Review
Cancer prevention in Asia: resource-stratified guidelines from the Asian Oncology Summit 2013 Arb-aroon Lertkhachonsuk, Cheng Har Yip, Thiravud Khuhaprema, Ding-Shinn Chen, Martyn Plummer, Sun Ha Jee, Masakazu Toi, Sarikapan Wilailak
With economic growth in Asia, cancer has become increasingly prominent as a major health problem. However, discrepancies in infrastructure, economics, and development exist within and between Asian countries. We assess means of primary and secondary prevention for cervical, breast, colorectal, and hepatocellular cancer, and offer recommendations according to resource levels. Primary prevention by health education, lifestyle modification, and avoidance of risk factors should be made available at all resource levels. When resources allow, human papillomavirus and hepatitis B vaccinations should be given to reduce the risk of cervical and hepatocellular cancer, and genetic testing should be offered to detect increased susceptibility to colorectal and breast cancer. Secondary prevention by effective yet affordable screening for precancerous lesions or by early detection of cancer should be offered, followed by appropriate treatment.
Introduction Cancer is one of the biggest health problems in Asia. In 2008, there were an estimated 6·1 million new cancer cases and 4·1 million deaths from cancer in Asia, with age-standardised incidence and mortality rates of 153·6 and 102·6 per 100 000 years, respectively.1,2 The control of cancer would be best achieved by prevention, with primary prevention by avoidance of known risk factors and secondary prevention by screening for early detection and treatment. Asia is a region with diverse ethnicities, cultures, and resources. Gross domestic product varies between countries, and discrepancies in resource levels are evident between regions within countries. Guidelines for Asian countries should therefore be tiered according to resources available. Here, we discuss the prevention of cervical, breast, colorectal, and hepatocellular cancer in Asia, based on resource stratification into a four-tier system (ie, basic, limited, enhanced, and maximum) as originally described by the Breast Health Global Initiative.3 The recommendations were formulated by a panel of gynaecological, surgical, and medical oncologists, and with hepatologists in a breakout session held as part of the fifth Asian Oncology Summit in Bangkok, Thailand, on March 24, 2013.
Cervical cancer Cervical cancer is the third most common cancer in women worldwide, after breast and colon cancer. In Asia, cervical cancer is the second most common after breast cancer. According to GLOBOCAN 2008, there were 160 000 new cases in Asia that year, with age-standardised incidence and mortality rates of 15·3 per 100 000 women per year and 7·9 per 100 000 women per year, respectively (table 1). The rates are highest in south-central Asia and lowest in west Asia. A generally downward trend in incidence and mortality was recorded in most parts of Asia.1,2 Panel 1 shows factors associated with cervical cancer. Most cervical cancers are caused by human papillomavirus www.thelancet.com/oncology Vol 14 November 2013
(HPV). Persistent infection of cervical epithelial cells by high-risk HPV subtypes can result in integration of the viral genome into cell DNA and start of carcinogenetic processes.4,5 Thus, any means that prevents HPV infection reduces the incidence of cervical cancer. Cigarette smoking is associated with increased risk of squamous-cell carcinoma, with a relative risk (RR) of 1·5 (95% CI 1·33–1·66).6 This increased risk might be explained by the decrease in number of Langerhan’s cells.7 Long-term use of oral contraceptive pills is also associated with increased incidence of cervical cancer. The risk seems to increase with duration of use, with an odds ratio (OR) of 2·82 (95% CI 1·46–5·42) after 5–9 years of use, increasing to 4·03 (2·09–8·02) after more than 10 years of use.8,9 Other reproductive factors associated with cervical cancer are high parity,10 large lifetime number of sexual partners,6 and early age at first sexual intercourse.11
