Cancer burden in Nepal, 1990–2017: An analysis of the Global Burden of Disease study

Introduction Cancer is the second leading cause of death and a major public health problem in the world. This study reports the trend and burden of cancer from 1990 to 2017 along with its risk factors in Nepal. Methods This study used the database of the Institute of Health Metrics and Evaluation’s Global Burden of Diseases on cancer from Nepal to describe the most recent data available (2017) and trends by age, gender, and year from 1990 to 2017. The data are described as incidence, prevalence, disability-adjusted life years (DALY), and percentage change. Results In 2017, the age-standardized cancer incidence and mortality rates were 101.8/100,000 and 86.6/100,000 respectively in Nepal. Cancer contributed to 10% of total deaths and 5.6% of total DALYs in Nepal. The most common cancers were the breast, lung, cervical, stomach and oral cavity cancers. The number of new cancer cases and deaths in Nepal have increased from 1990 to 2017 by 92% and 95% respectively. On the other hand, age-standardized incidence and mortality rates decreased by 5% and 7% respectively. The leading risk factors of cancer were tobacco use, dietary factors, unsafe sex, air pollution, drug use, and physical inactivity. Conclusions This study highlighted the burden of cancer in Nepal, contributing to a significant number of new cancer cases, deaths and DALY. A comprehensive approach including prevention, early diagnosis and treatment, and rehabilitation should be urgently taken to reduce the burden of cancer.


Introduction
• Disability-adjusted life years (DALY) is a summary measure that combines time lost through premature death and time lived in states of less than optimal health, loosely referred to as "disability" [17].
• Age-standardized rate is a weighted average of the age-specific rates per 100,000 persons, where the weights are the proportions of persons in the corresponding age groups of the WHO standard population [18].
• Uncertainty interval (UI) is a range of values that is likely to include the correct estimate of disease burden for a given cause. Narrow UI indicates that evidence is strong, while wide UI shows that evidence is weaker.   (Table 4). Among all forms of cancer, the major contributors for mortality in both sexes are lung cancer (12.7%), stomach cancer (9.1%), breast cancer (8.4%), colorectal cancer (6.9%) and esophageal cancer (6%) in 2017. Overall, in both sexes, there has been a significant increase in The five most common causes of death from cancer among males were lung cancer (15%), stomach cancer (10.1%), esophageal cancer (7.8%), lip and oral cavity cancer (7.1%) and prostate cancer (7.1%). Prostate and esophageal cancers have an increasing trend of mortality with percentage change of 27.38 and 8.38 respectively from 1990 to 2017. While, a decreasing trend of mortality was found with a percentage change of 3.70, 28.03, and 16.68. for lung, stomach, and oral cavity cancer from 1990 to 2017.
Among females, the five most common causes of death from cancer were breast cancer (16.6%), lung cancer (10.4%), cervical cancer (10.1%), stomach cancer (8.1%), and colorectal cancer (7.0%). Breast, lung, and colorectal cancer have an increasing trend of incidence with a percentage change of 3.22, 2.61, and 2.20, respectively from 1990 to 2017. Table 2 shows the number of deaths is highest among people of age-group 65-69 years. The age-specific mortality rate was highest among people aged 80 years and older for both males 1113.54 (918.02-1300.48) and females 749.56 (603.06-902.34) per 100,000 population in 2017 (Table 4).

Disability-adjusted life years
Cancer accounted for 5.6% of total DALYs in both sexes in 2017 mostly attributed to lung cancer followed by breast and stomach cancer. DALYs (rates per 100,000 population) for all forms

Liver cancer
Male

Risk factors
The leading risk factors associated with the highest DALYs were tobacco 315.

