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Review Article
Management of Malignancies Developing in AYA
Clin Pediatr Hematol Oncol 2021;28:1-13.
Published online April 30, 2021
© 2021 Korean Society of Pediatric Hematology-Oncology

Alex WK. Leung1,3,4, Herbert HF. Loong2, Teresa Tse2 and Chi-kong Li1,3,4

Departments of 1Pediatrics and 2Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, 3Department of Pediatrics and Adolescent Medicine, Hong Kong Children Hospital, 4Hong Kong Hub of Pediatric Excellence, The Chinese University of Hong Kong, Hong Kong SAR, China
Correspondence to: Chi-kong Li
Department of Pediatrics, The Chinese University of Hong Kong, 6/F, Clinical Science Building, Prince of Wales Hospital, Shatin, NT, Hong Kong SAR, China
Tel: +852-35052849
Fax: +852-26497859
E-mail: ckli@cuhk.edu.hk
ORCID ID: orcid.org/0000-0002-2810-5758
Received October 5, 2020; Revised December 31, 2020; Accepted January 15, 2021.
Abstract
Adolescent and young adult (AYA) with cancers have distinct spectrum of cancers as compared to younger and older age groups. The definition of age limits of AYA varies among countries, from 15-25 years to 12-39 years. The differences in age definition lead to variation in report of incidence, types of cancers and survival. In younger AYA patients, hematological malignancies are leading cause of cancers. In older AYA patients, testicular cancers are common in males while breast cancers and cervical cancers are predominant types in females. There is increasing incidence of AYA cancers worldwide in the past two decades. Overall survival and treatment outcome of AYA cancer has been improving in the last few decades. Specialized centers for AYA with cancers provide more comprehensive care and have been reported to have superior outcome. About 80% of AYA with cancers survive at 5 years after diagnosis but they are higher risk of developing second malignancies. Barriers to AYA cancer treatment included social economic status, insurance system and accessibility to clinical trials. Survivors of AYA cancers are also at higher risk dying from cardiovascular diseases and respiratory diseases. Survivorship program should be in place to enhance education and surveillance.
Graphical Abstract

Keywords: Adolescent, Young adult, Cancer, Outcome
Introduction

Adolescence and young adulthood represents a unique period in life with many important events going on, that includes but not limit to pursuing of higher education, starting of career, getting married and becoming parents. Severe illness like cancer during this stage of life would be a major impact to an individual. The uniqueness of adolescent and young adult (AYA) cancers has gained much attention in the last two decades. The AYA Oncology Progress Review Group (PRG) of the National Cancer Institute (NCI) and the Lance Armstrong Foundation (LAF) published a report in 2006 focusing on issues related to AYA cancer. It concerned the lack of progress in treatment and survival of AYA with cancer when compared to younger children and older adults. It also acknowledged this discrepancy in survival improvement and designated this group of patients as vulnerable. Recommen-dations were made aiming at closing the survival gap between AYA and other age groups with cancer [1,2]. Much work is ongoing in the research of AYA cancers and there is now a better insight of the distinct epidemiology, biology, therapeutic needs, patterns of long term outcome, co-morbidities and psychosocial needs of this group of patients.

Definition of AYA

Young people aged 15 to 19 are usually being regarded as adolescents, while age over 20 as young adults. How-ever, there is no internationally unified definition on AYA age range [3,4]. In the past, the Surveillance, Epi-demiology, End Result (SEER) program of the NCI defined 29 years as the upper limit of age for young adults. In 2005, a broader age range of 15-39 years was proposed by the PRG of the NCI and LiveStrong Foundation in the US [1]. With the extension of upper limit of age range definition, there is increase in proportion of epithelial tumors (carcinoma) including breast, liver and lung tumors in AYA cancer spectrum [5]. Meanwhile, the age-group definition for AYA cancer service remains inconsistent across the world: age 15-25 years in France, 15-29 years in Italy, 14-30 years in Spain, and 15-24 years in United Kingdom and Australia [6,7]. Recent surveys in Europe and Asia also found significant variation in perceived definition of age range for AYA among health care providers (HCP) [4,8].