Primary prevention The aim of primary cervical cancer prevention is to prevent HPV infection. Because most cases of cervical cancer are caused by HPV infection, vaccination against high-risk HPV infection decreases incidence of cervical cancer. Two types of vaccine are available—quadrivalent and bivalent. Both vaccines were designed to prevent infection by HPV 16 and 18—the two most common high-risk HPV types that cause roughly 70% of cervical cancers worldwide. The quadrivalent vaccine also protects against HPV types 6 and 11, which cause genital condyloma. Both vaccines showed more than 90% efficacy in prevention of HPV 16 and 18-related cervical intraepithelial neoplasia (CIN) of grade 3 or worse, especially in young women who had not been infected with HPV.12,13 Evidence suggests that the vaccines also provide cross-protection against other less common HPV types that cause cervical cancer.14 Similar to other vaccines, HPV vaccines would be most beneficial if administered before HPV exposure—ie, before first sexual intercourse. HPV vaccination has been
Lancet Oncol 2013; 14: e497–507 Department of Obstetrics and Gynecology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand (A-a Lertkhachonsuk MD); Sime Darby Medical Centre, Subang Jaya, Malaysia (C H Yip FRCS); Surgical Oncology Division, National Cancer Institute, Bangkok, Thailand (T Khuhaprema MD); Department of Internal Medicine, National Taiwan University College of Medicine and Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan (Prof D-S Chen MD); Infections and Cancer Epidemiology Group, International Agency for Research on Cancer, Lyon, France (M Plummer PhD); Department of Epidemiology, Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, South Korea (Prof S H Jee PhD); Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan (Prof M Toi PhD); and Department of Obstetrics and Gynaecology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand (Prof S Wilailak MD) Correspondence to: Prof Sarikapan Wilailak, Department of Obstetrics and Gynaecology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Rama VI Road, Bangkok 10400, Thailand [email protected]
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Cervical cancer
Breast cancer
Colon cancer: women
Colon cancer: men
Liver cancer: women
Liver cancer: men
Incidence Mortality
Incidence Mortality
Incidence Mortality
Incidence Mortality
Incidence Mortality
Incidence Mortality
Nepal
32·4
17·6
23·5
11·9
4·8
3·5
5·3
4·0
1·1
1·1
1·7
1·6
Bangladesh
29·8
17·9
27·2
13·6
4·0
3·0
4·5
3·7
3·5
3·5
4·1
4·1
India
27·0
15·2
22·9
11·1
3·5
2·5
4·3
3·2
1·2
1·1
3·2
3·0
Thailand
24·5
12·8
30·7
10·8
13·4
6·5
13·2
6·4
19·9
16·6
40·6
35·1
Malaysia
17·9
5·6
37·0
14·7
15·5
10·1
19·6
13·0
3·0
2·9
8·4
8·1
South Korea 10·9
2·8
38·9
5·3
25·6
7·4
46·9
13·9
10·6
7·3
38·4
28·4
Taiwan
38·2
10·2
4·6
52·8
9·9
29·7
10·6
40·2
15·6
20·0
14·1
52·0
Japan
9·8
2·6
42·7
9·1
22·8
8·9
41·7
15·2
5·8
4·7
17·6
14·5
China
9·6
4·3
21·6
5·7
12·2
5·9
16·3
8·0
13·7
13·1
37·4
34·1
Singapore
6·8
3·5
59·9
13·6
28·3
10·7
41·6
18·1
3·8
4·5
17·0
14·0
Table 1: Age-standardised incidence and mortality rates per 100 000 for cervical, breast, colon, and liver cancer in Asia
1
Panel 1: Factors associated with cervical cancer HPV inection • Cigarette smoking • Long-term use of oral contraceptive pills • Other: high parity, number of sexual partners, early age of sexual intercourse
implemented as a national programme in many developed countries. In the UK, the vaccine is given to all girls aged 12–13 years, with a catch-up programme to vaccinate those up to 18 years of age.15 In the USA, the Centers for Disease Control and Prevention recommended vaccination to girls and boys at the age of 11 or 12 years, and a catch-up programme for those who did not get the vaccine up to the age of 26 years for women and 21 years for men.16 WHO recommended giving the vaccine to girls aged 9–13 years, before they become sexually active.17 In developing countries, the cost of the vaccine is still high in relation to their gross domestic product. However, Bhutan and Malaysia have introduced HPV vaccination successfully in their national programmes.18 The GAVI Alliance can support these countries by cofinancing the vaccine, and has negotiated a price of US$5 per dose. In 2013, eight developing countries, including Laos, were announced to be the first countries to receive support from the GAVI Alliance. In countries that cannot afford the HPV vaccine, provision of health education about cervical cancer, HPV, risk factors, methods of spread, prevention, and screening to not only girls, but also the whole community, would be valuable for the prevention of disease.
