. In prospective screening studies of women with a very high risk of breast cancer, MRI may be the only modality to detect a breast cancer37,43.

Using the same logic as is sometimes used to advocate screening US, it could then be argued that MRI should be used to routinely screen for breast cancer instead. However, it must be remembered that both tests are associated with an increase in false-positive needle biopsies. The addition of either test on a routine basis definitely increases the cost of cancer detection40,42, with no proven impact on survival. Ultimately, adding any test routinely to screening mammography adds cost and potential morbidity with no survival benefit. Using a test such as an US simply because it is cheaper and more widely available than breast MRI is not scientifically valid.

B Breast US and MRI can both detect cancers that are occult on mammography. However, they should not be used for routine breast screening outside of clinical trials.

Grade B, Level IIa

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10.4.4 Nuclear scintimammography

Certain radioactive tracers have been able to detect mammographically occult breast cancers using nuclear medicine gamma cameras. This procedure has been termed scintimammography. In particular, the tracers Tc99m-sesta-MIBI and Tc99m-Tetrofosmin, both developed for cardiac nuclear scanning, have been reported to detect breast cancers with a high sensitivity and specificity when compared to mammography44,45. However, scintimammography achieves best results if combined with mammography46, and has no significant advantage over breast MRI47. A major disadvantage of scintimammography is its poor anatomic localisation and inability to guide needle biopsy procedures. There have been no prospective RCTs of scintimammography for early breast cancer detection, and there is no mortality data.

B Nuclear scintimammography shows promise as an adjunct technique for detection of breast cancer in limited circumstances, usually in conjunction with mammography. Its use for breast screening is unwarranted.

Grade B, Level III

10.4.5 Thermography and electrical impedance scanning

Thermography can detect invasive breast cancers on the basis of increased blood flow due to tumour angiogenesis. This technique has been shown to be insensitive and inaccurate as a screening tool for breast cancer48. However, recent technical advances have led to re-exploration of this technology as a method of breast cancer detection. In small uncontrolled studies, thermography has been shown to detect invasive breast cancers though either with limited sensitivity and accuracy49,50, or else with a very high false positive rate51. However, it is unproven for detection of ductal carcinoma in situ, and has not been studied in any RCT.

Electrical impedance scanning has been recently developed as an investigational technique for suspected breast cancer. Claims for increased tissue specificity when a focal lesion is found have been made, but not subjected to RCT. Recent reports suggest that there is

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only moderate sensitivity for breast cancer and tissue classification52,53. No studies have been performed using this technology for screening.

C Thermography and Electrical Impedance Scanning must be regarded as investigational techniques. Their use for breast screening is not warranted.

Grade C, Level IV 10.5 Other situations

10.5.1 Women with prior breast cancer

Women with prior breast cancer have an increased risk of tumour recurrence locally, metachronously in the opposite breast, or distant metastatic disease. It is well-established that local chest wall recurrence after mastectomy or ipsilateral breast recurrence after excision and radiotherapy does not affect survival. It is unclear whether a second contralateral cancer has any effect on survival.

It is common practice to recommend annual mammography of the remnant breast on the ipsilateral side (if breast conservation has been performed) and the contralateral breast, with US added if necessary. However, there is no good evidence to support this practice. A recent study of local recurrence rates after breast conserving surgery and radiotherapy showed extremely low recurrence rates at 12 months, even for women at high risk of local recurrence, and recommended biannual surveillance screening for women who have had breast conservation54. However, this is not yet widespread standard practice.

For the first few years after diagnosis, women are considered to be under surveillance. The American Society of Clinical Oncology recommends monthly BSE, at least 6-monthly CBE, and annual mammography of the remnant and contralateral breast55. After 5 years disease-free, women can be usually allocated to a routine screening group. This practice is entirely empirical.

GPP Women with prior breast cancer should receive annual screening mammography of the remnant and contralateral breasts. At 5 years disease-free post-surgery, they may return to the standard screening interval for asymptomatic women of the same age.

GPP

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10.5.2 Women with breast implants

There is no evidence that women with breast implants have increased risk of breast cancer compared to age-matched women56. In fact, epidemiological studies have suggested a reduced risk of breast cancer in women with silicone implants57,58 though these findings do not reach statistical significance, and no RCT has been conducted to address this question. While screening mammography is more challenging in these women as more views must be performed in order to visualise the breast tissue adequately, there is also no evidence that it increases the risk of implant rupture or subsequent breast cancer if correctly performed. These women should be screened on the same basis as normal risk, asymptomatic women.

A Women with breast implants are recommended to have routine screening mammography once every 1-2 years, depending on their age.

Grade A, Level Ia

10.5.3 Women with silicone breast injections

Women with freely injected silicone oil in the breast tissues are not uncommon in Asia. The silicone oil acts to prevent accurate detection of breast cancer using any available method. Radiographically, the oil is extremely dense, thus, obscuring all mammographic detail. Ultrasonically, the oil combines with breast tissue to produce dense shadowing from virtually all the breast parenchyma, again obscuring visualisation. Clinically, the oil results in reactive foreign body granulomas which cause marked hardening and produce multiple breast lumps, making clinical evaluation impossible. In addition, silicone granulomas may cause false-positive enhancement on breast MRI. This makes this test less useful. However, there have been case reports of breast cancer in such women detected using MRI59.

GPP When encountered, women with free silicone or paraffin oil injections in their breasts should be clinically examined and counselled as to the futility of screening using any currently available test. MRI may be useful in highly selected cases where there is a strong suspicion of breast cancer.

GPP

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10.6 Summary

There is strong evidence that mammographic screening once every 2 years is beneficial for women at normal risk of breast cancer over the age of 50, and there is some evidence to support annual screening mammography for women from 40-49. HRT adds only slightly to the risk of developing breast cancer, and does not warrant more frequent mammographic screening than for other women of similar age. Other imaging technologies are not recommended for screening. BSE and CBE do NOT affect survival but is recommended from age 30 as it increases awareness of breast disease. Screening in very high risk women, and the protocol used, remains empirical.

References 1. Chia KS, Seow A, Lee HP, et al.. Cancer Incidence on Singapore 1993-

1997. Singapore Cancer Registry Report No. 5: 2000. 2. Australian Institute of Health and Welfare. Breast cancer in Australian

women 1982–1996 (AIHW Cancer Series). Australasian Association of Cancer Registries & NHMRC National Breast Cancer Centre, Canberra, 1999.

3. Mann GB, Borgen PI. Breast cancer genes and the surgeon. J Surg Oncol

1998; 67:267-74. 4. Vahteristo P, Eerola H, Tamminen A, et al. A probability model for

predicting BRCA1 and BRCA2 mutations in breast and breast-ovarian cancer families. Br J Cancer 2001; 84:704-8.

5. Chia KS, Lee JJM, Wong JLL, et al. Cancer Incidence in Singapore, 1998

to 1999. Ann Acad Med Singapore 2002; 31:745-50. 6. Ng EH, Ng FC, Tan PH, et al. Results of intermediate measures from a

population-based, randomized trial of mammographic screening prevalence and detection of breast carcinoma among Asian women: the Singapore Breast Screening Project Cancer 1998; 82:1521-8.

7. Yankaskas BC, Cleveland RJ, Schell MJ, et al. Association of recall rates

with sensitivity and positive predictive values of screening mammography. AJR Am J Roentgenol 2001; 177:543-9.

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8. Laming D, Warren R. Improving the detection of cancer in the screening

of mammograms. J Med Screen 2000; 7:24-30. 9. Denton ER, Field S. Just how valuable is double reporting in screening

mammography? Clin Radiol 1997; 52:466-8. 10. Blanks RG, Wallis MG, Moss SM. A comparison of cancer detection

rates achieved by breast cancer screening programmes by number of readers, for one and two view mammography: results from the UK National Health Service breast screening programme. J Med Screen 1998; 5:195-201.

11. Thurfjell E. Mammography screening methods and diagnostic results.

Acta Radiol Suppl 1995; 395:1-22. 12. Gao F, Chia KS, Ng FC, et al. Interval cancers following breast cancer

screening in Singaporean women. Int J Cancer 2002; 101:475-9. 13. Everington D, Gilbert FJ, Tyack C, et al. The Scottish breast screening

programme's experience of monitoring interval cancers. J Med Screen 1999; 6:21-7.

14. Fielder H, Rogers C, Gower-Thomas K, et al. Results from 10 years of

breast screening in Wales. J Med Screen 2001; 8:21-3. 15. Fracheboud J, de Koning HJ, Beemsterboer PM, et al. Interval cancers in

the Dutch breast cancer screening programme. Br J Cancer 1999;81:912-7. 16. de Rijke JM, Schouten LJ, Schreutelkamp JL, et al. A blind review and

an informed review of interval breast cancer cases in the Limburg screening programme, the Netherlands. J Med Screen 2000; 7:19-23.

17. Tabar L, Vitak B, Chen HH, et al. Update of the Swedish Two-County

Trial of breast cancer screening: histologic grade-specific and age-specific results. Swiss Surg 1999; 5:199-204.

18. Garne JP, Aspegren K, Balldin G, et al. Increasing incidence of and

declining mortality from breast carcinoma. Trends in Malmo, Sweden, 1961-1992. Cancer 1997; 79:69-74.

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19. Larsson LG, Nystrom L, Wall S, et al. The Swedish randomised

mammography screening trials: analysis of their effect on the breast cancer related excess mortality. J Med Screen 1996; 3:129-32.

20. Nystrom L, Larsson LG, Wall S, et al. An overview of the Swedish

randomised mammography trials: total mortality pattern and the representivity of the study cohorts. J Med Screen 1996; 3:85-7.

21. Gaudette LA, Silberberger C, Altmayer CA, et al. Trends in breast cancer

incidence and mortality. Health Rep 1996; 8:29-37(Eng); 31-40(Fre). 22. Hermon C, Beral V. Breast cancer mortality rates are levelling off or

beginning to decline in many western countries: analysis of time trends, age-cohort and age-period models of breast cancer mortality in 20 countries. Br J Cancer 1996; 73: 955-60.

23. Gotzsche PC, Olsen O. Is screening for breast cancer with mammography

justifiable? Lancet 200; 355:129-34. 24. Olsen O, Gotzsche PC. Cochrane review on screening for breast cancer

with mammography. Lancet 2001; 358:1340-2. 25. Nystrom L, Andersson I, Bjurstam N, et al. Long-term effects of

mammography screening: updated overview of the Swedish randomised trials. Lancet 2002; 359:909-19.

26. Bjurstam N, Bjorneld L, Duffy SW, et al. The Gothenburg breast

screening trial: first results on mortality, incidence, and mode of detection for women ages 39-49 years at randomization. Cancer 1997; 80:2091-9.

27. Miller AB, Baines CJ, To T, et al. Canadian National Breast Screening

Study: 1. Breast cancer detection and death rates among women aged 40 to 49 years. Can Med Assoc J 1992; 147:1459-76.

28. Tabar L, Fagerberg G, Chen HH, et al. Efficacy of breast cancer

screening by age. New results from the Swedish Two-County Trial. Cancer 1995; 75:2507-17.

29. Kopans DB. Chapter 4: Screening for Breast Cancer in Breast imaging.

Lippincott-Raven, Philadelphia; 1998:55-100.

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30. Larsson LG, Andersson I, Bjurstam N, et al. Updated overview of the

Swedish Randomized Trials on Breast Cancer Screening with Mammography: age group 40-49 at randomization. J Natl Cancer Inst Monogr 1997; 22:57-61.

31. Jansen JT, Zoetelief J. Assessment of lifetime gained as a result of

mammographic breast cancer screening using a computer model. Br J Radiol 1997; 70:619-28.

32. Kricker A, Jelfs P. Breast cancer in Australian women 1921-1994.

Commonwealth of Australia, 1996; Vol 2003. 33. Cancer Statistics. National Cancer Institute Surveillance, Epidemiology

and End-Results, 2003; Vol 2003.

34. Leitch AM, Dodd GD. American Cancer Society guidelines for the early detection of breast cancer: update 1997. CA Cancer J Clin 1997; 47: 150-3.

35. Royal New Zealand College of General Practitioners. Early detection of breast cancer. 1999. Royal New Zealand College of General Practitioners, Wellington, New Zealand.

36. Collaborative Group on Hormonal Factors in Breast Cancer. Breast

cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997; 350:1047-59.

37. Kuhl, CK, Schmutzler RK, Leutner CC, et al. Breast MR imaging

screening in 192 women proved or suspected to be carriers of a breast cancer susceptibility gene: preliminary results. Radiology 2000; 215:267-79.

38. Thomas DB, Gao DL, Ray RM, et al. Randomized trial of breast self-

examination in Shanghai: final results. J Natl Cancer Inst 2002; 94:1445-57.

39. Shapiro S, Venet W, Strax P, Venet L. Periodic Screening for Breast

Cancer: The Health Insurance Plan Project and its Sequelae, 1963-1986. Johns Hopkins University Press, Baltimore, 1988.

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40 Miller AB, Baines CJ, To T, et al. Canadian National Breast Screening

Study: 2. Breast cancer detection and death rates among women aged 50 to 59 years. Can Med Assoc J 1992; 147:1477-88.

41 Kaplan SS. Clinical utility of bilateral whole-breast US in the evaluation

of women with dense breast tissue. Radiology 2001; 221:641-9. 42. Davis PL, McCarty KS, Jr. Sensitivity of enhanced MRI for the detection

of breast cancer: new, multicentric, residual, and recurrent. Eur Radiol 1997; 7:289-98.

43. Tilanus-Linthorst MM, Obdeijn IM, Bartels KC, et al. First experiences

in screening women at high risk for breast cancer with MR imaging. Breast Cancer Res Treat 2000; 63:53-60.

44. Polan RL, Klein BD, Richman RH. Scintimammography in patients with

minimal mammographic or clinical findings. Radiographics 2001; 21:641-53; discussion 653-5.

45. Lumachi F, Ferretti G, Povolato M. et al. Sestamibi scintimammography

in pT1 breast cancer: alternative or complementary to X-ray mammography? Anticancer Res 2001; 21:2201-5.

46. Buscombe JR, Cwikla JB, Holloway B, et al. Prediction of the usefulness

of combined mammography and scintimammography in suspected primary breast cancer using ROC curves. J Nucl Med 2001; 42:3-8.

47. Imbriaco M, Del Vecchio S, Riccardi A, et al. Scintimammography with

99mTc-MIBI versus dynamic MRI for non-invasive characterization of breast masses. Eur J Nucl Med 2001; 28:56-63.

48. Williams KL, Phillips BH, Jones PA, et al. Thermography in screening

for breast cancer. J Epidemiol Community Health 1990; 44:112-3. 49. Ng EY, Fok SC, Peh YC, et al. Computerized detection of breast cancer

with artificial intelligence and thermograms. J Med Eng Technol 2002; 26:152-7.

50. Negri S, Bonetti F, Capitanio A, et al. Preoperative diagnostic accuracy

of fine-needle aspiration in the management of breast lesions: comparison of specificity and sensitivity with clinical examination, mammography,

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echography, and thermography in 249 patients. Diagn Cytopathol 1994; 11:4-8.

51. Parisky YR, Sardi A, Hamm R. et al. Efficacy of computerized infrared

imaging analysis to evaluate mammographically suspicious lesions. AJR Am J Roentgenol 2003; 180:263-9.

52. Martin G, Martin R, Brieva MJ, et al. Electrical impedance scanning in

breast cancer imaging: correlation with mammographic and histologic diagnosis. Eur Radiol 2002; 12:1471-8.

53. Melloul M. Paz A, Ohana G, et al. Double-phase 99mTc-sestamibi

scintimammography and trans-scan in diagnosing breast cancer. J Nucl Med 1999; 40:376-80.

54. Weight SC, Windle R, Stotter AT. Optimizing surveillance

mammography following breast conservation surgery. Eur J Surg Oncol 2002; 28:11-3.

55. Smith TJ, Davidson NE, Schapira DV, et al.. American Society of

Clinical Oncology 1998 update of recommended breast cancer surveillance guidelines. J Clin Oncol 1999; 17, 1080-2.

56. Petit JY, Le M, Rietjens M, et al. Does long-term exposure to gel-filled

silicone implants increase the risk of relapse after breast cancer? Tumori 1998; 84:525-8.

57. Kern KA, Flannery JT, Kuehn PG. Carcinogenic potential of silicone

breast implants: a Connecticut statewide study. Plast Reconstr Surg 1997; 100:737-47; discussion 748-9.

58. Deapen DM, Bernstein L, Brody GS. Are breast implants

anticarcinogenic? A 14-year follow-up of the Los Angeles Study. Plast Reconstr Surg 1997; 99:1346-53.

59. Peng HL, Wu CC, Choi WM, et al. Breast cancer detection using

magnetic resonance imaging in breasts injected with liquid silicone. Plast Reconstr Surg 1999; 104:2116-20.

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94

11 Screening for cervical cancer 11.1 Introduction

Cervical cancer is the 4th most common cancer among Singapore women1. The age-standardized incidence rate has been gradually declining from 18 per 100,000 population per year (1968–1972) to 14.2 per 100,000 population per year (1993-1997). The age-standardized mortality rate for cervical cancer is 6.1 per 100,000 population per year (1993-1997).

11.2 Definition

The peak incidence of cervical intraepithelial neoplasia (CIN) 3 in Singapore is between 35-39 years of age1. Only a very small number of women aged 15-19 (1.25%) have significant CIN. Women between 20-25 years of age make up 7.7% of the total number with CIN 3. The following groups are considered to be at higher risk for cervical cancer: • Human Immunodeficiency Virus positive women2 • Cigarette smoking3 • Immunosuppression4 • Infection with oncogenic Human Papillomavirus5 • History of sexually transmitted infections6 • Multiple sexual partners (either partner)7, 8 • Onset of sexual intercourse at an early age9 The following groups are considered to be at low risk for cervical cancer: • Women who have had a hysterectomy in which the cervix was

removed unless the hysterectomy was performed because of cervical cancer or its precursors10-14

• Women who have never had sexual intercourse15,16 Therefore all women who had ever had sexual intercourse are advised to have their first Pap smear by the age of 25 years.

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The Papanicolaou or Pap smear fulfils many of the WHO recommendations for a screening test. Cervical cancer is firstly an important public health problem. There is accepted treatment for patients with preinvasive disease (CIN) of the cervix. The Pap smear is a suitable test to pick up CIN of the cervix, and it is an acceptable test to the public. The natural history of CIN and cervical cancer and its development from the preinvasive to the invasive disease is well-documented17. The Pap smear is a cheap and a cost-effective test. B A well-run population-based cervical cancer screening programme with good coverage reduces the incidence and mortality of cervical cancer18,19.

Grade B, Level IIa

In a meta-analysis, the mean sensitivity of the Pap smear as a screening test was 58% while the mean specificity was 69%20.

11.4 Age and gender for screening

B All women who have ever had sexual intercourse are advised to have their first Pap smear by the age of 25 years1.

Grade B, Level III

B A woman can be discharged from screening at 65 years of age if the smear taken at 65 years is negative and the previous smears were negative21.

Grade B, Level III

However, women who have had sexual intercourse but have never had a Pap smear should still undergo screening irrespective of age.


B Pap smear screening should be performed every 3 years22. Grade B, Level IIa

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Women who have never had sexual intercourse need not have Pap smear screening15,16. However if these women have any symptoms, they should consult a doctor.

B There is evidence to show that HIV positive women should be screened earlier and more frequently2, preferably annually.

