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Review Article
Epidemiology of childhood cancer in India Arora RS, Eden TOB1, Kapoor G2 Clinical research Fellow, Cancer Research UK Paediatric and Familial Cancer Research Group, University of Manchester, Manchester, UK, 1Teenage Cancer Trust Professor of Teenage and Young Adult Cancer, Christie Hospital NHS Foundation Trust, Manchester, UK, 2Consultant Pediatric Hematologist/Oncologist, Rajiv Gandhi Cancer, Institute & Research Centre, Delhi, India Correspondence to: Dr. Ramandeep Singh Arora, E-mail:
[email protected]
Abstract There has been enormous progress in the treatment of childhood cancer in the developed world and the epidemiology in these countries is well described. Hitherto, there has been no attempt to systematically study the burden of childhood cancer in India or to understand how the occurrence and outcome of the disease varies across the country. We have reviewed the epidemiology (incidence, survival, and mortality) of childhood cancer across different population-based cancer registries in India and also compared it with data from the resource-rich countries. Incidence and mortality data were obtained from the National Cancer Registry Program Reports and the Cancer Incidence in 5 Continents publications. Further, a comprehensive review of medical literature was done for information on individual cancers as well as survival data. 1.6 to 4.8% of all cancer in India is seen in children below 15 years of age and the overall incidence of 38 to 124 per million children, per year, is lower than that in the developed world. The considerable inter-regional variation in incidence and mortality rates across India suggests a possible deficiency in ascertainment of cases and death notification, particularly in rural areas. The marked male preponderance of Hodgkin’s disease, lower incidence of central nervous system tumors, and higher incidence of retinoblastoma merit further analysis. Key words: Childhood cancer, cancer registry, epidemiology, India, incidence, longitudinal trends, mortality, survival
DOI: 10.4103/0019-509X.55546
PMID: *****
Introduction Thirteen percent of the annual deaths worldwide are cancer-related and 70% of these are in the low- and middle-income countries.[1] In India, the leading causes of cancer-related death are carcinoma of the cervix in women and carcinoma of the lung and lower airways in men.[2] The focus of the National Cancer Control Program of India has been on primary prevention, by promoting tobacco control and genital hygiene; secondary prevention by screening for cervical cancer, breast cancer, and oropharyngeal cancer; and palliative care. [3] Although child health continues to be the priority health issue, childhood cancer is not yet a major area of focus. The emphasis is on reduction in mortality of infants and under-fives, by promotion of breastfeeding, rational antibiotic therapy for acute respiratory infections, oral rehydration for diarrhea, an extensive immunization program, and appropriate prevention and treatment of malaria.[4] Worldwide, the annual number of new cases of 264
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childhood cancer exceeds 200,000 and more than 80% of these are from the developing world.[5] Seven out of 10 children with cancer in the resource-rich countries are cured, with a five-year survival for certain cancers, for example, Hodgkin’s disease and retinoblastoma, now 95%.[6,7] Recent studies have shown that this success in survival can be replicated in the developing world through twinning programs and shared expertise.[8-11] As we make progress in reducing infection-related childhood deaths in India, it is no longer acceptable to ignore children with cancer, who have an increasing likelihood of cure with appropriate treatment. A fundamental step in caring for these children is to estimate the current burden of childhood cancer in India and to understand how the occurrence and outcome of the disease varies across the country. In this context, this study aims to describe the epidemiology of childhood cancer in India. This will serve as a reference source for clinicians, epidemiologists, researchers, and health administrators. It should also be the stimulus for further research on the etiology of childhood cancer. Indian Journal of Cancer | October–December 2009 | Volume 46 | Issue 4
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Methods Information for this review was obtained from multiple sources. Current incidence and mortality rates were derived from the 2006 National Cancer Registry Program (NCRP) reports, from thirteen population-based cancer registries (PBCRs) across India - rural Ahmedabad, Barshi, Bangalore, Bhopal, Chennai, Delhi, Mumbai, and North-East (Aizawl District, Dibrugarh District, Kamrup Urban District, Silchar Town, Imphal West District, Sikkim State).[12,13] Data from Cancer Incidence in Five Continents Volume V to IX, published by the International Agency for Research in Cancer (IARC) were used to calculate longitudinal incidence trends from 1978 to 2002.[14,15] Besides this, a comprehensive review of medical literature was done, for information on individual cancers as well as survival data.