Secondary prevention The aim of secondary cervical cancer prevention is early detection by screening followed by treatment. The most common methods of screening are cytological screening for precancerous lesions, visual inspection with acetic acid (VIA), and HPV DNA testing. Cervical cytology has been e498
the standard method for cervical cancer screening since the 1940s, although sensitivity and specificity of the technique varied in earlier studies. Findings from a metaanalysis in 1995 showed that the conventional Pap smear had a mean sensitivity of 58% (range 11–99%) and specificity of 69% (14–97%).19 Liquid-based cytology (LBC) was introduced in the 1990s to solve the problems of sample inadequacy; however, conclusions from metaanalyses of non-randomised trials were conflicting. In a large randomised study in Italy, LBC had a greater sensitivity for CIN1 than did conventional Pap smear, with similar sensitivity for CIN2 or worse. Positive predictive value was lower for liquid-based cytology.20 Results of a large randomised trial in the Netherlands did not show significant differences in sensitivity or positive predictive values between the two methods.21 The advantages of liquid-based cytology are lower frequency of unsatisfactory smears, automated slide preparation, and the possibility to use the solution in liquid-based cytology for subsequent reflex HPV DNA testing. In developing countries, problems arise from poor infrastructure and low numbers of trained cytotechnologists; LBC is also more expensive than the conventional Pap smear. VIA is a method of preinvasive cervical cancer detection that can be simply done by trained health personnel. The procedure involves soaking the cervix with 3–5% acetic acid for about 1 min before simple visual inspection for colour changes (figure). Results from a meta-analysis showed that VIA had a sensitivity of 79–82% and specificity of 91–92% with a false positive rate of 8–9%.22 Appropriate cases (non-pregnant women with abnormal lesion 2 mm of the cryoprobe nor into the cervical canal) can be immediately treated by cryotherapy with a freezethaw-freeze technique in the same visit.23 In a large cluster-randomised trial in Tamil Nadu, India, cervical cancer incidence (hazard ratio 0·75, 95% CI 0·55–0·95) and mortality (0·65, 0·47–0·89) were reduced by one round of VIA.24 In a study comparing Pap smear, VIA, and HPV DNA testing, VIA at 5-year intervals in women aged 35–55 years with immediate treatment was the least www.thelancet.com/oncology Vol 14 November 2013
Review
expensive method and saved the highest number of lives.25 The limitation of this technique is that in some women the squamo-columnar junction cannot be viewed adequately, especially in menopause. The method is useful in settings with limited resources, where coverage of cytological screening is low. HPV DNA testing has sensitivity of 66–100% and specificity of 61–96%. The two most common methods are signal amplification (hybrid capture) and target amplification (PCR). Hybrid capture generally has lower sensitivity than target amplification, but higher specificity. HPV DNA testing can be used as a primary screening test, as a triage after cytological abnormalities, or as a co-test with cytology. Investigators of a systematic review in 2011 reported that primary HPV testing is more sensitive, but less specific than cytology for detection of CIN2–3, whereas HPV cotesting showed conflicting results.26 In a cost-effectiveness analysis in the Netherlands, researchers calculated that primary HPV DNA testing with cytology triage is the most cost-effective strategy from a societal perspective. The investigators concluded that increasing of the interval between screenings, and changing of the primary test from cytology to HPV testing can improve the costeffectiveness of cervical cancer screening in their country.27 In a large cluster-randomised trial in rural India comparing HPV DNA testing, cytological screening, and VIA, versus no screening, single HPV testing was associated with significant reduction in advanced cervical cancer and deaths.28 However, the cost of HPV DNA testing is still high for developing countries; cheaper HPV DNA tests are now being piloted. Results of a study in rural China showed that the low-cost HPV test had similar accuracy to Hybrid Capture 2 (QIAGEN Inc, Gaithersburg, MD, USA) with a sensitivity of 90·0% and specificity of 84·2%.29 Screen-positive cases should undergo diagnostic colposcopy and biopsy for definite diagnosis. Standard treatment for CIN1 is either close observation or cryotherapy. Cryotherapy can cure 94% of CIN1, 92% of CIN2, and 85% of CIN3.30 Most cases of CIN2 or CIN3 can be treated by conisation, either by large loop excision of transformation zone, loop electrosurgical excision procedure, laser, or cold knife, all of which showed comparable effectiveness and safety profile with large loop excision of transformation zone yielding the most reliable specimen for pathology and least morbidity.31 The role of hysterectomy in the treatment of preinvasive cervical cancer is limited to adenocarcinoma in situ or selected cases of recurrent CIN2 or CIN3. After treatment, follow-up with cytology and HPV cotest is recommended yearly for 2 years and every 3 years thereafter.32 Table 2 shows resource-stratified guidelines for cervical cancer prevention. For primary prevention, health education for the whole community should be available at all resource levels. HPV vaccine should be given as a www.thelancet.com/oncology Vol 14 November 2013
Figure: Cervix soaked in acetic acid during VIA
national programme for girls aged 9–13 years in countries with more enhanced resources. For countries with maximum resources, boys can be included. In countries with limited resources, the HPV vaccine can be given if they seek support from the GAVI Alliance. For secondary prevention in regions with basic resources, VIA as single visit approach (screen and treat) should be offered to women aged between 30 and 45 years, once in their lifetime or every 5–10 years. In limited-resource settings, VIA as single visit approach should be used from the age of 30–45 years, every 5 years along with conventional Pap smear (for those with unsatisfactory VIA) from the age of 30–60 years, every 5 years or, if a low-cost HPV test is available, it can be offered every 5–10 years. Liquid-based cytology can replace conventional Pap smear in highresource settings, with the possibility of using HPV test as a cotest or for triage. At the maximum level of resource, liquid-based cytology with HPV cotest can be offered with a 5-year screening interval. Treatment with cryotherapy as single visit approach is acceptable in low-resource settings, and large loop excision of transformation zone or loop electrosurgical excision procedure are preferred in more advanced resource settings.
