ORIGINAL CLINICAL STUDY
Predicted Trends in the Incidence of Retinoblastoma in the Asia-Pacific Region Rustam H. Usmanov, MD*Þ and Tero Kivela¨, MD, FEBOÞþ
Purpose: The aim of this study is to predict the incidence trends of retinoblastoma in the Asia-Pacific region. Design: Statistical prediction is based on the assumption of uniform incidence among live-born children. Methods: The number of live births was projected from population sizes and birth rates, corrected for infant mortality, and taken from the 2012 Revision of the World Population Prospects by the United Nations. The uniform incidence of 1:16,642 was derived from an earlier birth cohort analysis. Western Asia was excluded from calculations. Results: Six of 15 countries with over 100 retinoblastomas annually and responsible for 43% of 8099 retinoblastomas predicted for 2013 are Asia-Pacific nations. The predicted incidence of retinoblastoma in the Asia-Pacific peaked in 1988 at 4772 children and is 4167 and 3859, respectively, in 2012 and 2023. The 10 countries that account for 90% of retinoblastomas in the Asia-Pacific are India (1486 and 1435 children in 2013 and 2023, respectively), China (1103 and 911), Indonesia (277 and 265), Pakistan (260 and 261), Bangladesh (184 and 172), the Philippines (142 and 152), Iran (87 and 74), Vietnam (85 and 72), Japan (64 and 58), and Afghanistan (59 and 59). Largest relative decreases are predicted for China (j17%), Vietnam and Iran (j15%), and Sri Lanka (j13%). Conclusions: Reported retinoblastomas during the last decade in the Asia-Pacific account for less than half of predicted numbers, which can be used as surrogates for evaluating completeness of registration and for advocacy toward reducing deaths and blindness from retinoblastoma. Key Words: epidemiology, eye cancer, cancer incidence, malignant neoplasms, retinoblastoma (Asia Pac J Ophthalmol 2014;3: 151Y157)
malignancy globally with an estimated number of 7202 to 8102 new patients annually, outnumbering uveal melanoma by a margin of 523 to 1007 patients in 2006.2 Continuing population growth still increases the global number of incident retinoblastomas approximately by 100 children per year. In 2006, an estimated minimum of 3001 to 3376 children died annually of retinoblastoma.2 Given that both intraocular and metastatic retinoblastoma can be effectively managed by focal treatments, chemotherapy, and radiotherapy, there is definite hope that morbidity and mortality from retinoblastoma can be reduced. If all retinoblastomas could be referred to national or regional retinoblastoma centers, mortality might decrease by 62% to 1200 children per year.2 Because no effective treatment is available for metastatic uveal melanoma, possibilities of reducing mortality from eye cancer currently are best with regard to retinoblastoma. To plan and execute a national program with the aim of promoting early diagnosis, prompt treatment, and enhanced treatment compliance, and to raise money and awareness for such a program, it is essential to know the number of children affected by retinoblastoma. Ideally, this is accomplished through a national retinoblastoma registry with complete ascertainment of incident cases. For geographical, administrative, financial, and political reasons, this is achievable to a variable extent in practice. In case national statistics are unavailable, incomplete, or inaccurate, a reasonable starting point is the incidence estimated from available epidemiological and population statistics. We provide here such countrywise estimates of the incidence of retinoblastoma for the Asia-Pacific region for the years 2013 and 2023.
MATERIALS AND METHODS
R
etinoblastoma is well known for being the most common intraocular cancer for children ever after its first description as an entity by James Wardrop just over 200 years ago.1 Moreover, it is established that retinoblastoma is the most frequent primary intraocular cancer overall in nonwhite populations because of the rarity of uveal melanoma in Asian and African populations.2 Indeed, the faster population growth in the Asia-Pacific and the Middle EastYAfrican regions has recently made retinoblastoma the most frequent intraocular
Aims of the Study Our aim is to predict the incidence of retinoblastoma in each country of the Asia-Pacific region to provide numbers against which the number of registered retinoblastoma patients can be compared so as to estimate the completeness of the registration. Our predictions can also be used in advocacy as regards planning, financing, and execution of national treatment programs for retinoblastoma.
Statistical Methods From the *Department of Onco-Ophthalmology, National Oncological Research Center, Tashkent, Uzbekistan; †Ocular Oncology Service, and ‡Pediatric Ophthalmology Service, Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland. Received for publication July 22, 2013; accepted May 08, 2014. Conflicts of Interest and Source of Funding: Dr Usmanov was a recipient of a 3-month-long International Council of Ophthalmology Fellowship in the Ocular Oncology Service from October to December 2012. None for the other author. Reprints: Tero Kivela¨, MD, FEBO, Department of Ophthalmology, Helsinki University Central Hospital, Haartmaninkatu 4 C, PL 220, FI-00029 HUS, Helsinki, Finland. E-mail: tero.kivela@helsinki.fi. Copyright * 2014 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0000000000000060
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The incidence of retinoblastoma can be calculated from observational data in several ways, depending on the perceived population at risk, such as children of a particular age living at a given moment. Because retinoblastoma is a developmental cancer, we have argued that unnecessary variation to incidence estimates is introduced by different growth rates of retinoblastomas that may have initiated even before birth.3 Delays in diagnosis in regions with limited access to specialized health care add to this variation in age at diagnosis. A report of the incidence of retinoblastoma in Sweden and Finland is informative because these northern European countries have had comprehensive national cancer registries for over 5 decades.3 This study found that retinoblastoma incidence rates based on age
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cohorts were the most volatile and that most stable estimates were obtained by assigning each child with an incident retinoblastoma to his or her birth cohort. The birth cohort method both minimized the effect of variable age at the time of diagnosis of this developmental cancer and showed that apparent trends in incidence rates that were present in traditional age cohort analysis disappeared in birth cohort analysis. We are unaware of any study that would have documented the incidence of retinoblastoma to be unequivocally and consistently different from our estimate.3 We consequently used the birth cohortYbased estimate of 6.0 [95% confidence interval (CI), 5.4Y6.6] retinoblastomas per 100,000 live births or 1 in 16,642 (95% CI, 15,105Y18,528) as the best predictor for the global incidence of retinoblastoma. The number of live-born children can be conveniently calculated from total population size and crude birth statistics made available by the United Nations for all countries. We used the 2012 Revision of the World Population Prospects, published in June 2013, which is the 23rd edition of global demographic estimates and projections published by the Population Division of the Department of Economic and Social Affairs of the United Nations Secretariat.4 We applied the table for total population, both sexes (file POP/1-1, median fertility table, population in a country, area, or region as of July 1) and years 2010Y2015 and 2020Y2025 crude birth rate estimates, respectively (file FERT/3, median fertility table, the number of births over 5-year periods running from July 1 to June 30 of the initial and final years, respectively, divided by the person-years lived by the population over that period and expressed as the average annual number of births per 1000 population). The estimates for the intervening years were derived by linear extrapolation. Given that infant mortality varies widely, we corrected the crude number of live-born children by deducting the estimate of infant deaths for the years 2010Y2015 and 2020Y2025, respectively (file MORT/1-1, median fertility table, probability of dying between birth and exact age 1 year expressed as average annual deaths per 1000 births). The infant mortality estimates include some deaths due to retinoblastoma, but their proportion is a minute fraction of all infant mortality. We calculated the median predicted number of incident retinoblastomas with its lower and upper bound CIs for the years 2013 and 2023 using the Stata software (version 10; Stata Corp, College Station, Tex). We excluded countries assigned by the United Nations to western Asia because these belong to the Middle EastYAfrican region. In addition, we calculated the yearly incidence estimates for the entire AsiaPacific region and Japan until 2050 and plotted the predicted incidence against population size for countries with a minimum of 10 million inhabitants. Because the data set in the original birth cohort analysis had few familial retinoblastomas (ie, children who had a previous family member with retinoblastoma), these pregnancies with a high risk (1:2) of producing offspring with retinoblastoma are effectively not accounted for in our predicted numbers and must be added to them.
RESULTS The predicted annual incidence of retinoblastoma (excluding familial retinoblastoma, see Methods) based on the year 2013 population projections reaches 100 children in 15 countries worldwide, of which 6 (40%) are located in the Asia-Pacific region (Table 1A). Together, these 6 countries are predicted to have 3452 children with retinoblastoma annually or 43% of the predicted global burden of 8099 retinoblastomas to be diagnosed.
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TABLE 1A. Countries in Which Predicted Annual Incidence of Retinoblastoma Is 100 or More in 2013 Country India China Nigeria Indonesia Pakistan United States of America Bangladesh Ethiopia Brazil Democratic Republic of the Congo Philippines Mexico Egypt Tanzania Russian Federation
Region
Incidence of Retinoblastoma*
Asia-Pacific Asia-Pacific Africa Asia-Pacific Asia-Pacific North America Asia-Pacific Africa South America Africa
1486 (1335Y1638) 1103 (991Y1215) 400 (359Y440) 277 (249Y305) 260 (233Y286) 252 (227Y278) 184 (166Y203) 179 (161Y197) 179 (160Y197) 155 (139Y171)
Asia-Pacific North America Africa Africa Europe
142 (128Y157) 135 (121Y148) 113 (101Y124) 111 (99Y122) 100 (90Y111)
*Median prediction with 95% confidence interval, Asia-Pacific countries highlighted with bold typeface; not corrected for familial cases, see text.
