Abstract
Recent estimates suggest that the lower middle income countries in Asia carry the heaviest burden of cancer among adolescents and young adults (AYAs) (defined as age 15–39 years). A larger proportion of the population in Asia is aged 15–39 compared with the developed countries. This age group is different from the pediatric or the adult group in terms of physical, social, psychological, and financial needs. Cancer incidence, disability, survivorship needs, financial toxicity, psychosocial issues, and so on are underestimated in this group, and available literature is scarce. Global data show an increasing trend of adult-onset cancers such as colorectal, breast, pancreas, and lung in the AYA population. Data suggest that the disease biology and prognosis are different in this group; however, further research is needed. An ESMO/SIOPE/SIOP Asia survey on the care of AYA cancer patients in Asia found a suboptimal availability of AYA specialized centers in the region and identified several unmet needs including lack of training, clinical trials, and high rates of treatment abandonment. There is an urgent need for cancer care systems in Asia to develop specialized services to be able to cater to this growing burden. Training and research in this area also need to be upscaled with the goal of establishing a sustainable infrastructure and quality services to ensure that this vulnerable group receives appropriate care. Management guidelines and national health policies should consider giving special attention to this group as the World Health Assembly reinforces the inclusion of children and adolescents in cancer control programs.
Introduction
Asia is home to almost 60% of the current world population (United Nations. Population trends. https://asiapacific.unfpa.org/en/node/15207.PublishedJanuary2021). The estimated incidence of cancer in Asia in 2020 was 9.5 million, accounting for nearly half of all the annual worldwide cancer incidences and more than one half of all the cancer mortalities. The population pyramid in Asia is significantly different from the West in terms of age distribution with a relatively larger number of adolescents and young adults (AYAs). AYAs constitute more than 40% of the total population in some lower middle income countries (LMICs). The median age of the Asian population is 32 years and around a third of the population comprised AYAs (https://www.worldometers.info/world-population/asia-population/).
Recent estimates suggest that worldwide about 1.2 million new cases of invasive cancer are diagnosed annually among AYAs 1 (ages 15–39 years), which constitutes around 6.6% of all cancer diagnoses. This age group is unique in terms of psychosocial and economic factors and constitutes a highly heterogeneous population based on the diverse cultural, ethnic, socioeconomic environments in various countries. The Adolescent and Young Adult Oncology Progress Review Group report, 2005–2006, included measures and recommendations to improve the standard of care for this special group (https://www.cancer.gov/types/aya/research/ayao-august-2006.pdf).
Oncology centers and professional societies in several developed countries have devised their own special programs for AYAs with cancer, but several gaps remain. 2 The profile of cancers in AYAs is different from their pediatric and adult counterparts and is often a mix of both childhood and adult types of cancers. In addition, improvements in survival in this group have lagged behind those in childhood and adult cancers. 3
Incidence and Burden of AYA Cancers
The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, reported that cancer was the fourth leading cause of mortality in this population and the tenth leading cause of disability adjusted life years (DALYs). Age-standardized DALYs were highest in parts of Asia, southern sub-Saharan Africa, and South America. DALYs of AYA cancers were higher than those of childhood and adult cancers in low- and low-middle sociodemographic index (SDI) countries. 4 The trends of cancers in AYAs from 41 countries were collated from the Cancer in Five Continents database for a period of 15 years (1998–2012). AYA cancers contributed to a total of 1,846,588 new cancer cases. 5 There was an increasing trend in the overall incidence in 23 countries with a rise in obesity-related cancers such as uterine, pancreatic, gallbladder, and liver.