Breast cancer Incidence Breast cancer is the most common cancer in women worldwide, accounting for 23% of all cancer in women and the second most common cancer overall. Generally, incidence of breast cancer in Asia is lower than in western countries. However, incidence is rising rapidly. According to GLOBOCAN 2008, the age-standardised incidence and mortality rates in Asia were 26·0 per 100 000 women per year and 9·5 per 100 000 women per year, respectively (table 1).1 Panel 2 shows factors associated with an increased risk of breast cancer. BRCA1 and BRCA2 mutations are well known to be associated with breast cancer in western countries. e499
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Primary prevention
Secondary prevention Screening
Treatment
Basic resource level
Community information and education
VIA at 30–45 years, every 5–10 years or once in a lifetime
Cryotherapy (SVA)
Limited resource level
Community information and education; HPV vaccination (with support from GAVI Alliance)
VIA at 30–45 years, every 5 years ± conventional pap smear at 30–60 years, every 5 years ± low cost HPV test at 30–60 years, every 5–10 years
Cryotherapy (SVA) ± LLETZ/ LEEP*
Enhanced resource level
HPV vaccination; national programme for girls aged 9–13 years; community information and education
Conventional Pap smear/LBC at 20–65 years, every 2–3 years ± HPV test (co-test/triage) at 30–65 years, every 5 years
LLETZ/LEEP*
Maximum resource level
HPV vaccination; national programme for girls and boys aged 9–13 years up to age 26 years; opportunistic for all women; community information and education
LBC + HPV test (co-test) at 30–65 years, every 5 years
LLETZ/LEEP*
VIA=visual inspection with acetic acid. SVA=single visit approach. HPV=human papilloma virus. LBC=liquid-based cytology. LLETZ=large loop excision of transformation zone. LEEP=loop electrosurgical excision procedure. *Cold knife conisation can be undertaken in selected cases.
Table 2: Resource-stratified guidelines for cervical cancer prevention
Panel 2: Factors associated with breast cancer • Genetics: BRCA1 and BRCA2 mutations • Reproductive and hormonal factors • Lifestyle: soy food intake, physical activity, weight gain, alcohol
However, much less information exists about the prevalence of these mutations in Asia. Moreover, genetic testing is expensive and not affordable in most Asian settings. A strong family history suggestive of a deleterious mutation in BRCA1 or BRCA2 is defined as: two or more first-degree or second-degree relatives on the same side of the family with breast cancer or ovarian cancer at any age; two or more first-degree or seconddegree relatives on the same side of the family with breast cancer, one of whom was diagnosed at younger than 50 years of age; one first-degree relative with breast cancer at younger than 40 years of age; one first-degree relative with breast and ovarian cancer at any age; one first-degree relative with bilateral breast cancer at any age; or one first-degree relative with male breast cancer.33 Breast cancer is strongly associated with hormonal factors, including early menarche, and late menopause, nulliparity, and older age at first childbirth.34 Epidemiological studies have shown that the longer that women breastfeed for, the greater their protection against breast cancer—the RR decreased by 4·3% for every 12 months of breastfeeding, in addition to 7% for each birth.35 Data from the Women’s Health Initiatives (WHI) showed that combination (oestrogen and progestin) hormonal replacement therapy in menopausal women is associated with RR of 1·26 (95% CI 1·00–1·59) of developing breast cancer after 5·2 years of treatment.36 Findings from a meta-analysis of studies done in Asian populations with high-soy diets showed a significantly decreased risk of breast cancer with increasing dietary soy intake.37 Women who engaged in regular strenuous e500
physical activity at the age of 35 years had a 14% decreased risk of breast cancer (RR 0·86, 95% CI 0·78–0·95).38 The Nurses’ Health Study in the USA showed that women who gained 25 kg or more after the age of 18 years were at increased risk for breast cancer (1·45, 1·27–1·66).39 From the WHI study, in women who never use hormonal therapy, those with body-mass index (BMI) of more than 31·1 kg/m² had a higher risk of breast cancer than did those with BMI less than 26 (RR 2·52, 95% CI 1·62–3·93).40 Women who consumed 35–44 g of alcohol (equivalent to about four units) per day were 1·32 times (95% CI 1·19–1·45, p
Cancer prevention in Asia: resource-stratified guidelines from the Asian Oncology Summit 2013 Arb-aroon Lertkhachonsuk, Cheng Har Yip, Thiravud Khuhaprema, Ding-Shinn Chen, Martyn Plummer, Sun Ha Jee, Masakazu Toi, Sarikapan Wilailak
With economic growth in Asia, cancer has become increasingly prominent as a major health problem. However, discrepancies in infrastructure, economics, and development exist within and between Asian countries. We assess means of primary and secondary prevention for cervical, breast, colorectal, and hepatocellular cancer, and offer recommendations according to resource levels. Primary prevention by health education, lifestyle modification, and avoidance of risk factors should be made available at all resource levels. When resources allow, human papillomavirus and hepatitis B vaccinations should be given to reduce the risk of cervical and hepatocellular cancer, and genetic testing should be offered to detect increased susceptibility to colorectal and breast cancer. Secondary prevention by effective yet affordable screening for precancerous lesions or by early detection of cancer should be offered, followed by appropriate treatment.