Grade B, Level III The adequacy of Pap smears depends on the presence of cells from both the ectocervix and endocervix.

11.7 Summary

It is well established that cervical cancer incidence and mortality can be reduced with regular Pap smear screening performed every 3 years.

References 1.

2.

3.

4.

5.

Chia KS, Seow A, Lee HP, et al. Cancer Incidence in Singapore 1993-1997. Singapore Cancer Registry Report No. 5, 2000.

Abercrombie PD, Korn AP. Lower genital tract neoplasia in women with HIV infection. Oncology 1998; 12:1735-9.

Brinton LA, Schairer C, Haenszel W, et al. Cigarette smoking and invasive cervical cancer. JAMA 1986; 255; 3265-9.

Fraumeni JF, Hoover R. Immunosurveillance and cancer : Epidemiological observations. In : Epidemiology and Cancer Registries in the Pacific Basin, Natural Cancer Institute Monograph 1977; No. 47, pp 121-6.

Campion MJ. Human papillomavirus and anogenital neoplasia. In : Munoz N, Bosch FX, Jensen OM (eds). Human papillomavirus and cervical cancer. IARC Scientific Publications 1989; No. 94, International Agency for Research on Cancer ; Lyon, pp 41-65.

97

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

Levin ML, Kress LC, Goldstein H. Syphilis and cancer. New York State J Med 1942; 41:1737.

Brinton LA, Hamman RF, Huggins GR, et al. Sexual and reproductive risk factors for invasive squamous cell cervical cancer. J Natl Cancer Inst 1987; 79:23.

Buckley JD, Doll R, Harris RWC, et al. Case-control study of husbands of women with dysplasia or carcinoma of the cervix uteri. Lancet 1981; ii:1010.

La Vecchia C, Franceschi S, Decarli A, et al. Sexual factors, venereal diseases and the risk of intraepithelial and invasive cervical neoplasia. Cancer 1986; 58:935.

Fetters MD, Fischer G, Reed BD. Effectiveness of vaginal Papanicolaou smear screening after total hysterectomy for benign disease. JAMA 1996; 275:940-7.

Miller JM, Chambers DC, Miller JM. The need for Pap tests after hysterectomy for benign disease. Results of a study of black patients. Postgrad Med 1987; 82:200-2, 205.

Piscitelli JT, Bastian LA, Wilkes A, et al. Cytologic screening after hysterectomy for benign disease. Am J Obstet Gynecol 1995; 173:424-30.

Roman LD, Morris M, Eifel PJ, et al. Reasons for inappropriate simple hysterectomy in the presence of invasive cancer of the cervix. Obstet Gynecol 1992; 79:485-9.

Chen RJ, Chang DY, Yen ML, et al. Independent clinical factors which correlate with failures in diagnosing early cervical cancer. Gynecol Oncol 1995; 58:356-61.

Kjaer SK, Chackerian B, Van Den Brule AJ, et al. High-risk human papillomavirus is sexually transmitted : Evidence from a follow-up study of virgins starting sexual activity (intercourse). Cancer Epidemiol Biomarkers Prev 2001; 10:101-6.

Broso PR. The age for beginning and the frequency for performing the Pap test. Minerva Ginecol 1994; 46:565-9.

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17.

18.

19.

20.

21.

22.

McIndoe WA, McLean MR, Jones RW, et al. The invasive potential of carcinoma in situ of the cervix. Obstet Gynecol 1984; 64:451-8.

Anderson GH, Boyes DA, Benedet JL, et al. Organisation and results of the cervical cytology screening programme in British Columbia, 1995-85. BMJ 1988;296:975-8.

Laara E, Day NE, Hakama M. Trends in mortality from cervical cancer in the Nordic countries : association with organized screening programmes. Lancet 1987; 1:1247-9.

Fahey MT, Irwig L, Macaskill P. Meta-analysis of Pap test accuracy. Am J Epidemiol 1995; 141:680-9.

Eddy DM. Screening for cervical cancer. Ann Intern Med 1990; 113:214-26.

IARC Working Group on evaluation of cervical cancer screening programmes. Screening for squamous cervical cancer: duration of low risk after negative results of cervical cytology and its implication for screening policies. Br Med J (Clin Res Ed) 1986; 293:659-64.

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12 Screening for uterine cancer 12.1 Introduction

Uterine cancer is the 8th most common cancer among Singapore women1. In Singapore the disease has shown an increase over time, from an age-standardized incidence rate of 4.8 per 100,000 population in 1968-1972, to 8.2 per 100,000 population in 1993-97.

12.2 Definition2

Average Risk Women with no identified risk factors

Increased Risk

History of unopposed estrogen therapy Late menopause Tamoxifen therapy Nulliparity Infertility or failure to ovulate Obesity Diabetes Hypertension

High Risk Women with or at risk of hereditary non-polyposis colorectal cancer (HNPCC)

12.3 Screening tests and effectiveness

B There is insufficient evidence to establish whether a decrease in mortality from endometrial cancer occurs with screening by endometrial sampling or transvaginal ultrasound3, 4.

Grade B, Level IIb

C Although the diagnosis of endometrial cancer occasionally originates with an abnormal Pap test of cytological material from the uterine cervix, this method has been evaluated and found to be insensitive for endometrial screening5.

Grade C, Level IV

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B There is no indication that screening is warranted for women who are at average or increased risk for endometrial cancer4,5.

Grade B, Level IIb

C Hereditary Non-Polyposis Colorectal Cancer is a syndrome in which there is an inherited tendency to develop colorectal cancer. Women with or at risk for hereditary non-polyposis colorectal cancer (HNPCC-Appendix 1)6 are considered high risk and should be offered annual screening for endometrial cancer with endometrial biopsy by age 35.

Grade C, Level IV

Women in this high-risk group should be informed about the risks and symptoms of endometrial cancer, and should be informed about potential benefits, risks, and limitations of testing for early endometrial cancer2, preferably by tertiary centres.


Although screening is inappropriate for the general population, a strategy of early evaluation of postmenopausal bleeding with judicious use of hysteroscopy and endometrial biopsy is important for the early detection of endometrial cancer7.

12.5 Summary

There is currently insufficient evidence to screen for uterine cancers other than in women with or at high risk for hereditary non-polyposis colorectal cancer.

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Appendix 1. International Collaborative Group Clinical Criteria for Diagnosing HNPCC (Amsterdam II)6

1) There should be at least 3 relatives with an HNPCC-associated cancer

(cancer of colorectum [CRC], endometrium, small bowel, ureter or renal pelvis).

2) One relative should be a first degree relative of the other two. 3) At least two successive generations should be affected. 4) At least one case should have been diagnosed before age 50 years. 5) Familial adenomatous polyposis should be excluded in the CRC case(s) if

any.

References 1. Chia KS, Seow A, Lee HP, et al. Cancer Incidence in Singapore 1993-

1997. Singapore Cancer Registry Report No. 5, 2000. 2. American Cancer Society guidelines on testing for early endometrial

cancer detection - update 2001. In: American Cancer Society guidelines for the early detection of cancer. Cancer J Clin 2001; 51:54-9.

3. Pritchard KI. Screening for endometrial cancer: is it effective? Ann Int

Med 1989; 110: 177-9. 4. Eddy D. ACS Report on the cancer-related health checkup. CA: Cancer J

Clin 1980; 30:193-240. 5. Burke JR, Lehman HF, Wolf FS. Inadequacy of papanicolaou smears in

the detection of endometrial carcinoma. N Eng J Med 1974; 291:191-2. 6. Vasen HF, Watson P, Mecklin JP, et al. New clinical criteria for

hereditary nonpolyposis colorectal cancer (HNPCC) syndrome proposed by the International Collaborative group on HNPCC. Gastro-enterology 1999; 116:1453–6.

7. Menon U, Jacobs IJ. Tumor markers and screening. In : Berek JS, Hacker

NF (eds). Practical Gynecologic Oncology. Philadelphia : Lippincott Williams & Wilkins, 2000: 51.

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13 Screening for ovarian cancer 13.1 Introduction

Ovarian cancer is the 6th most common cancer among Singapore women1. The age-standardized incidence rate is 11.4 per 100,000 population per year (1993-1997). The age-standardized mortality rate of ovarian cancer is 4.3 per 100,000 population per year (1993-1997).

13.2 Definition

Average Risk Asymptomatic pre- and post-menopausal women2

High Risk Those with 2 or more first degree relatives with ovarian cancer and those with strong evidence of a hereditary predisposition for ovarian cancer2,3 (including women with or at high risk for hereditary breast-ovarian cancer and hereditary non-polyposis colorectal cancer)


Average Risk

Routine pelvic examination, ultrasound, transvaginal sonography (TVS), serum tumour antigens or combination have poor positive predictive value for early detection of ovarian carcinoma. The effectiveness of screening is unknown2, 4-10. B Routine population screening for ovarian cancer by ultrasound, the measurement of tumour markers, or pelvic examination is not recommended.

Grade B, Level IIa High Risk There is evidence of higher positive predictive value for detection, because of higher prevalence in this group but the effectiveness of screening is unknown2.

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These women should be referred to tertiary centres11 for annual multimodal screening with pelvic exam, TVS and Ca 125*3. However, there is no data demonstrating that screening this group of high risk women reduces their mortality from ovarian cancer3. GPP There is insufficient evidence to recommend for or against the screening of asymptomatic women at increased risk of developing ovarian cancer. Experts suggest referral of these women to tertiary centres for multimodal screening.

GPP

*The tumour-associated antigen, Ca 125, is a high molecular weight glycoprotein noted to be elevated in many ovarian cancers.

13.4 Summary

There is insufficient evidence to establish that routine screening for ovarian cancer with Ca 125, transvaginal ultrasound or pelvic examination in women at average risk is beneficial. Women at high risk for ovarian cancer should be referred to a tertiary centre.

References 1. Chia KS, Seow A, Lee HP, et al. Cancer Incidence in Singapore 1993-

1997. Singapore Cancer Registry Report No. 5, 2000. 2. Gladstone CQ. Screening for ovarian cancer. Canadian Task Force on

Preventive Health Care. Systematic reviews & recommendations. 1994; 870-81.

3. National Institutes of Health. Ovarian cancer: screening, treatment, and

follow-up. National Institutes of Health Consensus Conference Statement, 1994.

4. Van Nagell JR Jr, DePriest PD, Reedy MB, et al. The efficacy of

transvaginal sonographic screening in asymptomatic women at risk for ovarian cancer. Gynecol Oncol 2000; 77:350-6.

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5. Grover S, Quinn MA, Weideman P Koh H, et al. Screening for ovarian

cancer using serum Ca125 and vaginal examination: report on 2550 females. Int J Gynecol Cancer 1995; 5:291-5.

6. Einhorn N, Bast R, Knapp R, et al. Long-term follow-up of the

Stockholm Screening Study on ovarian cancer. Gynecologic Oncology 2000; 79:466-70.

7. DePriest PD, Gallion HH, Pavlik EJ, et al. Transvaginal sonography as a

screening method for the detection of early ovarian cancer. Gynecol Oncol 1997; 65:408-14.

8. Van NJ, Jr, Gallion HH, Pavlik EJ, et al. Ovarian cancer screening.

Cancer 1995; 76:2086-91. 9. Menon U, Jacobs I. Ovarian cancer screening in the general population.

Ultrasound Obstet Gynecol 2000; 15:350-3. 10. Woolf SH. Report of the US Preventative Services Task Force. Guide to

Clinical Preventive Services, Second Edition. Screening for ovarian cancer.

11. American College of Physicians. Screening for ovarian cancer. Ann Int

Med 1994; 121:141-2.

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108

14 Screening for tuberculosis

14.1 Introduction

There has been a world-wide resurgence of Tuberculosis (TB) in the last decade. The World Health Organisation declared TB a global emergency in 1993 based on estimates that every year, there would be about 8 million new TB cases and 2-3 million TB deaths world wide1. About one third of the world’s population (2 billion) are infected by the TB bacillus, and several tens of millions of these have been infected by the multi-drug resistant TB germ. Despite Singapore’s economic progress and improvements in living standards and health care, its TB incidence has remained high (49-56 per 100,000) in the decade from 1987 through 1997, being 5-10 times that of developed countries in the West2. It is likely that the rates have not declined because there is still significant ongoing transmission of TB in the community due to delays in diagnosis and treatment. Moreover, it is also likely that many patients are not adhering to and completing treatment, hence remaining infectious or being at high risk for disease relapse. The rates of HIV and TB drug resistance are low at present and the standard short course TB regimens are still effective2. The key priority of Singapore’s national control programme is therefore to reduce the infectious pool in the community by early diagnosis, and the prompt and complete treatment of all infectious cases. Appropriate contact screening plays an important, though secondary, role in the national programme3.

14.2 The Pathogenesis of TB

TB is spread primarily by tiny airborne particles (droplet nuclei) containing the tubercle bacillus or Mycobacterium tuberculosis expelled by a person who has infectious TB. If another person inhales these droplet nuclei, transmission may occur. Persons who are thus infected (but who do not have TB disease) are asymptomatic and are considered to have Latent TB Infection (LTBI). They may be identified by a positive tuberculin skin test. However, the test only becomes positive 4 to 12 weeks after infection. Because they do not have TB disease, persons with LTBI are not infectious to others.

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About 10% of recently infected persons will develop TB disease at some time in their lives, but the risk is highest in the first year or so following the acquisition of infection. Persons who are immunosuppressed, especially those with HIV infection are also more likely to develop active TB disease following infection. Even though TB is spread by the airborne route, it is far less infectious than the viral airborne illnesses such as chicken pox and measles. Whereas viral illnesses may be contracted during very short exposures (less than a few hours), TB transmission generally requires prolonged exposures (weeks of sharing air with an untreated infectious index case). Thus, as a rule, TB contact investigations are not performed on casual contacts of a TB case. Screening for LTBI may be performed in high risk groups. These include close contacts of an infectious TB case (Index case), persons with HIV infection, persons with certain medical conditions (diabetes mellitus, head and neck cancers, haematologic malignancies, chronic malabsorption, end-stage renal disease, and prolonged immunosuppressive therapy) and persons who use illicit intravenous drugs. In Singapore, priority has been accorded to the screening for LTBI in close contacts of an Index case.

14.3 Screening for LTBI with the Tuberculin Skin Test

(TST) for preventive treatment of infected contacts

TST screening for LTBI is recommended only for identifying candidates for treatment of latent TB infection (generally with isoniazid, INH). Therefore, it is recommended only in persons at high risk of breakdown to TB disease. Indiscriminate screening or erroneous selection of subjects could lead to the needless administration of INH and the unnecessary exposure of these subjects to the risk of hepatitis which in some cases can be fatal4. The administration and reading of the TST is very operator dependent5. Intra-observer and inter-observer variability is increased with untrained personnel, and personnel who do not perform the test on a regular basis. Both false positive and false negative readings can result from technical as well as biological factors. In the TB Control Unit, the Mantoux test is performed using the 1 TU RT-23 tuberculin

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from the Serum Statens Institute, Denmark according to a WHO recommendation6. Therefore contact investigations should be carefully performed by trained and experienced personnel, and always begin with an identified Index case. (In the absence of data around the Index case, it would therefore be impossible to perform meaningful contact investigations, as can be seen by the discussion below.) In assessing the probability of transmission, the investigator considers the infectiousness of the Index case, the susceptibility of the contact, the environment in which the exposure occurred, and the duration of exposure during the infectious episode. The key is to determine the infectiousness of the Index case and this is assessed by the site of TB disease (pulmonary, laryngeal), the presence of cavities on the chest radiograph, the bacteriological status (whether sputum smear or culture positive), and the presence and duration of cough7. Exposures of long duration (weeks rather than days) are given higher priority for testing. Closed environments, especially if poorly ventilated, are more likely to result in transmission. Also, recently infected contacts are much more likely to develop active TB disease than subjects infected in the remote past. To determine these factors, the TB Control Unit staff conduct the contact investigations which involve interviewing the Index case, interviewing the contacts, and not infrequently, performing a site visit (the workplace, home, prison or nursing home). The TST reaction is then interpreted in the light of the data obtained from the investigations. Contact investigations should not be equated with merely performing a TST and taking an arbitrary cut-off level as “positive”. Such results may occur in persons with Mycobacteria Other Than Tuberculosis (MOTT) infection, remote TB infection (without risk factors), or even previous BCG vaccination, none of whom should be given INH chemoprophylaxis as they would be needlessly exposed to the risk of drug-induced hepatitis. In Singapore, there is almost universal BCG vaccination at birth, and BCG re-vaccination of schoolchildren has been practised until recently8. Also, MOTT is prevalent in Singapore. These factors would confound the interpretation of the TST in our population. As shown in Table 4, when contact investigations have appropriately identified a high risk group, a positive TST may have a positive predictive value of 86% i.e. 9 of 10 contacts would be correctly

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prescribed preventive treatment. However, when indiscriminate TSTs are done in low risk groups, a positive TST may have a positive predictive value of only 50% or lower i.e. 5 of 10 persons thus identified may be needlessly exposed to the hepatotoxic effects of INH.

Table 4: Example for the Dependence of the Predictive Value of a Positive Test on the Prevalence

Example 1: Example 2:

90% Sensitivity 90% Sensitivity 90% Specificity 90% Specificity 40% Prevalence 10% Prevalence

Condition Condition

Test present absent total Test present absent totalpos 360 60 420 pos 90 90 180neg 40 540 580 neg 10 810 820tot 400 600 1000 tot 100 900 1000

Predictive value of a positive test: 360 / 420 = 86%

Predictive value of a positive test: 90 / 180 = 50%

Two situations with the same operating characteristics sensitivity and specificity) of the test, but a different prevalence of the condition in the population. In the first example, the prevalence is 40% in the population, thus 400 of these 1,000 people have the condition. Using the sensitivity shows that 90% of these 400, thus 360 people are correctly and 40 incorrectly identified as having the condition. Using specificity information shows that 90% of 600, thus 540 are correctly and 60 incorrectly identified as not having the condition. The predictive value of a positive test result in this situation is 86%. In other words, a positive test truly identifies about 9 out of 10 cases and in the 10th the test is wrong. In the second example, the prevalence is much lower. Using the same test with the same operating characteristics, a positive test is correct in only half of the cases: the test is virtually useless in this situation. Ref: www.tbrieder.org – Updated: 26-Jan-01.

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14.3.1 Health Care Workers (HCW) Contact investigation with TST screening is only done when there is an identified infectious Index case. The only exception to this rule is the screening of HCWs. Because HCWs are constantly exposed to untreated or even undiagnosed cases of infectious TB, it is often impossible to assign an episode of exposure. Therefore, HCWs form a special group of contacts who should be screened periodically (annually) with the TST if the initial TST is negative9. If the TST converts from negative to positive during annual screening, preventive treatment should be given.

14.3.2 A In summary, screening for latent TB infection with the Tuberculin Skin Test (TST) is recommended only for identifying candidates for treatment of latent TB infection (generally with INH). Therefore, it is recommended only in persons at high risk of breakdown to TB disease4.

Grade A, Level 1b Indiscriminate screening or erroneous selection of subjects could lead to the needless administration of INH and the unnecessary exposure of these subject to the risk of drug-induced hepatitis which in some cases may be fatal.