The predicted incidence of retinoblastoma in 2023 likewise reaches 100 children in 15 countries, of which 6 (40%) are in the Asia-Pacific region (Table 1B). Together, these 6 countries are predicted to have 3196 (reduced by 256) retinoblastomas annually or 40% of the predicted global burden of 8062 (reduced by 37) retinoblastomas. An increase in the incidence is predicted for the United States and the Philippines as well as for all African countries except Egypt, with Uganda replacing the Russian Federation on the list and Pakistan showing an essentially stable incidence. A decreasing trend in the incidence of retinoblastoma in the Asia-Pacific region started in 1988 when the predicted rate peaked at 4772 children (Fig. 1A). A trough was reached in 2003 with an estimated 4020 children with diagnosed retinoblastoma. After 2003, a modest increase to 4166 children in 2013 is predicted to occur. A period of slow decline in incident retinoblastomas in the Asia-Pacific region, based on population projections, is predicted from here on. Excluding China, the peak incidence occurred in 1992 with 3128 retinoblastomas; whereafter, the incidence rate has only slightly declined to 3063 patients in 2013. More rapid decrease is predicted from 2015 onward. The predicted incidence of retinoblastoma by country in the Asia-Pacific region in 2013 ranges from 1486 children in India to less than 2 children per decade in several Oceanian island nations (Table 2). The 9 countries with the next largest numbers of incident retinoblastomas are China (1103 children), Indonesia (277 children), Pakistan (260 children), Bangladesh (184 children), the Philippines (142 children), Iran (87 children), Vietnam (85 children), Japan (64 children), and Afghanistan (59 children). Taken together, these 10 countries will have 3747 (90%) of the 4167 retinoblastomas predicted to occur in the Asia-Pacific region in 2013. The corresponding incidence rates in 2023 will range from 1435 children (reduced by 51) in India to less than 1 child in 5 years (Table 2). The other 9 countries with most retinoblastomas will be China (911 children, reduced by 192), Pakistan (261 children, increased by 1), Indonesia (265 children, reduced * 2014 Asia Pacific Academy of Ophthalmology
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Retinoblastoma Incidence in Asia-Pacific Region
TABLE 1B. Countries in Which Predicted Annual Incidence of Retinoblastoma Is 100 or More in 2023 Country
Region
India China Nigeria United States of America Indonesia Pakistan Ethiopia Democratic Republic of the Congo Bangladesh Brazil Philippines Tanzania Mexico Uganda Egypt
Incidence of Retinoblastoma*
Asia-Pacific Asia-Pacific Africa North America Asia-Pacific Asia-Pacific Africa Africa
1435 (1289Y1581) 911 (819Y1004) 483 (434Y532) 268 (240Y295) 265 (238Y292) 261 (234Y287) 195 (175Y214) 183 (165Y202)
Asia-Pacific South America Asia-Pacific Africa North America Africa Africa
172 (155Y190) 167 (150Y185) 152 (137Y168) 134 (120Y147) 126 (113Y139) 114 (102Y126) 109 (98Y120)
*Median prediction with 95% confidence interval, Asia-Pacific countries highlighted with bold typeface; not corrected for familial cases, see text.
by 12), Bangladesh (172 children, reduced by 12), the Philippines (152 children, increased by 10), Iran (74 children, reduced by 13), Vietnam (72 children, reduced by 13), Japan (58 children, reduced by 6), and Afghanistan (59 children, unchanged). Taken together, they will have 3459 (90%) of the 3859 retinoblastomas to be diagnosed in the Asia-Pacific region in 2023. It is possible to directly compare our predicted numbers with observed ones using the data reported by the Japanese National Registry of Retinoblastoma for the years 1975 to 2011 (Fig. 1B).5 The predicted numbers match the observed ones, especially in recent years when the coverage of the registry is likely to be most complete. A reduction of 359 (7%) incident retinoblastomas is predicted for the Asia-Pacific region for the next decade, with the largest absolute changes (Fig. 1C) in China (192 children), India (51 children), Iran and Vietnam (13 children), and Bangladesh and Indonesia (12 children). An absolute increase larger than 10 children is not predicted for any Asia-Pacific country. The largest relative declines in countries with at least 10 million inhabitants are predicted for China (j17%); Iran and Vietnam (j15%); Sri Lanka (j13%); Kazakhstan (j10%); Cambodia, Japan, and Myanmar (j9%); Uzbekistan (j8%); Bangladesh (j7%); and Thailand (j5%).
DISCUSSION Our predictions of the incidence rate of retinoblastoma in the Asia-Pacific region are based on birth cohort analysis of northern European data for 1959 to 1998, which showed a stable incidence over 40 decades.3 We believe that the results are applicable to other regions as well, although many have claimed a higher incidence in certain regions and countries.6 Such studies were, however, based on small populations, short periods, and typically on children of a particular age range, which introduces bias from childhood mortality and population migration.3,6 The annual incidence can vary widely in such instances, and we caution against drawing conclusions from such analyses.3 Moreover, no convincing external cause * 2014 Asia Pacific Academy of Ophthalmology
FIGURE 1. Predicted past (solid line) and projected (dashed line) annual incidence of retinoblastoma (A) in the entire Asia-Pacific region and (B) Japan from 1950 to 2050 with 95% CI (shaded area) and predicted incidence (C) for Asia-Pacific countries with 10 million inhabitants or more projected for the years 2013 (black symbols) and 2023 (gray symbols) and plotted against population size (logarithmic scale). Note that the incidence rate for the entire region reflects changes in family planning policy of China and essentially plateaus for other countries in 1992, whereas a moderate decline is projected for the future; any changes in family planning policies will greatly affect future projected incidence rates (A). Observed annual numbers of nonfamilial retinoblastomas (white symbols) and the corresponding locally weighted scatterplot smoothed data (dotted line) from the Japanese National Registry for Retinoblastoma5 are superimposed on the predicted past (solid line) and projected (dashed line) numbers for Japan; familial retinoblastomas are not accounted for in our predicted numbers because of different risk level; note that the locally weighted scatterplot smoothed data for incident nonfamilial retinoblastomas coincide with the 95% CI of the prediction (shaded area), approaching predicted numbers during the last decade (B). The plot against population size highlights the influence of birth rate on the projected incidence of retinoblastoma; note, for example, that Cambodia and Sri Lanka are predicted to have the same number of retinoblastomas although their populations differ in size. Afghanistan is predicted to have approximately 2 times as many retinoblastomas as Malaysia although their populations are comparable, and more than 30% more retinoblastomas are predicted to be diagnosed in India as compared with China, although the latter has a larger population (C). www.apjo.org
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Asia-Pacific Eastern Asia China China, Hong Kong China, Macau Japan Democratic People’s Republic of Korea Republic of Korea Mongolia Other areas Central Asia Kazakhstan Kyrgyzstan Tajikistan Turkmenistan Uzbekistan Southern Asia Afghanistan Bangladesh Bhutan India Iran Maldives Nepal Pakistan Sri Lanka Southeastern Asia Brunei Cambodia Indonesia Laos Malaysia Myanmar Philippines Singapore Thailand Timor-Leste Vietnam Oceania Australia
Country
17.5 12.9 13.4 9.4 10.1 8.4 14.4
9.6 22.8 9.3 23.3 20.5 27.4 33.3 21.5 21.6 21.3 34.5 20.3 19.8 20.7 19.0 22.3 21.1 25.4 18.1 18.4 15.8 25.8 18.9 26.9 17.7 17.3 24.6 9.9 10.4 35.7 15.6 17.1 13.2
49.3 2.8 23.3 64.4 16.4 5.5 8.2 5.2 28.9 1749 30.6 156.6 0.8 1252 77.4 0.3 27.8 182.1 21.2 618.8 0.4 15.1 249.9 6.8 29.7 53.3 98.4 5.4 67.0 1.1 91.7 38.3 23.3
Crude Birth Rate
4091 1621 1386 7.2 0.6 127.1 24.9
Population, Million
www.apjo.org 3.4 25.8 4.2 41.1 24.6 33.1 56.8 46.7 44.0 44.5 67.3 32.3 30.7 43.8 15.7 10.4 35.5 65.1 9.0 23.7 4.2 40.6 25.6 36.2 4.1 48.9 21.0 1.8 9.9 39.3 14.1 20.2 3.9
28.3 12.3 13.0 1.9 4.1 2.2 22.0
Infant Mortality Rate
473,366 63,064 215,235 1,437,507 328,686 146,700 257,790 107,195 597,431 35,523,456 983,371 3,068,629 14,483 24,736,806 1,448,889 7626 566,446 4,320,506 380,840 11,127,160 6554 375,324 4,608,832 175,231 525,175 878,232 2,366,429 53,730 688,326 38,835 1,414,523 640,918 307,229