Epidemiology

Cancer is one of the leading causes of non-accidental death among AYA subjects in high income countries (HIC) [7,9-11]. The incidence rate of cancer in AYA population has been reported to be 4 to 8 times higher than in children age below 15 [9,12]. In the United States, nearly 70,000 AYA aged between 15-39 years are diagnosed with cancer each year and this accounted for 5% of all cancer cases [12,13]. Estimated at over 60,000 new patients per year, this group accounts for 2% of all invasive cancers in Europe [6]. A survey in Japan reported the AYA population contributes to 3.6% of all cancer cases in the country [11]. Globally, 1.2 million AYA aged 15-39 years were diagnosed to have cancer in 2018, with incidence of 42.2 per 100,000 person per year and this was accountable for 6.8% of all cancer diagnosis [9].

In many countries, incidence of AYA cancer is increasing over the last few decades [14], with an estimated increase of 30% from the time period 1975-1979 to 2011-2015 and the rate is higher than that seen in younger and older individuals [9,13,15]. An increase of annual incidence rate of 0.6-2% was reported in England, Korea, the Netherlands, Latin America and in males in Australia [10].

From 2005 through 2014, incidence of AYA cancer increased by 0.6% to 1.4% per year in the US [9]. In Europe, during the period from 1991-2007, the annual percent change (APC) of cancer in male and female was 0.85% and 0.8%, respectively [6]. A recent analysis of global trend of AYA cancer found significant increase in cancer burden in 23 out of 41 countries, with the greatest increase observed in South Korea [14]. In South Korea, APC of cancer in AYA aged 15-39 year was 8.5% in the period from 2002-2012 [10]. This was due to a significant increase in incidence rate of thyroid cancer in female [10,14]. Diagnosis of thyroid cancer in AYA female in Korea is approximately 6 times more common than in male [10]. In another report, APC of cancer among Korea AYA aged 15-29 was 6.3% between 1999 to 2010 and it was 1.8% when thyroid cancer was excluded from analysis [10]. This dramatic increase in incidence of thyroid cancer is attributable to increase in surveillance and “over-diagnosis” of indolent lesions which would not affect the individual if left-untreated [9,16,17].

Cancer in AYA is characterized by female predominance with incidence rate two times higher than male [3,9,18]. Top ranking cancers are breast cancer, thyroid cancer and cancer of cervix uteri (Fig. 1) [3,9,10]. Thyroid cancer has a significant sex predominance with age-standardized rate (ASR) at least 4 times higher in female than in male among young adults [3]. The sex predominance is not observed in younger AYAs aged between 15-24 according to reports in France and Australia [7,19].

Figure 1. Cancer diagnosis among AYA aged 15-39 years with data retrieved from the International Agency for Research on CI5plus database (http://ci5.iarc.fr/CI5plus). All except data from Japan is from year 2012 while data from Japan registry is from year 2010. There are regional variations in spectrum of cancer across the registries, especially for melanoma which is far more common in US, UK, and Australia than in China, Japan, and Korea; while Korea has a much higher incidence of thyroid cancer. (A) Cancer diagnosis in AYA male. (B) Cancer diagnosis in AYA female. ASR, Age-standardized rate.

Socio-economic development is also associated with burden of cancer in different regions of the world. Socio-economic development of a region can be categorized by low, middle, high and very high according to Human Development Index (HDI). Regions with very high HDI have increased incidence rate of AYA cancer when compared with low or medium HDI regions, with estimated ASR of 64.5 vs. 46.2 cancer cases per 100,000 person per year [3]. Nevertheless, mortality rate from AYA cancer is lower in very high HDI regions than in low HDI regions [3,9]. The spectrum of cancer across the 4 HDI levels also varies, with thyroid cancer, testicular cancer and melanoma more frequently occurring in high HDI regions. Infection-related cancers, including those related to hepa-titis B virus, human papilloma virus (HPV), Helicobacter pylori, are relatively more prevalent in regions under transition. Nevertheless, breast cancer and cancer of cervix uteri are among the top five most common AYA cancers across the four HDI categories [3].

Spectrum of AYA Cancer

It is observed that the incidence of cancer in AYA increases steadily with age [9,10]. Among AYA with cancers, approximately 10% of subjects are aged 15 to 24 years and 90% are aged 25 to 39 years [11]. The spectrum of cancers in patients aged 15-39 years is distinct from that in younger and older age groups [6,20]. It also varies with age within the AYA group. In general, there is decrease in percentage of embryonal tumors with increasing age, while percentage of carcinoma increases [12]. Fig. 1 depicts the spectrum of cancer diagnosis among AYA with data retrieved from registries in North America, Europe, and Asia, in the International Agency for Re-search on Cancer’s CI5plus database (http://ci5.iarc.fr/CI5plus).