the underlying population structure but other factors like completeness of cancer registration as well as geographical variation in exposure to risk factors need to be considered. Despite there being a higher proportion of childhood cancer in India relative to the developed world, it has not been a priority in healthcare. This is because of its contribution to overall childhood mortality. Excluding neonatal deaths, infectious and parasitic diseases are the most common cause of death in children in India. Only 2% of all deaths in this age group are reported to be cancer-related deaths.[16] This contrasts with data from England and Wales where injuries are the most common cause of death in children overall (21%) and cancer the most common cause of disease-related death (20%).[17] Incidence of Childhood Cancer
Burden of childhood cancer Cancer is generally regarded as a disease of adults. In England only 0.5% of all cancer cases occur in children less than 15 years of age. In India however, this proportion appears higher at 1.6–4.8% with variation by place of residence [Table 1]. This is related to the population structure (33% of the population in India is less than 15 years of age compared to 18% in England) and to a lower incidence in India of adult cancers attributed to a western life-style (e.g. carcinoma of the breast, large bowel, lung and prostate). Similarly, the differences in proportion of childhood cancer among different areas in India can also be a result of
Overall incidence: The incidence of childhood cancer in most populations in the world ranges from 75 to 150 per million children per year.[18,19] However, the reported age of the standardized incidence rate for India ranges from 38 to 124 per million children per year [Table 1]. The highest incidence is reported from Chennai and the lowest from rural Ahmedabad. This suggests that either there is truly a lesser incidence of childhood cancer in some areas of India, or as is more likely, there is underascertainment of cases. The reported incidence in urban areas (Bangalore, Bhopal, Chennai, Delhi, Mumbai) is generally higher than from rural areas (Barshi and Ahmedabad district) and more comparable with the
Table 1: Average Annual Number (AAN) of cases of cancer* and cancer incidence rates standardized for world population (ASR) in children 0 to 14 years of age† Population based cancer registry‡
AAN**
Male % of all cancer
ASR††
AAN
Female % of all cancer
ASR
AAN
Total % of all cancer
ASR
Ahmedabad§ (Rural)
15
3.8
51
5
1.9
23
20
3.1
38
Bangalore (Urban)
69
3.5
87
50
2.1
69
119
2.8
78
Barshi (Rural)
6
5.6
69
4
3.7
53
10
4.6
62
Bhopal (Urban)
16
3.1
58
13
2.8
55
29
2.9
57
Chennai (Urban)
78
3.9
150
47
2.2
97
125
3.0
124
Delhi (Urban)
335
6.5
146
152
3.1
76
487
4.8
113
Mumbai (Urban)
173
3.9
105
117
2.6
79
290
3.2
93
North East||
25
1.2
39
34
2.1
51
59
1.6
45
*All neoplasms with a behavior code of '3' as defined by the International Classification of Diseases - Oncology, (3 edition) and ICD 10 disease codes C00-C75 and C81-C95. †Data derived from the reports of the Indian Council of Medical Research, National Cancer Registry Program[12,13]. ‡These cover 4.3% of India’s population and 0.5% of the geographical area. §Ahmedabad District other than Ahmedabad Urban. ||North East comprises six PBCRs - Aizawl District, Dibrugarh District, Kamrup Urban District, Silchar Town, Imphal West District, and Sikkim State. **Average annual number calculated for Bangalore, Barshi, Bhopal, Delhi, and Mumbai PBCRs for period 2001-2003, for North East PBCRs for period 2003-2004, and for Ahmedabad for period 2004. ††Expressed per million children per year rd
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cancer in males seen in India. Gender bias in seeking healthcare, including treatment of cancer, is one possible explanation. [5] The male preponderance for most of the individual cancers types in Delhi would suggest this. One has to also consider other possibilities. Even after accounting for gender bias in seeking healthcare and the well-documented male preponderance of Hodgkin’s disease (HD), the observation of a 12-fold higher incidence of HD in male children in Delhi is truly remarkable and novel, and needs to be further investigated. Also new is the observation that the incidence of childhood cancer in females in the North East is higher. It remains to be determined if this is a true difference or a registration artifact (cancer registration in the North East started in 2003).