69,325,304 20,596,066 18,357,404 67,709 5691 1,064,874 351,293
Live Births, Adjusted
Estimates for 2013
28 (26Y31) 4 (3Y4) 13 (12Y14) 86 (78Y95) 20 (18Y22) 9 (8Y10) 15 (14Y17) 6 (6Y7) 36 (32Y40) 2135 (1917Y2352) 59 (53Y65) 184 (166Y203) 1 (1Y1) 1486 (1335Y1638) 87 (78Y96) 1 every 2 y 34 (30Y38) 260 (233Y286) 23 (21Y25) 669 (601Y737) 1 every 2.5 y 23 (20Y25) 277 (249Y305) 11 (9Y12) 32 (28Y35) 53 (47Y58) 142 (128Y157) 3 (3Y4) 41 (37Y46) 2 (2Y3) 85 (76Y94) 39 (35Y42) 18 (17Y20)
4167 (3743Y4590) 1238 (1112Y1364) 1103 (991Y1215) 4 (4Y4) 1 every 3 y 64 (57Y70) 21 (19Y23)
Retinoblastoma Incidence, Children
51.3 3.2 23.6 72.8 17.9 6.4 10.2 5.9 32.4 1960 38.0 174.7 0.8 1393 86.6 0.4 30.9 212.3 22.7 684.5 0.5 17.7 277.1 8.0 34.1 57.1 115.7 6.2 67.9 1.4 98.9 43.7 26.3
4442 1681 1444 7.7 0.7 124.2 26.1
Population, Million
TABLE 2. The Predicted Annual Incidence of Retinoblastoma in the Asia-Pacific Region for the Next Decade*
9.2 17.6 8.4 19.0 16.7 21.8 26.7 18.0 17.6 18.1 27.4 16.7 16.0 17.7 14.4 16 18.3 21.6 14.7 16.0 13.4 20.5 16.2 22.0 16.2 14.7 22.3 9.8 8.9 35.1 12.2 15.8 12.4
14.8 10.4 10.6 8.4 9.8 7.8 13.9
Crude Birth Rate
2.1 18.3 3.0 34.8 20.8 27.8 46.9 40.2 37.2 33.7 52.6 19.0 19.0 33.0 9.4 6 22.8 52.9 6.7 18.7 2.7 27.7 19.8 22.2 2.9 42.2 17.6 1.3 7.3 24.9 11.2 18.1 3.1
22.0 9.2 9.9 1.5 2.9 1.7 14.6
Infant Mortality Rate
473,358 55,489 197,434 1,336,807 292,273 135,743 259,105 101,069 549,015 34,205,828 987,896 2,864,057 13,313 23,876,128 1,239,235 6425 552,218 4,337,781 331,209 10,721,116 6250 352,772 4,404,400 172,303 549,910 802,057 2,537,491 60,962 600,706 46,703 1,192,664 677,529 325,189
64,233,538 17,292,016 15,165,921 64,357 6438 972,275 357,150
Live Births, Adjusted
Estimates for 2023
28 (26Y31) 3 (3Y4) 12 (11Y13) 80 (72Y89) 18 (16Y19) 8 (7Y9) 16 (14Y17) 6 (5Y7) 33 (30Y36) 2055 (1846Y2265) 59 (53Y65) 172 (155Y190) 1 (1Y1) 1435 (1289Y1581) 74 (67Y82) 1 every 2.5 y 33 (30Y37) 261 (234Y287) 20 (18Y22) 644 (579Y710) 1 every 2.5 y 21 (19Y23) 265 (238Y292) 10 (9Y11) 33 (30Y36) 48 (43Y53) 152 (137Y168) 4 (3Y4) 36 (32Y40) 3 (3Y3) 72 (64Y79) 41 (37Y45) 20 (18Y22)
3859 (3467Y4255) 1039 (933Y1145) 911 (819Y1004) 4 (3Y4) 1 every 2.5 y 58 (52Y64) 21 (19Y24)
Retinoblastoma Incidence, Children
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13,594 4334 4646 2540 12.6 4.8 15.7 17.7 19.0 14.3 23.3 22.7 0.7 0.3 0.2 0.1 1 (1Y1) 1 every 3.5 y 1 every 3.5 y 1 every 6 y 14,122 4538 4928 2655 21.3 16.5 26.4 25.7 0.7 0.3 0.2 0.1
15.7 6.9 19.7 20.4
13.8 27.9 20.7 15.7 29.1 31.1 26.9 19.8 17.5 23.3 23.6
New Zealand Melanesia Fiji New Caledonia Papua New Guinea Solomon Islands Vanuatu Micronesia† Guam Kiribati Federated States of Micronesia Polynesia† French Polynesia Samoa Tonga
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*Population data are from the 2012 Revision of the World Population Prospects,4 and the crude birth and infant mortality rates are expressed per 1000 population and 1000 births, respectively; the retinoblastoma incidence per live births adjusted for infant mortality (lower and upper 95% CIs in parentheses) was based on a previous birth cohort analysis3; not corrected for familial cases, see text (eg, China, 3%Y7%16,18,19; Hong Kong, 0%20,21; Iran, 0%Y7%31Y34; Japan, 6%5; Korea, 1%22; Malaysia, 1%51; Nepal, 0%36; Pakistan, 1%Y10%11,42; Philippines, 7%Y8%53,54; and Singapore 6%13). † Estimates are not available for Marshall Islands, Nauru, Northern Mariana Islands, and Palau in Micronesia and for American Samoa, Cook Islands, Niue, Tokelau, Tuvalu, and Wallis and Futuna Islands in Polynesia,4 which all are predicted to have less than 1 incident retinoblastoma in a decade.
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1 (1Y1) 1 every 4 y 1 every 3.5 y 1 every 6.5 y
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4.5 9.3 0.9 0.3 7.3 0.6 0.3 0.5 0.2 0.1 0.1
4.3 43.6 16.0 13.1 47.6 38.0 23.9 23.3 9.7 34.3 32.7
62,077 247,877 17,907 3964 202,646 16,777 6626 9809 2859 2307 2360
4 (3Y4) 15 (13Y16) 1 (1Y1) 1 every 4 y 12 (11Y13) 1 (1Y1) 1 every 2.5 y 1 (1Y1) 1 every 6 y 1 every 7 y 1 every 7 y
4.9 11.1 0.9 0.3 8.9 0.7 0.3 0.6 0.2 0.1 0.1
12.8 24.9 17.2 14.3 26.0 26.6 23.7 18.3 16.2 22.0 24.0
3.5 39.4 12.8 10.1 43.2 30.0 17.3 18.6 7.3 24.6 28.7
63,007 265,843 15,687 4103 221,365 17,518 7211 10,135 2995 2560 2634
4 (3Y4) 16 (14Y18) 1 (1Y1) 1 every 4 y 13 (12Y15) 1 (1Y1) 1 every 2.5 y 1 (1Y1) 1 every 5.5 y 1 every 6.5 y 1 every 6.5 y
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for retinoblastoma has been documented, although several have been proposed.6 Except in familial cases, they seem to arise by chance from random mutations. The proof of our concept will lie in comparison with the national registry data with complete coverage. Except for Japan, which organized its National Registry of Retinoblastoma already in 1975,5,7 such registries for retinoblastoma do not exist in Asia-Pacific countries yet, although some general cancer registries report retinoblastomas separately and new national registries for retinoblastoma are being created. In Australia, an average of 15 retinoblastomas was diagnosed annually from 1997 to 2006,8 exactly our prediction for those years (currently 20). In Singapore, an average of 2.8 retinoblastomas was registered from 2003 to 2007,9 close to our prediction of 2.9 (currently 3.2). An average of 36 retinoblastomas from 1991 to 1993 was reported to a national registry in the Republic of Korea,10 corresponding to 88% of the 41 (currently 28) cases predicted to occur. As will be seen, reported numbers approach but do not exceed our predicted ones. Our predictions need to be corrected for familial retinoblastomas and foreign referrals. In a retinoblastoma family, the chance of producing an affected child is 1:2 rather than 1:16,642, the general risk.3 This is about 8300 times higher than we calculated. Familial cases are thus effectively not included in our predictions and must be added to the numbers. In the AsiaPacific, familial cases account for 1% to 10% of retinoblastoma (Table 2, footnote). For example, the National Registry of Retinoblastoma in Japan filed during the last decade an average of 75 retinoblastomas per year, of which 6 were familial and 69 were not known to be familial.5 Our estimate for those years was 67 (currently 64). Adding to this, the 6 observed familial tumors produce a close corrected estimate of 73 retinoblastomas. Correction also is needed if patients are admitted from neighboring countries. For example, several children from Afghanistan were treated in Pakistan11; some children from Kazakhstan, Kyrgyzstan, Tajikistan, and Turkmenistan were treated in Uzbekistan,12 and 2 times as many from Brunei, India, Indonesia, Malaysia, Myanmar, the Philippines, Sri Lanka, and Vietnam were treated in Singapore compared with Singaporean ones.13 Based on the 2006 population data, an average of 4279 retinoblastomas per year was earlier predicted for Asia (including Western Asia) and 28 for Oceania3 as compared with 4128 and 39 retinoblastomas in 2013 (excluding Western Asia), respectively. Our new calculations show that the incidence of retinoblastoma likely reached its peak in Asia in 1988, preceded and followed by increases and decreases reflecting primarily the family planning actions of China, especially the 1-child policy introduced in 1979.14 The increase in the estimated incidence of retinoblastoma in China after 1990 seems to reflect gradual reforms to this policy,14 and potential forthcoming relaxations cast uncertainty to future predictions.15 However, the incidence rate has stabilized also in other regions of the Asia-Pacific concurrently with that of China because of lower birth rates in general. The incidence of retinoblastoma in the Asia-Pacific is predicted to continue its steady decline, although it is still rising in some countries such as Australia and the Philippines, according to our calculations. As regards China,16Y18 incidence figures are available from major hospitals in 2 large cities, Beijing17 and Shanghai,18 from 2005 to 2009. These hospitals managed annually an average of 157 and 31 children, respectively, which translated to an average of 19% of the 1015 (currently 1103) predicted retinoblastomas. In 2009, the hospital in Beijing alone treated already 244 children19 or 23% of the 1047 predicted retinoblastomas that year. www.apjo.org