Discussion
Nepal is facing fluctuations in cancer prevalence and DALYs over the past 27 years. The top 5 cancers according to the age-standardized incidence rate, both sexes are breast, lung, cervical, stomach and oral cavity cancer. The burden of cancer particularly; cancer-associated mortality rate and disability-adjusted life years due to cancer is increasing. With the increased

PLOS ONE
Cancer burden in Nepal  availability of advanced and sensitive diagnostic modalities for early detection, the incidence of asymptomatic cancers with an indolent course like pancreatic, ovarian, liver, kidney and thyroid cancer is increasing over 27 years in both sexes while the incidence of symptomatic but hidden cancers like larynx cancer, esophageal cancer, nasopharynx cancer, Hodgkin lymphoma, and cervical cancer is decreasing. Although the incidence of cancer was seen highest in the age group 60-70 years in both sexes, the age-specific incidence rate is highest among people aged 80 years because increasing age is a major risk factor for cancer due to decreasing telomerase activity, increasing exposure, and a slower rate of cell development [19]. This corroborates with global data as 60% of cancers occur in people 65 years of age or older worldwide. The elderly population often miss out on health education and awareness campaigns; hence strategies should be formulated to address this population while planning and conducting public health campaigns.

Lung cancer
Lung cancer ranked the top in terms of incidence and prevalence and also had the highest death rate. It is the most common cancer in males and the second most common cancer in females according to ASIR. In women, lung cancer has an increasing trend of incidence, but a decreasing trend was observed in males with a male-female ratio of 1.625. This increase in trend due to advanced and sensitive diagnosis with low dose-CT leading to early detection. However, there has been significant development in the radiotherapy and chemotherapy modalities, but ongoing risk factors continue to be a threat.
The most important risk factor for lung cancer is smoking. Most smokers start at a young age and a cumulative exposure to smoking over the years leads to multiple cancers [20]. Like many South Asian countries, Nepal is an agricultural country that produces tobacco as a cash crop and has a population that indulges in chewing tobacco, using hookah or pipes for  smoking tobacco; and tobacco is sold widely in cheap brands [21,22]. World Health Organization's STEPwise approach to non-communicable disease risk factor surveillance (STEPS) survey in 2019 showed that 28.0% of men and 7.5% of women smoked tobacco products; 33.3% of The government has formulated a tobacco control law, utilized mass media for health education, an excise tax on tobacco, banned smoking in public places, and made efforts to reduce the supply of tobacco products [25]. The high burden of lung cancer in women despite less burden of smoking could be attributed to the inhalation of indoor smoke, and second-hand smoke among rural women [10].

Breast cancer and cervical cancer
Among females, cancer is the second leading cause of death worldwide with breast, colorectal, and lung cancers leading the charts [26]. But even globally, between 2007 and 2017, cervical cancer incidence and mortality rates have increased by 19% each [27]. This contrasts with our data where the second most common cancer in the female is cervical cancer. Female-related cancers, namely, breast cancer followed by cervical cancer have an increasing trend of agestandardized incidence in Nepal. In our study, cervical cancer has a decreasing trend of incidence among females. The national agenda to curb diseases such as cervical cancer and breast cancer might have potentially played a role. Early detection of breast cancer is available through awareness and screening. However, coverage of mammography is still limited, and most women are diagnosed in a late stage leading to suboptimal survival. Despite ongoing public health efforts, there is low knowledge of breast cancer among Nepalese women [28]. Factors that contribute to an increasing trend in breast cancer incidence among Asian women are not fully understood but thought to reflect lifestyle changes associated with westernization, including late childbearing, having fewer children, and consumption of calorie-dense food, physical inactivity, and obesity [29]. The increasing trend in our study may reflect a collaboration of changed environmental factors, including the delay of childbearing, increases in the levels of obesity, and early cancer screening.
The higher burden of cervical cancer among Nepalese women is due to Human papillomavirus (HPV) infection. In developing countries like Nepal, women belonging to lower socioeconomic status higher levels of illiteracy are uncomfortable sharing the symptoms like abnormal vaginal bleeding such as post-coital bleeding, intermenstrual bleeding, or post-menopausal bleeding immediately after onset leading to late diagnosis [30]. However, the increased incidence and decreased trend in mortality can be credited to the cervical cancer screening programs leading to its early detection and treatment. Visual Inspection with acetic acid as recommended by WHO in low-income countries for the early detection of cervical cancer has been advocated in the public health system of Nepal making the procedure freely available from the health post to the tertiary care center [31]. Nepal has an intermediate burden of HPV infection and theoretically, approximately 80% of cervical cancer is preventable by HPV vaccines [32]. There have been a few pilot programs for the demonstration of the HPV vaccine in some districts of Nepal [33,34]. But still, the HPV vaccine is not available in the National Immunization Program.