In young adolescents aged 15-19, there is a higher percentage of cancers being hematological malignancies and brain tumors when compared with young adults aged 20-39 [13]. In younger subjects aged 15-24, hematolo-gical malignancies are the commonest type of cancers [11]. Incidence of acute lymphoblastic leukemia (ALL) is higher in younger AYA than in elder subjects [21]. Among those aged 25-39 years, testicular cancer is the most common type of cancer in male, whereas breast cancer and cancer of cervix uteri are the two most common type of cancers in female [11]. Osteosarcoma, Ewing sarcoma, gonadal germ cell tumor (GCT) and Hodgkin lymphoma are more frequent among AYA than in other age groups [9,12].

Globally in 2012, the most common cancer among young adults aged 20-39 are breast cancer, cervical cancer, thyroid cancer, leukemia and colorectal cancer [3]. Table 1 listed incidence rate and spectrum of cancer in different parts of the world.

Table 1 . Incidence rate and common cancer types in different regions of the world.

Country/regionAge range (years)Study periodAnnual incidence/100,000Most common cancer site/type
Global [3]20-392012ASRBreast cancer, cervical cancer, thyroid cancer, leukaemia, colorectal cancer
43.4
Global [9]15-39201842.2Breast cancer, cervical cancer, thyroid cancer
Australia [7]15-242000-200931.7Melanoma, HL, testicular tumor, thyroid cancer, NHL
Australian Cancer Database
France [19]15-242000-2008ASR (per million)Male
Gonadal GCT, Hodgkin disease, ALL
254.1Female
Hodgkin disease, thyroid cancer, melanoma
Netherlands [69]15-292003-2009ESRMale
Testicular cancer, Hodgkin disease, melanoma
Netherlands Cancer RegistryMale: 39.1
Female: 37.1Female
Melanoma, breast cancer, Hodgkin disease
Japan [18]15-392009-2011ASR (per million)20-29 years:
Malignant germ cell gonadal tumour
Monitoring of Cancer Incidence in Japan Project488.3
Male: 33330-39 years:
Female breast cancer
Female: 649.5
Korea [10]19-291999-2010ASR (per million)Thyroid, NHL, stomach carcinoma, breast carcinoma, AML
Korea Central Cancer Registry279.9
Male: 196.4
Female: 367.8

ASR, age-standardized rate; ESR, European Standardized rate..



In view of the uniqueness of cancer spectrum in AYA, the International Classification on Childhood Cancer (ICCC) does not precisely reflect and capture the full spectrum of diseases. According to ICCC, many of the AYA cancers would fall into the category of “Other and unspecified carcinoma”, which includes carcinoma of breast, lung, gastrointestinal tract and urological system [22]. A dedicated classification scheme tailored to the circumstances and spectrum of AYA cancer is therefore proposed by Barr and Birch [23,24].

Acute Lymphoblastic Leukemia

ALL is one of the cancers which improvement is lagging behind in AYA when compared with children. Most of the survival difference between children and AYA in Europe and the US was due to more significant improvement of ALL survival in children [25]. In the last few decades, multi-institutional trials and progressive refinement of multi-agent protocols have resulted in significant improvement of treatment outcome for childhood ALL. However, similar improvement was not seen in AYA ALL. 5-year event free survival of 50% to 60% is still not optimal when compared to pediatric patients [2,21,26].

Differences in biology of disease between AYA and young children could be a contributing factor to the inferior outcome. Increasing age is known to be associated with poor prognostic biological features including higher presenting white cell count, T-immunophenotype, Ph chromosome positive and Ph-like ALL [13]. Treatment protocols administered, site of treatment (pediatric vs. adult cancer treatment units), rate of enrollment on clinical trials, adherence to treatment and social issues including insurance coverage are all possible factors attributing to the worse outcome [21,27,28]. Meta-analysis of 11 comparative studies including 2,489 patients showed pediatric-inspired regimen was superior to conventional adult therapy in treating AYA ALL age 16-39, albeit none of the studies was randomized trials. Pediatric-inspired regimen was having better event-free survival, lower all-cause mortality and relapse rate [27].