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In eastern Asia, the Hong Kong Eye Hospital saw an average of 2.8 retinoblastomas annually from 2001 to 2006,20 and 2 regional hospitals in Hong Kong reported 0.6 retinoblastomas in Hong Kong citizens between 1996 and 2005.21 Together, they managed 3.4 children per year, which was 97% of the predicted number of 3.5 (currently 4.1). The latter 2 hospitals treated additionally 1 patient in 10 years from Macau,21 in which 2 (currently 3) retinoblastomas were predicted to occur in a decade. In the Republic of Korea, 2 hospitals diagnosed an average of 10 and 6 retinoblastomas from 2000 to 2008,22,23 over 55% of the 29 (currently 28) tumors predicted. In Central Asia, comprehensive incidence figures have been published from Uzbekistan,12,24 in which an average of 30 Uzbek children were diagnosed annually with retinoblastoma from 2001 to 2010.12 This represents 88% of the predicted 34 cases (currently 36) for those years. Data from single eye and cancer hospitals and hospitalbased cancer registries in India25Y28 cover only a small proportion of retinoblastomas.29 Accordingly,30 5 national cancer registry program hospitals reported 74 retinoblastomas per year in 1994 to 2003 or 5% of the predicted average of 1511 (currently 1486) children. In 2009, the Indian Council of Medical Research began to organize a National Retinoblastoma Registry, which in 2011 was receiving registrations from 10 centers but has not reported its data yet.29 In southern Asia, Iran,31Y34 Nepal,35Y39 Pakistan,11,40Y43 and Sri Lanka44 report data from hospital-based registries, but sketchy data at best are available from countries such as Bangladesh.45 In Iran, 3 referral hospitals managed from 1995 to 2010 annually from 4 to 17 retinoblastomas each32Y34 to a total of 27, which is 35% of the predicted average of 78 (currently 87). The capital of Nepal filed 17 retinoblastomas annually from 1999 to 2000,37 corresponding to 40% of the 43 (currently 34) predicted patients. A Nepalese regional referral center reported an average of 6 children from 1995 to 2008,35,36,38 which increases coverage to 55% of our prediction. One supraregional referral center in Pakistan managed from 1999 to 2002 an average of 18 retinoblastomas, excluding referrals from Afghanistan,11 and during this time, 2 more Iranian referral hospitals reported annually 20 and 23 children.40,41 Thus, 61 or 24% of the predicted 254 (currently 260) retinoblastomas were covered. In Southeast Asia, 3 hospital-based registries in Indonesia each reported 6 to 15 retinoblastomas in 1999 to 2009 to a total of 29 children or 11% of the predicted 274 (currently 277) tumors.46Y48 A provincial cancer registry was founded in 2007 in Jakarta,49 but its data have not been published. In Malaysia, a hospital-based cancer registry recently reported 87 patients from 6 years, which was 50% of the predicted 29 (currently 32).50,51 The recently established Malaysian Retinoblastoma Registry tracks patients diagnosed in 3 major centers.52 The average number of registered children from 2007 to 2010 was 1852, which is 62% of the predicted number. In the Philippines, a tertiary ocular oncology unit, allegedly receiving most referrals, reported an average of 15 to 33 retinoblastomas between 1997 and 2008, depending on the report,53,54 which was 11% to 24% of the predicted 136 (currently 142) children. The need for a national retinoblastoma registry was recently voiced,54 and the Philippine Canserve Project aims to enhance access to treatment to 50% of children with cancer. In Thailand, 18 centers affiliated with the Thai Pediatric Oncology Group, allegedly receiving all childhood cancer referrals from 2003 to 2005, registered 32 retinoblastomas per year,55 which corresponds to 63% of the 51 (currently 41) predicted tumors.
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In summary, we provide predicted numbers of retinoblastomas in 2013 and 2023 for Asia-Pacific countries assuming that the incidence is constant across the world. Comparison with literature shows that 5% to 100% of our predicted numbers are accounted for in recent reports, supporting the validity of using the predicted numbers as surrogates for registered retinoblastomas whenever national statistics are not yet available or complete. ACKNOWLEDGMENTS The authors are most grateful for the grant provided to Dr Rustam Usmanov from the International Council of Ophthalmology and to Dr Shigenobu Suzuki for his invaluable guidance with the Japanese National Registry of Retinoblastoma data.
REFERENCES 1. Kivela¨ T. 200 years of success initiated by James Wardrop’s 1809 monograph on retinoblastoma. Acta Ophthalmol. 2009;87:810Y812. 2. Kivela¨ T. The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death. Br J Ophthalmol. 2009;93:1129Y1131. 3. Seregard S, Lundell G, Svedberg H, et al. Incidence of retinoblastoma from 1958 to 1998 in Northern Europe: advantages of birth cohort analysis. Ophthalmology. 2004;111:1228Y1232. 4. United Nations Department of Economic and Social Affairs. World Population Prospects, the 2012 Revision. June 13, 2013. Available at: http://esa.un.org/wpp/index.htm. Accessed June 15, 2013. 5. Azuma N. Suggestion for the registry of retinoblastoma in Japan [in Japanese]. Nihon Ganka Gakkai Zasshi. 2013;117:172Y174. 6. Orjuela M. Epidemiology. In: Rodriguez-Galindo C, Wilson MW, eds. Retinoblastoma. New York, NY: Springer; 2010:11Y23. 7. Anonymous. Survival rate and risk factors for patients with retinoblastoma in Japan. The Committee for the National Registry of Retinoblastoma. Jpn J Ophthalmol. 1992;36:121Y131. 8. Youlden D, Baade P, Ward L, et al. Childhood cancer incidence in Australia, 1983Y2006. Brisbane, Queensland: Viertel Centre for Research in Cancer Control, Cancer Council Queensland and the Australian Paediatric Cancer Registry; 2009. 9. Moy TA, Ha C. Singapore Childhood Cancer Registry 2003Y2007. Singapore: Singapore Childhood Cancer Registry; 2010. 10. Kim JH, Yu YS. Incidence (1991~1993) and survival rates (1991Y2003) of retinoblastoma in Korea. J Korean Ophthalmol Soc. 2010;51:542Y551. 11. Arif M, Iqbal Z, Zia-ul I. Retinoblastoma in NWFP, Pakistan. J Ayub Med Coll Abbottabad. 2009;21:60Y62. 12. Bahritdinova F, Islamov Z. Clinical characteristics and differential diagnosis of retinoblastoma. Med Health Sci J. 2012;12:2Y6. 13. Aung L, Chan YH, Yeoh EJ, et al. Retinoblastoma: a recent experience at the National University Hospital, Singapore. Ann Acad Med Singapore. 2009;38:693Y698. 14. Wang C. History of the Chinese Family Planning program: 1970Y2010. Contraception. 2012;85:563Y569. 15. Alcorn T. China’s new leaders cut off one-child policy at the root. Lancet. 2013;381:983. 16. Chang CY, Chiou TJ, Hwang B, et al. Retinoblastoma in Taiwan: survival rate and prognostic factors. Jpn J Ophthalmol. 2006;50:242Y249.
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17. Zhao J, Li S, Shi J, et al. Clinical presentation and group classification of newly diagnosed intraocular retinoblastoma in China. Br J Ophthalmol. 2011;95:1372Y1375. 18. Gao YJ, Qian J, Yue H, et al. Clinical characteristics and treatment outcome of children with intraocular retinoblastoma: a report from a Chinese cooperative group. Pediatr Blood Cancer. 2011;57:1113Y1116. 19. Huang D, Zhang Y, Zhang W, et al. Study on clinical therapeutic effect including symptoms, eye preservation rate, and follow-up of 684 children with retinoblastoma. Eur J Ophthalmol. 2013;23:532Y538. 20. Lau CS, Choy KW, Fan DS, et al. Prenatal screening for retinoblastoma in Hong Kong. Hong Kong Med J. 2008;14:391Y394. 21. Yam JCS, Ko STC, Chan CWN. A 10-year retrospective study of retinoblastoma in 2 regional hospitals in Hong Kong. Hong Kong J Ophthalmol. 2007;12:7Y10.
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37. Saiju R, Thakur J, Karmacharya PC, et al. Retinoblastoma in Nepal: a clinical profile of 30 cases. Nepal Med Coll J. 2006;8:171Y175. 38. Lavaju P, Arya SK, Sinha A, et al. Pattern of ocular tumors in the eastern region of Nepal. Nepal J Ophthalmol. 2009;1:9Y12. 39. Kumar R, Adhikari RK, Sharma MK, et al. Pattern of ocular malignant tumors in Bhairahawa, Nepal. Internet J Ophthalmol Vis Sci. 2009;7 [serial online]. 2009;7(1). Available at: http://ispub.com/IJOVS/7/1/ 13381. Accessed June 15, 2013. 40. Bhurgri Y, Muzaffar S, Ahmed R, et al. Retinoblastoma in Karachi, Pakistan. Asian Pac J Cancer Prev. 2004;5:159Y163. 41. Arif M, Iqbal Z, Zia-ul I. Retinoblastoma presenting as metastasis. J Ayub Med Coll Abbottabad. 2010;22:109Y111.
22. Chung SE, Sa HS, Koo HH, et al. Clinical manifestations and treatment of retinoblastoma in Korea. Br J Ophthalmol. 2008;92:1180Y1184.
42. Noorani S, Ahmed J, Shaikh ZA. Retinoblastoma: clinical picture and grouping at the time of first presentation. Pak J Med Sci. 2011;27:1055Y1059.