A review of 98 studies from various countries showed a clear trend of increase in the incidence of breast, colorectal, pancreatic, kidney, and uterine cancers in young adults. Only two studies in this review were from Asia. 6
Although Asia contributes the largest burden, data on AYA cancers from Asian countries are sparse. The GBD 2019 included only limited data from a few cancer registries/centers in Asian countries and comprehensive country-specific data are unavailable. Epidemiological data examining incidence and trends of cancers in AYAs are limited and largely absent in many LMICs. The low incidence of AYA cancers reported from low SDI countries suggests significant misdiagnosis and underreporting. Except for a few high-income countries such as Japan and Singapore, there are no specialized services for AYAs with cancer in most parts of Asia. The CALGB 10403 showed that outcomes were significantly better when AYAs with acute leukemia were treated using risk-adapted pediatric chemotherapy protocols. 7 However, due to lack of specific guidelines and specialized services, AYAs often receive suboptimal care in adult oncology settings.
Other issues that compromise outcomes in this subgroup include lack of screening, delays in diagnosis, and absence of adequate psychosocial and survivorship care. An ESMO/SIOPE/SIOP Asia survey of cancer care professionals in Asia revealed that a large majority (78%) did not have access to specialized services for AYAs with cancer and 73% did not have any information about any AYA-focused research initiatives. Alarmingly, almost half (47%) reported issues with treatment compliance or abandonment. Ninety-three percent of the survey respondents worked in urban locations and 52% worked in academic medical centers where most of the advanced cancer care services are located indicating that the situation could be much worse in rural settings and LMICs. Overall only about 15% of the survey respondents had access to specialized services for AYAs in contrast to 33% of their European counterparts. 8
Unique Biology of AYA Cancers
While some cancers such as those of the nasopharynx are known to occur more commonly in the young Asian population, recent trends suggest that many adult-onset cancers such as breast and colorectal are showing a significant increase in the AYA population. Data from GBD 2019 study showed that colorectal cancer (CRC) incidence rates more than doubled over the last decade with a significant rise in AYAs. 9 China and India had the highest CRC mortality rates. Five out of six of the CRCs in individuals younger than 50 years are apparently sporadic with no associated germ line mutation. 10 CRC in AYAs is more aggressive and presents in more advanced stages. 11 Reasons for this alarming increase are not clear, but evidence is increasingly pointing toward a complex interplay of environmental exposures and genetic susceptibility.
Breast cancer is the leading cause of disability and mortality in AYA females, and emerging data show a rising trend in this group. Several studies have documented a higher proportion of breast cancer (11%–23% of all breast cancers) diagnosed at younger ages (<40 years) in LMICs compared with high-income countries (HICs) (5%–7%). 12 Studies from Korea, 13 China, 14 Taiwan, 15 and India 16 show that breast cancers in AYAs are associated with a higher proportion of adverse molecular features and poorer prognosis. AYAs with breast cancer therefore need more aggressive treatment leading to a higher risk of acute and long-term toxicities. Survivors also deal with several psychosocial and financial challenges in addition to issues with fertility, body image, and sexuality. 12
Prospective studies focusing on identifying clinicopathological–biological characteristics and their association with treatment outcomes are needed in Asian AYAs to improve understanding of disease biology and provide impetus for translational research.
Environmental Exposures and Risk of Cancers in AYAs
Analysis from the GBD 2019 suggested that 44.4% of cancers are attributable to modifiable risk factors. 17 Temporal trends demonstrate an increased risk of many different types of cancers with adoption of Western diets, sedentary lifestyles, and increased consumption of tobacco and alcohol. These along with other well-known risk factors such as hepatitis and human papilloma viruses, however, do not fully explain the increasing trend in AYA cancers. Recent data show an increasing incidence of cancers in successive birth cohorts since the mid-20th century. 18 Carcinogenesis resulting from obesity and alteration of the gut microbiome associated with various factors such as highly processed food, red meat, sugary drinks, food additives, and overuse of antibiotics is an active area of research in AYA cancers. Other potential etiological factors include environmental pollution, chemical and pesticide exposures, changing sleep patterns, decreasing parity and breastfeeding, and increasing exposures to electromagnetic frequency radiation.