Introduction Cancer is one of the biggest health problems in Asia. In 2008, there were an estimated 6·1 million new cancer cases and 4·1 million deaths from cancer in Asia, with age-standardised incidence and mortality rates of 153·6 and 102·6 per 100 000 years, respectively.1,2 The control of cancer would be best achieved by prevention, with primary prevention by avoidance of known risk factors and secondary prevention by screening for early detection and treatment. Asia is a region with diverse ethnicities, cultures, and resources. Gross domestic product varies between countries, and discrepancies in resource levels are evident between regions within countries. Guidelines for Asian countries should therefore be tiered according to resources available. Here, we discuss the prevention of cervical, breast, colorectal, and hepatocellular cancer in Asia, based on resource stratification into a four-tier system (ie, basic, limited, enhanced, and maximum) as originally described by the Breast Health Global Initiative.3 The recommendations were formulated by a panel of gynaecological, surgical, and medical oncologists, and with hepatologists in a breakout session held as part of the fifth Asian Oncology Summit in Bangkok, Thailand, on March 24, 2013.
Cervical cancer Cervical cancer is the third most common cancer in women worldwide, after breast and colon cancer. In Asia, cervical cancer is the second most common after breast cancer. According to GLOBOCAN 2008, there were 160 000 new cases in Asia that year, with age-standardised incidence and mortality rates of 15·3 per 100 000 women per year and 7·9 per 100 000 women per year, respectively (table 1). The rates are highest in south-central Asia and lowest in west Asia. A generally downward trend in incidence and mortality was recorded in most parts of Asia.1,2 Panel 1 shows factors associated with cervical cancer. Most cervical cancers are caused by human papillomavirus www.thelancet.com/oncology Vol 14 November 2013
(HPV). Persistent infection of cervical epithelial cells by high-risk HPV subtypes can result in integration of the viral genome into cell DNA and start of carcinogenetic processes.4,5 Thus, any means that prevents HPV infection reduces the incidence of cervical cancer. Cigarette smoking is associated with increased risk of squamous-cell carcinoma, with a relative risk (RR) of 1·5 (95% CI 1·33–1·66).6 This increased risk might be explained by the decrease in number of Langerhan’s cells.7 Long-term use of oral contraceptive pills is also associated with increased incidence of cervical cancer. The risk seems to increase with duration of use, with an odds ratio (OR) of 2·82 (95% CI 1·46–5·42) after 5–9 years of use, increasing to 4·03 (2·09–8·02) after more than 10 years of use.8,9 Other reproductive factors associated with cervical cancer are high parity,10 large lifetime number of sexual partners,6 and early age at first sexual intercourse.11
Primary prevention The aim of primary cervical cancer prevention is to prevent HPV infection. Because most cases of cervical cancer are caused by HPV infection, vaccination against high-risk HPV infection decreases incidence of cervical cancer. Two types of vaccine are available—quadrivalent and bivalent. Both vaccines were designed to prevent infection by HPV 16 and 18—the two most common high-risk HPV types that cause roughly 70% of cervical cancers worldwide. The quadrivalent vaccine also protects against HPV types 6 and 11, which cause genital condyloma. Both vaccines showed more than 90% efficacy in prevention of HPV 16 and 18-related cervical intraepithelial neoplasia (CIN) of grade 3 or worse, especially in young women who had not been infected with HPV.12,13 Evidence suggests that the vaccines also provide cross-protection against other less common HPV types that cause cervical cancer.14 Similar to other vaccines, HPV vaccines would be most beneficial if administered before HPV exposure—ie, before first sexual intercourse. HPV vaccination has been