23. Lee BJ, Kim JH, Kim DH, et al. The validity of routine brain MRI in detecting post-laminar optic nerve involvement in retinoblastoma. Br J Ophthalmol. 2012;96:1237Y1241.
43. Khan AA, Bukhari MH, Mehboob R. Association of retinoblastoma with clinical and histopathological risk factors. Natural Sci. 2013;5:437Y444.
24. Mouratova T. Retinoblastoma in Uzbekistan. Bull Soc Belge Ophtalmol. 2003;63Y69.
44. Jayatilake RS. Multimodal treatment in the management of paediatric malignancies in Sri Lanka. Sri Lanka J Child Health. 2000;29:70Y84.
25. Yeole BB, Advani S. Retinoblastoma: an epidemiological appraisal with reference to a population in Mumbai, India. Asian Pac J Cancer Prev. 2002;3:17Y21.
45. Awal MA, Yusuff SM, Mitra T, et al. Pattern of malignancies among the patients attending the department of radiotherapy, Chittagong Medical College Hospital in the year 2007. Bangalore Oncol J. 2009;4:44Y50.
26. Shanmugam MP, Biswas J, Gopal L, et al. The clinical spectrum and treatment outcome of retinoblastoma in Indian children. J Pediatr Ophthalmol Strabismus. 2005;42:75Y81.
46. Nafianti S. Retinoblastoma in children in Haji Adam Malik Hospital Medan. Majalah Kedokteran Nusantara. 2006;39:147Y150.
27. Bakhshi S, Gupta S, Gogia V, et al. Compliance in retinoblastoma. Indian J Pediatr. 2010;77:535Y540. 28. Kumar A, Moulik NR, Mishra RK, et al. Causes, outcome and prevention of abandonment in retinoblastoma in India. Pediatr Blood Cancer. 2013;60:771Y775. 29. Khetan V, Sengupta S. Twenty-year trends of retinoblastoma under five hospital-based cancer registries: few observations. Indian J Cancer. 2011;48:371Y372. 30. Sachdeva S. Trend of reported cases of retinoblastoma under five hospital based cancer registries. Indian J Cancer. 2010;47:473Y474. 31. Naseripour M, Falavarjani KG, Bakhtiari P, et al. Retinoblastoma survival in Iran: 10 years experience of a referral center. Iran J Ophthlamol. 2009;21:17Y24. 32. Naseripour M, Nazari H, Bakhtiari P, et al. Retinoblastoma in Iran: outcomes in terms of patients’ survival and globe survival. Br J Ophthalmol. 2009;93:28Y32. 33. Salehi A, Owji N, Malekmakan L, et al. Epidemiologic features of retinoblastoma in Shiraz, Southern Iran. Iran Red Crescent Med J. 2011;13:452Y457. 34. Nabie R, Taheri N, Fard AM, et al. Characteristics and clinical presentations of pediatric retinoblastoma in North-western Iran. Int J Ophthalmol. 2012;5:510Y512. 35. Thakur SK, Sah SP, Lakhey M, et al. Primary malignant tumours of eye and adnexa in Eastern Nepal. Clin Experiment Ophthalmol. 2003;31:415Y417. 36. Badhu B, Sah SP, Thakur SK, et al. Clinical presentation of retinoblastoma in Eastern Nepal. Clin Experiment Ophthalmol. 2005;33:386Y389.
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47. Asih D, Gatot D, Sitorus RS. Computed tomography findings of retinoblastoma patients at Cipto Mangunkusumo Hospital Jakarta. Med J Indones. 2009;18:239Y243. 48. Ali K, Sutaryo S, Purwanto I, et al. Yogyakarta Pediatric Cancer Registry: an international collaborative project of University Gadjah Mada, University of Saskatchewan, and the Saskatchewan Cancer Agency. Asian Pac J Cancer Prev. 2010;10:131Y136. 49. Wahidin M, Noviani R, Hermawan S, et al. Population-based cancer registration in Indonesia. Asian Pac J Cancer Prev. 2012;13:1709Y1710. 50. Menon BS, Alagaratnam J, Juraida E, et al. Late presentation of retinoblastoma in Malaysia. Pediatr Blood Cancer. 2009;52:215Y217. 51. Jamalia R, Sunder R, Alagaratnam J, et al. Retinoblastoma registry reportVHospital Kuala Lumpur experience. Med J Malaysia. 2010;65:128Y130. 52. Rahmat J. Retinoblastoma registry. In: Mohammad Aziz Salowi, Goh PP, eds. The 4th report of the National Eye Database 2010. Kuala Lumpur, Malaysia: National Eye Database; 2012:79Y85. 53. Espiritu RB, de Jesus AA, Valera EG, et al. Epidemiological pattern of retinoblastoma at the Philippine General Hospital. Philippine J Ophthalmol. 2004;29:136Y139. 54. Noguera SI, Mercado GJV, Santlago DE. Clinical epidemiology of retinoblastoma at the Philippine General Hospital: 1998Y2008. Philippine J Ophthalmol. 2011;36:28Y32. 55. Wiangnon S, Veerakul G, Nuchprayoon I, et al. Childhood cancer incidence and survival 2003Y2005, Thailand: study from the Thai Pediatric Oncology Group. Asian Pac J Cancer Prev. 2011;12:2215Y2220.
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Predicted Trends in the Incidence of Retinoblastoma in the Asia-Pacific Region Rustam H. Usmanov, MD*Þ and Tero Kivela¨, MD, FEBOÞþ
Purpose: The aim of this study is to predict the incidence trends of retinoblastoma in the Asia-Pacific region. Design: Statistical prediction is based on the assumption of uniform incidence among live-born children. Methods: The number of live births was projected from population sizes and birth rates, corrected for infant mortality, and taken from the 2012 Revision of the World Population Prospects by the United Nations. The uniform incidence of 1:16,642 was derived from an earlier birth cohort analysis. Western Asia was excluded from calculations. Results: Six of 15 countries with over 100 retinoblastomas annually and responsible for 43% of 8099 retinoblastomas predicted for 2013 are Asia-Pacific nations. The predicted incidence of retinoblastoma in the Asia-Pacific peaked in 1988 at 4772 children and is 4167 and 3859, respectively, in 2012 and 2023. The 10 countries that account for 90% of retinoblastomas in the Asia-Pacific are India (1486 and 1435 children in 2013 and 2023, respectively), China (1103 and 911), Indonesia (277 and 265), Pakistan (260 and 261), Bangladesh (184 and 172), the Philippines (142 and 152), Iran (87 and 74), Vietnam (85 and 72), Japan (64 and 58), and Afghanistan (59 and 59). Largest relative decreases are predicted for China (j17%), Vietnam and Iran (j15%), and Sri Lanka (j13%). Conclusions: Reported retinoblastomas during the last decade in the Asia-Pacific account for less than half of predicted numbers, which can be used as surrogates for evaluating completeness of registration and for advocacy toward reducing deaths and blindness from retinoblastoma. Key Words: epidemiology, eye cancer, cancer incidence, malignant neoplasms, retinoblastoma (Asia Pac J Ophthalmol 2014;3: 151Y157)
malignancy globally with an estimated number of 7202 to 8102 new patients annually, outnumbering uveal melanoma by a margin of 523 to 1007 patients in 2006.2 Continuing population growth still increases the global number of incident retinoblastomas approximately by 100 children per year. In 2006, an estimated minimum of 3001 to 3376 children died annually of retinoblastoma.2 Given that both intraocular and metastatic retinoblastoma can be effectively managed by focal treatments, chemotherapy, and radiotherapy, there is definite hope that morbidity and mortality from retinoblastoma can be reduced. If all retinoblastomas could be referred to national or regional retinoblastoma centers, mortality might decrease by 62% to 1200 children per year.2 Because no effective treatment is available for metastatic uveal melanoma, possibilities of reducing mortality from eye cancer currently are best with regard to retinoblastoma. To plan and execute a national program with the aim of promoting early diagnosis, prompt treatment, and enhanced treatment compliance, and to raise money and awareness for such a program, it is essential to know the number of children affected by retinoblastoma. Ideally, this is accomplished through a national retinoblastoma registry with complete ascertainment of incident cases. For geographical, administrative, financial, and political reasons, this is achievable to a variable extent in practice. In case national statistics are unavailable, incomplete, or inaccurate, a reasonable starting point is the incidence estimated from available epidemiological and population statistics. We provide here such countrywise estimates of the incidence of retinoblastoma for the Asia-Pacific region for the years 2013 and 2023.
MATERIALS AND METHODS
R
etinoblastoma is well known for being the most common intraocular cancer for children ever after its first description as an entity by James Wardrop just over 200 years ago.1 Moreover, it is established that retinoblastoma is the most frequent primary intraocular cancer overall in nonwhite populations because of the rarity of uveal melanoma in Asian and African populations.2 Indeed, the faster population growth in the Asia-Pacific and the Middle EastYAfrican regions has recently made retinoblastoma the most frequent intraocular
Aims of the Study Our aim is to predict the incidence of retinoblastoma in each country of the Asia-Pacific region to provide numbers against which the number of registered retinoblastoma patients can be compared so as to estimate the completeness of the registration. Our predictions can also be used in advocacy as regards planning, financing, and execution of national treatment programs for retinoblastoma.