14.4 Screening for active TB disease with the chest X-ray

Because TB affects the lungs in >80% cases, it would be reasonable to assume that the chest X-ray (CXR) could be used as a tool to detect early pre-symptomatic TB disease. However, the yield is so low that mass X-ray screening is not recommended by TB experts10-12. Data from Singapore showed that of 10,598 screening CXRs done from October 1997 to November 1998, only 4 bacteriologically confirmed cases were detected, a yield of only 0.04%. The Ministry of Health stopped performing mass CXR screening on Oct 2001. It is much more cost effective to perform CXRs on patients who present with prolonged cough (>3 weeks). There are certain special circumstances when screening CXR may be beneficial:

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1. Before admission into long term residential facilities in

congregate settings, e.g. nursing homes, correctional facilities, it may be beneficial to perform a screening CXR to pick up active PTB because (a) entrants into such facilities may belong to groups at high risk of PTB; (b) an undetected and untreated case of PTB can infect many other persons because of the closeness of contacts in such congregate settings. (Note that even in such congregate settings annual CXR screening is not recommended.)

2. High risk TB infected persons who have been identified by

contact investigations for the treatment of LTBI must have CXRs done4. Here, the CXR is performed to exclude active TB disease before commencement of INH preventive treatment. This is to ensure that INH monotherapy is not inadvertently given to patients with TB disease, in which case the monotherapy would not only be ineffective but also dangerous as it would engender the development of drug-resistance.

B Therefore, as a rule, mass CXR screening for TB is not recommended13.

Grade B, Level III 14.5 Summary

Screening in TB Screening is possible for Latent TB Infection (LTBI) and Active TB Disease.

1.

2. Definition

Latent TB Infection (LTBI): A TST screening for latent TB infection is recommended only for identifying candidates for treatment of latent TB infection (generally with INH). Therefore, it is recommended only in persons at high risk of breakdown to TB disease.

Grade A, Level Ib Indiscriminate screening or erroneous selection of subjects could lead to the needless administration of INH and the unnecessary exposure of these subject to the risk of drug-induced hepatitis which in some cases maybe fatal.

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Active TB Disease: B As a rule, mass CXR screening for active TB is not recommended.

Grade B, Level III 3. Screening test and effectiveness

Latent TB Infection (LTBI): The TST only provides a better positive predictive value when high risk groups are screened. In Singapore, TST screening for LTBI is performed in carefully identified close contacts of infectious Index cases. Active TB Disease: CXR screening in asymptomatic subjects is not recommended as the yield is extremely low13.

4. Age and gender for screening

Latent TB Infection (LTBI): There is no age or gender restriction, once a high risk group is identified4. Active TB Disease: Mass CXR screening should not be performed regardless of age or gender.

5. Frequency of screening Latent TB Infection (LTBI): Contact screening investigations are performed only once around

an infectious Index case7. Repeat investigations are not indicated except in tuberculin–negative health care workers who are continually exposed to infectious TB cases.

Active TB Disease: Annual CXR screening is not recommended13.

References 1. Raviglione MC, Snider DE Jr, Kochi A. Global epidemiology of

tuberculosis. Mortality and Morbidity of a worldwide epidemic. JAMA 1995; 273:220-6.

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2. Singapore: Department of Clinical Epidemiology, Communicable

Disease Centre, Tan Tock Seng Hospital and Ministry of Health, Communicable Disease Surveillance Report 1997.

3. Chee CBE, Wang YT. Political Will - The Singapore Tuberculosis

Elimination Programme. In Tuberculosis: A Comprehensive International Approach. Reichman LB and Hershfield ES, editors. New York: Marcel Dekker; 2000; 727-44.

4. American Thoracic Society. Targetted Tuberculin Testing and

Treatment of latent tuberculous infection. Am. J. Respir Crit Care Med 2000; 161:S221-47.

5. Menzies RI. Tuberculin Skin Testing. In Reichman LB, Hershfield

ES, eds. Tuberculosis. A Comprehensive International Approach. 2nd edition. Marcel Dekker. 2000; 279-322.

6. World Health Organisation. The WHO standard tuberculin test.

WHO/TB/Techn. Guide/3:1-19. Geneva:World Health Organisation;1963.

7. Etkind SC, Veen J. Contact Follow-up in High-and low- prevalence

countries. In Reichman LB, Hershfield ES, eds. Tuberculosis. A Comprehensive International Approach. 2nd edition. Marcel Dekker 2000: 377-99.

8. Chee CBE, Soh CH, Boudville IC, Chor SS, Wang YT. Interpretation

of the Tuberculin skin test in Mycobacterium bovis BCG vaccinated Singaporean schoolchildren. Am J Respir Crit Care Med 2001; 164:958-61.

9. Blumberg HM. Tuberculosis infection control. In Reichman LB,

Hershfield ES, eds. Tuberculosis. A Comprehensive International Approach. 2ndedition. Marcel Dekker. 2000; 609-43.

10. ReichmanLB. Tuberculosis screening and chest X-ray films. Chest

1975; 68S:448-51. 11. Toman K. Mass Radiography in tuberculosis control. WHO Chron

1976; 30:51-7.

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12. Swallow J, Sbarbaro JA. Analysis of tuberculosis casefinding in

Denver, Colorado, 1965-70. Health Services Rep 1972; 87:375-84. 13. Reider H. Case finding in high- and low- prevalences countries. In

Reichman LB, Hershfield ES, eds. Tuberculosis. A Comprehensive International Approach. 2nd edition. Marcel Dekker 2000: 323-39.

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15 Screening for hepatitis B 15.1 Introduction

Hepatitis B Virus (HBV) infection is a common disorder in Singapore. In Singapore, about 6% of the population have chronic hepatitis B infection1. Chronic hepatitis B results from infection during the perinatal period and in early childhood. Most infections in the above age groups are sub-clinical and remain asymptomatic. They are detected in adulthood incidentally during blood donation, health screening or screening prior to vaccination.

HBV infection and its complications are major worldwide health problems. There are approximately 300 million people with chronic HBV infection in the world and more than half live in the Asia Pacific region. Twenty-five percent of those infected are at risk of serious illness and eventual death from cirrhosis and/or primary hepatocellular carcinoma (PHC)2.

In Singapore, hepatocellular carcinoma is one of the top 10 cancers affecting males in Singapore and Hepatitis B infection is the main etiological factor.

15.2 Definition

15.2.1 Chronic hepatitis B infection It is now accepted that the term Hepatitis B "carrier" be dropped as the term connotes a benign state. A person is considered to develop chronic hepatitis B infection if he fails to clear Hepatitis B surface antigen (HBsAg) within 6 months following an acute infection. In most patients, the clinical course of the chronic disease is mild and indolent until the late stages. However, the pattern of chronic HBV infection and its clinical outcome can be markedly variable. While some patients remain asymptomatic, others develop progressive liver disease leading to cirrhosis and primary hepatocellular carcinomas.

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The natural progression of neonatally and childhood acquired chronic HBV infection may be divided into three phases:-

(1) A high viral replicative (immune-tolerant) phase is usually

seen in patients younger than 20 years old. This phase is characterised by high titres of HBsAg, HBeAg, and serum HBV-DNA but relatively mild or even unrecognized clinical illnesses with normal aminotransferase levels (ALT/AST). Minimal or no liver damage is found on liver biopsies3.

(2) A low viral replicative (immune-elimination/clearance or 'e'

sero-conversion) phase occurs in subjects between the ages of 20 and 40 years. A clinical picture indistinguishable from that of acute hepatitis may be seen during this phase. Liver biopsy usually shows the presence of chronic hepatitis and/or active cirrhosis4.

(3) A non-replicative (latent infection) phase is usually seen in

patients aged about 40 years of age. HBsAg persists during this phase. There is now no serological or histological evidence of active HBV replication. Serum ALT/AST levels may become normal although histologic progression to cirrhosis and PHC may occur. About 1-2% of patients will lose their HBsAg and develop anti-HBs each year. About 40% of subjects with chronic HBV infection will develop cirrhosis at a rate of about 2% per year4.

15.3 Screening for hepatitis B infection 15.3.1 Accuracy of Screening Tests The principal screening test for detecting current (acute or chronic) HBV infection is the identification of HBsAg. Tests for HBsAg are 98% sensitive and specific for detecting chronic hepatitis B carrier5. Spontaneous clearance of HBsAg occurs each year in 1% of persons with chronic HBV infection.

15.3.2 Who to screen

A All pregnant women should be tested for HBsAg during the early antenatal visit. The test may be repeated in the third trimester if acute hepatitis is suspected, an exposure to hepatitis has occurred or the

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woman practices a high-risk behaviour such as intravenous drug abuse6,7.

Grade A, Level Ib

A Serological screening for HBsAg and anti-HBs should be performed pre-vaccination for all except newborns6,7.

Grade A, Level Ib A Persons who remain at risk of HBV infection such as health care workers and dialysis patients should be screened using HBsAg and anti-HBs and vaccinated against hepatitis B if the test is negative. Such individuals should then be tested for response to the vaccination8.

Grade A, Level Ib B Screening high risk individuals like those with a family history of hepatitis B infection, liver cancer or those at high behavioural risk should be performed. They should be tested at baseline and whenever exposure is suspected.

Grade B, Level IIa C Routine screening for HBV infection in the general population is not recommended but recommendations for screening may be made based on cost-effectiveness analyses. Such analyses suggest that screening can be cost-effective in groups with an HBV marker prevalence >20%9.

Grade C, Level IV

15.4 Summary

In practice, screening for chronic hepatitis B infection is recommended as part of the antenatal screening for all women. It is also recommended for individuals engaged in high-risk activities for acquiring hepatitis B infection. Screening for HBsAg and anti-HBs should be performed pre-vaccination for all except newborns. Screening for hepatitis B infection in our general population is not recommended as the prevalence of hepatitis B infection in Singapore is only 5-6%.

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References 1. Goh KT, Ding JL, Monteiro EH, et al. Hepatitis B infection in

households of acute cases. Journal of Epidemiology & Community Health. 1985; 39:123-8.

2. Wu G, Zhou Y, Zhao W, et al. Study on the natural history of chronic

hepatitis B.Chung Hua Kan Tsang Ping Tsa Chih. 2002; 10:46-8. 3. Lok ASF, Lai CL. A longitudinal follow-up of asymptomatic hepatitis B

surface antigen positive Chinese children. Hepatol 1998; 5:1130-3. 4. Chan HL, Ghany M, Lok ASF. Hepatitis B. In Schiff’s Disease of the

Liver, 8th edition. Ed. Schiff ER, Sorrell MF, Maddrey WC. Lippincott-Raven publishers. Philadelphia 1999.

5. McCreedy JA, Morens D, Fields HA, et al. Evaluation of enzyme

immunoassay (EIA) as a screening method for hepatitis B markers in an open population. Epidemiol Infect 1991; 107:673-84.

6. American Academy of Pediatrics and American College of Obstetricians

and Gynecologists. Guidelines for perinatal care. 3rd ed, Washington DC: American College of Obstetricians and Gynecologists. 1992.

7. American Academy of Pediatrics. Hepatitis B. In: Peter G. ed. 1994 Red

Book: Report of the Committee on Infectious Diseases. 23rd ed. Eik Grove Village. IL: American Academy of Pediatrics. 1994:224-38.

8. Lok ASF, McMahon BJ. Chronic Hepatitis B. Hepatology 2001;

34:1225-41. 9. American College of Physicians Task Force on Adult Immunization and

Infectious Diseases Society of America. Guide for adult immunization. 3rd ed. Philadelphia: American College of Physicians. 1994.

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16 Screening for renal diseases 16.1 Introduction

At the end of May 1997, there were 1968 patients on hemodialysis and another 340 on peritoneal dialysis in Singapore1. By December 2000, the prevalent dialysis population increased to 2830 patients with 2321 on hemodialysis and 509 on peritoneal dialysis2. The number of new patients with end stage renal disease (ESRD) in Singapore is about 650 patients a year and diabetes mellitus is the commonest cause accounting for 47% of cases, followed by chronic glomerulonephritis, which accounts for 29% and hypertensive nephrosclerosis accounting for 9%3. The incidence and prevalence of end stage renal disease are expected to increase unless urgent measures are taken to rectify this. In fact, it has been reported by the United States Renal Data System that Singapore has the third highest ESRD incidence rate in the world4. It is reasonable to believe that patients with end stage renal failure represent only a small fraction of all individuals with chronic renal disease. This is further compounded by the fact that chronic renal insufficiency is asymptomatic and mild renal disease may often go undiagnosed and untreated. In the United States, it has been shown that about 10% of men and a smaller proportion of women have mild renal insufficiency5,6. However, the exact number of people affected in Singapore is unknown as there has been no national survey in this regard. This is unfortunate in view of the growing number of effective interventions available to retard the progression of renal disease and ameliorate many of its co-morbid conditions.

16.2 Prevalence and significance of proteinuria

The Australian Diabetes, Obesity and Lifestyle (AusDiab) Study7 found proteinuria in 2.5% of the study population. A more recent US study estimated that 1.5% of people aged 6 years and over have proteinuria8. Locally, a cohort from the Central Man Power Base (CMPB) screening programme was studied in the 1970’s. Approximately 2% of young adult males who register for compulsory national service at the age of 16 years were found to have urinary abnormalities9. The majority of these subjects have a mild form of

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glomerulonephritis. However, 6% did progress to end stage renal disease over a period of 6 years10. Proteinuria has been reported to be a potent predictor of ESRD and is associated with a 15-fold increased risk of developing end stage renal disease within 10 years11. Patients with greater than 1 gram proteinuria were more likely to have progression of the disease, and aggressive reduction of the blood pressure is beneficial12. There are instances where proteinuria is transient and due to the upright position (postural proteinuria). This is frequently benign. There are a number of other events such as exercise, fever, sleep apnea, or congestive heart failure that can transiently increase urinary protein excretion. These factors must be considered in the evaluation of the patient. Recent screening data using urine dipstick in Singapore have shown that proteinuria (≥ 1+ or 30 mg/dl) was detected in 1% of the screened young adult working population13.

16.3 Who do we need to screen

Screening for renal disease in the general population is not presently recommended by the US Preventive Services Task Force14 and it is believed that the types of evidence required for such a recommendation are not available15. The Canadian Task Force on Periodic Health Examination in its 1994 report16 also did not recommend dipstick proteinuria screening of asymptomatic adults to prevent progressive renal disease. The rationale then was that effective, nontoxic therapy to arrest or slow disease progression was not available for most renal disorders. However, there is now good evidence that ACE inhibitors have renal-protecting properties independent of their antihypertensive effect. ACE inhibitors reduce urinary protein excretion in both diabetic and non-diabetic patients17,18. In addition, the results of a meta-analysis demonstrated a 30% reduction in the relative risk of developing end stage renal disease in patients treated with ACE inhibitors compared with conventional antihypertensives19. More recently, the Irbesartan in Diabetic Nephropathy Trial (IDNT)20 and Reduction of Endpoints in NIDDM with Angiotensin II Antagonist Losartan Study (RENAAL)21 were prospective randomized controlled trials that demonstrated the renal protective effects of angiotensin receptor blockers in patients with Type II diabetes and nephropathy.

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C A healthy asymptomatic individual may undergo opportunistic screening with urine dipstick examination22.

Grade C, Level IV

The US Multiple Risk Factor Intervention Trial23 had also showed that older age, smoking, hypertension and diabetes were significant risk factors for end stage renal disease. Familial aggregation of renal disease, in excess of that predicted by clustering of diabetes and hypertension, had also been reported in a population-based case-control study24. C Specific individuals at increased risk (e.g. age over 50 years, hypertension, smoking, diabetes and family history of renal disease) of chronic renal disease should undergo annual dipstick testing for proteinuria25.

Grade C, Level IV 16.4 Screening tests and effectiveness

Dipstick testing for proteinuria is widely available and easily performed by asking the person to collect a clean-catch, midstream, and random urine specimen. It is cheap and costs about $0.50 per test. An abnormal urine result was defined as the presence of ≥ 1+ protein (equivalent to ≥ 30 mg/dl) as poor discrimination between negative and trace-positive dipstick readings had been previously reported26. The test has about 85% sensitivity and specificity25. About 15% of people without proteinuria have a falsely positive result and those who have a positive dipstick result should have their protein excretion rate quantified. Measurement of the 24-hour urinary protein excretion rate has long been the gold standard but is inconvenient, cumbersome and expensive for the patient. Collecting a clean, mid-stream, “spot” urine for measurement of protein or albumin-to-creatinine ratio is an alternative method to quantitate proteinuria. Single voided urine protein creatinine ratio provides a relatively accurate estimation of 24-hour urine protein excretion27,28. However this must be done under standardized conditions (first voided, morning clean mid-stream sample) as there are variations in 24-hour protein excretion. C Individuals with a positive dipstick proteinuria should have a spot urinary protein-creatinine ratio test to quantitate their proteinuria27,28.

Grade C, Level IV

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Most dipsticks also test the urine for blood, glucose, leukocytes or nitrites. The presence of hematuria, especially among smokers and in the older persons, should prompt the exclusion of a urinary tract malignancy. The interpretation and further diagnostic steps required to evaluate the presence of hematuria and/or proteinuria on urinalysis have been discussed in a previous set of Clinical Practice Guidelines on Glomerulonephritis29. The frequency of isolated dipstick haematuria (≥1+) has been reported to be 9% of young adults13. Serum creatinine can be used as a crude marker for glomerular filtration rate and is easily available. Dietary intake, total muscle mass and certain medication may interfere with renal creatinine excretion. This may, therefore, make it difficult to detect patients in earlier stages of chronic renal disease30. In a study of patients with chronic renal disease, it was noted that at least 50% reduction in glomerular filtration rate was needed before a rise in serum creatinine above the normal levels (defined as > 123 µmol/l)31 occurred. The prevalence of elevated creatinine (>132 µmol/l in man and >123 µmol/l in woman) has been estimated at around 8-9% for both males and females5. However, a much larger study, the Third National Health and Nutritional Examination Survey (NHANES III), reported that in the total US population, 9.7% of males and 1.8% of females have a creatinine level of ≥ 132 µmol/l (about 10.9 million people)6. The presence of hypertension has been associated with elevated serum creatinine32. High diastolic blood pressure has been identified as a significant predictor of ESRD in a screened population33. Screening for hypertension (≥ 140/90 mmHg) and control of blood pressure may retard the progression of renal disease12.

C Individuals at increased risk of developing chronic renal disease should undergo testing of serum creatinine in order to estimate the glomerular filtration rate34.

Grade C, Level IV 16.5 Summary

Previously, universal screening was not recommended because of the lack of treatments to improve outcomes and the prevalence of chronic renal disease was much lower. There is now good evidence to suggest

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that the prevalence of earlier stages of chronic renal disease is higher than previously known and earlier detection would allow institution of treatment to prevent or delay the progression of renal disease.

References

1. Woo KT, Lee GSL. First Report of the Singapore Renal Registry 1997, Singapore, Continental Press, 1998.

2. Woo KT. Final End of Term Report from National Committee on Renal

Care, Singapore, 2001. 3. Woo KT. Chairman, National Committee on Renal Care, personal

communication. 4. United States Renal Data System: International comparisons of ESRD

therapy. In: USRDS 1999 Annual Data Report, Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases 1999; 173-84.

5. Culleton BF, Larson MG, Evan JC, et al. Prevalence and correlates of

elevated serum creatinine levels: The Framingham Heart Study. Arch Intern Med 1999;159:1785-90.

6. Jones CA, McxQuillan GM, Kusek JW, et al. Serum creatinine levels in

the US population: Third National Health and Nutrition Examination Survey. Am J Kidney Disease; 32: 992-9.