Lancet Oncol 2013; 14: e497–507 Department of Obstetrics and Gynecology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand (A-a Lertkhachonsuk MD); Sime Darby Medical Centre, Subang Jaya, Malaysia (C H Yip FRCS); Surgical Oncology Division, National Cancer Institute, Bangkok, Thailand (T Khuhaprema MD); Department of Internal Medicine, National Taiwan University College of Medicine and Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan (Prof D-S Chen MD); Infections and Cancer Epidemiology Group, International Agency for Research on Cancer, Lyon, France (M Plummer PhD); Department of Epidemiology, Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, South Korea (Prof S H Jee PhD); Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan (Prof M Toi PhD); and Department of Obstetrics and Gynaecology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand (Prof S Wilailak MD) Correspondence to: Prof Sarikapan Wilailak, Department of Obstetrics and Gynaecology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Rama VI Road, Bangkok 10400, Thailand [email protected]
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Cervical cancer
Breast cancer
Colon cancer: women
Colon cancer: men
Liver cancer: women
Liver cancer: men
Incidence Mortality
Incidence Mortality
Incidence Mortality
Incidence Mortality
Incidence Mortality
Incidence Mortality
Nepal
32·4
17·6
23·5
11·9
4·8
3·5
5·3
4·0
1·1
1·1
1·7
1·6
Bangladesh
29·8
17·9
27·2
13·6
4·0
3·0
4·5
3·7
3·5
3·5
4·1
4·1
India
27·0
15·2
22·9
11·1
3·5
2·5
4·3
3·2
1·2
1·1
3·2
3·0
Thailand
24·5
12·8
30·7
10·8
13·4
6·5
13·2
6·4
19·9
16·6
40·6
35·1
Malaysia
17·9
5·6
37·0
14·7
15·5
10·1
19·6
13·0
3·0
2·9
8·4
8·1
South Korea 10·9
2·8
38·9
5·3
25·6
7·4
46·9
13·9
10·6
7·3
38·4
28·4
Taiwan
38·2
10·2
4·6
52·8
9·9
29·7
10·6
40·2
15·6
20·0
14·1
52·0
Japan
9·8
2·6
42·7
9·1
22·8
8·9
41·7
15·2
5·8
4·7
17·6
14·5
China
9·6
4·3
21·6
5·7
12·2
5·9
16·3
8·0
13·7
13·1
37·4
34·1
Singapore
6·8
3·5
59·9
13·6
28·3
10·7
41·6
18·1
3·8
4·5
17·0
14·0
Table 1: Age-standardised incidence and mortality rates per 100 000 for cervical, breast, colon, and liver cancer in Asia
1
Panel 1: Factors associated with cervical cancer HPV inection • Cigarette smoking • Long-term use of oral contraceptive pills • Other: high parity, number of sexual partners, early age of sexual intercourse
implemented as a national programme in many developed countries. In the UK, the vaccine is given to all girls aged 12–13 years, with a catch-up programme to vaccinate those up to 18 years of age.15 In the USA, the Centers for Disease Control and Prevention recommended vaccination to girls and boys at the age of 11 or 12 years, and a catch-up programme for those who did not get the vaccine up to the age of 26 years for women and 21 years for men.16 WHO recommended giving the vaccine to girls aged 9–13 years, before they become sexually active.17 In developing countries, the cost of the vaccine is still high in relation to their gross domestic product. However, Bhutan and Malaysia have introduced HPV vaccination successfully in their national programmes.18 The GAVI Alliance can support these countries by cofinancing the vaccine, and has negotiated a price of US$5 per dose. In 2013, eight developing countries, including Laos, were announced to be the first countries to receive support from the GAVI Alliance. In countries that cannot afford the HPV vaccine, provision of health education about cervical cancer, HPV, risk factors, methods of spread, prevention, and screening to not only girls, but also the whole community, would be valuable for the prevention of disease.