average world incidence. Again, one can speculate that this can wholly or partly be attributed to underascertainment of cases and registration in rural areas, but this remains to be confirmed. It is also necessary to investigate if there are factors associated with urban living like overcrowding, air pollution, and so on, which contribute to a relatively higher incidence of childhood cancers in such areas. Variation by sex: Overall cancer in childhood is more common among males than females and the male to female ratio in the most resource-rich countries is around 1.2:1. [7,20] However, some cancers like retinoblastoma, Wilms’ tumor, osteosarcoma, and germ cell tumor actually show a slight female preponderance. The reported incidence of childhood cancer in India in males (39-150 per million children per year) is higher than in females (23-97 per million children per year) in all PBCRs except in North East India [Table 1], and this gives a male to female ratio [Table 2] that is much higher than what is seen in the developed world. As incidence rates automatically adjust for the sex ratio in the underlying population, there have to be other reasons for this relatively higher incidence of childhood
Variation by cancer type: [Tables 3 and 4] Leukemia is the most common childhood cancer in India with relative proportion varying between 25 and 40%. Sixty to 85% of all leukemias reported are acute lymphoblastic leukemia (ALL). Compared to the developed world, the biology of ALL appears different in India, with a higher proportion of T-Cell ALL (2050% as compared to 10-20% in the developed world),
Table 2: Male to female ratio of major childhood cancer types in each population based cancer registry* Cancer type (ICD 10 Code)
Ahmedabad
Bangalore
Barshi
Bhopal
Chennai
Delhi
Mumbai
North East
Leukemia
0.95
1.20
1.86
0.69
1.55
2.26
1.21
1.09
Lymphoid leukemia (C91)
0.70
1.51
1.32
0.81
1.64
2.60
1.26
1.32
Myeloid leukemia (C92-94)
-†
0.77
-
0.29
0.92
1.79
1.54
0.46
Leukemia unspecified (C95)
-
0.32
2.99
0.62
1.82
1.44
0.82
1.41
Lymphoma
-
4.29
1.56
11.26
3.25
4.93
2.19
0.75
Hodgkin's disease (C81)
-
3.84
3.57
-
3.71
11.85
3.11
0.00
Non Hodgkin’s lymphoma (C82-85, C96)
-
4.81
0.00
7.78
2.81
3.11
1.74
0.98
Brain, nervous system (C70-72)
-
1.66
2.09
0.31
1.74
1.37
1.65
0.00
Adrenal gland (C74)
-
0.27
-
-
0.81
1.81
1.23
0.00
Eye (C69)
-
0.60
0.90
0.92
1.10
1.90
0.95
1.17
Kidney (C64)
-
1.21
0.00
2.05
1.31
1.31
1.38
1.13
Liver (C22)
-
0.15
-
0.00
0.20
3.04
2.02
-
Bone (C40-41)
-
1.39
1.50
1.10
1.34
1.52
1.23
0.66
Connective and soft tissue (C47, C49)
-
0.83
-
0.82
0.91
1.53
0.82
1.62
Gonadal (C56, C62)
-
0.00
-
0.31
1.16
0.32
0.89
0.88
Other specified and unspecified
1.63
0.83
0.55
5.91
1.12
1.42
0.92
0.31
All Sites
2.24
1.26
1.29
1.07
1.55
1.92
1.34
0.75
*See footnotes on Table 1 for details of cancer coding and registries. Data derived from the reports of the Indian Council of Medical Research, National Cancer Registry Program[12,13]. †No value for the ratio has been given when the incidence of childhood cancer in females is 0
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Table 3: Cancer incidence rates standardized for world population (ASR) and relative proportion of each cancer type in male children, 0 to 14 years of age* Cancer Type†
Ahmedabad
Bangalore
Barshi
Bhopal
Chennai
Delhi
Mumbai
North East ASR
ASR‡
%
ASR
%
ASR
%
ASR
%
ASR