7. Diabesity and associated disorders in Australia – 2000: the accelerating

epidermic. Final report of the Australian Diabetes, Obesity and Lifestyle Study. Melbourne: International Diabetes Institute, 2001.

8. Jones CA, Francis ME, Eberhardt MS, et al. Microalbuminuria in the US

population: third National Health and Nutrition Examination Survey. Am J Kidney Disease 2002; 39: 445-59.

9. Pwee HS et al. Clinical aspects of asymptomatic hematuria and

proteinuria. Ann Acad Med Singapore 1975; 4:7-10.

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10. Pwee HS et al. Clinical course of asymptomatic hematuria and

proteinuria – a six year study. In: Proceedings of 3rd Colloquium in Nephrology, Toyko, 1979; 20-7.

11. Iseki K, Iseki C, Ikemiya Y, et al. Risk of developing end-stage renal

disease in a cohort of mass screening. Kidney Int 1996; 49:800-5. 12. Peterson JC, Adler S, Burkart JM, et al. Blood pressure control,

proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med 1995; 123:754-62.

13. Ramirez SPB, McClellan W, Port FK, et al. Risk factors for proteinuria in

a large, multiracial, SouthEast Asian population. J Am Soc Nephrol 2002; 13:1907-17.

14. US Preventive Services Task Force: Guide to Clinical Preventive

Services, 2nd Edition, Rockville, MD, US Preventive Services Task Force, 1996.

15. Harris RP, Helfand M, Woolf SH,et al., for the Methods Work Group,

Third US Preventive Services Task Force: Current methods of the US Preventive Services Task Force: A review process. Am J Prev Med 2001; 20 (Sppl 3):21-35.

16. Nagai R, Wang EEL, Feldman W. Dipstick proteinuria screening of

asymptomatic adults to prevent progressive renal disease. In: Canadian Task Force on the Periodic Health Examination. Canadian Guide to Clinical Preventive Health Care. Ottawa: Health Canada, 1994; 436-45.

17. Lewis EJ, Hunsicker LG, Bain RP, et al., for the Collaborative Study

Group. The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993; 329:1456-62.

18. The GISEN Group. Randomized placebo-controlled trial of effect of

ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997; 349:1857-63.

19. Giatras I, Lau J, Levey AS for the Angiotensin-Converting-Enzyme

Inhibition and Progressive Renal Disease Study Group. Effect of angiotensin-converting enzyme inhibitors on the progression of

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nondiabetic renal disease: a meta-analysis of randomized trials. Ann Intern Med 1997; 127:337-45.

20. Lewis EJ, Hunsicker LG, Clarke WR, et al for the Collaborative Study

Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345:851-60.

21. Brenner BM, Cooper ME, de Zeeuw D, et al for the RENAAL Study

Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345:861-79.

22. Keane WF, Eknoyan G for the Committee. Proteinuria, albuminuria, risk,

assessment, detection, elimination (PARADE): A Position Paper of the National Kidney Foundation. Am J Kidney Dis 1999; 33:1004-10.

23.

24.

25.

26.

27.

28.

29.

Klag MJ, Whelton PK, Randall BL, et al. End–stage renal disease in African-American and white men: 16-year MRFIT findings. JAMA 1997; 277:1293-8.

Lei HH, Perneger TV, Klag MJ, et al. Familial aggregation of renal disease in a population-based case-control study. J Am Soc Nephrol 1998; 9:1270-6.

Cass A. Kidney disease: are you at risk? Med J Aus 2002; 176: 515-6.

Harrison NA, Rainford DJ, White GA, Cullen SA, Strike PW: Proteinuria: What value is the dipstick? Br J Urol 1989; 63: 202-8.

Ginsberg JM, Chang BS, Matarese RA, et al. Use of single voided urine samples to estimate quantitative proteinuria. N Engl J Med 1983; 309:1543-6.

Schwab SJ, Christensen RL, Dougherty K, et al. Quantitation of proteinuria by use of protein-to-creatinine ratios in single urine samples. Arch Intern; 147:943-4.

Clinical Practice Guidelines: Glomerulonephritis. MOH Clinical Practice Guidelines 6/2001. Singapore, 2001.

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30.

31.

32.

33.

34.

Perrone RD, Madias NE, Levey AS. Serum creatinine as an index of renal function: new insights into old concepts. Clin Chem 1992; 38: 1933-1953.

Shemesh O, Golbetz H, Kriss JP, et al. Limintations of creatinine as a filtration marker in glomerulopathic patients. Kidney Int. 1985; 28:830-8.

Coresh J, Wei GL, McQuillan G, et al. Prevalence of high blood pressure and elevated serum creatinine level in United States: Findings from the Third National Health and Nutrition Examination Survey (1988-1994). Arch Intern Med 2001; 161:1207-16.

Iseki K, Ikemiya Y, Fukiyama K. Blood pressure and risk of end-stage renal disease in a screened cohort. Kidney Int 1996; 55:S69-71.

K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, classification and stratification. Am J Kidney Dis 2002; 39: S72-5.

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17 Screening for osteoporosis

This guideline on osteoporosis screening complements the Ministry of Health Clinical Practice Guidelines 2/2002 on Osteoporosis.

17.1 Introduction

Fractures are the most serious complication of osteoporosis, and constitute an evolving public health problem in terms of disability, mortality and cost in Singapore as in the rest of Asia where the population is ageing rapidly1. The incidence of all osteoporotic fractures, such as forearm2, vertebral2,3 and hip fracture, increases with age2-4. The incidence of fragility fractures is higher in women than in men, for any given age2,3. The age-adjusted hip fracture incidence rates in men and women in Singapore above the age of 50 years have risen 1½-fold and 5-fold respectively since the 1960s4, and are among the highest in Asia. Hip fractures in Singapore have been associated with a mortality of 20% at two years5. Of the survivors, 20% became semi- or fully dependent, 42% became less or non-ambulant, and only 8% were cared for by chronic health care facilities suggesting that the main social and economic burden was borne by the families of those affected. Vertebral fractures are also associated with significant complications including back pain, height loss, kyphosis and limitation of activity6, and increased mortality3.

17.2 Definition

Bone mineral density (BMD) is currently central to the diagnosis of osteoporosis in the absence of a fracture7. An individual experiencing a fragility fracture (fracture due to minimal trauma, such as after fall from standing height or less) also has osteoporosis, regardless of bone density. Operationally, osteoporosis is defined as a value for BMD that is 2.5 standard deviations or more below the mean value in young adults (T-score ≤ –2.5 SD)8. The problem of osteoporosis can be approached in several ways. Firstly, a population-based strategy addresses lifestyle issues such as good nutrition, exercise, and avoidance of smoking and alcohol abuse in an attempt to improve the overall health of the population, although there is little evidence about the effect of changing these behaviours

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on fracture risk. Secondly, a high-risk strategy, targets interventions at individuals at high risk for osteoporosis either by screening (where those who meet set criteria are evaluated) or case-finding (where those who have risk factors are evaluated). C Although the definition of osteoporosis is based on BMD, it is not advisable to screen BMD in the whole population since BMD measurements are costly, and the cost-benefit or cost-effectiveness of such a strategy has not been demonstrated7,9. There is no cheap, easily available screening test for the detection of osteoporosis. Hence, the emphasis should be on proper selection of individuals for diagnostic BMD testing, preferably guided by the presence of risk factors for osteoporosis in a case-finding approach7,9.

Grade C, Level IV


a. Bone Mineral Density

In recent years, several techniques have been available for the measurement of BMD10. Prospective studies have shown that the risk of fracture increases progressively with decreasing BMD, the gradient of risk varying according to the measurement site and technique used11. i. Dual-energy x-ray absorptiometry (DXA) of hip and spine DXA measurements at the unfractured or non-dominant hip fulfill the role of a ‘gold standard’ for diagnosing osteoporosis, having the best overall predictive value for hip fractures and other osteoporotic fractures, and having been validated against fracture risk in many prospective studies9,12. The lumbar spine (anteroposterior projection) is the preferred site for monitoring therapeutic response since in most trials, the largest changes in BMD with treatment have occurred at this site13. ii. Single energy X-ray absorptiometry (SXA) and DXA of forearm or heel (peripheral) iii. Quantitative ultrasound (QUS) of the heel or tibia iv. Quantitative computed tomography (QCT) of the spine

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The advantages of the peripheral systems and QUS are small size, portability, low or absent radiation exposure, ease of operation, shorter scan times and lower cost. QUS correlates fairly well with DXA and predicts fracture risk independently of DXA14. The use of QCT as a screening tool has not been well investigated8, and it has a relatively higher radiation dose10.

Current status of different BMD techniques: Current BMD measurement techniques have different degrees of precision errors (1-4%) and accuracy errors (2-15%), and this is a limitation in the use of these techniques12. Concordance of BMD measurements between different sites and techniques has been poor12. Heterogeneity exists between skeletal sites, in that low BMD at one site does not necessarily confirm low BMD at another15. T-scores at different sites and with different techniques yield different information on fracture risk, and are not interchangeable16. The role of central DXA (hip and spine) in diagnosis and therapeutic monitoring is well-established, and should remain the method of choice for measuring BMD. There is emerging data that peripheral bone densitometry measurements using DXA, SXA and QUS (T-scores ≤ –2.5 SD) may be useful for the diagnosis of osteoporosis17. However, peripheral techniques have not been used as entry criterion in osteoporosis intervention trials, and it is uncertain if therapies are beneficial in women using these techniques to diagnose osteoporosis7. Their role in monitoring response to therapy appears limited18,19.

b. Biochemical Markers of Bone Turnover

There is currently no role for bone turnover markers in the diagnosis of osteoporosis. Biochemical indices of bone turnover have the potential of aiding in fracture risk assessment and predicting rates of bone loss, and have been used in monitoring the response to treatment9, 20.


a. C All individuals with prior fragility fractures during adulthood

should be considered for BMD measurement and osteoporosis treatment.

Grade C, Level IV

133

b. Postmenopausal women

C Several clinical evaluation tools have been developed to assist in the case-finding strategy for detecting osteoporosis21-25, all of which perform similarly. BMD should be measured in individuals at highest risk for osteoporosis identified using such tools.

Grade C, Level IV

The US National Osteoporosis Foundation (NOF) guidelines, which use an age criterion, has recommended BMD testing in all women over the age of 65 years21, and in postmenopausal women under 65 years of age with risk factors for hip fracture independent of bone density, including history of previous fracture as an adult, family history of fracture, body weight <57 kg or current cigarette smoking. It is not yet clear if these criteria are applicable to Asians. C The Osteoporosis Self-assessment Tool for Asians (OSTA), which is based on age and weight, categorises postmenopausal Asian women into high, moderate and low risk of having osteoporosis on subsequent BMD measurement22, and may be used as a basis for case-finding (Tables 5, 6 and 7).

Grade C, Level IV

TABLE 5: Osteoporosis Self-Assessment Tool for Asians (OSTA)

Weight (kg) Age

(yr) 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-7945-49 50-54 55-59 Low Risk 60-64 65-69 Moderate Risk 70-74 75-79 High Risk 80-84 85-89

Copyright 2001, MSD, Whitehouse Station, NJ, USA. All rights reserved. Reproduced with permission.

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TABLE 6: Approximate calculation method to categorize osteoporosis risk from OSTA, and recommended action based on OSTA risk category

Osteoporosis Risk

Estimated % with

osteoporosis22

Approximate Calculation :

Age (yr) minus Weight (kg)

Recommended Action

High 44 – 61 > 20 Recommend BMD measurement.

Moderate 10 - 15 0 – 20 Evaluate for risk factors* (Table 7), and measure BMD if these are present.

Low 1 - 3 < 0 Osteoporosis prevalence is low. Can defer BMD unless has past fragility fracture or has condition known to be associated with osteoporosis.

* The number of risk factors for osteoporosis which should be present in an individual to improve the likelihood of detecting osteoporosis in this category remains unclear.

TABLE 7: Risk factors for low bone mass for which BMD measurement might be considered

Non-modifiable • Personal history of previous fracture as an adult • History of fracture in a first degree relative (especially maternal) • Low body weight & older age Potentially Modifiable • Current cigarette smoking • Alcohol abuse (stronger data in men) • Early natural or surgical menopause before age 45 years, or prolonged

premenopausal amenorrhea lasting > 1 year • Drugs e.g. corticosteroids (equivalent to prednisolone > 7.5 mg/day for

more than 6 months), excess thyroxine, anticonvulsants • Ongoing disease conditions e.g. hypogonadism, hyperthyroidism,

hyperparathyroidism, Cushing’s syndrome, chronic obstructive airways disease, liver disease, malabsorption, chronic renal failure, rheumatoid arthritis, organ transplantation and anorexia nervosa

• Prolonged immobilization, poor health or frailty • Lifelong low calcium intake (< 500 mg/day among Asians) • Lack of regular physical activity

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Other indications for measuring bone density7,9 C The following are other indications for measuring bone density: 1. Radiological evidence of osteopenia or vertebral deformity 2. Women who are considering therapy for osteoporosis, if BMD

testing would facilitate the decision to initiate therapy 3. Monitoring of treatment

Grade C, Level IV

c. Premenopausal women C Screening for osteoporosis in premenopausal women is not recommended7,9. There are very few recognised interventions for premenopausal women with osteoporosis. Nevertheless, BMD measurement may be considered in those with significant risk factors for fracture.

Grade C, Level IV d. Men

C There is as yet no recommendation for screening of osteoporosis in men. There is an unresolved controversy with regard to deriving the T-scores using 2.5 SD or more below the mean for young women12, or for young men26 as the diagnostic threshold for osteoporosis in men. The relationship between risk factors and osteoporosis and fractures in men is less well-studied. Established interventions for men with osteoporosis are few. Measuring BMD in those with significant risk factors for osteoporosis is a reasonable strategy.

Grade C, Level IV

e. Patients on long-term corticosteroid therapy In the context of corticosteroid-induced osteoporosis, a higher incidence of fractures has been observed, with fractures appearing to occur at higher BMDs27. Clinical risk factors for steroid-associated fractures include low bone density, cumulative steroid dose, age, low body weight, smoking, diseases associated with low bone density such as rheumatoid arthritis, sex hormone deficiency in both sexes, a family history of osteoporosis28, and probably a prior history of fracture and immobilization. C It would be reasonable to consider patients scheduled for, or already on, long-term (>6 months), higher-dose (>7.5 mg/day)

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corticosteroid therapy with clinical risk factors for steroid-associated fractures, for BMD measurement at baseline and after an interval of 6 months to a year to detect bone loss29. It has been suggested that a T-score of -1.5 SD or below at the femoral neck and/or spine be used as the intervention threshold for corticosteroid-induced osteoporosis30.

Grade C, Level IV 17.5 Frequency of screening

Women with osteoporosis, who are being monitored for progression or who are being treated, should have a follow-up bone density measurement, usually at an interval of at least one year. The anteroposterior lumbar spine measurement would usually show the more obvious changes with treatment, but in the elderly where spurious elevations of spine BMD may occur, e.g. from lumbar facet joint osteoarthritis or aortic calcification, the hip measurement may be more reliable for monitoring treatment response. C In women with osteopenia (BMD between 1 and 2.5 S.D. below the mean peak bone mass of young adults) a reasonable interval for a follow-up BMD might be 1 to 2 years, while in those with normal BMD (more than -1 S.D. below the mean peak bone mass of young adults) a more reasonable interval may be 2 to 5 years9.

Grade C, Level IV 17.6 Other relevant information

There are several limitations with BMD measurements. There have been few controlled trials on whether women who receive bone density screening have better outcomes in terms of fewer fractures than women who are not screened. Although BMD remains the best method of detecting and diagnosing osteoporosis, a significant number of women with osteoporosis do not fracture, and conversely, a significant number of women with fragility fractures do not have low bone density. Nevertheless, there is emerging data that BMD measurement has some advantages. It has been found that treatment of individuals after fragility fractures remains inadequate31,32. However, BMD measurements appear to have resulted in modifications of

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lifestyle33,34, and improved treatment initiation rates35,36. The effects of these on overall fracture rates remains to be determined.

17.7 Summary

C All individuals with prior fragility fractures during adulthood

should be considered for BMD measurement and osteoporosis treatment.

Grade C, Level IV

C Population screening using BMD is not recommended for postmenopausal women. A case-finding strategy is preferred, measuring BMD in individuals at highest risk for osteoporosis identified using clinical evaluation tools such as OSTA or NOF guidelines, and clinical risk factor evaluation.

Grade C, Level IV

C Women with osteoporosis, who are being monitored for progression or who are being treated, should have a follow-up bone density measurement, usually at an interval of at least one year. In women with osteopenia, a reasonable interval might be 1 to 2 years, while in those with normal BMD, a more reasonable interval may be 2 to 5 years.

Grade C, Level IV

C Screening is not recommended for premenopausal women and men. BMD measurement should be considered in those at high risk for fracture.

Grade C, Level IV

C BMD measurement should be considered in patients with high risk for steroid-associated fractures, who are initiating or already on long-term higher-dose corticosteroid therapy.

Grade C, Level IV

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References 1. Gullberg B, Johnell O, Kanis JA. World-wide projections for hip

fracture. Osteoporos Int 1997; 7:407-13. 2. Riggs BL, Melton LJ III. Involutional osteoporosis. N Engl J Med 1986;

314:1676-86. 3. Center J, Nguyen T, Schneider D, et al. Mortality after all major types of

osteoporotic fracture in men and women: an observational study. Lancet 1999; 353:878-82.

4. Koh LKH, Saw SM, Lee JJM, et al. Hip fracture incidence rates in

Singapore 1991-1998. Osteoporos Int 2001; 12:311-8. 5. Mitra AK, Low CK, Chao AK, et al. Social aspects in patients following

proximal femoral fractures. Ann Acad Med Singapore 1994; 23:876-8. 6. Ross P. Clinical consequences of vertebral fractures. Am J Med 1997;

103:30S-42S; discussion 42S-3S. 7. NIH Consensus Development Panel on Osteoporosis prevention,

diagnosis, and therapy. JAMA 2001; 285:785-95. 8. Assessment of fracture risk and its application to screening for

postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser 1994; 843:1-129.

9. National Osteoporosis Foundation. Osteoporosis: review of the evidence

for prevention, diagnosis and treatment and cost-effectiveness analysis. Osteoporos Int 1998; 8:S1-80.

10. Genant HK, Engelke K, Fuerst T, et al. Noninvasive assessment of bone

mineral and structure: state of the art. J Bone Miner Res 1996; 11:707-30.

11. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of

bone mineral density predict occurrence of osteoporotic fractures. BMJ 1996; 312:1254-9.

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12. Kanis J, Gluer C. An update on the diagnosis and assessment of

osteoporosis with densitometry. Committee of Scientific Advisors, International Osteoporosis Foundation. Osteoporos Int 2000; 11:192-202.

13. Hochberg MC, Greenspan S, Wasnich RD, et al. Changes in bone

density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J Clin Endocrinol Metab 2002; 87:1586-92.

14. Bauer D, Gluer C, Cauley J, et al. Broadband ultrasound attenuation

predicts fractures strongly and independently of densitometry in older women. A prospective study. Study of Osteoporotic Fractures Research Group. Arch Intern Med 1997; 157:629-34.