Secondary prevention The aim of secondary cervical cancer prevention is early detection by screening followed by treatment. The most common methods of screening are cytological screening for precancerous lesions, visual inspection with acetic acid (VIA), and HPV DNA testing. Cervical cytology has been e498
the standard method for cervical cancer screening since the 1940s, although sensitivity and specificity of the technique varied in earlier studies. Findings from a metaanalysis in 1995 showed that the conventional Pap smear had a mean sensitivity of 58% (range 11–99%) and specificity of 69% (14–97%).19 Liquid-based cytology (LBC) was introduced in the 1990s to solve the problems of sample inadequacy; however, conclusions from metaanalyses of non-randomised trials were conflicting. In a large randomised study in Italy, LBC had a greater sensitivity for CIN1 than did conventional Pap smear, with similar sensitivity for CIN2 or worse. Positive predictive value was lower for liquid-based cytology.20 Results of a large randomised trial in the Netherlands did not show significant differences in sensitivity or positive predictive values between the two methods.21 The advantages of liquid-based cytology are lower frequency of unsatisfactory smears, automated slide preparation, and the possibility to use the solution in liquid-based cytology for subsequent reflex HPV DNA testing. In developing countries, problems arise from poor infrastructure and low numbers of trained cytotechnologists; LBC is also more expensive than the conventional Pap smear. VIA is a method of preinvasive cervical cancer detection that can be simply done by trained health personnel. The procedure involves soaking the cervix with 3–5% acetic acid for about 1 min before simple visual inspection for colour changes (figure). Results from a meta-analysis showed that VIA had a sensitivity of 79–82% and specificity of 91–92% with a false positive rate of 8–9%.22 Appropriate cases (non-pregnant women with abnormal lesion 2 mm of the cryoprobe nor into the cervical canal) can be immediately treated by cryotherapy with a freezethaw-freeze technique in the same visit.23 In a large cluster-randomised trial in Tamil Nadu, India, cervical cancer incidence (hazard ratio 0·75, 95% CI 0·55–0·95) and mortality (0·65, 0·47–0·89) were reduced by one round of VIA.24 In a study comparing Pap smear, VIA, and HPV DNA testing, VIA at 5-year intervals in women aged 35–55 years with immediate treatment was the least www.thelancet.com/oncology Vol 14 November 2013
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expensive method and saved the highest number of lives.25 The limitation of this technique is that in some women the squamo-columnar junction cannot be viewed adequately, especially in menopause. The method is useful in settings with limited resources, where coverage of cytological screening is low. HPV DNA testing has sensitivity of 66–100% and specificity of 61–96%. The two most common methods are signal amplification (hybrid capture) and target amplification (PCR). Hybrid capture generally has lower sensitivity than target amplification, but higher specificity. HPV DNA testing can be used as a primary screening test, as a triage after cytological abnormalities, or as a co-test with cytology. Investigators of a systematic review in 2011 reported that primary HPV testing is more sensitive, but less specific than cytology for detection of CIN2–3, whereas HPV cotesting showed conflicting results.26 In a cost-effectiveness analysis in the Netherlands, researchers calculated that primary HPV DNA testing with cytology triage is the most cost-effective strategy from a societal perspective. The investigators concluded that increasing of the interval between screenings, and changing of the primary test from cytology to HPV testing can improve the costeffectiveness of cervical cancer screening in their country.27 In a large cluster-randomised trial in rural India comparing HPV DNA testing, cytological screening, and VIA, versus no screening, single HPV testing was associated with significant reduction in advanced cervical cancer and deaths.28 However, the cost of HPV DNA testing is still high for developing countries; cheaper HPV DNA tests are now being piloted. Results of a study in rural China showed that the low-cost HPV test had similar accuracy to Hybrid Capture 2 (QIAGEN Inc, Gaithersburg, MD, USA) with a sensitivity of 90·0% and specificity of 84·2%.29 Screen-positive cases should undergo diagnostic colposcopy and biopsy for definite diagnosis. Standard treatment for CIN1 is either close observation or cryotherapy. Cryotherapy can cure 94% of CIN1, 92% of CIN2, and 85% of CIN3.30 Most cases of CIN2 or CIN3 can be treated by conisation, either by large loop excision of transformation zone, loop electrosurgical excision procedure, laser, or cold knife, all of which showed comparable effectiveness and safety profile with large loop excision of transformation zone yielding the most reliable specimen for pathology and least morbidity.31 The role of hysterectomy in the treatment of preinvasive cervical cancer is limited to adenocarcinoma in situ or selected cases of recurrent CIN2 or CIN3. After treatment, follow-up with cytology and HPV cotest is recommended yearly for 2 years and every 3 years thereafter.32 Table 2 shows resource-stratified guidelines for cervical cancer prevention. For primary prevention, health education for the whole community should be available at all resource levels. HPV vaccine should be given as a www.thelancet.com/oncology Vol 14 November 2013
Figure: Cervix soaked in acetic acid during VIA
national programme for girls aged 9–13 years in countries with more enhanced resources. For countries with maximum resources, boys can be included. In countries with limited resources, the HPV vaccine can be given if they seek support from the GAVI Alliance. For secondary prevention in regions with basic resources, VIA as single visit approach (screen and treat) should be offered to women aged between 30 and 45 years, once in their lifetime or every 5–10 years. In limited-resource settings, VIA as single visit approach should be used from the age of 30–45 years, every 5 years along with conventional Pap smear (for those with unsatisfactory VIA) from the age of 30–60 years, every 5 years or, if a low-cost HPV test is available, it can be offered every 5–10 years. Liquid-based cytology can replace conventional Pap smear in highresource settings, with the possibility of using HPV test as a cotest or for triage. At the maximum level of resource, liquid-based cytology with HPV cotest can be offered with a 5-year screening interval. Treatment with cryotherapy as single visit approach is acceptable in low-resource settings, and large loop excision of transformation zone or loop electrosurgical excision procedure are preferred in more advanced resource settings.