Emerging evidence suggests that although some chemicals may not be directly mutagenic, they can enhance cancer risk through endocrine disruption, metabolic effects, and obesity. These endocrine disruption chemicals (e.g., bisphenol-A, triclosan), which are present in many common daily use products, can potentially reprogram genes and affect future gene expression.19,20 Per- and polyfluoroalkyl substances 21 are increasingly being used in a wide array of products including personal care products, cleaning chemicals, and furniture and building products. These are extremely persistent in the environment and epidemiological evidence suggests a possible link with increased risk of cancer.
Polluted air contains dozens of known and suspected chemical contaminants which are known or suspected carcinogens. A study from the United States followed 2444 children and 13,459 AYAs and showed higher cancer-related and all-cause mortality, with higher levels of fine particulate matter air pollution (PM2.5). 22 PM2.5 accounts for an estimated 43% of global deaths related to lung cancer. 23 The concentration of PM2.5 is increasing in most Asian countries and is alarmingly high in LMICs. Chlorine, used for disinfection, reacts with organic compounds in water to form several by-products including chloroform and trihalomethanes, which can increase the risk of various cancers. 24 A significant association of brain tumors was seen in young people with exposure to pesticides and pollutants in water. 25 Employment of children in factories, industries, and agriculture is a common practice in many LMICs.
Several studies have shown high levels of various carcinogenic substances such as lead, chromium, cadmium, pesticides, solvents, and endocrine disrupting chemicals in the blood and urine of these children. 26 Dumping sites for industrial wastes are largely unregulated in most developing countries and can potentially result in soil and water pollution. One study found that concentrations of polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and coplanar polychlorinated biphenyls in soils from dumping sites in the Philippines, Cambodia, India, and Vietnam often exceeded environmental guideline values. 27 Various pesticides are classified as known or suspected carcinogens. Early-life exposure to pesticides including in utero exposures has been linked to an increased risk of leukemia and brain tumors.28,29
Research on cancer risk due to pollution and chemical exposures is sparse and it is difficult to tease out the impact of multiple individual risk factors and confounders. The true burden of environmentally induced cancer remaining unknown is likely grossly underestimated. 18 Further research is needed to understand and mitigate various potential risk factors in this population.
Special Issues in AYAs with Cancer
Various domains of unmet needs have been identified in AYAs with cancer, including, but not limited to, physical and emotional well-being, availability and affordability of health care, social integration, relationships, re-establishing normalcy, career, employment, education, and financial concerns. 30
Diagnostic and therapeutic delays
Diagnostic and therapeutic delays in AYA care are multifactorial and their impact on outcomes is relatively understudied. Lack of suspicion in this age group often leads to diagnostic delays and inappropriate management with detriment in outcomes. 31 This age group is usually not included in screening programs, which usually target older age groups. Screening may also not be economically justifiable for this population and data on optimal approaches and modalities are lacking. Studies suggest that diagnostic delays are higher in AYAs compared with adults and children. 32 A cross-sectional analysis of the BRIGHTLIGHT cohort showed that diagnostic delays significantly correlate with a higher incidence of depression and anxiety. 33 Delays may be further exacerbated in LMICs due to issues with access and affordability. 34 Poor adherence to treatment has also been observed in AYAs especially among those belonging to the low socioeconomic strata. 35
A study from India reported a treatment abandonment rate of 25% among patients aged 15–29. 36 Distance from the oncology center, rural location, being a student/unemployed/unmarried, and preference for alternative therapy were associated with higher rates of abandonment. 36 Significant acute toxicities associated with intense chemotherapy protocols and suboptimal supportive care services may limit tolerance to pediatric chemotherapy protocols especially when these patients are managed in adult oncology settings. Initiatives such as the Abandonment of Treatment Working Group, established under the aegis of the International Society of Pediatric Oncology (SIOP) in 2010, to address this issue in pediatric oncology 37 are also needed for the AYA group.