Statistical Methods From the *Department of Onco-Ophthalmology, National Oncological Research Center, Tashkent, Uzbekistan; †Ocular Oncology Service, and ‡Pediatric Ophthalmology Service, Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland. Received for publication July 22, 2013; accepted May 08, 2014. Conflicts of Interest and Source of Funding: Dr Usmanov was a recipient of a 3-month-long International Council of Ophthalmology Fellowship in the Ocular Oncology Service from October to December 2012. None for the other author. Reprints: Tero Kivela¨, MD, FEBO, Department of Ophthalmology, Helsinki University Central Hospital, Haartmaninkatu 4 C, PL 220, FI-00029 HUS, Helsinki, Finland. E-mail: tero.kivela@helsinki.fi. Copyright * 2014 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0000000000000060
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The incidence of retinoblastoma can be calculated from observational data in several ways, depending on the perceived population at risk, such as children of a particular age living at a given moment. Because retinoblastoma is a developmental cancer, we have argued that unnecessary variation to incidence estimates is introduced by different growth rates of retinoblastomas that may have initiated even before birth.3 Delays in diagnosis in regions with limited access to specialized health care add to this variation in age at diagnosis. A report of the incidence of retinoblastoma in Sweden and Finland is informative because these northern European countries have had comprehensive national cancer registries for over 5 decades.3 This study found that retinoblastoma incidence rates based on age
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cohorts were the most volatile and that most stable estimates were obtained by assigning each child with an incident retinoblastoma to his or her birth cohort. The birth cohort method both minimized the effect of variable age at the time of diagnosis of this developmental cancer and showed that apparent trends in incidence rates that were present in traditional age cohort analysis disappeared in birth cohort analysis. We are unaware of any study that would have documented the incidence of retinoblastoma to be unequivocally and consistently different from our estimate.3 We consequently used the birth cohortYbased estimate of 6.0 [95% confidence interval (CI), 5.4Y6.6] retinoblastomas per 100,000 live births or 1 in 16,642 (95% CI, 15,105Y18,528) as the best predictor for the global incidence of retinoblastoma. The number of live-born children can be conveniently calculated from total population size and crude birth statistics made available by the United Nations for all countries. We used the 2012 Revision of the World Population Prospects, published in June 2013, which is the 23rd edition of global demographic estimates and projections published by the Population Division of the Department of Economic and Social Affairs of the United Nations Secretariat.4 We applied the table for total population, both sexes (file POP/1-1, median fertility table, population in a country, area, or region as of July 1) and years 2010Y2015 and 2020Y2025 crude birth rate estimates, respectively (file FERT/3, median fertility table, the number of births over 5-year periods running from July 1 to June 30 of the initial and final years, respectively, divided by the person-years lived by the population over that period and expressed as the average annual number of births per 1000 population). The estimates for the intervening years were derived by linear extrapolation. Given that infant mortality varies widely, we corrected the crude number of live-born children by deducting the estimate of infant deaths for the years 2010Y2015 and 2020Y2025, respectively (file MORT/1-1, median fertility table, probability of dying between birth and exact age 1 year expressed as average annual deaths per 1000 births). The infant mortality estimates include some deaths due to retinoblastoma, but their proportion is a minute fraction of all infant mortality. We calculated the median predicted number of incident retinoblastomas with its lower and upper bound CIs for the years 2013 and 2023 using the Stata software (version 10; Stata Corp, College Station, Tex). We excluded countries assigned by the United Nations to western Asia because these belong to the Middle EastYAfrican region. In addition, we calculated the yearly incidence estimates for the entire AsiaPacific region and Japan until 2050 and plotted the predicted incidence against population size for countries with a minimum of 10 million inhabitants. Because the data set in the original birth cohort analysis had few familial retinoblastomas (ie, children who had a previous family member with retinoblastoma), these pregnancies with a high risk (1:2) of producing offspring with retinoblastoma are effectively not accounted for in our predicted numbers and must be added to them.
RESULTS The predicted annual incidence of retinoblastoma (excluding familial retinoblastoma, see Methods) based on the year 2013 population projections reaches 100 children in 15 countries worldwide, of which 6 (40%) are located in the Asia-Pacific region (Table 1A). Together, these 6 countries are predicted to have 3452 children with retinoblastoma annually or 43% of the predicted global burden of 8099 retinoblastomas to be diagnosed.
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TABLE 1A. Countries in Which Predicted Annual Incidence of Retinoblastoma Is 100 or More in 2013 Country India China Nigeria Indonesia Pakistan United States of America Bangladesh Ethiopia Brazil Democratic Republic of the Congo Philippines Mexico Egypt Tanzania Russian Federation
Region
Incidence of Retinoblastoma*
Asia-Pacific Asia-Pacific Africa Asia-Pacific Asia-Pacific North America Asia-Pacific Africa South America Africa
1486 (1335Y1638) 1103 (991Y1215) 400 (359Y440) 277 (249Y305) 260 (233Y286) 252 (227Y278) 184 (166Y203) 179 (161Y197) 179 (160Y197) 155 (139Y171)
Asia-Pacific North America Africa Africa Europe
142 (128Y157) 135 (121Y148) 113 (101Y124) 111 (99Y122) 100 (90Y111)
*Median prediction with 95% confidence interval, Asia-Pacific countries highlighted with bold typeface; not corrected for familial cases, see text.
The predicted incidence of retinoblastoma in 2023 likewise reaches 100 children in 15 countries, of which 6 (40%) are in the Asia-Pacific region (Table 1B). Together, these 6 countries are predicted to have 3196 (reduced by 256) retinoblastomas annually or 40% of the predicted global burden of 8062 (reduced by 37) retinoblastomas. An increase in the incidence is predicted for the United States and the Philippines as well as for all African countries except Egypt, with Uganda replacing the Russian Federation on the list and Pakistan showing an essentially stable incidence. A decreasing trend in the incidence of retinoblastoma in the Asia-Pacific region started in 1988 when the predicted rate peaked at 4772 children (Fig. 1A). A trough was reached in 2003 with an estimated 4020 children with diagnosed retinoblastoma. After 2003, a modest increase to 4166 children in 2013 is predicted to occur. A period of slow decline in incident retinoblastomas in the Asia-Pacific region, based on population projections, is predicted from here on. Excluding China, the peak incidence occurred in 1992 with 3128 retinoblastomas; whereafter, the incidence rate has only slightly declined to 3063 patients in 2013. More rapid decrease is predicted from 2015 onward. The predicted incidence of retinoblastoma by country in the Asia-Pacific region in 2013 ranges from 1486 children in India to less than 2 children per decade in several Oceanian island nations (Table 2). The 9 countries with the next largest numbers of incident retinoblastomas are China (1103 children), Indonesia (277 children), Pakistan (260 children), Bangladesh (184 children), the Philippines (142 children), Iran (87 children), Vietnam (85 children), Japan (64 children), and Afghanistan (59 children). Taken together, these 10 countries will have 3747 (90%) of the 4167 retinoblastomas predicted to occur in the Asia-Pacific region in 2013. The corresponding incidence rates in 2023 will range from 1435 children (reduced by 51) in India to less than 1 child in 5 years (Table 2). The other 9 countries with most retinoblastomas will be China (911 children, reduced by 192), Pakistan (261 children, increased by 1), Indonesia (265 children, reduced * 2014 Asia Pacific Academy of Ophthalmology
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Retinoblastoma Incidence in Asia-Pacific Region
TABLE 1B. Countries in Which Predicted Annual Incidence of Retinoblastoma Is 100 or More in 2023 Country
Region
India China Nigeria United States of America Indonesia Pakistan Ethiopia Democratic Republic of the Congo Bangladesh Brazil Philippines Tanzania Mexico Uganda Egypt
Incidence of Retinoblastoma*
Asia-Pacific Asia-Pacific Africa North America Asia-Pacific Asia-Pacific Africa Africa
1435 (1289Y1581) 911 (819Y1004) 483 (434Y532) 268 (240Y295) 265 (238Y292) 261 (234Y287) 195 (175Y214) 183 (165Y202)
Asia-Pacific South America Asia-Pacific Africa North America Africa Africa
172 (155Y190) 167 (150Y185) 152 (137Y168) 134 (120Y147) 126 (113Y139) 114 (102Y126) 109 (98Y120)
*Median prediction with 95% confidence interval, Asia-Pacific countries highlighted with bold typeface; not corrected for familial cases, see text.
by 12), Bangladesh (172 children, reduced by 12), the Philippines (152 children, increased by 10), Iran (74 children, reduced by 13), Vietnam (72 children, reduced by 13), Japan (58 children, reduced by 6), and Afghanistan (59 children, unchanged). Taken together, they will have 3459 (90%) of the 3859 retinoblastomas to be diagnosed in the Asia-Pacific region in 2023. It is possible to directly compare our predicted numbers with observed ones using the data reported by the Japanese National Registry of Retinoblastoma for the years 1975 to 2011 (Fig. 1B).5 The predicted numbers match the observed ones, especially in recent years when the coverage of the registry is likely to be most complete. A reduction of 359 (7%) incident retinoblastomas is predicted for the Asia-Pacific region for the next decade, with the largest absolute changes (Fig. 1C) in China (192 children), India (51 children), Iran and Vietnam (13 children), and Bangladesh and Indonesia (12 children). An absolute increase larger than 10 children is not predicted for any Asia-Pacific country. The largest relative declines in countries with at least 10 million inhabitants are predicted for China (j17%); Iran and Vietnam (j15%); Sri Lanka (j13%); Kazakhstan (j10%); Cambodia, Japan, and Myanmar (j9%); Uzbekistan (j8%); Bangladesh (j7%); and Thailand (j5%).