Breast cancer Incidence Breast cancer is the most common cancer in women worldwide, accounting for 23% of all cancer in women and the second most common cancer overall. Generally, incidence of breast cancer in Asia is lower than in western countries. However, incidence is rising rapidly. According to GLOBOCAN 2008, the age-standardised incidence and mortality rates in Asia were 26·0 per 100 000 women per year and 9·5 per 100 000 women per year, respectively (table 1).1 Panel 2 shows factors associated with an increased risk of breast cancer. BRCA1 and BRCA2 mutations are well known to be associated with breast cancer in western countries. e499
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Primary prevention
Secondary prevention Screening
Treatment
Basic resource level
Community information and education
VIA at 30–45 years, every 5–10 years or once in a lifetime
Cryotherapy (SVA)
Limited resource level
Community information and education; HPV vaccination (with support from GAVI Alliance)
VIA at 30–45 years, every 5 years ± conventional pap smear at 30–60 years, every 5 years ± low cost HPV test at 30–60 years, every 5–10 years
Cryotherapy (SVA) ± LLETZ/ LEEP*
Enhanced resource level
HPV vaccination; national programme for girls aged 9–13 years; community information and education
Conventional Pap smear/LBC at 20–65 years, every 2–3 years ± HPV test (co-test/triage) at 30–65 years, every 5 years
LLETZ/LEEP*
Maximum resource level
HPV vaccination; national programme for girls and boys aged 9–13 years up to age 26 years; opportunistic for all women; community information and education
LBC + HPV test (co-test) at 30–65 years, every 5 years
LLETZ/LEEP*
VIA=visual inspection with acetic acid. SVA=single visit approach. HPV=human papilloma virus. LBC=liquid-based cytology. LLETZ=large loop excision of transformation zone. LEEP=loop electrosurgical excision procedure. *Cold knife conisation can be undertaken in selected cases.
Table 2: Resource-stratified guidelines for cervical cancer prevention
Panel 2: Factors associated with breast cancer • Genetics: BRCA1 and BRCA2 mutations • Reproductive and hormonal factors • Lifestyle: soy food intake, physical activity, weight gain, alcohol
However, much less information exists about the prevalence of these mutations in Asia. Moreover, genetic testing is expensive and not affordable in most Asian settings. A strong family history suggestive of a deleterious mutation in BRCA1 or BRCA2 is defined as: two or more first-degree or second-degree relatives on the same side of the family with breast cancer or ovarian cancer at any age; two or more first-degree or seconddegree relatives on the same side of the family with breast cancer, one of whom was diagnosed at younger than 50 years of age; one first-degree relative with breast cancer at younger than 40 years of age; one first-degree relative with breast and ovarian cancer at any age; one first-degree relative with bilateral breast cancer at any age; or one first-degree relative with male breast cancer.33 Breast cancer is strongly associated with hormonal factors, including early menarche, and late menopause, nulliparity, and older age at first childbirth.34 Epidemiological studies have shown that the longer that women breastfeed for, the greater their protection against breast cancer—the RR decreased by 4·3% for every 12 months of breastfeeding, in addition to 7% for each birth.35 Data from the Women’s Health Initiatives (WHI) showed that combination (oestrogen and progestin) hormonal replacement therapy in menopausal women is associated with RR of 1·26 (95% CI 1·00–1·59) of developing breast cancer after 5·2 years of treatment.36 Findings from a meta-analysis of studies done in Asian populations with high-soy diets showed a significantly decreased risk of breast cancer with increasing dietary soy intake.37 Women who engaged in regular strenuous e500
physical activity at the age of 35 years had a 14% decreased risk of breast cancer (RR 0·86, 95% CI 0·78–0·95).38 The Nurses’ Health Study in the USA showed that women who gained 25 kg or more after the age of 18 years were at increased risk for breast cancer (1·45, 1·27–1·66).39 From the WHI study, in women who never use hormonal therapy, those with body-mass index (BMI) of more than 31·1 kg/m² had a higher risk of breast cancer than did those with BMI less than 26 (RR 2·52, 95% CI 1·62–3·93).40 Women who consumed 35–44 g of alcohol (equivalent to about four units) per day were 1·32 times (95% CI 1·19–1·45, p