15. Davis J, Ross P, Wasnich R. Evidence for both generalized and regional

low bone mass among elderly women. J Bone Miner Res 1994; 9:305-9. 16. Faulkner KG, Von Stetten E, Miller P. Discordance in patient

classification using T-scores. J Clin Densitom 1999; 2:343-50. 17. Siris E, Miller P, Barrett-Connor E, et al. Identification and fracture

outcomes of undiagnosed low bone mineral density in postmenopausal women: results from the National Osteoporosis Risk Assessment. JAMA 2001; 286:2815-22.

18. Drake WM, Brown JP, Banville C, et al. Use of phalangeal bone mineral

density and multi-site speed of sound conduction to monitor therapy with alendronate in postmenopausal women. Osteoporos Int 2002; 13:249-56.

19. Gonnelli S, Cepollaro C, Montagnani A, et al. Heel ultrasonography in

monitoring alendronate therapy: a four-year longitudinal study. Osteoporos Int 2002; 13:415-21.

20. Delmas P, Eastell R, Garnero P, et al. The use of biochemical markers of

bone turnover in osteoporosis. Committee of Scientific Advisors of the International Osteoporosis Foundation. Osteoporos Int 2000; 11:S2-17.

21. Physician's guide to prevention and treatment of osteoporosis.

Washington D.C.: National Osteoporosis Foundation, 1998.

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22. Koh LKH, Ben Sedrine WB, Torralba TP, et al. A simple tool to identify

Asian women at increased risk of osteoporosis. Osteoporos Int 2001; 12:699-705.

35. Weinstein L, Ullery B. Identification of at-risk women for osteoporosis

screening. Am J Obstet Gynecol 2000; 183:547-9. 24. Lydick E, Cook K, Turpin J, et al. Development and validation of a

simple questionnaire to facilitate identification of women likely to have low bone density. Am J Manag Care 1998; 4:37-48.

25. Cadarette S, Jaglal S, Kreiger N, et al. Development and validation of

the Osteoporosis Risk Assessment Instrument to facilitate selection of women for bone densitometry. CMAJ 2000; 162:1289-94.

26. Orwoll E. Assessing bone density in men. J Bone Miner Res 2000;

15:1867-70. 27. Eastell R, Reid D, Compston J, et al. A UK Consensus Group on

management of glucocorticoid-induced osteoporosis: an update. J Intern Med 1998; 244:271-92.

28. Michel B, Bloch D, Wolfe F, et al. Fractures in rheumatoid arthritis: an

evaluation of associated risk factors. J Rheumatol 1993;20:1666-9. 29. Recommendations for the prevention and treatment of glucocorticoid-

induced osteoporosis: 2001 update. American College of Rheumatology Ad Hoc Committee on Glucocoritcoid-Induced Osteoporosis. Arthritis Rheum 2001; 44:1496-503.

30. Compston J, Audran M, Avouac B, et al. Recommendations for the

registration of agents used in the prevention and treatment of glucocorticoid-induced osteoporosis. Calcif Tissue Int 1996;59:323-7.

31. Cuddihy MT, Gabriel SE, Crowson CS, et al. Osteoporosis intervention

following distal forearm fractures: a missed opportunity? Arch Intern Med 2002; 162:421-6.

32. Bellantonio S, Fortinsky R, Prestwood K. How well are community-

living women treated for osteoporosis after hip fracture? J Am Geriatr Soc 2001; 49:1197-204.

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33. Rolnick SJ, Kopher R, Jackson J, et al. What is the impact of

osteoporosis education and bone mineral density testing for postmenopausal women in a managed care setting? Menopause 2001; 8:141-8.

34. Marci CD, Anderson WB, Viechnicki MB, et al. Bone mineral

densitometry substantially influences health-related behaviors of postmenopausal women. Calcif Tissue Int 2000; 66:113-8.

35. Fitt NS, Mitchell SL, Cranney A, et al. Influence of bone densitometry

results on the treatment of osteoporosis. CMAJ 2001; 164:777-81. 36. Pressman A, Forsyth B, Ettinger B, et al. Initiation of osteoporosis

treatment after bone mineral density testing. Osteoporos Int 2001; 12:337-42.

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18 Screening for visual acuity for the elderly 18.1 Introduction

Vision problems are common and potentially serious amongst older people, and lead to an increased risk of falls and accidents.

The most common causes of visual impairment amongst the elderly include cataract, uncorrected refractive errors, presbyopia, age-related macular degeneration, diabetic retinopathy and glaucoma1.


In the elderly, screening and the correction of correctable visual problems lead to a restoration of vision and subjective improvements in a variety of vision-related functions, as well as improvements in objective measures of physical and intellectual function.

Vision problems are more likely in persons over 65 years, and they are more likely to lead to serious consequences such as accidental injuries.

Routine screening with visual acuity testing in people over 65 years leads to improvements in measured visual acuity.

There is little chance that the screening method will lead to any harm2.


B The population to be screened includes any person age 65 years and above, and the screening test involves using a Snellen chart to test each eye2.

Grade B, Level III

Asking screening questions about visual function has yielded mixed results when compared to the use of a Snellen acuity chart. The question “Do you have difficulty seeing distant objects?” had a sensitivity of 28% in detecting visual acuity worse than 6/12 3.

Poor vision can be easily detected by the use of a Snellen chart. Ophthalmoscopy can be used to detect ocular media opacities like

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cataracts. However, there is little data on the sensitivity and specificity of these examinations in both healthcare and community settings.

B Any person screened and found to have vision worse than 6/12 can be referred for assessment and treatment2.

Grade B, Level III


C The optimal frequency for screening is not known and is left to the discretion of the screener2.

Grade C, Level IV 18.5 Other relevant information

C Besides visual acuity testing using the Snellen chart, there is insufficient evidence to recommend for or against routine screening with ophthalmoscopy by the primary care physician in an asymptomatic elderly patient2.

Grade C, Level IV 18.6 Summary

Routine vision screening using Snellen chart acuity testing is recommended for those 65 years and above. The test is fairly objective and more useful than asking about visual function.

References 1. American Academy of Ophthalmology: Comprehensive adult eye

evaluation, preferred practice pattern. San Francisco: American Academy of Ophthalmology 1996.

2. USPSTF “Guide to Clinical Preventive Services” Recommendations -

Screening for visual impairment. 2nd edition; 1996. 3. Stone DH, Shannon DJ. Screening for impaired visual acuity in middle

age in general practice. BMJ 1978; 2:859-61.

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19 Screening for sexually transmitted infection 19.1 Introduction

The control and prevention of sexually transmitted infections (STI) remains a major global public health problem. STI can result in unnecessary human suffering and financial cost. Some STI can be cured, but for others, there is no effective treatment. All STI, however, can be prevented and therefore health education, prevention and screening programmes play an important role in STI control. There has been a change in the trends of STI in Singapore over the last two decades1. Important advances in medicine, particularly the development of antibiotics, have resulted in effective treatment for several bacterial STI. Increasing public awareness and health education programmes have been introduced to prevent STI transmission. In addition, the HIV pandemic has influenced social and sexual behaviour to a certain extent. On the other hand, increasing affluence and globalisation of the economy result in increased travel and high-risk behaviour.

19.2 Screening for chlamydia trachomatis infection

Chlamydia trachomatis is a major cause of urethritis in men and cervicitis and pelvic inflammatory disease (PID) in women. It can lead to sequelae of ectopic pregnancy and infertility. In Singapore, a case control longitudinal study of 100 subfertile women in a tertiary teaching hospital revealed an 8% prevalence of genital Chlamydia trachomatis infection, with the highest incidence in women aged below 25 years old2. The authors suggested routine screening for chlamydial infection for subfertile couples, especially if patients are in the younger age group. In the DSC Clinic, 46% of chlamydial infections in females were detected in those under 25 years of age.

19.2.1 Screening women

Women and adolescents through age 20 years are at highest risk for chlamydial infection. However, most reported data indicate that infection is prevalent among women aged 20-25 years. Age is the most important risk factor, and continues to be the best predictor of

145

chlamydial infection in young women, with most studies evaluating cut-offs at age younger than 25 years3. The US Preventive Services Task Force (USPSTF) strongly recommends that clinicians routinely screen all sexually active women aged 25 years and younger and other asymptomatic women at increased risk for infection, for chlamydia3. The Centers for Disease Control and Prevention (CDC) also uses age as the primary determinant for screening. It recommends at least annual screening for sexually active women aged 20-24 years who meet either of the following criteria: inconsistent use of a barrier contraceptive or more than one sexual partner during the last 3 months4. The UK National guidelines identify age less than 25 years, a new sexual partner or more than one sexual partner in the recent past, lack of barrier contraception, the use of the oral contraceptive pill and women undergoing termination of pregnancy as risk factors for chlamydial infection5. The Expert Advisory Group for the Chief Medical Officer in the UK recommends that clinicians should consider opportunistic screening of any woman undergoing instrumentation of the uterus because even in low prevalence groups there may be a resultant risk of ascending infection6. It also recommends that screening for chlamydial infection be undertaken in the following clinical scenarios: women presenting with pelvic inflammatory disease (PID), mucopurulent cervicitis, vaginal discharge and lower abdominal pain; men presenting with urethral discharge, epididymitis, non-specific urethritis and reactive arthritis, and in infants and parents of infants with ophthalmia neonatorum or neonatal pneumonitis. It is suggested that patients attending STD clinics, as well as their partners, should be targeted for screening as they represent high-risk groups. The strongest evidence supporting screening is a well-designed randomized trial in Seattle which demonstrated that screening women at risk (prevalence of infection 7%) reduced the incidence of PID from 28 per 1000 woman-years to 13 per 1000 woman-years7. In addition, two ecological analyses in Sweden reported reductions in ectopic pregnancy and PID with the advent of community-based screening for chlamydial infection8, 9 .

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A Sexually active women with the following risk factors may be at higher risk of chlamydial infection and should be considered for screening: those aged 25 years and younger, who have a new sexual partner, who have partners with symptoms of an STI or who have had two or more partners in the past 12 months and lack the use of barrier contraception.

Grade A, Level Ib

A Women undergoing termination of pregnancy with risk factors (as above) should be screened.

Grade A, Level Ib

C Women undergoing instrumentation of the uterus should be considered for screening on an individual case basis because even in low prevalence groups, there may be a resultant risk of ascending infection.

Grade C, Level IV

The optimal interval for screening is uncertain. For women with a previous negative screening test, the interval for re-screening should take into account changes in sexual partners. Re-screening at 6 to 12 months may be appropriate for previously infected women because of high rates of reinfection.

19.2.2 Screening pregnant women

There is evidence from 3 separate studies at the University of Washington, each involving a different study design, that links antenatal chlamydial infection with prematurity, defined by preterm delivery, and/or low birth weight10-12. B Pregnant women aged 25 years and younger and other pregnant women at higher risk for infection (i.e. women who have had two or more sexual partners in the past 12 months, or partners with symptoms of an STI) should be considered for screening.

Grade B, Level IIb

The optimal timing of screening in pregnancy is uncertain. Screening early in pregnancy provides greater opportunity to improve pregnancy outcomes, but screening in the third trimester may be more effective at preventing transmission of chlamydial infection to the newborn.

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There is little evidence regarding the effectiveness of screening asymptomatic pregnant women who are not in high-risk groups.

19.2.3 Screening men

There is no data on established guidelines for screening men, and no data regarding aged-based recommendations on screening in men. C Asymptomatic men with high-risk behaviour such as frequent partner change, lack of use of barrier protection or sex with prostitutes can be considered for screening. These patients should be referred to specialist centres for counselling, and investigation13.

Grade C, level IV

GPP In men, a Gram-stained urethral smear taken 4 hours from the last void of urine showing presence of 5 or more leukocytes per high-power field indicates urethritis. This may be due to Chlamydia trachomatis or other organisms, as well as other factors that may not be sexually transmitted. These patients should be assessed by specialist centres for counselling and advice.

GPP

19.2.4 Screening methods

A number of tests are available to identify chlamydial infection that uses endocervical or urethral swab specimens and urine specimens. Until recently, culture has been accepted as the most specific test but it requires specialized handling and laboratory services. A Screening can be performed using cultures or enzyme immunoassays (EIA) on endocervical swabs in women and urethral swabs in men3,4,7.

Grade A, Level Ia At present the chlamydia culture test is not done by any laboratory in Singapore. Antigen detection tests such as enzyme immunoassay (EIA) can be used. It is inexpensive but has a sensitivity of between 70-80% only, although specificity remains high (96-100%). A Nucleic acid amplification tests (NAAT) using polymerase chain reaction (PCR) or ligase chain reaction (LCR) can also be used in

148

screening on endocervical or urethral swabs, and have the advantage of being used on non-invasive specimens such as urine.

Grade A, Level Ia

The sensitivities and specificities of NAAT are all high, ranging from 82-100%14. NAATs perform equally well on endocervical, urethral swabs and urine samples15. However, as obtaining an invasive sample is likely to deter asymptomatic individuals, urine testing offers considerable advantages. These tests are much more costly though. LCR and PCR testing requires dedicated equipment, air conditioned rooms and experienced staff to run effectively and it is unlikely to be cost effective for all laboratories to offer such a testing service15. Local agreement on testing methods and how to organize testing is required to ensure effective use of resources. Although urine testing offers considerable advantages for asymptomatic populations, it may not be the most appropriate or cost effective procedure for all situations. In situations where visualization of the cervix is required as part of the medical examination, obtaining an endocervical swab would probably be more appropriate. The actual prevalence of chlamydial infections among the local population has not been studied. Appropriate screening strategies need to take into account the characteristics of the patient population to further identify risk groups. More local epidemiological studies should be performed. It is important to ensure high validity for any test used in low prevalence populations as incorrect results may have serious consequences for the individuals concerned. Therefore antigen detection as well as NAAT methods can be used for screening, depending on resources available and populations tested. C Serological tests based on genus-specific complement fixation test are not useful in the diagnosis of chlamydial genital infections, with the possible exception of lymphogranuloma venereum16.

Grade C, Level IV

GPP The optimal frequency of screening is a matter of clinical discretion. Screening for chlamydia infection should be performed about 1 week after high-risk exposure or change of sex partner.

GPP

149

19.3 Screening for syphilis

Syphilis is caused by infection with the bacterium Treponema pallidum, which can be transmitted congenitally or by sexual contact. In 2001, there were 159 cases of infectious syphilis, 798 cases of non-infectious syphilis, and 4 cases of congenital syphilis notified in Singapore. Infectious syphilis comprises primary and secondary syphilis and early latent syphilis, which is defined as a period of 1 year from acquisition of infection. The incidence of infectious and non-infectious syphilis has shown a steady decline over the past 2 decades. This is also reflected in the decline in number of cases of congenital syphilis, with 20 cases detected in 1978, to 4 cases last year. Congenital syphilis can result in fetal or perinatal death, as well as an increased risk of medical complications in surviving newborns17.

19.3.1 Screening men and women

Early detection of syphilis in asymptomatic persons permits the initiation of antibiotic therapy to eradicate the infection, thereby preventing both clinical disease and transmission to sexual contacts. The American College of Physicians recommends serologic screening for syphilis in high-risk adults (prostitutes, persons who engage in sex with multiple partners in areas in which syphilis is prevalent, contacts of persons with active syphilis)18. C All men and women at increased risk for infection, including sex workers, persons who exchange sex for money or drugs, persons with other STIs (including HIV) and genital ulceration, and sexual contacts of persons with active syphilis should be screened.

Grade C, Level IV

19.3.2 Screening pregnant women

Early detection and penicillin treatment during pregnancy has the added benefit of reducing the risk to the fetus of acquiring congenital syphilis19. The American College of Obstetricians and Gynecologists and the American Academy of Pediatrics recommend routine prenatal

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screening for syphilis at the first prenatal visit, after exposure to an infected partner and in the third trimester for patients at high risk20. The USPSTF strongly recommends routine serologic testing for syphilis for all pregnant women and for persons at increased risk for infection21. The CDC recommends obtaining serology for syphilis from all women at the first antenatal visit22. Routine screening for all pregnant women is justified in view of the severe neonatal morbidity and mortality associated with congenital syphilis, as well as its potential preventability. There is evidence from several studies which demonstrate that prenatal screening for syphilis is cost-effective, even when the prevalence of the disease among pregnant women is as low as 0.005%23,24. B Pregnant women should be screened at their first antenatal visit.

Grade B, Level III

C Pregnant women at higher risk of infection (i.e. women who have partners with symptoms of an STI, or continue to engage in sexual activity with multiple partners, or a partner who has sex with multiple partners) should have screening repeated in the third trimester.

Grade C, Level IV


The testing strategy varies depending on several factors, including whether the aim is to detect all stages of syphilis or only infectious syphilis. In the USA, France and Belgium, non-treponemal tests are used for screening. This does not detect most adequately treated cases, thus simplifying patient assessment. There are however a few disadvantages. It may yield false negative reactions in early infections (prozone phenomenon) and with concomitant HIV infection, and it lacks sensitivity in late stage infections. In Germany and Holland, the TPHA test is used for screening. This provides a good screen for all stages beyond the early primary stage.

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The UK has adopted the VDRL/TPHA combination for screening as this detects more primary infections. However, this combination is labour intensive, requires subjective interpretation and cannot be easily automated. More recently, specific EIA tests have been used as a screening test. The advantages of this technique are objective results, the ability to link to computer systems (thus reducing human errors) and automated processing25. These tests have not been fully evaluated in Singapore. In Singapore nontreponemal tests (VDRL, RPR) are used for screening. The sensitivity of these tests varies with the levels of antibodies present during the stages of disease18. 19.3.4 Interpretation of test results

In early primary syphilis, when antibody levels may be too low to detect, results may be nonreactive, and the sensitivity of nontreponemal tests is 62-76%.26 Antibody levels rise as disease progresses; titres usually peak during secondary syphilis, when the sensitivity of nontreponemal tests approaches 100%. In late syphilis, titres decline; in untreated late syphilis, test sensitivity averages 70%26. Nontreponemal tests titres decline or revert to normal after successful treatment. Positive screening tests must be confirmed by a specific test such as Treponema pallidum hemeagglutination or particle agglutination (TPHA and TPPA) or fluorescent treponemal antibody absorption (FTA-ABS). C Screening for syphilis is performed using nontreponemal tests such as RPR or VDRL. Positive results should be confirmed with a specific test such as TPPA or TPHA. Both nontreponemal and treponemal tests can be combined for use in screening, although this would be more costly and labour-intensive.

Grade C, Level IV

GPP The optimal frequency of screening is a matter of clinical discretion. Screening for syphilis should be performed 1 month after exposure, and repeated again after 3 months.

GPP

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C Follow up serologic tests should be obtained to document declines in titres after treatment. They should be performed using the same test initially used to document infection (e.g. VDRL or RPR) to ensure compatibility27.

Grade C, Level IV

At DSC, the intervals for follow-up serology testing are at 3, 6, 12, 18 and 24 months after diagnosis27.

19.4 Screening for gonorrhoea

Gonorrhoea is caused by Neisseria gonorrhoeae. Gonococcal infections produce urethritis, epididymitis, and proctitis in men, but few long-term complications. It causes pelvic inflammatory disease in women, and pregnant women with gonorrhoea are at increased risk of obstetric complications (e.g. stillbirth, low birthweight). Pharyngeal gonorrhoea usually occurs in association with anogenital infection, and can result in transmission through oral sex28. Early detection and treatment of gonococcal infection in asymptomatic persons offer the potential benefits of complete cure, prevents future complications of infection, reduces transmission to uninfected partners, and identifies sexual contacts who are likely to be infected. Due to ethical considerations that preclude placebo-controlled trials of treatment, the benefits of early detection are based largely on indirect evidence. 19.4.1 Screening women and men The USPSTF recommends routine screening for N. gonorrhoeae in asymptomatic women in high-risk groups29. High-risk groups include commercial sex workers, persons with a history of repeated episodes of gonorrhoea, and young women (under age 25 years) with two or more sexual partners in the last year. Actual risk, however, will depend on the local epidemiology of the disease. The Canadian Task Force on the Periodic Health Examination advises against routine screening for gonorrhoea in the general population but recommends screening of high-risk patients 30.