Disease- and treatment-related effects
Physical symptoms including hair loss, body image, fatigue, pain, premature menopause, fertility issues, and late effects are highly distressing for AYAs, significantly impacting their quality of life. Studies show that complex pain is more prevalent in this population and may need higher doses of opiods. 38 Early integration of palliative and supportive care is significantly limited by availability and access especially in LMICs. AYA survivors are at higher risk of developing chronic health conditions including cardiovascular disease, endocrine dysfunction, neurocognitive decline, and sexual dysfunction in addition to a higher risk of development of second malignancies. 39 Physicians are often not adequately trained to recognize and manage treatment-related late effects including endocrinopathies, neurocognitive effects, and bone health. Treatment-related late effects have been understudied and underreported in the AYA group. 40
Psychosocial support and communication needs
AYAs are at a period of rapid physical and emotional changes as they establish functional and financial autonomy. Their communication and information needs differ significantly from their adult counterparts. Lack of adequate psychosocial support and communication has been identified as the most common unmet need in AYA oncology. 41 A large majority of AYAs desire an honest communication of prognosis. 42 Common unmet communication needs in AYA care include discussions on fertility, sexual health, financial toxicity (FT), prognosis, and end-of-life (EoL) care. 43 Lack of training, time, and manpower and a desire to shield the patient and family from distress can hamper effective communication. A high incidence of mental distress has been reported in AYAs from the time of diagnosis and extending throughout the survivorship. AYAs with cancer often experience social isolation and anxiety regarding loss of autonomy and an uncertain future. 44 Relationship issues can arise due to health issues, fertility concerns, and financial uncertainties. 45
Other issues include post-traumatic stress disorder and suicidal ideation. 46 There is a lack of research on communication needs and preferences in the Asian AYA population. It is important to develop capacity toward effective communication and psychosocial support in an age-appropriate and culturally sensitive context.
Clinical trial participation
Studies have shown that the proportion of clinical trials focusing on AYAs is relatively low, especially with novel therapeutics, and there is poor accrual to clinical trials. 47 In HICs, various organizations and cooperative trial groups have made efforts to bridge this gap. The Southwest Oncology Group (SWOG) and the Children's Oncology Group (COG) have constituted specific AYA-focused committees and modified the age eligibility for trials. International events such as the Global AYA Cancer Congress, which first met in 2016, also serve to enhance knowledge and research in AYA cancers. Clinical trial activity in many Asian countries is low and there is a dearth of AYA-focused research initiatives. 8 It is important to enhance this capacity to enable high-quality evidence-based care.
Palliative and EoL care
Diagnostic delays, financial issues, and limited access to care result in a high proportion of patients presenting with advanced stage disease, especially in LMICs. There is a lack of adequate palliative care services in many parts of Asia. Lack of access to opioids is another issue in this region. 34
AYAs are more likely to receive aggressive EoL care, and various psychosocial and economic issues may limit the optimal use of palliative care. Specific priorities for EoL care in this population include honest communication of prognosis, addressing the unique psychological needs of patients and caregivers, discussion, and documentation of advance directives. Various factors such as lack of effective communication, inadequate training, and reluctance of providers/caregivers to initiate EoL discussions may hinder optimal palliative care and EoL decisions. A population-based retrospective cohort study from Canada showed that a large proportion of AYAs (43.8%) received high-intensity EoL care. 48 A survey of caregivers in the United States suggested that major barriers to optimal EoL care were inadequate communication of prognosis, inadequate emotional support of patients and caregivers, and lack of effective home care models. 49
Studies have also shown that receipt of intense inappropriate EoL measures is higher in economically disadvantaged populations. 50 AYAs with cancer have distinct priorities for EoL care and require unique considerations to improve patient- and family-centered care.