DISCUSSION Our predictions of the incidence rate of retinoblastoma in the Asia-Pacific region are based on birth cohort analysis of northern European data for 1959 to 1998, which showed a stable incidence over 40 decades.3 We believe that the results are applicable to other regions as well, although many have claimed a higher incidence in certain regions and countries.6 Such studies were, however, based on small populations, short periods, and typically on children of a particular age range, which introduces bias from childhood mortality and population migration.3,6 The annual incidence can vary widely in such instances, and we caution against drawing conclusions from such analyses.3 Moreover, no convincing external cause * 2014 Asia Pacific Academy of Ophthalmology
FIGURE 1. Predicted past (solid line) and projected (dashed line) annual incidence of retinoblastoma (A) in the entire Asia-Pacific region and (B) Japan from 1950 to 2050 with 95% CI (shaded area) and predicted incidence (C) for Asia-Pacific countries with 10 million inhabitants or more projected for the years 2013 (black symbols) and 2023 (gray symbols) and plotted against population size (logarithmic scale). Note that the incidence rate for the entire region reflects changes in family planning policy of China and essentially plateaus for other countries in 1992, whereas a moderate decline is projected for the future; any changes in family planning policies will greatly affect future projected incidence rates (A). Observed annual numbers of nonfamilial retinoblastomas (white symbols) and the corresponding locally weighted scatterplot smoothed data (dotted line) from the Japanese National Registry for Retinoblastoma5 are superimposed on the predicted past (solid line) and projected (dashed line) numbers for Japan; familial retinoblastomas are not accounted for in our predicted numbers because of different risk level; note that the locally weighted scatterplot smoothed data for incident nonfamilial retinoblastomas coincide with the 95% CI of the prediction (shaded area), approaching predicted numbers during the last decade (B). The plot against population size highlights the influence of birth rate on the projected incidence of retinoblastoma; note, for example, that Cambodia and Sri Lanka are predicted to have the same number of retinoblastomas although their populations differ in size. Afghanistan is predicted to have approximately 2 times as many retinoblastomas as Malaysia although their populations are comparable, and more than 30% more retinoblastomas are predicted to be diagnosed in India as compared with China, although the latter has a larger population (C). www.apjo.org
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Asia-Pacific Eastern Asia China China, Hong Kong China, Macau Japan Democratic People’s Republic of Korea Republic of Korea Mongolia Other areas Central Asia Kazakhstan Kyrgyzstan Tajikistan Turkmenistan Uzbekistan Southern Asia Afghanistan Bangladesh Bhutan India Iran Maldives Nepal Pakistan Sri Lanka Southeastern Asia Brunei Cambodia Indonesia Laos Malaysia Myanmar Philippines Singapore Thailand Timor-Leste Vietnam Oceania Australia
Country
17.5 12.9 13.4 9.4 10.1 8.4 14.4
9.6 22.8 9.3 23.3 20.5 27.4 33.3 21.5 21.6 21.3 34.5 20.3 19.8 20.7 19.0 22.3 21.1 25.4 18.1 18.4 15.8 25.8 18.9 26.9 17.7 17.3 24.6 9.9 10.4 35.7 15.6 17.1 13.2
49.3 2.8 23.3 64.4 16.4 5.5 8.2 5.2 28.9 1749 30.6 156.6 0.8 1252 77.4 0.3 27.8 182.1 21.2 618.8 0.4 15.1 249.9 6.8 29.7 53.3 98.4 5.4 67.0 1.1 91.7 38.3 23.3
Crude Birth Rate
4091 1621 1386 7.2 0.6 127.1 24.9
Population, Million
www.apjo.org 3.4 25.8 4.2 41.1 24.6 33.1 56.8 46.7 44.0 44.5 67.3 32.3 30.7 43.8 15.7 10.4 35.5 65.1 9.0 23.7 4.2 40.6 25.6 36.2 4.1 48.9 21.0 1.8 9.9 39.3 14.1 20.2 3.9
28.3 12.3 13.0 1.9 4.1 2.2 22.0
Infant Mortality Rate
473,366 63,064 215,235 1,437,507 328,686 146,700 257,790 107,195 597,431 35,523,456 983,371 3,068,629 14,483 24,736,806 1,448,889 7626 566,446 4,320,506 380,840 11,127,160 6554 375,324 4,608,832 175,231 525,175 878,232 2,366,429 53,730 688,326 38,835 1,414,523 640,918 307,229
69,325,304 20,596,066 18,357,404 67,709 5691 1,064,874 351,293
Live Births, Adjusted
Estimates for 2013
28 (26Y31) 4 (3Y4) 13 (12Y14) 86 (78Y95) 20 (18Y22) 9 (8Y10) 15 (14Y17) 6 (6Y7) 36 (32Y40) 2135 (1917Y2352) 59 (53Y65) 184 (166Y203) 1 (1Y1) 1486 (1335Y1638) 87 (78Y96) 1 every 2 y 34 (30Y38) 260 (233Y286) 23 (21Y25) 669 (601Y737) 1 every 2.5 y 23 (20Y25) 277 (249Y305) 11 (9Y12) 32 (28Y35) 53 (47Y58) 142 (128Y157) 3 (3Y4) 41 (37Y46) 2 (2Y3) 85 (76Y94) 39 (35Y42) 18 (17Y20)
4167 (3743Y4590) 1238 (1112Y1364) 1103 (991Y1215) 4 (4Y4) 1 every 3 y 64 (57Y70) 21 (19Y23)
Retinoblastoma Incidence, Children
51.3 3.2 23.6 72.8 17.9 6.4 10.2 5.9 32.4 1960 38.0 174.7 0.8 1393 86.6 0.4 30.9 212.3 22.7 684.5 0.5 17.7 277.1 8.0 34.1 57.1 115.7 6.2 67.9 1.4 98.9 43.7 26.3
4442 1681 1444 7.7 0.7 124.2 26.1
Population, Million
TABLE 2. The Predicted Annual Incidence of Retinoblastoma in the Asia-Pacific Region for the Next Decade*
9.2 17.6 8.4 19.0 16.7 21.8 26.7 18.0 17.6 18.1 27.4 16.7 16.0 17.7 14.4 16 18.3 21.6 14.7 16.0 13.4 20.5 16.2 22.0 16.2 14.7 22.3 9.8 8.9 35.1 12.2 15.8 12.4
14.8 10.4 10.6 8.4 9.8 7.8 13.9
Crude Birth Rate
2.1 18.3 3.0 34.8 20.8 27.8 46.9 40.2 37.2 33.7 52.6 19.0 19.0 33.0 9.4 6 22.8 52.9 6.7 18.7 2.7 27.7 19.8 22.2 2.9 42.2 17.6 1.3 7.3 24.9 11.2 18.1 3.1
22.0 9.2 9.9 1.5 2.9 1.7 14.6
Infant Mortality Rate
473,358 55,489 197,434 1,336,807 292,273 135,743 259,105 101,069 549,015 34,205,828 987,896 2,864,057 13,313 23,876,128 1,239,235 6425 552,218 4,337,781 331,209 10,721,116 6250 352,772 4,404,400 172,303 549,910 802,057 2,537,491 60,962 600,706 46,703 1,192,664 677,529 325,189
64,233,538 17,292,016 15,165,921 64,357 6438 972,275 357,150
Live Births, Adjusted
Estimates for 2023
28 (26Y31) 3 (3Y4) 12 (11Y13) 80 (72Y89) 18 (16Y19) 8 (7Y9) 16 (14Y17) 6 (5Y7) 33 (30Y36) 2055 (1846Y2265) 59 (53Y65) 172 (155Y190) 1 (1Y1) 1435 (1289Y1581) 74 (67Y82) 1 every 2.5 y 33 (30Y37) 261 (234Y287) 20 (18Y22) 644 (579Y710) 1 every 2.5 y 21 (19Y23) 265 (238Y292) 10 (9Y11) 33 (30Y36) 48 (43Y53) 152 (137Y168) 4 (3Y4) 36 (32Y40) 3 (3Y3) 72 (64Y79) 41 (37Y45) 20 (18Y22)
3859 (3467Y4255) 1039 (933Y1145) 911 (819Y1004) 4 (3Y4) 1 every 2.5 y 58 (52Y64) 21 (19Y24)
Retinoblastoma Incidence, Children
Usmanov and Kivela¨ Asia-Pacific Journal of Ophthalmology
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13,594 4334 4646 2540 12.6 4.8 15.7 17.7 19.0 14.3 23.3 22.7 0.7 0.3 0.2 0.1 1 (1Y1) 1 every 3.5 y 1 every 3.5 y 1 every 6 y 14,122 4538 4928 2655 21.3 16.5 26.4 25.7 0.7 0.3 0.2 0.1
15.7 6.9 19.7 20.4
13.8 27.9 20.7 15.7 29.1 31.1 26.9 19.8 17.5 23.3 23.6
New Zealand Melanesia Fiji New Caledonia Papua New Guinea Solomon Islands Vanuatu Micronesia† Guam Kiribati Federated States of Micronesia Polynesia† French Polynesia Samoa Tonga
* 2014 Asia Pacific Academy of Ophthalmology
*Population data are from the 2012 Revision of the World Population Prospects,4 and the crude birth and infant mortality rates are expressed per 1000 population and 1000 births, respectively; the retinoblastoma incidence per live births adjusted for infant mortality (lower and upper 95% CIs in parentheses) was based on a previous birth cohort analysis3; not corrected for familial cases, see text (eg, China, 3%Y7%16,18,19; Hong Kong, 0%20,21; Iran, 0%Y7%31Y34; Japan, 6%5; Korea, 1%22; Malaysia, 1%51; Nepal, 0%36; Pakistan, 1%Y10%11,42; Philippines, 7%Y8%53,54; and Singapore 6%13). † Estimates are not available for Marshall Islands, Nauru, Northern Mariana Islands, and Palau in Micronesia and for American Samoa, Cook Islands, Niue, Tokelau, Tuvalu, and Wallis and Futuna Islands in Polynesia,4 which all are predicted to have less than 1 incident retinoblastoma in a decade.