%
ASR
%
ASR
%
%
Leukemia
13.0
25.6
33.1
38.1
31.1
45.2
15.1
25.9
56.2
37.4
51.1
35.1
34.1
32.5
15.8 40.8
Lymphoid leukemia
9.7
19.0
27.9
32.1
17.9
26.0
11.8
20.3
47.1
31.4
38.4
26.3
21.5
20.5
11.3
29.2
Myeloid leukemia
0.0
0.0
3.8
4.4
3.8
5.5
1.0
1.8
5.1
3.4
7.0
4.8
7.3
7.0
1.9
4.9
Leukemia unspecified 3.3
6.5
1.3
1.5
9.5
13.8
2.2
3.8
4.0
2.7
5.7
3.9
5.3
5.0
2.6
6.8
Lymphoma
6.4
12.5
17.8
20.5
11.3
16.4
14.3
24.5
35.3
23.6
25.0
17.2
17.9
17.0
4.5
11.6
Hodgkin's disease
3.3
6.5
8.7
9.9
11.3
16.4
4.4
7.6
19.6
13.1
12.5
8.6
8.2
7.8
0.0
0.0
Non Hodgkin’s lymphoma
3.0
6.0
9.2
10.5
0.0
0.0
9.9
17.0
15.7
10.5
12.5
8.6
9.6
9.1
4.5
11.6
Brain, nervous system
6.4
12.5
16.8
19.3
8.5
12.3
2.8
4.8
17.0
11.3
15.0
10.3
21.1
20.1
0.0
0.0
Bone
3.0
6.0
4.1
4.7
4.7
6.9
5.3
9.1
7.5
5.0
8.4
5.8
6.0
5.8
4.5
11.6
Kidney
7.4
14.5
4.4
5.1
0.0
0.0
7.3
12.5
8.5
5.7
8.5
5.8
4.2
4.0
1.9
5.0
Eye
0.0
0.0
3.0
3.5
8.5
12.3
1.2
2.0
8.0
5.3
8.1
5.6
2.3
2.2
3.9
10.1
Connective and soft tissue
0.0
0.0
1.1
1.2
0.0
0.0
3.9
6.6
4.7
3.1
7.3
5.0
2.9
2.8
3.7
9.6
Adrenal gland
0.0
0.0
0.4
0.5
0.0
0.0
0.0
0.0
4.1
2.7
5.2
3.6
2.6
2.4
0.0
0.0
Testes
0.0
0.0
0.0
0.0
0.0
0.0
1.6
2.8
2.9
1.9
1.0
0.7
2.4
2.3
1.5
4.0
Liver
0.0
0.0
0.4
0.5
0.0
0.0
0.0
0.0
0.6
0.4
3.5
2.4
3.3
3.1
0.0
0.0
Other specified and unspecified
14.7
28.9
5.9
6.7
4.7
6.9
6.8
11.7
5.3
3.5
12.3
8.5
8.3
7.9
2.8
7.1
All Sites
50.9 100.0 87.0
100.0 68.8 100.0 58.3 100.0 150.0 100.0 14.5.6 100.0 105.1 100.0 38.7 100.0
*See footnotes on Table 1 for details of cancer coding and registries. Data derived from the reports of the Indian Council of Medical Research, National Cancer Registry Program[12,13]. †See Table 2 for ICD codes for each cancer type. ‡Expressed per million children per year
hypodiploidy and translocations t(1;19), t(9;22), and t(4;11), all of which contribute to a poorer prognosis of this leukemia.[21-24] It has been proposed that T-Cell ALL predominates in economically disadvantaged areas, but with urbanization, industrialization, and increasing affluence, common ALL, which peaks in incidence between the age of 2 and 5 years, increases.[25] In the developed world, CNS tumors are the second most common childhood cancer (22-25%) and lymphomas a distant third (10%). [7,20] In contrast, in India lymphomas often exceed CNS tumors, particularly in males. Not only is the proportion of lymphomas higher in India, but HD exceeds nonHodgkin’s lymphoma (NHL), a pattern opposite to that seen in the developed world. This specifically seems to be a result of the high incidence of HD in male children in India (incidence rate of 8.2-19.6 per million children, per year, in Bangalore, Chennai, Delhi, and Mumbai PBCRs compared to 5.7 in USA and 6.4 in Britain). [7,20] In contrast, the incidence of HD in Indian Journal of Cancer | October–December 2009 | Volume 46 | Issue 4
females and of NHL in both sexes is not very different from the incidence in the developed world. Besides differences in incidence, the pathobiology of these cancers is also different. Among NHL, the proportion of T-cell lymphoblastic lymphoma and diffuse large B-cell lymphoma is much higher and the proportion of mature B-cell (Burkitt’s and Burkitt-like) lymphoma much lower in India than that seen in the developed world.