A retrospective study examined the treatment response and outcome on AYAs 16-20 years old with ALL who received treatment according to either Children Cancer Group (CCG) trials or Cancer and Leukaemia Group B (CALGB) trials, which were pediatric and adult cooperative group trials, respectively. The CALGB trials enrolled 759 patients (aged 16-81 years) and 124 of them were aged 16-20. Seven-year event free survival and overall survival (OS) were 63% and 67%, respectively for CCG treated patients and significantly better than patients enrolled on CALGB trials (EFS 34%; OS 46%) despite similar complete remission rate. This study suggested superior efficacy of CCG approach in treating AYA ALL. However, patients in CCG trials were younger, with 85% of them aged 16-17, when compared with CALGB trials with 80% of them aged 18-20 year [29].

The Japan Adult Leukemia Study Group (JALSG) studied the feasibility and toxicity of ALL202-U protocol, a pediatric-based regimen, in adolescents and young adults aged 15 to 24 with Ph-negative ALL. It also demonstrated marked improvement in outcome with ALL202-U protocol when compared with JALSG ALL97 adult protocol with 5-year OS of 73% and 45% and disease free survival of 67% and 44%, respectively, with acceptable toxicity profile [30].

The National Comprehensive Cancer Network (NCCN) clinical practice guideline on ALL strongly recommends treatment in specialized centers [31]. Studies have examined whether treating at adult centers or pediatric treatment units would affect outcome. Retrospective comparative studies suggested AYAs with ALL who received treatment at pediatric centers were having better outcome than at adult centers. The difference was, at least in part, related to the treatment protocol intensity instead of site of treatment [28]. Population-based study in Canada on 290 ALL patients age 15-19 at the time of diagnosis found comparable outcome among patients treated at pediatric and adult centers, which was probably due to early introduction of pediatric-based regimens in adult centers [28]. The CALGB10430 study, based on a pediatric regimen of Children’s Oncology Group AALL0232 protocol, also demonstrated the feasibility, safety and significant improvement in survival in treating AYA ALL patients at adult treatment centers, with 3-years EFS of 59% and OS of 73% [32]. Treating AYA ALL at either pediatric or adult centers with pediatric-based regimen appears to be a preferred option.

Soft Tissue Sarcoma

Soft tissue sarcoma (STS) is relatively uncommon and contributes to only 1% of all adult cancers and about 8% of all cancers in AYA [20,33,34]. Little was known about the true epidemiology of this heterogeneous group of disease in AYA. Comparison of data is difficult with inconsistency in age range definition of AYA across different studies [33-35]. Accrual in clinical trials is sub-optimal and is limited by the lack of tailored trials for this heterogeneous group of disease [35]. Its importance in AYA, however, should not be overlooked due to worse treatment outcome when compared with other AYA cancers like melanoma, Hodgkin lymphoma and germ cell tumors [9]. Patients with STS need multi-disciplinary management which usually involves medical or pediatric oncologist, radiation oncologist, and orthopedic surgeon. The value of multi-disciplinary management is best illustrated by management of sarcoma patients. A study in France on subjects aged >15 years with sarcoma observed that presentation to multi-disciplinary tumor board before initiation of treatment is beneficial with 2-year local relapse free survival 76.9% compared to 65.4% in those presented after initiation of treatment [36]. Cen-tralizing treatment in specialized centers for management of STS could be beneficial and enrolling patients in clinical trials should be advocated [35,37].

A report from the European Organization for Research and Cancer Treatment (EORTC) compared prognostic factors of STS in AYA and adults, with AYA defined as aged 15-29 and adults as over 30, who were enrolled in two randomized trial for STS. In both age groups, lower histological grading and smaller tumors were favorable prognostic factors. In the younger age group, tumor in extremities was a favorable prognostic factor while benefit of adjuvant therapy was only seen in adults aged ≥30 years [35].

In 2019, a population-based study of the Scandinavian Sarcoma Group Central Registry on 5,000 patients with STS, including AYA aged 18-39 years and older adults age over 40, reported differences between the two groups with regard to presentation, size of tumor, histological sub-type, treatment and survival outcome. There was no difference with regard to metastatic disease at the time of presentation. Better survival outcome was seen in AYA compared with older adults (Median survival 5.36 years vs. 3.96 years) with the exception of malignant peripheral nerve sheath tumor [33].