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The American College of Obstetricians and Gynecologists (ACOG) recommends obtaining endocervical culture in pregnant women on their first antenatal visit only if they are in one of the high-risk categories for gonorrhoea31.

C Women at high risk of infection – including sex workers, women with a history of repeated episodes of gonorrhoea, and women with two or more sex partners in the previous year should be screened.

Grade C, Level IV

GPP Homosexual men with frequent partner change or other high-risk behaviour (i.e. those who have sex with partners with symptoms of an STI, those who do not use barrier protection including unprotected receptive and insertive oral and anal intercourse) should be considered for screening.

GPP


The most sensitive and specific test for detecting gonococcal infection in asymptomatic persons is direct culture from sites of exposure (urethra, endocervix, throat, and rectum). Under quality-controlled conditions, the sensitivity of culture is high for both male and female anogenital gonorrhoea and for pharyngeal gonococcal infections. In women and men, a single endocervical or urethral swab culture is estimated to have a sensitivity of 80-95%32,33. Microscopic examination of Gram-stained urethral or cervical specimens can detect infection with N. gonorrhoeae. The sensitivity of Gram-stained urethral specimens is higher in symptomatic men (90-95%) than in asymptomatic men34. The sensitivity of Gram-stained cervical specimens is lower (60-70%). Culture of endocervical specimens in women and urethral specimens in men is therefore the preferred method for screening. C The ideal screening test is isolation of Neisseria gonorrhoeae by culture from the appropriate sites.

Grade C, Level IV

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GPP Sites to be sampled will be determined by the history of sexual contact – urethra, cervix, rectum or pharynx.

GPP

GPP The optimal frequency of screening is a matter of clinical discretion. Screening for gonorrhoea should be performed about 1 week after exposure.

GPP

19.5 Screening for genital Herpes Simplex Virus Infection

Both Herpes Simplex Virus (HSV) types 1 and 2 can cause genital herpes, but HSV-2 causes the majority of primary and recurrent genital herpes infections35. There is insufficient evidence to recommend routine screening for genital HSV in asymptomatic persons, using culture, serology, or other tests. The USPSTF does not recommend routine screening for HSV infection in asymptomatic persons, including asymptomatic pregnant women36. GPP Routine screening for genital herpes simplex virus (HSV) infection by viral culture, serology or other means is not recommended for asymptomatic men or women, including asymptomatic pregnant women.

GPP History and physical examination are not adequate screening tests for either active or latent genital HSV infection. If a test were to be used, viral culture still remains the “gold standard”. However, the sensitivity of the test is dependent on the time at which it is performed. Viral cultures have a sensitivity of 93% for vesicles, to 72% for ulcers and 27% for crusted lesions37. The present serological tests available locally are not specific enough to reliably distinguish HSV-1 and 2 in some circumstances, and are not recommended.

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The newer type-specific serological tests are based on HSV-specific glycoprotein G2 for the diagnosis of infection with HSV-2 and glycoprotein G1 for the diagnosis of infection with HSV-1. Currently, the FDA-approved, gG-based type-specific assays include POCkit™ HSV-2 (manufactured by Diagnology) and HerpeSelect™-1 ELISA IgG or HerpeSelect™-2 ELISA IgG (manufactured by Focus Technology, Inc)38. Because almost all HSV-2 infections are sexually acquired, type-specific HSV-2 antibody indicates anogenital infection, but the presence of HSV-1 antibody does not distinguish anogenital from orolabial infection. The CDC in Atlanta recommends that although serologic assays for HSV-2 should be made available to persons who request them, screening for HSV-1 and HSV-2 infection in the general population is not recommended.

19.6 Screening for Human Immunodeficiency Virus Infection

C Clinicians should assess risk factors for human immunodeficiency virus (HIV) infection in all persons by carefully obtaining a sexual history and inquiring about injecting drug use.

Grade C, Level IV

19.6.1 Risk groups

C Counselling and testing for HIV should be offered to all persons at increased risk of infection. These include those with STI, men who have sex with men39, past or present injecting drug users39, persons who exchange sex for drugs or money and their sex partners40, persons whose past or present sex partners were HIV-infected, and persons who have had a blood transfusion or an organ transplant that had not previously been screened41.

Grade C, Level IV 19.6.2 Screening pregnant women

Although there is insufficient evidence to show that routine antenatal screening for HIV in low prevalence areas is beneficial, a policy of offering screening to pregnant women may still be considered because

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timely institution of anti-retroviral therapy can prevent mother-to-child HIV transmission42. GPP Pregnant women should be offered the test in the first trimester.

GPP

19.6.3 Screening methods C Screening for HIV is performed using ELISA. A positive result requires 2 reactive ELISA tests and confirmation with the Western Blot (WB) assay, performed by experienced laboratories that receive regular external proficiency testing13.

Grade C, Level IV

19.6.4 Frequency of screening

Persons with nonreactive test results should be given post-test counselling. The frequency of testing of seronegative individuals is a matter of clinical discretion.

C Persons who continue to exhibit high-risk behaviour should have screening tests on a regular basis. The frequency at which these individuals are screened is a matter of clinical discretion. Screening for HIV should be performed 6-monthly in a person who continues to exhibit high-risk behaviour.

Grade C, Level IV C Persons with recent high-risk behaviour should be screened at 1 month, 3 months and 6 months after the last high-risk exposure to rule out a possible initial false negative initial result42.

Grade C, Level IV 19.7 Screening for Genital Human Papillomavirus (HPV)

infection

Genital HPV infection is a viral infection that is common among sexually active adults. Infection is almost always sexually transmitted. However, the incubation period is variable and it is often difficult to determine the source of infection13.

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C Women with a history of STI may be at increased risk for cervical cancer, which is linked to certain HPV types. However, the HPV types that frequently cause anogenital warts do not cause cancer13. The Pap smear is a screening test for cervical carcinoma and not a screening test for STIs, and women who have external genital warts do not need to have Pap smears more frequently than women who do not have warts.

Grade C, Level IV In patients without visible warts, subclinical infection may exist. In this situation, manifestations of HPV infection occur in the absence of external genital warts. Subclinical infection may sometimes be detected with the use of acetic acid application, but this is not a specific test for HPV infection, and the sensitivity and specificity of this procedure for screening have not been defined13. The CDC in Atlanta does not recommend the use of this procedure or any other means to detect subclinical infection. It also recommends that women with anogenital warts do not require Pap smears more frequently than women without warts13. C Clinical examination with the unaided eye is the oldest diagnostic technique in detection of genital warts. However, “subclinical” genital HPV infection, a condition used to refer to manifestations of infection in the absence of genital warts, may still exist. No screening tests for subclinical infection are available, and there are no recommendations for routine screening.

Grade C, Level IV References

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Ang P, Chan RK. Sexually transmitted diseases in Singapore – trends in the last two decades. Ann Acad Med 1997; 26:827-33.

Yeong CT, Lim TLW, Lin R, et al. Routine screening for Chlamydia trachomatis in subfertile women – is it time to start? Singapore Med J 2000; 41:111-3.

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Centers for Disease Control and Prevention. Recommendations for prevention and management of Chlamydia trachomatis infections. MMWR 1993; 42:1-39.

Clinical Effectiveness Group (Association of Genitourinary Medicine and the Medical Society for the Study of Venereal Diseases). National guideline for the management of Chlamydia trachomatis genital tract infection. Sex Transm Inf 1999; 75:S4-S8.

CMO’s Expert Advisory group Chlamydia trachomatis. London; Department of Health 1998.

Scholes D, Stergachis A, Heidrich FE, et al. Prevention of pelvic inflammatory disease by screening for cervical chlamydial infection. N Engl J Med 1996; 334:1362-6.

Kamwendo F, Forslin L, Bodin L, et al. Decreasing incidences of gonorrhoea and chlamydia associated acute pelvic inflammatory disease. A 25-year study from an urban area of central Sweden. Sex Transm Dis 1996; 23:384-91.

Egger M, Low N, Smith GD, et al. Screening for chlamydial infections and the risk of ectopic pregnancy in a county in Sweden: ecologic analysis. BMJ 1998; 316:1776-80.

Martin DH et al. Prematurity and perinatal mortality in pregnancies complicated by maternal Chlamydia trachomatis infections. JAMA 1982; 247:1585-8.

Sweet RL, et al. Chlamydia trachomatis infection and pregnancy outcome. Am J Obstet Gynecol 1987; 156:824-33.

Martius J, et al. Relationship of vaginal Lactobacillus species, cervical Chlamydia trachomatis, and bacterial vaginosis to preterm birth. Obstet Gynecol 1989; 129:1247-57.

Centers for Disease Control. Sexually Transmitted Diseases Treatment Guidelines 2002. MMWR 2002; 51:88-97.

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Nelson HD, Helfand M. Screening for Chlamydial infection. Am J Prev Med 2001; 20:95-107.

Quinn TC. DNA amplification assays: a new standard for diagnosis of chlamydia trachomatis infections. Ann Acad Med Singapore 1995; 24:627-33.

Puolakkainen M, Koussa M, Saikku P. Clinical conditions associated with positive complement fixation serology for Chlamydiae. Epidemiol Infect 1987; 98:101-8.

Marx R, Aral SG, Rolfs RT, et al. Guidelines for the prevention and control of congenital syphilis. MMWR 1988; 37:1-13.

Hart G. Syphilis test in diagnostic and therapeutic decision making. In Sox HC Jr, ed. Common diagnostic tests: use and interpretation. 2nd ed. Philadelphia: Lea & Febiger, 1986.

Marx R, Aral SG, Rolfs RT, et al. Congenital syphilis, United States, 1983-1985. MMWR 1986; 35:625-8.

American Academy of Pediatrics and American College of Obstetricians and Gynecologists. Guidelines for perinatal care. 3rd ed. Washington, DC, 1992; 133-5.

USPSTF “Clinical Preventive Services” Recommendations – Screening for syphilis. 2nd ed., 1996.

Centers for Disease Control and Prevention. Sexually transmitted disease guidelines. MMWR 1998; 47:40.

Stray-Pedersen B. Economic evaluation of maternal screening to prevent congenital syphilis. Sex Transm Dis 1983; 10:167-72.

Williams K. Screening for syphilis in pregnancy: an assessment of the costs and benefits. Commun Med 1985; 7: 37-42.

Eaglestone SI, Turner AJL. Serological diagnosis of syphilis. Comm Dis Public Health 2000; 3:158-62.

Hart G. Syphilis tests in diagnostic and therapeutic decision making. Ann Intern Med 1986; 104: 368-76.

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Ed: R Chan. Sexually transmitted diseases management guidelines 1999. National Skin Centre, Singapore.

Hutt DM, Judson FN. Epidemiology and treatment of oropharyngeal gonorrhoea. Ann Intern Med 1986; 104:655-8.

USPSTF “Clinical Preventive Services” Recommendations – Screening for gonorrhoea. 2nd ed., 1996.

Canadian Task Force on the Periodic Health Examination. Canadian guide to clinical preventive health care. Ottawa: Canada Communication Group. 1994; 168-175.

American College of Obstetricians and Gynecologists. Gonorrhoea and chlamydial infections. ACOG Technical Bulletin no. 190. Washington, DC: American College of Obstetricians and Gynecologists, 1994.

Goh BT, Varia KB, Ayliffe PF, et al. Diagnosis of gonorrhoea by gram-stained smears and cultures in men and women: role of the urethral smear. Sex Transm Dis 1985; 12: 135-9.

Romanowski B, Harris JRW, Wood H, et al. Improved diagnosis of gonorrhoea in women. Sex Transm Dis 1986; 13:93-6.

Centers for Disease Control. Guide for the diagnosis of gonorrhoea using culture and Gram-stained smear. Atlanta: Centers for Disease Control, 1991.

Corey L, Adams HG, Brown ZA, et al. Genital herpes simplex virus infections: clinical manifestations, course, and complications. Ann Intern Med 1983; 98:973-83.

USPSTF “Clinical Preventive Services” Recommendations – Screening for Genital Herpes Simplex. 2nd ed., 1996.

Corey L, Holmes KK. Genital herpes simplex virus infections: current concepts in diagnosis, therapy, and prevention. Ann Intern Med 1983; 98:973-83.

Center for Disease Control. Sexually Transmitted Diseases Treatment Guidelines 2002. MMWR 2002; 51:19-20.

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Centers for Disease Control and Prevention. Update: Public health surveillance for HIV infection – United States, 1989 and 1990. MMWR 1990; 39:853,859-61.

Centers for Disease Control and Prevention. HIV/AIDS surveillance report 1995; 7:1-34.

Centers for Disease Control and Prevention. Treatment guidelines 2002. MMWR 2002; 51:88-97.

USPSTF “Clinical Preventive Services” Recommendations – Screening for Human Immunodeficiency Virus infection. 2nd ed., 1996.

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20 Clinical audit

There are no clinical audit indicators recommended for general screening per se. This is because the denominator, in reference to the population that consults in the general clinic setting, cannot be determined.

This is in contrast to national screening programmes where potential clinical audit indicators can be monitored and measured.

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Self-assessment (MCQs) After reading the Clinical Practice Guidelines, you can claim one CME point under Category III (Self-Study) of the SMC Online CME System. Before you login to claim the CME point, we encourage you to evaluate whether you have mastered the key points in the Guidelines by completing this set of MCQs. This is an extension of the learning process and is not intended to “judge” your knowledge and is not compulsory. The answers can be found at the end of the section. Instruction : Choose the best answer 1. The cholesterol screening guidelines recommend screening in the

following individuals regardless of age: A. all diabetics (True/False) B. all subjects with BMI greater than 30 kg/m2 (True/False)

C. subjects with impaired glucose tolerance but not impaired fasting glycaemia (True/False)

D. subjects with intermittent claudication (True/False) E. all subjects with pre-existing coronary heart disease (True/False)

2. Subjects must be considered for cholesterol screening if: A. undergoing multiphasic health examination at 45 years of age (True/False) B. ex-smoker aged 30 years (True/False) C. family history of diabetes mellitus (True/False) D. family history of hypertension (True/False) E. family history of lipid problems (True/False) 3. Hypertension is defined as resting blood pressure A. ≥ 130/85mmHg B. ≥ 140/85mmHg C. ≥ 140/90mmHg D. ≥ 140/95mmHg E. ≥ 160/100mmHg 4. Screening of hypertension is carried out in the following situations, except

A. at least two yearly for all adults aged 21 years and above who have normal blood pressure

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B. routinely during the antenatal care for pregnant mothers C. routinely for children above the age of 7 years old D. yearly for those who are at risk such as those with diabetes mellitus,

or borderline high blood pressure E. any patient aged 21 years and above who comes to consult the doctor

in the clinic 5. Concerning screening for type 2 diabetes mellitus: A. community screening in healthy individuals is recommended B. best performed on an opportunistic basis in at risk individuals C. should be conducted in all women during pregnancy D. a repeat screen in individuals previously found to have impaired

glucose tolerance (IGT), should be conducted at 3 yearly intervals E. subject with no risk factors should be screened starting at age 20 years 6. The recommended screening test for diabetes mellitus is measurement of: A. random capillary blood glucose B. fasting plasma glucose C. glycosylated haemoglobin (HbA1c) D. urine microalbumin 7. Which of the following diagnostic modalities have been shown to be cost-

effective in screening heavy smokers for early lung cancer? A. physical examination B. sputum cytology C. chest x-ray D. plasma carcinoembryonic antigen assay E. low-dose spiral computed tomography F. none of the above 8. A 55-year-old shipyard worker with an 80 pack-year smoking history

consults you for a symptomatic exacerbation of bronchitis over the last three weeks. Hemoptysis is denied, and physical examination and chest X-ray are unremarkable. You prescribe a course of antibiotics, and also advise him:

A. to stop smoking B. to have an immediate ESR and sputum cytology performed C. to return for a follow-up chest X-ray in six months’ time, just in case

he is in the ‘window period’ prior to early radiologic screen detection D. if he is very worried about early lung cancer, he should proceed to

bronchoscopy at this time, and follow up with further bronchoscopies each year for the next five years

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E. if money is no object, he should now have a low-dose spiral CT to

exclude surgically curable lung cancer 9. Hepatocellular carcinoma (HCC) surveillance

A. is proven strongly to result in better survival in patients with hepatitis B

B. is accurate based on alfa-fetoprotein level alone C. uses CT scan or MRI as a rountine screen

D. is not proven to show survival advantage but provides assurance to the individual patient

10. One of the roles of HCC screening in Hepatitis B patient is:

A. early detection of small cancer which may benefit from surgical resection

B. to track the disease progression C. offer palliative care D. so that the whole family can be alerted and sent for screening for HCC 11. The following may be considered at high risk of developing colorectal

cancer except A. patient with a past history of colonic polyps B. sister whose brother developed colon cancer at the age of 40 years C. son whose father developed rectal cancer at the age of 80 years D. patient with longstanding ulcerative colitis 12. A man at the age of 50 years wishes to be screened for colon cancer,

option would include: A. CT scan of the abdomen B. Serum CEA C. Faecal Occult Blood Testing D. Serum AFP 13. Screening for high risk group for prostate cancer should start at age: A. 30 years B. 40 years C. 50 years D. 60 years E. 70 years 14. For a premenopausal 35 year old woman who has no symptoms or family

history of breast or ovarian cancer, the most suitable method of breast screening is:

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A. mammography B. mammography with ultrasound C. ultrasound alone D. regular self-examination E. clinical examination 15. For a 55-year old asymptomatic woman on conventional hormone

replacement therapy, breast screening is best performed using: A. mammography only at yearly intervals B. mammography only at two yearly intervals C. mammography with ultrasound at one year intervals D. mammography with ultrasound at two year intervals E. regular clinical examination 16. Population based cancer screening is appropriate for the following

gynaecological cancers: A. Ovarian Cancer B. Cervical Cancer C. Uterine Cancer D. All of the above 17. In a woman who has been having regular Pap smear tests, screening can be

discontinued at age: A. 55 years B. 60 years C. 65 years D. 70 years 18. The following factors place a woman at an increased risk for endometrial

cancer except: A. early menopause B. tamoxifen therapy C. nulliparity D. obesity 19. The following statements concerning screening for uterine cancer are true

except: A. there is insufficient evidence to establish a decrease in mortality from

uterine cancer with screening by transvaginal ultrasound B. pap smear tests are very useful for uterine cancer screening C. women with hereditary non-polyposis colorectal cancer are considered

to be at high risk for uterine cancer

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D. early evaluation of postmenopausal bleeding is important for early

detection of uterine cancer 20. The following tests have high positive predictive value for early detection

of ovarian carcinoma in women at average risk: A. routine pelvic examination B. transvaginal sonography C. serum tumour antigens D. combinations of the above E. none of the above 21. The following are true for women at high risk of ovarian carcinoma

except: A. they may have 2 or more first degree relatives with ovarian cancer B. they should be referred to tertiary centres for multimodal screening C. annual screening will reduce their mortality from ovarian cancer D. there is evidence of higher positive predictive value in screening 22. In the context of Screening for Latent TB Infection (LTBI) with the