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1 (1Y1) 1 every 4 y 1 every 3.5 y 1 every 6.5 y
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4.5 9.3 0.9 0.3 7.3 0.6 0.3 0.5 0.2 0.1 0.1
4.3 43.6 16.0 13.1 47.6 38.0 23.9 23.3 9.7 34.3 32.7
62,077 247,877 17,907 3964 202,646 16,777 6626 9809 2859 2307 2360
4 (3Y4) 15 (13Y16) 1 (1Y1) 1 every 4 y 12 (11Y13) 1 (1Y1) 1 every 2.5 y 1 (1Y1) 1 every 6 y 1 every 7 y 1 every 7 y
4.9 11.1 0.9 0.3 8.9 0.7 0.3 0.6 0.2 0.1 0.1
12.8 24.9 17.2 14.3 26.0 26.6 23.7 18.3 16.2 22.0 24.0
3.5 39.4 12.8 10.1 43.2 30.0 17.3 18.6 7.3 24.6 28.7
63,007 265,843 15,687 4103 221,365 17,518 7211 10,135 2995 2560 2634
4 (3Y4) 16 (14Y18) 1 (1Y1) 1 every 4 y 13 (12Y15) 1 (1Y1) 1 every 2.5 y 1 (1Y1) 1 every 5.5 y 1 every 6.5 y 1 every 6.5 y
Asia-Pacific Journal of Ophthalmology
Retinoblastoma Incidence in Asia-Pacific Region
for retinoblastoma has been documented, although several have been proposed.6 Except in familial cases, they seem to arise by chance from random mutations. The proof of our concept will lie in comparison with the national registry data with complete coverage. Except for Japan, which organized its National Registry of Retinoblastoma already in 1975,5,7 such registries for retinoblastoma do not exist in Asia-Pacific countries yet, although some general cancer registries report retinoblastomas separately and new national registries for retinoblastoma are being created. In Australia, an average of 15 retinoblastomas was diagnosed annually from 1997 to 2006,8 exactly our prediction for those years (currently 20). In Singapore, an average of 2.8 retinoblastomas was registered from 2003 to 2007,9 close to our prediction of 2.9 (currently 3.2). An average of 36 retinoblastomas from 1991 to 1993 was reported to a national registry in the Republic of Korea,10 corresponding to 88% of the 41 (currently 28) cases predicted to occur. As will be seen, reported numbers approach but do not exceed our predicted ones. Our predictions need to be corrected for familial retinoblastomas and foreign referrals. In a retinoblastoma family, the chance of producing an affected child is 1:2 rather than 1:16,642, the general risk.3 This is about 8300 times higher than we calculated. Familial cases are thus effectively not included in our predictions and must be added to the numbers. In the AsiaPacific, familial cases account for 1% to 10% of retinoblastoma (Table 2, footnote). For example, the National Registry of Retinoblastoma in Japan filed during the last decade an average of 75 retinoblastomas per year, of which 6 were familial and 69 were not known to be familial.5 Our estimate for those years was 67 (currently 64). Adding to this, the 6 observed familial tumors produce a close corrected estimate of 73 retinoblastomas. Correction also is needed if patients are admitted from neighboring countries. For example, several children from Afghanistan were treated in Pakistan11; some children from Kazakhstan, Kyrgyzstan, Tajikistan, and Turkmenistan were treated in Uzbekistan,12 and 2 times as many from Brunei, India, Indonesia, Malaysia, Myanmar, the Philippines, Sri Lanka, and Vietnam were treated in Singapore compared with Singaporean ones.13 Based on the 2006 population data, an average of 4279 retinoblastomas per year was earlier predicted for Asia (including Western Asia) and 28 for Oceania3 as compared with 4128 and 39 retinoblastomas in 2013 (excluding Western Asia), respectively. Our new calculations show that the incidence of retinoblastoma likely reached its peak in Asia in 1988, preceded and followed by increases and decreases reflecting primarily the family planning actions of China, especially the 1-child policy introduced in 1979.14 The increase in the estimated incidence of retinoblastoma in China after 1990 seems to reflect gradual reforms to this policy,14 and potential forthcoming relaxations cast uncertainty to future predictions.15 However, the incidence rate has stabilized also in other regions of the Asia-Pacific concurrently with that of China because of lower birth rates in general. The incidence of retinoblastoma in the Asia-Pacific is predicted to continue its steady decline, although it is still rising in some countries such as Australia and the Philippines, according to our calculations. As regards China,16Y18 incidence figures are available from major hospitals in 2 large cities, Beijing17 and Shanghai,18 from 2005 to 2009. These hospitals managed annually an average of 157 and 31 children, respectively, which translated to an average of 19% of the 1015 (currently 1103) predicted retinoblastomas. In 2009, the hospital in Beijing alone treated already 244 children19 or 23% of the 1047 predicted retinoblastomas that year. www.apjo.org
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In eastern Asia, the Hong Kong Eye Hospital saw an average of 2.8 retinoblastomas annually from 2001 to 2006,20 and 2 regional hospitals in Hong Kong reported 0.6 retinoblastomas in Hong Kong citizens between 1996 and 2005.21 Together, they managed 3.4 children per year, which was 97% of the predicted number of 3.5 (currently 4.1). The latter 2 hospitals treated additionally 1 patient in 10 years from Macau,21 in which 2 (currently 3) retinoblastomas were predicted to occur in a decade. In the Republic of Korea, 2 hospitals diagnosed an average of 10 and 6 retinoblastomas from 2000 to 2008,22,23 over 55% of the 29 (currently 28) tumors predicted. In Central Asia, comprehensive incidence figures have been published from Uzbekistan,12,24 in which an average of 30 Uzbek children were diagnosed annually with retinoblastoma from 2001 to 2010.12 This represents 88% of the predicted 34 cases (currently 36) for those years. Data from single eye and cancer hospitals and hospitalbased cancer registries in India25Y28 cover only a small proportion of retinoblastomas.29 Accordingly,30 5 national cancer registry program hospitals reported 74 retinoblastomas per year in 1994 to 2003 or 5% of the predicted average of 1511 (currently 1486) children. In 2009, the Indian Council of Medical Research began to organize a National Retinoblastoma Registry, which in 2011 was receiving registrations from 10 centers but has not reported its data yet.29 In southern Asia, Iran,31Y34 Nepal,35Y39 Pakistan,11,40Y43 and Sri Lanka44 report data from hospital-based registries, but sketchy data at best are available from countries such as Bangladesh.45 In Iran, 3 referral hospitals managed from 1995 to 2010 annually from 4 to 17 retinoblastomas each32Y34 to a total of 27, which is 35% of the predicted average of 78 (currently 87). The capital of Nepal filed 17 retinoblastomas annually from 1999 to 2000,37 corresponding to 40% of the 43 (currently 34) predicted patients. A Nepalese regional referral center reported an average of 6 children from 1995 to 2008,35,36,38 which increases coverage to 55% of our prediction. One supraregional referral center in Pakistan managed from 1999 to 2002 an average of 18 retinoblastomas, excluding referrals from Afghanistan,11 and during this time, 2 more Iranian referral hospitals reported annually 20 and 23 children.40,41 Thus, 61 or 24% of the predicted 254 (currently 260) retinoblastomas were covered. In Southeast Asia, 3 hospital-based registries in Indonesia each reported 6 to 15 retinoblastomas in 1999 to 2009 to a total of 29 children or 11% of the predicted 274 (currently 277) tumors.46Y48 A provincial cancer registry was founded in 2007 in Jakarta,49 but its data have not been published. In Malaysia, a hospital-based cancer registry recently reported 87 patients from 6 years, which was 50% of the predicted 29 (currently 32).50,51 The recently established Malaysian Retinoblastoma Registry tracks patients diagnosed in 3 major centers.52 The average number of registered children from 2007 to 2010 was 1852, which is 62% of the predicted number. In the Philippines, a tertiary ocular oncology unit, allegedly receiving most referrals, reported an average of 15 to 33 retinoblastomas between 1997 and 2008, depending on the report,53,54 which was 11% to 24% of the predicted 136 (currently 142) children. The need for a national retinoblastoma registry was recently voiced,54 and the Philippine Canserve Project aims to enhance access to treatment to 50% of children with cancer. In Thailand, 18 centers affiliated with the Thai Pediatric Oncology Group, allegedly receiving all childhood cancer referrals from 2003 to 2005, registered 32 retinoblastomas per year,55 which corresponds to 63% of the 51 (currently 41) predicted tumors.
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In summary, we provide predicted numbers of retinoblastomas in 2013 and 2023 for Asia-Pacific countries assuming that the incidence is constant across the world. Comparison with literature shows that 5% to 100% of our predicted numbers are accounted for in recent reports, supporting the validity of using the predicted numbers as surrogates for registered retinoblastomas whenever national statistics are not yet available or complete. ACKNOWLEDGMENTS The authors are most grateful for the grant provided to Dr Rustam Usmanov from the International Council of Ophthalmology and to Dr Shigenobu Suzuki for his invaluable guidance with the Japanese National Registry of Retinoblastoma data.
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