Breast Cancer

Breast cancer is one of the most common cancer in young adult females with increasing incidence with age. The proportion of breast cancer increases significantly with age, accounting for less than 1% in adolescents and 29% in those aged 30-39 years [13]. Overall, 5.6% of all invasive breast cancer patients are diagnosed in AYA females younger than age of 40 [38].

The proportion of AYA breast cancer being stage II to IV disease is higher in AYA than in women aged over 40 [38]. Likewise, in comparison with older females, the chance of having familial cancer predisposition, more aggressive clinical course and triple negative cancer is also higher in AYA females, thus conferring to a worse outcome of AYA with breast cancer [9,38]. In the US, 5-year survival rate for age less than 30 years and 40-49 years were 80.2% and 88.9%, respectively [38,39]. Similar finding is also reported in Korea, with 5-year relative survival (RS) of 86.8% and 91% for patients aged 15-29 years and ≥40 years, respectively [10].

Colon Cancer

In contrast to decreasing trend of incidence of colorectal cancer in older individuals, the incidence rate of colon cancer in AYA is on the rise, [40-42] with left side of colon and rectum being more frequently involved [42,43]. However, there is variation of incidence trend between countries. In 2020, Gupta et al reported cancer incidence with data from CI5plus database in the time period between 1998 to 2012. Among 41 countries, colon cancer incidence was increasing in 17 countries and stable in 24 countries [14]. Australia and New Zealand have the highest incidence of CRC. In the period between 1982 to 2007, incidence of CRC among AYA aged 15-39 increased by 3% per year in Western Australia [41]. Akin to breast cancer, a higher proportion of aggressive tumor subtypes of colon cancer with associated poorer survival are found in the AYA population as opposed to adults. This includes colon cancers with mucinous histology, and presence of mis-match repair defect and high microsatellite instability [43]. Nevertheless, a report from Japan on 502 AYA with stage II to III CRC, 5-year OS was better when compared with adults aged 65-74, with OS 100% vs. 93.6% for stage II and 87.4% vs. 82.2% for stage III disease [44]. It was also observed that among CRC patients with completely resected stage I to III disease, disease specific survival of AYA and older adults aged >40 was similar and was 86% and 87%, respectively, although more AYA received adjuvant therapy. These observations suggested that early diagnosis is important in AYA CRC and education of AYA on CRC symptoms and early colonoscopy should be emphasized.

Testicular Cancer

Testicular cancer is the commonest cancer in AYA males with peak incidence in late 20s to early 30s [45]. The incidence rate showed significant geographical variations, with the highest incidence in Europe with age-standardized rate of 137.4 per million and lowest in Asia with ASR of 27.1 per million [45]. Mixed malignant GCT is the most common histological type among adolescents while the proportion of seminoma increases with age and it is the most common histology in older AYA subjects [46].

A population based study in the US showed adolescents were having more frequent regional or distant metastasis compared with adults. Nevertheless, cancer spe-cific survival for adolescents and adults were comparable (95% and 94%, respectively) and the favorable outcome was probably achieved at the cost of more aggressive surgical and other adjuvant treatments in younger subjects [47]. Long term treatment related morbidities including ototoxicity, increase risk of cardiovascular disease and second malignant neoplasms, hypogonadism, pulmonary and kidney impairment should not be overlooked [46].

Cervical Cancer

Globally, cervical cancer is among the top 10 ranking cancers in incidence and mortality and is one of the 3 most common cancer in AYA females. HPV infection, especially high-risk types 16 and 18, is a well-known etiological factor for cervical cancer and is transmitted via sexual activity. There are wide variations in surveillance data among different regions of the world and developed countries are having lower age-standardized incidence rate and death rate compared with developing countries [48]. Global surveillance data also revealed variations in incidence trend among AYAs in different nations, with one third of countries showing decrease in incidence while some countries are observing increase in incidence [14]. As there is a lag time of 10 to 20 years for precancerous changes to evolve into cervical cancer, widespread adoption of screening for precancerous changes by Pap test or high risk HPV virus surveillance and early intervention reduces incidence and mortality of cervical cancer [49,50]. The US Preventive Service Task Force recommends screening of females from age 21 onwards [50]. Other preventive measures include use of condom, mutual monogamy and HPV vaccination [51]. HPV vaccine can be given to females as early as age of 9 years. For girls age between 9-14 years, two doses of HPV vaccine are recommended whereas 3 doses are needed for those aged 15-26 years [50]. A study done in Taiwan, however, found only 11.5% of adolescent females were informed of HPV vaccination by HCP [51]. Appropriate and timely delivery of information to adolescent girls on prevention of HPV infection should not be under-em-phasized.