[26] Similar to T-cell ALL, the higher proportion of T-cell NHL may be linked to lower socioeconomic status. Mixed cellularity is the most common Hodgkin’s disease subtype and is responsible for the incidence peak at a younger age, as seen in India, compared to the peak seen at ages 16 to 30 years in the developed world, where nodular sclerosis is most common.[19] The high proportion of mixed cellularity in India is thought to be related to early childhood Ebstein Barr virus exposure.[27] In the larger urban areas of Bangalore, Chennai, Delhi, and Mumbai, the incidence rate of CNS tumors is 1020 per million children, per year, which is half of that 267
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Table 4: Cancer incidence rates standardized for world population (ASR) and relative proportion of each cancer type in female children 0 to 14 years of age* Cancer Type†
Ahmedabad
Bangalore
Barshi
Bhopal
Chennai
Delhi
Mumbai
North East
ASR‡
%
ASR
%
ASR
%
ASR
%
ASR
%
ASR
%
ASR
%
ASR
%
Leukemia
13.7
60.5
27.7
40.3
16.7
31.4
21.7
39.7
36.3
37.5
22.6
29.9
28.3
36.0
14.6
28.4
Lymphoid leukemia
13.7
60.5
18.5
26.9
13.5
25.4
14.6
26.7
28.6
29.6
14.7
19.5
17.1
21.7
8.5
16.7
Myeloid leukemia
0.0
0.0
5.0
7.2
0.0
0.0
3.6
6.6
5.5
5.7
3.9
5.2
4.8
6.0
4.2
8.1
Leukemia unspecified
0.0
0.0
4.2
6.1
3.2
6.0
3.5
6.5
2.2
2.3
4.0
5.3
6.5
8.2
1.9
3.6
Lymphoma
0.0
0.0
4.2
6.0
7.2
13.6
1.3
2.3
10.9
11.2
5.1
6.7
8.2
10.4
6.0
11.7
Hodgkin's disease
0.0
0.0
2.3
3.3
3.2
6.0
0.0
0.0
5.3
5.5
1.1
1.4
2.6
3.4
1.4
2.7
NHL
0.0
0.0
1.9
2.8
4.1
7.6
1.3
2.3
5.6
5.8
4.0
5.3
5.5
7.0
4.6
9.0
Brain, nervous system
0.0
0.0
10.1
14.7
4.1
7.6
9.2
16.8
9.7
10.1
10.9
14.4
12.8
16.3
5.1
9.9
Bone
0.0
0.0
2.9
4.3
3.2
6.0
4.9
8.9
5.6
5.8
5.5
7.3
4.9
6.2
6.8
13.2
Kidney
0.0
0.0
3.7
5.3
4.1
7.6
3.5
6.5
6.5
6.7
6.4
8.5
3.0
3.9
1.7
3.4
Eye
0.0
0.0
5.1
7.4
9.5
17.8
1.3
2.3
7.3
7.5
4.3
5.7
2.4
3.1
3.3
6.5
Conn. and soft tissue
0.0
0.0
1.3
1.8
0.0
0.0
4.7
8.6
5.1
5.3
4.8
6.3
3.6
4.5
2.3
4.5
Adrenal gland
0.0
0.0
1.5
2.2
0.0
0.0
0.0
0.0
5.1
5.2
2.9
3.8
2.1
2.6
1.0
2.0
Ovary
0.0
0.0
2.7
3.9
0.0
0.0
5.2
9.6
2.5
2.6
3.2
4.3
2.7
3.4
1.7
3.4
Liver
0.0
0.0
2.7
3.9
0.0
0.0
1.8
3.2
3.1
3.2
1.2
1.5
1.6
2.1
0.0
0.0
Other specified and unspecified
9.0
39.7
7.1
10.3
8.5
16.1
1.2
2.1
4.7
4.9
8.7
11.4
9.0
11.5
8.8
17.2
All Sites
22.7 100.0 68.8 100.00 53.2 100.0 54.7 100.0 96.8 100.0 75.7 100.0 78.7 100.0 51.3 100.0
*See footnotes on Table 1 for details of cancer coding and registries. Data derived from the reports of Indian Council of Medical Research, National Cancer Registry Program[12,13]. †See Table 2 for ICD codes for each cancer type. ‡Expressed per million children per year.
in the developed world. Interestingly, the incidence of CNS tumors in children in the developed world has increased in the last 30-40 years with increasing availability of CT and MRI scanners. [28] A relative paucity of neurodiagnostic and neurosurgical facilities, which leads to missed diagnosis in those presenting with headache, seizures, and altered sensorium, could explain the differences in incidence in India. Neuroblastoma, which is the second most common solid tumor in childhood after CNS tumors,, is much less frequently reported in India. Retinoblastoma has an incidence rate of three to five per million children, per year, and accounts for 2.5 to 4% of all childhood cancers in most developed countries. Barshi, Chennai, and Delhi report a 2-3 fold higher incidence of tumors of the eye (majority of which will be retinoblastoma in children