Stomach cancer
Stomach cancer ranks fourth in the national cancer burden. Stomach cancer has a decreasing trend of incidence in both males and females. Dietary patterns also ranked the third risk factor associated with DALY. The decreasing trend of incidence and prevalence of this cancer can be explained by the increased availability of upper gastro-intestinal endoscopic screening leading to early detection and management and hence higher survival rates of stomach cancer. It is known that apart from smoking, Helicobacter pylori infection is a known risk factor for stomach cancer which was found to be around 16% among the study population that increased among the lower socio-economic population as found by Ansari et al. in their hospital-based study [35]. There is a decreasing prevalence of H. pylori infection due to highly effective antimicrobial therapies; cheaper and sensitive laboratory tests like serum antigen detection and H. pylori urea breath testing; improved living conditions, and healthy and hygienic food practices lead to the declining rates.

Oral cavity cancer
In our study, there is a decreasing trend in the incidence of oral cavity cancer in both sexes. It is the second most common cancer among men in South-Central Asia [36]. This region has high incidence rates for oral cancer because, in addition to tobacco smoking, tobacco chewing as well as chewing betel quid and areca nut also poses a major risk in acquiring oral cavity cancer. In a study, tobacco consumption and alcohol drinking were responsible for almost 85.3% of head and neck cancers with a population attributable fraction (PAF) of 24.3% for smoking, 39.9% for tobacco chewing, and 23.0% for alcohol drinking [37]. The interplay of the trends of the two risk factors to which the highest proportion of cancer DALYs in Nepal could be attributed to tobacco and alcohol use; and their consumption in Nepal has increased during this period [9].

Colorectal cancer (CRC)
Globally, while there is a declining trend of CRC incidence worldwide, there is an increasing trend of incidence and mortality for CRC in Asian countries [38]. In this study, there is also an increased incidence of CRC among both sexes in Nepal. Similar to our findings, the other studies conducted in Tribhuvan University Teaching Hospital (Kathmandu, Nepal) from 1990 to 2008 and in B.P. Koirala Memorial Cancer Hospital (Chitwan, Nepal) from 2014 to 2018 also reported an increasing proportion of younger age groups in CRC incidence with slight male preponderance [39,40]. Globally, the declining trend of CRC has largely been associated with an increase in screening rates in 50 years or older age groups but the incidence rates are increasing among adults under 50 years, for whom screening is not recommended [41].
Unfavorable increased colorectal cancer rates are thought to reflect changes in dietary patterns, obesity, and smoking rates, often seen in economically transitioning countries. Apart from predominant modifiable risk factors like tobacco and alcohol consumption in Nepal, a poor diet like low consumption of fruits and vegetables which are rich in fiber; and high consumption of red or processed meat ranks significantly high in contributing to DALY [42]. With public health strategies addressing to make modest changes in the consumption of alcohol and red-processed meat, weight loss and increased levels of physical activity may translate into significant reductions in the incidence of colorectal cancer [43].

Other cancers
In our study, among the male-related cancers, there is a rapid rise in prostate cancer incidence and a decrease in the incidence of testicular cancer. Worldwide in 2017, prostate cancer had the highest incidence among men in 114 countries and was the fifth leading cause of death from cancer among men in 56 countries [27]. In contrast to the declining incidence of prostate cancer in Western countries, the rates have increased in some Asian countries including India

Conclusions
This study highlighted the burden of different types of cancer in Nepal over 27 years. Cancer is a major public health problem and accounted for 10% of total deaths in Nepal. The incidence and mortality due to cancer are in an increasing trend with a high impact on DALYs. Breast followed by lung, cervical, stomach and oral cavity cancers were the topmost cancers. Tobacco use, unhealthy food, and unsafe sexual behaviors are the predominant risk factors for cancer. This calls for urgent measures to raise awareness by health education intervention and implement effective cancer screening programs all over the country.