Tuberculin Skin Test (TST), the following statements are True or False : A. the TST is recommended only for identifying candidates who are at

high risk of breakdown into TB disease, and who will therefore benefit from preventive treatment. (True/False)

B. reliable TST readings are easily obtained because intra-observer and inter-observer errors are negligible. (True/False)

C. the TST is so specific that the positive predictive value remains high even when the tested population is at a low risk of TB infection. (True/False)

D. a reactive TST in a suspected contact should be interpreted as positive and indicating preventive treatment, even when no data about the Index case, the environment in which the contact occurred, and the duration of exposure, are available. (True/False)

E. because preventive treatment with isoniazid (INH) carries a small but definite risk of hepatitis, it should be prescribed only in carefully assessed and selected subjects. (True/False)

23. You will advise hepatitis B screening to one of the following patients in

your clinic, A. a 45 year old man attending your clinic for upper respiratory tract

infection B. a 32 year old man attending your clinic for urethritis

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C. a 75 year old lady who loves to eat cockles

D. a 12 year old girl who is sure that she was vaccinated at birth but is keen to know her present hepatitis B status

24. Which of the following statements is incorrect? A. dipstick testing for proteinuria is 85% specific B. dipstick testing for proteinuria is 95% sensitive

C. positive dipstick testing for proteinuria should have protein excretion rate documented

D. To avoid 24-hour protein collection, a spot urine for Protein-Creatinine ratio can be used to quantitate the proteinuria

E. dipstick for protein of >1+ is equivalent to 30mg/dl of proteinuria 25. With regard to screening for osteoporosis, A. dual energy x-ray absorptiometry (DXA) of the hip is a cheap,

effective method of widespread screening for osteoporosis (True/False)

B. forearm DXA or calcaneal or multi-site quantitative ultrasound (QUS) are cheap, effective methods of widespread screening for osteoporosis (True/False)

C. dual energy x-ray absorptiometry (DXA) of the hip is the technique of choice to diagnose osteoporosis in selected individuals identified to be at high risk of having osteoporosis (True/False)

D. low BMD measured at the calcaneus confirms that low BMD will be found at the hip or spine (True/False)

E. a reasonable interval for follow-up BMD testing in postmenopausal women is 6 monthly (True/False)

F. the utilization of BMD measurement in clinical practice has led to enhanced success in maintaining lifestyle modifications, and in improved rates of initiating therapies for osteoporosis (True/False)

26. The following are more likely to have osteoporosis: A. a woman aged 50 years compared to one aged 70 years (True/False) B. a woman weighing 70 kg compared to one weighing 40 kg (True/False) C. a smoker compared to a non smoker (True/False) D. an individual with a family history of fracture (True/False) E. a social drinker (True/False) F. individuals on long-term corticosteroid therapy (True/False)

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27. An effective way of assessing visual function in the elderly in a primary

healthcare setting is: A. asking a person about his visual problem B. checking the visual acuity of the eyes C. a torchlight examination D. an ophthalmoscope examination 28. Measuring distance visual acuity involves: A. testing both eyes simultaneously B. testing each eye one at a time C. testing distance should be 6 feet using a standard Snellen chart D. using a newspaper for testing 29. Regarding serological testing for syphilis:

A. a negative VDRL rules out diagnosis of syphilis (True/False) B. serological tests for syphilis is strongly recommended for all pregnant

women at the first antenatal visit (True/False) C. recent viral infections can cause a false positive VDRL result

(True/False) D. patients who remain positive for VDRL and TPHA results after

treatment for syphilis represent cases of therapeutic failure (True/False)

30. Regarding screening for sexually transmitted infections:

A. screening for chlamydia trachomatis infection in women is only indicated if they are symptomatic (True/False)

B. serological tests are useful in screening for gonorrhoea (True/False) C. screening for HIV is done using the Western Blot (WB) assay

(True/False) D. Nucleic acid amplification tests such as PCR or LCR can be used

accurately on urine specimens in men to detect Chlamydia trachomatis infection (True/False)

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Answers 1A. True 22A. True1B. False 22B. False1C. False 22C. False1D. True 22D. False1E. True 22E. True2A. True 23. B 2B. False 24. B2C. False 25A. False2D. False 25B. False2E. True 25C. True3. C 25D. False4. C 25E. False5. B 25F. True6. B 26A. False7. F 26B. False8. A 26C. True9. D 26D. True10. A 26E. False11. C 26F. True12. C 27. B 13. C 28. B14. D 29A. False15. B 29B. True16. B 29C. True17. C 29D. False18. A 30A. False19. B 30B. False20. E 30C. False21. C 30D. True 176

Workgroup members The members of the workgroup, who were appointed in their personal professional capacity, are: Chairman: Prof Chee Yam Cheng Chairman, Medical Board Tan Tock Seng Hospital Members: Dr Ang Chong Lye Director Singapore National Eye Centre Prof Aw Tar Choon

Senior Consultant, Department of Laboratory Medicine National University Hospital Dr Chee Tek Siong Consultant Cardiologist Chee Heart Specialists Pte Ltd East Shore Medical Centre Dr Christopher Cheng Head, Urology Department Singapore General Hospital Assoc Prof Cheong Pak Yean President, College of Family Physicians Singapore College of Medicine Building Assoc Prof Chia Kee Seng Department of Community, Occupational And Family Medicine National University of Singapore Assoc Prof Richard Epstein Director, Division of Academic Affairs National Cancer Centre

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Prof Fock Kwong Ming Chief, Department of Medicine Chairman, Medical Board Changi General Hospital Prof Goh Chee Leok Medical Director National Skin Centre Assoc Prof Ho Tew Hong Chief of Gynaecology KK Women’s And Children’s Hospital Dr Leonard Koh Senior Consultant, Department of Endocrinology Singapore General Hospital Assoc Prof Adrian Leong Chief, Surgery Department National University Hospital Dr Tan Chee Eng Head, Department of Endocrinology Singapore General Hospital Assoc Prof Thai Ah Chuan Consultant, Department of Medicine National University Hospital Assoc Prof Wang Shih Chang Chief, Diagnostic Imaging National University Hospital Assoc Prof Sonny Wang Yee Tang Director, Tuberculosis Control Department Tan Tock Seng Hospital Dr Wong Kok Seng Senior Consultant and Head Department of Renal Medicine Singapore General Hospital Secretariat: Health Promotion Board

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Acknowledgements The Committee would like to thank the following co-authors who have assisted in drafting the guidelines. Screening for renal diseases: Dr Chan Choong Meng Consultant, Department of Renal Medicine Singapore General Hospital Prof Woo Keng Thye Senior Consultant, Department of Renal Medicine Chairman, Division of Research and Medicine Singapore General Hospital Screening for cervical/ovarian/uterine cancers: Dr Jeffrey Low Jen Hui Consultant, Gynaecological Oncology Unit KK Women’s and Children’s Hospital Dr Pritam Singh Consultant, Gynaecology Associates Women’s Medical Centre Mount Elizabeth Medical Centre Dr Tay Eng Hseon Consultant and Head, Gynaecological Oncology Unit KK Women’s and Children’s Hospital Dr Adelina Wong Associate Consultant, Gynaecological Oncology Unit KK Women’s and Children’s Hospital Screening for obesity: Dr Jeannette Lee Department of Community, Occupational and Family Medicine National University of Singapore

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Screening for blood cholesterol: Dr Tai E Shyong Consultant, Department of Endocrinology Singapore General Hospital Screening for sexually transmitted infection: Dr Roy Chan Senior Consultant, National Skin Centre Head, Department of STD Control Dr Tan Hiok Hee Consultant, National Skin Centre Deputy Head, Department of STD Control Screening for hepatitis B and liver cancer: Dr Teo Eng Kiong Consultant, Department of Medicine Changi General Hospital Screening for prostate canceer: Dr Sim Hong Gee Registrar, Department of Urology Singapore General Hospital

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List of Endorsing Agencies List of agencies/committees endorsing chapters in the guidelines on screening and members providing feedback (in alphabetical order): Academy of Medicine: (Blood cholesterol) Dr Sum Chee Fang (Diabetes mellitus) Dr Sum Chee Fang Dr Sunil Sethi (Obesity) Dr Sum Chee Fang (Lung cancer) Dr Khoo Kei Siong (Hepatocellular carcinoma) Dr Khoo Kei Siong Dr Lucien Ooi Dr Sunil Sethi (Colorectal cancer) Dr Eu Kong Weng Dr Goh Poh Sun Dr Khoo Kei Siong Dr Sunil Sethi (Prostate cancer) Dr Khoo Kei Siong Dr Michael Wong Dr Tan Puay Hoon (Breast cancer) Dr Ann S A Tan Dr Chang Tou Choong Dr Chua Yang Dr Jeffrey J H Low Dr Khoo Kei Siong Dr Lai Fon Min Dr Samuel Ng Dr Suresh Nair Dr Tan Puay Hoon Dr Thoo Fei Ling

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(Cervical cancer) Dr Ann S A Tan Dr Chang Tou Choong Dr Chua Yang Dr Jeffrey J H Low Dr Khoo Kei Siong Dr Lai Fon Min Dr Suresh Nair (Uterine cancer) Dr Ann S A Tan Dr Chang Tou Choong Dr Chua Yang Dr Jeffrey J H Low Dr Khoo Kei Siong Dr Lai Fon Min Dr Suresh Nair (Ovarian Cancer) Dr Ann S A Tan Dr Chang Tou Choong Dr Chua Yang Dr Jeffrey J H Low Dr Khoo Kei Siong Dr Lai Fon Min Dr Suresh Nair (Tuberculosis) Dr Alan Ng W K Dr Tan Ai Ling (Hepatitis B) Dr Ooi Choon Jin Dr Tan Ai Ling (Osteoporosis) Dr Julian Thumboo (Visual acuity for the elderly) Dr Ong Sze Guan Dr Suresh Sahadevan (Sexually transmitted infections) Dr Ann S A Tan Dr Chang Tou Choong Dr Chua Yang Dr Jeffrey J H Low Dr Lai Fon Min Dr Tan Ai Ling Dr Suresh Nair

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College of Family Physicians, Singapore: A/Prof Cheong Pak Yean (All chapters) A/Prof Goh Lee Gan Dr Lee Kheng Hock Dermatological Society of Singapore: Dr Cheong Wai Kwong (Sexually transmitted infections) Dr Tan Hiok Hee Diabetic Society of Singapore: Dr Lim Su Chi (Blood cholesterol, Diabetes mellitus, Dr Sum Chee Fang Obesity, Renal disease) Dr Tan Hwee Huan Dr Tavintharan Dr Yeo Kim Teck Endocrine and Metabolic Society of Singapore: Dr Daphne Khoo (Blood cholesterol, Diabetes mellitus, Obesity, Osteoporosis) National Cancer Center of Singapore Pte Ltd: Prof Soo Kee Chee (Colorectal cancer) National Committee on Cancer Care: A/Prof Adrian Leong (Colorectal cancer) A/Prof Francis Seow Choen National Committee on Renal Care: Dr A. Vathsala (Renal disease) Dr Akira Wu A/Prof Evan Lee Dr Grace Lee Dr Li Man Kay Dr Lina Choong Hui Lin Dr Wong Kok Seng Prof Woo Keng Thye Prof Yap Hui Kim Co-opted Dr Gordon Ku Dr Pary Sivaraman Dr Stephen Chew Dr Tan Han Khim

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Obstetrical & Gynaecological Society of Singapore: Dr Chia Yin Nin (Cervical, Uterine and Ovarian cancers) Dr Tay Eng Hseon Osteoporosis Society (Singapore): Dr Lau Tang Ching (Osteoporosis) Dr Leonard Koh Dr Leong Keng Hong Ms Louisa Zhang Dr Noor Hafizah Dr Saw Seang Mei Prof Shamal Das De Dr Tan Seang Beng Singapore Cancer Society: Prof Low Cheng Hock (Colorectal cancer) A/Prof Michael Hoe Singapore Cardiac Society: Prof Chia Boon Lock (Blood cholesterol, Hypertension) Dr Low Lip Ping Singapore Diabetes Guidelines: A/Prof Thai Ah Chuan (Blood cholesterol) Singapore Lipid Guidelines Workgroup: Prof Chia Boon Lock (Blood cholesterol) Dr Tan Chee Eng Singapore Hypertension Society: Dr Low Lip Ping (Hypertension) Singapore National Heart Association: Dr Low Lip Ping (Blood cholesterol, Obesity) Singapore Radiological Society: Dr Andrew Tan Gee Seng (Breast cancer) Dr Anthony Goh Soon Huat Dr Gervais Wan Saicheong Dr Harvey Teo Eu Leong Dr Hoe Wei Ming John A/Prof Wang Shih Chang

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Singapore Society of Ophthalmology: Dr Aliza Jap (Visual acuity for the elderly) Dr Daniel Sim Han Jen Dr Francis Oen Tuck Soon Dr Geh Min Dr Hoh Sek Tien Dr Lim Boon Ang Dr Rahat Husain Dr Steve Seah Kah Leng Singapore Thoracic Society: Dr Alan Ng (Lung cancer, Tuberculosis) Dr Constance Lo

Dr John Abisheganaden Dr Kong Po Marn

Dr Lee Pyng Prof Lim Tow Keang Dr Loo Chian Min Dr Yap Wee See Singapore Urological Association: Dr Chin Chong Min (Prostate cancer) Dr Christopher Cheng Dr Damian Png Dr David Consigliere Dr I Swaminathan Dr James Tan Dr Lewis Liew Dr Ng Foo Cheong Dr Pearllyn Quek Dr Sam Peh Dr Weber Lau Kam On The Protem Committee of the Association of Colorectal Surgeons (Singapore): Dr Goh Hak Su (Colorectal cancer) The Society for Colposcopy and Cervical Pathology of Singapore: Dr Adelina Wong (Cervical, Uterine and Ovarian cancers) Dr Jeffrey Low Jen Hui Dr Pritam Singh Dr Tay Eng Hseon

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Agencies vetting chapters in the guidelines on screening: Gastroenterological Society of Singapore (Liver Group): Dr Dede Sutedja (Hepatocellular carcinoma & Hepatitis B) Dr Lui Hock Foong Prof Ng Han Seong Dr Ong Tze Zen Dr Roland Chong Siong Eng Dr Tan Chee Kiat Dr Teo Eng Kiong Dr Yap Chin Kong The Cancer Institute and A/Prof Benjamin Ong and Dr JJ Murkherjee (Lung cancer, Hepatocellular carcinoma, Colorectal cancer, Prostate cancer, Breast cancer)

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Health Screening (Summary Booklet)

NMRC

National Medical Research Council

Ministry of Health Mar 2003


Levels of evidence and grades of recommendation

Levels of evidence Level Type of Evidence

Ia

Ib

IIa

IIb

III

IV

Evidence obtained from meta-analysis of randomised controlled trials.

Evidence obtained from at least one randomised controlled trial.

Evidence obtained from at least one well-designed controlled study without randomisation

Evidence obtained from at least one other type of well-designed quasi-experimental study.

Evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies and case studies.

Evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities.

Grades of recommendation Grade Recommendation

A (evidence levels Ia,

Ib)

B (evidence levels IIa,

IIb, III)

C (evidence level IV)

GPP (good practice

points)

Requires at least one randomised controlled trial as part of the body of literature of overall good quality and consistency addressing the specific recommendation.

Requires availability of well conducted clinical studies but no randomised clinical trials on the topic of recommendation.

Requires evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities. Indicates absence of directly applicable clinical studies of good quality.

Recommended best practice based on the clinical experience of the guideline development group.

Executive summary of recommendations

Details of recommendations can be found in the main text at the pages indicated. Screening for blood cholesterol C In screening for cholesterol, the optimal test is a full lipid profile including LDL-cholesterol, fasting triglyceride and HDL cholesterol. (pg 25)

Grade C, Level IV

GPP If the results are optimal based on the current recommendations for Singapore, we recommend repeat screening at 3 yearly intervals. (pg 24)

GPP

B Screening should be carried out in all individuals above the age of 40 years on an opportunistic basis. (pg 24)

Grade B, Level IIb A All patients with pre-existing coronary heart disease, stroke or peripheral vascular disease should be screened irrespective of age. (pg 24)

Grade A, Level Ia A All patients with diabetes mellitus should be screened irrespective of age. (pg 24)

Grade A, Level Ib B All individuals with impaired fasting glycaemia or impaired glucose tolerance should be screened at any age. (pg 24)

Grade B, Level III B All individuals with a family history and/or clinical evidence of familial hyperlipidaemia should be screened after the age of 2 years. (pg 24)

Grade B, Level IIa GPP Earlier screening from age 30 should be considered for individuals with other risk factors for CHD e.g. smoking, hypertension, family history of premature CHD. (pg 24)

GPP

1

B Earlier screening from age 30 years should be considered for those of Indian ethnicity. (pg 24)

Grade B, Level III Screening for hypertension

C Blood pressure should be measured at least once every 2 years for adults aged 21 years and above with diastolic pressure below 85 mmHg and a systolic pressure below 130 mmHg (i.e. normal BP). (pg 30)

Grade C, Level IV A Measurements are recommended annually for persons with a diastolic blood pressure of 85-89 mmHg or systolic blood pressure of 130-139 mmHg (i.e. high normal BP). Persons with higher blood pressures or major coronary risk factor such as diabetes mellitus require more frequent measurement. (pg 30)

Grade A, Level Ib C Any person aged 21 years and above should have their blood pressure measured during any visit to a physician ("case finding"). (pg 31)

Grade C, Level IV A Sphygmomanometry is the recommended method for blood pressure measurement, and it should be performed in accordance with the recommended technique. (pg 31)

Grade A, Level Ia A Pregnant women should have their blood pressure checked routinely as part of the prenatal care. (pg 32)

Grade A, Level Ia A Routine counselling to promote physical activity and a healthy diet for the primary prevention of hypertension is recommended for all adults. (pg 31)

Grade A, Level Ia

Screening for diabetes mellitus C Screening of asymptomatic individuals at high risk for type 2 diabetes mellitus should be carried out on an opportunistic basis. (pg 35)

Grade C, Level IV

2

C Screening should begin at age 40 years, and be considered at an earlier age (e.g. 30 years) if risk factors for diabetes are present. (pg 35)

Grade C, Level IV

B Fasting plasma glucose (FPG) is the recommended test for screening in the clinical setting because it is easy to perform and convenient. Individuals with a FPG ≥ 7.0 mmol/L should have a repeat testing on a different day to confirm the diagnosis of diabetes. Individuals with FPG of 6.1-6.9 mmol/l on screening should undergo a 75g oral glucose tolerance test (OGTT) to determine precisely the degree of glucose intolerance. (pg 38)

Grade B, Level III B OGTT is also a suitable test for screening. (pg 38)

Grade B, Level III

C Individuals found to have normal glucose tolerance on screening and who do not have risk factors for developing diabetes should have repeat screening at 3 yearly intervals. For those with diabetes risk factors, repeat screening may be performed more frequently e.g. at annual interval.