Financial toxicity
Financial hardship related to cancer has been reported to be significantly greater in AYAs compared with other age groups. 51 Patients from many LMICs, where out-of-pocket costs represent a substantial portion of health care expenses, are at a disproportionately higher risk for FT. AYAs transitioning toward financial independence and domestic responsibilities can be severely affected by cancer-related costs, loss of employment, and lack of insurance. Caregiver financial burden is a significant component of FT for AYAs. 52
A meta-analysis of studies on FT of cancer in LMICs showed a pooled prevalence of objective FT of 56.96% reaching 93.38% in rural dwellers, however, there was a striking lack of studies addressing nonmedical costs such as transportation, accommodation, and meals, and indirect costs such as loss of income or disruption in education/employment. 53 Another systematic review of 105 studies found that cancer patients and caregivers in LMICs spent, on average, 42% of their annual income on out-of-pocket expenses related to cancer care, compared with 16% in HICs. 54 Objective tools to measure financial toxicities in people affected with cancer that have been developed and used in HICs might not be completely applicable in low-income and culturally diverse settings in Asia.
Asian countries are highly heterogeneous in terms of availability and affordability of cancer care including insurance coverage and access to cancer care centers. The ACTION study involving 9513 patients from Southeast Asia (ASEAN region) reported that 48% had experienced financial catastrophe within a year and less than a quarter were alive at 1 year without FT. 55
Even in Japan, which has a universal health insurance, patients bear 30% of the treatment costs, and material costs of cancer care were greater in AYAs compared with adults. 56 In a multicenter survey from China, where >95% of the population is covered by government insurance schemes since 2009, out-of-pocket expenditure represented about 57.5% of annual household income presenting catastrophic expenditure for 77.6% of families. 57 A survey of patients from South Korea showed that 40% of families affected by cancer experienced catastrophic health expenditure. 58 Studies from India also showed that FT was associated with poor quality of life and noncompliance to treatment. 59
It is imperative to integrate screening and discussions for FT in cancer care. Appropriate steps should be taken to mitigate FT taking into consideration the diverse socioeconomic and cultural climates in different regions. 60 Western data show that more than one half of AYAs report problems with return to work (RTW) or resuming education. 61 Survivors also face challenges such as stigma, discrimination, and late effects of disease or treatment, which can significantly affect return to employment/education. 62 A study from Singapore identified an eagerness among Asian cancer survivors to RTW and to be treated as “normal.” 63 However, there are very few studies from Asia addressing RTW. Further research and efforts are needed to develop and strengthen support services for resuming education/employment for AYA survivors.
Cancer Care for AYAs in Asia: A Call to Action
The complex needs of AYAs with cancer in Asia are largely understudied and remain unmet. There is a critical need for specialized multidisciplinary care and specialized services to address this gap and improve outcomes. This necessitates a multistakeholder commitment including policy makers, professional societies, cancer centers, health care professionals, nongovernmental organizations, patient advocates, communities, and families. Mainstream and social media can play a significant role by creating awareness and strengthening these efforts, and multidimensional research is crucial to generate evidence-based recommendations.
Etiological factors for the alarming rise of cancer in AYAs remain to be conclusively proven. Neither lifestyle nor genetic factors are sufficient to explain this phenomenon. These tumors show clinical patterns and genotypes that are distinct from adults and children. A comprehensive exploration of potential risk factors, including impact of diet, microbiome alteration, chemical exposures, and pollution, needs to be undertaken toward developing evidence-based preventive strategies and programs for mitigation of risk factors.
Global oncology societies and multinational organizations can play a vital role in increasing awareness, aggregating and analyzing data, and initiating, coordinating, and supporting efforts toward control and preventive strategies. It is vital that cancer centers and professional societies in Asia work toward building resource-sensitive sustainable programs toward improving clinical care, research, and outcomes in AYA oncology.
Footnotes
Authors' Contributions
M.M.: conceptualization (lead); methodology (lead); writing—original draft (lead); and writing—review and editing (equal). D.V.: writing—original draft (supporting); software (lead); and review and editing (equal). D.M.J.: formal analysis (lead); conceptualization (supporting); and writing—review and editing (equal).
Author Disclosure Statement
No competing financial interests exist.
Funding Information
No funding was received for this article.