(pg 39) Grade C, Level IV

B Those detected to have impaired fasting glycemia (IFG) or impaired glucose tolerance (IGT) should have repeated screening on an annual interval in view of the high rate of conversion to diabetes. (pg 39)

Grade B, Level III Screening for obesity B Body mass index (BMI) and waist circumference can be used to classify obesity and assess risk. (pg 41)

Grade B, Level III

C All individuals ≥18 years of age should be screened. (pg 42) Grade C, Level IV

GPP Screening should be done once a year for all individuals ≥ 18 years. (pg 42)

GPP

3

Screening for lung cancer A Neither chest X-ray nor sputum cytology is recommended for screening. (pg 46)

Grade A, Level Ib

C The screening efficacy of low-dose spiral CT is unknown at present. (pg 46)

Grade C, Level IV Screening for hepatocellular carcinoma (HCC) GPP There is no evidence to support population-based surveillance for HCC. However, HCC surveillance should be offered to patients with chronic hepatitis B infection, hepatitis C liver cirrhosis and liver cirrhosis from other etiologies. HCC surveillance should be performed periodically with alpha-fetoprotein 3 to 6 monthly and ultrasound of the liver at 6 to 12 monthly interval. There is no definite recommended age to start surveillance. However, it is noted that the local statistics showed that HCC detection starts to increase from the age of 30 years. (pg 52)

GPP

C Current accepted tests used for HCC surveillance include ultrasound of the hepato-biliary system and alpha feto-protein level. (pg 49)

Grade C, Level IV Screening for colorectal cancer A Asymptomatic individuals above the age of 50 years should undergo screening for colorectal cancer. This would include asymptomatic individuals with a family history limited to non-first degree relatives. The screening options would be faecal occult blood testing annually. (pg 62)

Grade A, Level Ia

B Alternatively, other methods that could be employed in this group include flexible sigmoidoscopy every 5 years; (pg 62)

Grade B, Level IIa

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B or colonoscopy every 10 years. (pg 62)

Grade B, Level IIb (Those with a positive faecal occult blood test would undergo colonoscopy or when technically not possible, a barium enema.)

B In individuals with a history of colorectal cancer in a first degree relative aged 45 years or younger or with a family history of two or more affected first degree relatives, colonoscopy is recommended every 3 years performed 10 years prior to the youngest case in the family. (pg 62)

Grade B, Level IIa

B In individuals who have a history of colorectal cancer in a first degree relative over the age of 45 years, colonoscopy is recommended every 10 years. The age of commencing colonoscopy is 10 years prior to the youngest case in the family or age 50 years whichever is earlier. (pg 62)

Grade B, Level IIb

A In individuals with a personal past history of colorectal polyps, colonoscopy is recommended one year after polypectomy in the presence of high risk features (polyp > 1cm, multiple, villous architecture) or three years after polypectomy in the absence of high risk features (solitary, tubular architecture). (pg 62)

Grade A, Level Ib

B In individuals with a personal past history of colorectal cancer, colonoscopy is recommended one year after resection provided that total imaging of the bowel was achieved prior to surgery. (pg 62)

Grade B, Level IIa

B In individuals with a family history of familial adenomatous polyposis, flexible sigmoidoscopy is recommended annually from the onset of puberty. (pg 62)

Grade B, Level IIb Genetic counselling should be considered.

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B In individuals with a family history of Hereditary Non-polyposis Colorectal Cancer, colonoscopy is recommended every two years 10 years prior to the diagnosis of colorectal cancer in the youngest family member. (pg 62)

Grade B, Level IIb

Genetic counselling should be considered. B In individuals with left-sided ulcerative colitis, colonoscopy is recommended every 1-2 years from the 15th year after diagnosis. For individuals with pan-colitis, colonoscopy is recommended every 1-2 years from the 8th year after diagnosis. (pg 62)

Grade B, Level IIb

C Plasma CEA (carcinoembryonic antigen) levels are not recommended for use in the screening of asymptomatic, average risk individuals. (pg 61)

Grade C, Level IV Screening for prostate cancer A Population screening for prostate cancer should not be recommended at present among Asians. (pg 68)

Grade A, Level Ia GPP High-risk men, such as men above 50 years of age with a history of a first degree relative with prostate cancer at a young age (<60 years), should be offered screening. (pg 68)

GPP

B Combined use of prostate specific antigen (PSA) and digital rectal examination (DRE) has a higher detection rate for prostate cancer than either test alone. (pg 68)

Grade B, Level IIb

B Transrectal ultrasound (TRUS)-guided biopsy for raised PSA and/or abnormal DRE is recommended. (pg 69)

Grade B, Level IIb

6

Screening for breast cancer A All normal risk, asymptomatic women 50-64 years of age should be screened with mammography only, every 2 years. Ultrasound and breast examination are not routinely required. (pg 80)

Grade A, Level Ia A In Western nations, the evidence supports mammographic screening every 2 years for all normal risk women 65-75 years of age. However, for Singaporean women the much lower incidence of breast cancer in this age group suggests that screening mammography may be less beneficial. If individual screening is performed, it should be at two-yearly intervals. Ultrasound and breast examination are not routinely required. (pg 80)

Grade A, Level Ia

A Women with breast implants are recommended to have routine screening mammography once every 1-2 years, depending on their age. (pg 87)

Grade A, Level Ia A Normal risk, asymptomatic women under 40 years should not undergo breast screening with any imaging modality. (pg 81)

Grade A, Level Ib

A Clinical breast examination has been proven to confer no mortality benefit in a screening population. (pg 83)

Grade A, Level Ib

B Breast ultrasound and MRI can both detect cancers that are occult on mammography. However, they should not be used for routine breast screening outside of clinical trials. (pg 84)

Grade B, Level IIa

B Nuclear scintimammography shows promise as an adjunct technique for detection of breast cancer in limited circumstances, usually in conjunction with mammography. Its use for breast screening is unwarranted. (pg 85)

Grade B, Level III

7

C Women at normal risk aged 40-49 years should be encouraged to have annual screening mammography. Ultrasound and breast examination are not routinely required. (pg 81)

Grade C, Level IV C Women on conventional hormone replacement therapy have a very slightly increased risk of breast cancer. They should have regular screening mammography. Those aged 40-49 years should be screened annually, and those aged 50-65 years biannually, for up to 5 years after cessation of HRT. (pg 81)

Grade C, Level IV C Women who are at very high risk of breast cancer by virtue of being a BRCA gene carrier, or a very strong first-degree family history of breast cancer, should perform monthly breast self examination, 6-monthly clinical breast examination and ultrasound, and annual mammography. Screening should start as early as 5 years before the age of onset of breast cancer in the youngest family member. Breast magnetic resonance imaging should be considered, but only if cost is not problematic and the expertise and equipment for MRI-guided breast needle biopsy and localisation are available. (pg 82)

Grade C, Level IV C Thermography and Electrical Impedance Scanning must be regarded as investigational techniques. Their use for breast screening is not warranted. (pg 86)

Grade C, Level IV GPP Women with prior breast cancer should receive annual screening mammography of the remnant and contralateral breasts. At 5 years disease-free post-surgery, they may return to the standard screening interval for asymptomatic women of the same age. (pg 86)

GPP

GPP Despite evidence that it has no survival benefits, BSE is generally recommended as it is felt to improve women’s awareness of their own breasts and breast cancer. As the incidence of breast cancer is extremely low before the age of 30 years, BSE is only recommended from the age of 30 years for normal risk women. (pg 84)

GPP

8

GPP When encountered, women with free silicone or paraffin oil injections in their breasts should be clinically examined and counselled as to the futility of screening using any currently available test. MRI may be useful in highly selected cases where there is a strong suspicion of breast cancer. (pg 87)

GPP

Screening for cervical cancer

B Well-run population-based cervical cancer screening programme with good coverage reduces the incidence and mortality of cervical cancer. (pg 96)

Grade B, Level IIa B All women who have ever had sexual intercourse should have a Pap smear by the age of 25 years. (pg 96)

Grade B, Level III B Pap smear screening should be performed every 3 years. (pg 96)

Grade B, Level IIa B Screening can be discontinued at age 65 years if the smear taken at age 65 years was negative and the previous smears were negative. (pg 96)

Grade B, Level III

B HIV positive women should be screened earlier and more frequently, preferably annually. (pg 97)

Grade B, Level III Screening for uterine cancer B There is no indication that screening is warranted for women who are at average or increased risk* for endometrial cancer. (pg 102)

Grade B, Level IIb *Women may be regarded as being average risk, increased risk or high risk for endometrial cancer. C Hereditary Non-Polyposis Colorectal Cancer is a syndrome in which there is an inherited tendency to develop colorectal cancer. Women with or

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at risk for hereditary non-polyposis colorectal cancer (HNPCC) are considered high risk and should be offered annual screening for endometrial cancer with endometrial biopsy by age 35 years. (pg 102)

Grade C, Level IV

Screening for ovarian cancer B Routine population screening for ovarian cancer by ultrasound, the measurement of tumour markers, or pelvic examination is not recommended. (pg 105)

Grade B, Level IIa

GPP There is insufficient evidence to recommend for or against the screening of asymptomatic women at increased risk of developing ovarian cancer. Experts suggest referral of these women to tertiary centres for multimodal screening. (pg 106)

GPP

Screening for tuberculosis A Tuberculin Skin Test (TST) screening for latent TB infection is recommended only for identifying candidates for treatment of latent TB infection (generally with isoniazid, INH). Therefore, it is recommended only in persons at high risk of breakdown to TB disease. (pg 113)

Grade A, Level Ib (Indiscriminate screening or erroneous selection of subjects could lead to the needless administration of INH and the unnecessary exposure of these subjects to the risk of drug-induced hepatitis which in some cases may be fatal.) B As a rule, mass chest X-ray screening for TB is not recommended. (pg 114)

Grade B, Level III Screening for hepatitis B A All pregnant women should be tested for HBsAg during the early antenatal visit. The test may be repeated in the third trimester if acute

10

hepatitis is suspected, an exposure to hepatitis has occurred or the woman practices a high-risk behaviour such as intravenous drug abuse. (pg 120)

Grade A, Level Ib A Serological screening for HBsAg and anti-HBs should be performed pre-vaccination for all except newborn. (pg 121)

Grade A, Level Ib A Persons who remain at risk of HBV infection such as health care workers and dialysis patients should be screened using HBsAg and anti-HBs and vaccinated against hepatitis B if the test is negative. Such individuals should then be tested for response to the vaccination. (pg 121)

Grade A, Level Ib B Screening high risk individuals like those with a family history of hepatitis B infection, liver cancer or those at high behavioural risk should be performed. They should be tested at baseline and whenever exposure is suspected. (pg 121)

Grade B, Level IIa C Routine screening for HBV infection in the general population is not recommended but recommendations for screening may be made based on cost-effectiveness analyses. Such analyses suggest that screening can be cost-effective in groups with an HBV marker prevalence >20%. (pg 121)

Grade C, Level IV Screening for renal diseases C A healthy asymptomatic individual may undergo opportunistic screening with urine dipstick examination. (pg 125)

Grade C, Level IV C Specific individuals at increased risk (e.g. age over 50 years, hypertension, smoking, diabetes and family history of renal disease) of chronic renal disease should undergo annual dipstick testing for proteinuria. (pg 125)

Grade C, Level IV

11

C Individuals at increased risk of developing chronic renal disease should undergo testing of serum creatinine in order to estimate the level of glomerular filtration rate. (pg 126)

Grade C, Level IV C Individuals with a positive dipstick proteinuria should have a spot urinary protein-creatinine ratio test to quantitate their proteinuria. (pg 125)

Grade C, Level IV Screening for osteoporosis C All individuals with prior fragility fractures during adulthood should be considered for BMD measurement and osteoporosis treatment. (pg 133)

Grade C, Level IV C Population screening using BMD is not recommended for postmenopausal women. A case-finding strategy is preferred, measuring BMD in individuals at highest risk for osteoporosis identified using clinical evaluation tools such as OSTA or NOF guidelines, and clinical risk factor evaluation. (pg 138)

Grade C, Level IV

C Women with osteoporosis, who are being monitored for progression or who are being treated, should have a follow-up bone density measurement, usually at an interval of at least one year. In women with osteopenia, a reasonable interval might be 1 to 2 years, while in those with normal BMD, a more reasonable interval may be 2 to 5 years. (pg 138)

Grade C, Level IV C Screening is not recommended for premenopausal women and men. BMD measurement should be considered in those at high risk for fracture. (pg 138)

Grade C, Level IV C BMD measurement should be considered in patients with high risk for steroid-associated fractures, who are initiating or already on long-term higher-dose corticosteroid therapy. (pg 138)

Grade C, Level IV

12

Screening for visual acuity for the elderly B The population to be screened includes any person 65 years and above, and the screening test involves using a Snellen chart to test each eye. (pg 143)

Grade B, Level III B Any person screened and found to have vision worse than 6/12 can be referred for assessment and treatment. (pg 144)

Grade B, Level III C The optimal frequency for screening is not known and is left to the discretion of the screener. (pg 144)

Grade C, Level IV C Besides visual acuity testing using the Snellen chart, there is insufficient evidence to recommend for or against routine screening with ophthalmoscopy by the primary care physician in asymptomatic elderly patient. (pg 144)

Grade C, Level IV Screening for other sexually transmitted infections Chlamydia trachomatis infection A Sexually active women with the following risk factors may be at higher risk of chlamydial infection and should be considered for screening: those aged 25 years and younger, who have a new sexual partner, who have partners with symptoms of an STI or who have had two or more partners in the past 12 months and lack the use of barrier contraception. (pg 147)

Grade A, Level Ib A Women undergoing termination of pregnancy with risk factors (as above) should be screened. (pg 147)

Grade A, Level Ib

B Pregnant women aged 25 years and younger and other pregnant women at higher risk for infection (i.e. women who have had two or more sexual partners in the past 12 months, or partners with symptoms of an STI) should be considered for screening. (pg 147)

Grade B, Level IIb

13

C Women undergoing instrumentation of the uterus should be considered for screening on an individual case basis because even in low prevalence groups, there may be a resultant risk of ascending infection. (pg 147)

Grade C, Level IV C Asymptomatic men with high-risk behaviour such as frequent partner change, lack of use of barrier protection or sex with prostitutes can be considered for screening. These patients should be referred to specialist centres for counselling, and investigation. (pg 148)

Grade C, Level IV A Screening can be performed using cultures or enzyme immunoassays (EIA) on endocervical swabs in women and urethral swabs in men. (pg 148)

Grade A, Level Ia A Nucleic acid amplification tests (NAAT) using polymerase chain reaction (PCR) or ligase chain reaction (LCR) can also be used in screening on endocervical or urethral swabs, and have the advantage of being used on non-invasive specimens such as urine. (pg 148)

Grade A, Level Ia C Serological tests based on genus-specific complement fixation test are not useful in the diagnosis of chlamydial genital infections, with the possible exception of lymphogranuloma venereum. (pg 149)

Grade C, Level IV GPP In men, a Gram-stained urethral smear taken 4 hours from the last void of urine showing presence of 5 or more leukocytes per high-power field indicates urethritis. This may be due to Chlamydia trachomatis or other organisms, as well as other factors that may not be sexually transmitted. These patients should be assessed by specialist centres for counselling and advice. (pg 148)

GPP

GPP The optimal frequency of screening is a matter of clinical discretion. Screening for chlamydia infection should be performed about 1 week after high-risk exposure or change of sex partner. (pg 149)

GPP

14

Syphilis C All women and men at increased risk for infection, including sex workers, persons who exchange sex for money or drugs, persons with other STIs (including HIV) and genital ulceration, and sexual contacts of persons with active syphilis should be screened. (pg 150)

Grade C, Level IV B Pregnant women should be screened at their first antenatal visit. (pg 151)

Grade B, Level III C Pregnant women at higher risk of infection (i.e. women who have partners with symptoms of an STI, or continue to engage in sexual activity with multiple partners, or a partner who has sex with multiple partners) should have screening repeated in the third trimester. (pg 151)

Grade C, Level IV C Screening for syphilis is performed using nontreponemal tests such as RPR or VDRL. Positive results should be confirmed with a specific test such as TPPA or TPHA. Both nontreponemal and treponemal tests can be combined for use in screening, although this would be more costly and labour-intensive. (pg 152)

Grade C, Level IV C Follow up serologic tests should be obtained to document declines in titres after treatment. They should be performed using the same test initially used to document infection (e.g. VDRL or RPR) to ensure compatibility. (pg 153)

Grade C, Level IV GPP The optimal frequency of screening is a matter of clinical discretion. Screening for syphilis should be performed 1 month after exposure, and repeated again after 3 months. (pg 152)

GPP

15

Gonorrhoea C Women at high risk of infection – including sex workers, women with a history of repeated episodes of gonorrhoea, and women with two or more sex partners in the previous year should be screened. (pg 154)

Grade C, Level IV GPP Homosexual men with frequent partner change or other high-risk behaviour (i.e. those who have sex with partners with symptoms of an STI, those who do not use barrier protection including unprotected receptive and insertive oral and anal intercourse) should be considered for screening. (pg 154)

GPP

C The ideal screening test is isolation of Neisseria gonorrhoeae by culture from the appropriate sites. (pg 154)

Grade C, Level IV GPP Sites to be sampled will be determined by the history of sexual contact – urethra, cervix, rectum or pharynx. (pg 155)

GPP

GPP The optimal frequency of screening is a matter of clinical discretion. Screening for gonorrhoea should be performed about 1 week after exposure. (pg 155)

GPP

Genital Herpes Simplex GPP Routine screening for genital herpes simplex virus (HSV) infection by viral culture, serology or other means is not recommended for asymptomatic men or women, including asymptomatic pregnant women. (pg 155)

GPP

HIV C Clinicians should assess risk factors for HIV infection in all persons by obtaining a careful sexual history and inquiring about drug use. (pg 156)

Grade C, Level IV

16

C Counselling and testing for HIV should be offered to all persons at increased risk of infection. These include those seeking treatment for STI; men who have sex with men; past or present injecting drug users; persons who exchange sex for drugs or money and their sex partners; persons whose past or present sex partners were HIV-infected, and persons who have had a blood transfusion or an organ transplant that had not previously been screened. (pg 156)

Grade C, Level IV GPP Pregnant women should be offered the test in the first trimester. (pg 157)

GPP

C Screening for HIV is performed using ELISA. A positive result requires 2 reactive ELISA tests and confirmation with the Western Blot (WB) assay, performed by experienced laboratories that receive regular external proficiency testing. (pg 157)

Grade C, Level IV C Persons who continue to exhibit high-risk behaviour should have screening tests on a regular basis. The frequency at which these individuals are screened is a matter of clinical discretion. Screening for HIV should be performed 6-monthly in a person who continues to exhibit high-risk behaviour. (pg 157)

Grade C, Level IV C Persons with recent high-risk behaviour should be screened at 1 month, 3 months and 6 months after the last high-risk exposure to rule out a possible initial false negative result. (pg 157)

Grade C, Level IV Genital Human Papillomavirus (HPV) infection C Women with a history of STI may be at increased risk for cervical cancer, which is linked to certain HPV types. However, the HPV types that frequently cause anogenital warts do not cause cancer. The Pap smear is a screening test for cervical carcinoma and not a screening test for STIs, and women who have external genital warts do not need to have Pap smears more frequently than women who do not have warts. (pg 158)

Grade C, Level IV

17

C Clinical examination with the unaided eye is the oldest diagnostic technique in detection of genital warts. However, subclinical genital HPV infection, a term used to refer to manifestations of infection in the absence of genital warts, may still exist. No screening tests for subclinical infection are available, and there are no recommendations for routine screening. (pg 158)

Grade C, Level IV

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Documents

These guidelines have been withdrawn · These guidelines have been withdrawn MOH clinical practice guidelines are considered withdrawn five years after publication unless otherwise