Thyroid Cancer

Thyroid cancer is one of the most common cancer among AYA and majority of them are papillary thyroid cancer (PTC) [52]. AYAs with differentiated thyroid cancer generally have favorable outcome [53] and disease free survival and overall survival are better compared with adults age over 40 [52]. With increase in utilization of ultrasonography screening, many countries are observing a surge of thyroid cancers due to over diagnosis [17]. From 1993 to 2011, incidence rate of thyroid cancer in Korea rocketed by a factor of 15, with 40,000 cases diagnosed in 2011, while mortality figure remained stable [17]. It is known that many PTC could remain subclinical and rarely result in mortality. Significant overdiagnosis and subsequent dramatic increase in number of patients receiving treatment, which is mainly surgery, should prompt reconsidering the role of screening for thyroid cancer [17].

Survival Outcome

Five-year OS of AYA with cancer was 71% in mid-1970s [13]. Overall survival and treatment outcome of cancer has been improving in the last few decades. However, in 2006, the SEER and COG published an epidemiology report on AYA with cancer and high-lighted a relative lack of progress in AYA cancer survival in the last quarter of the twentieth century when compared with younger and older individuals [12,54]. In retrospect, this lack of improvement could be explained by the human immunodeficiency virus/acquired immunodeficien-cy syndrome (HIV/AIDS) epidemic during the 1980s to 1990s, which resulted in a surge of HIV related Kaposi sarcoma and lymphoma with poorer survival outcome, before the development of effective treatment for HIV infection [55].

Five-year RS of AYA with cancers diagnosed in the period 2002-2006 was 82.5%, with 14 cancer types having improvement in outcome when compared with results in 1992 [56]. In Europe, among AYA with cancer diagnosed during the period 2000-2007, 81% were alive at 5 years after diagnosis [6]. For those diagnosed in the period from 2008 through 2014, 5-year OS was 86% [13]. World-wide, 5-year RS of AYA with cancer is now in the range of 79% to 89% [9]. Survival outcome varies between different regions of the world, partly because of the difference in age range on defining AYA, the inclusion of benign tumors in the analysis and the variation in incidence of types of cancer. Not to mention variations in socioeconomic status (SES) which significantly impact on outcome, with mortality to incidence ratio (MIR) being 3 to 4 times higher in very low HDI regions when compared to countries with HDI [9].

Despite the outcome of AYA with cancer is now slightly better than children younger than 15, treatment outcome remains inferior in some cancers occurring in children and AYA in both Europe and the US (Table 2) [9,25,56,57].

Table 2 . 5-year relative survival of AYA and children with cancer common to both groups. Europe data from 27 European countries participating in EUROCARE-5 for AYA and children with cancer diagnosed in 2000-2007. US Data from NCI SEER database in the period from 2002-2006.

ALLAMLRMSEwing’s sarcomaHodgkin lymphomaNHLAstrocytomaOsteosarcoma
The US [47]
AYA52%50%43%54%
Children90%66%69%77%
Europe [46]
AYA55.6%49.8%37.8%49.3%92.9%77.4%46.4%61.5%
Children85.8%60.5%66.6%66.6%95.1%83.0%61.9%66.8%

ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; RMS, rhabdomyosarcoma; NHL, Non-Hodgkin lymphoma..



Keegan at al. reported data form SEER in the period 2002-2006, 5-years RS of melanoma, non-Hodgkin lymphoma, thyroid cancer, testicular cancer and breast cancer were over 80%. Thyroid cancer was having the best survival outcome among all cancer types in AYA (5-year RS of 99.7%), followed by testicular cancer (96.1%) and melanoma (95.5%) [56]. On the contrary, AYAs with acute myeloid leukemia, rhabdomyosarcoma, high grade astrocytoma, carcinoma of lung, liver, pancreas and stomach had 5-year RS below 50%. AYAs with liver carcinomas had the lowest 5-year RS of 25.2% [56].

In the presence of distant metastatic disease at the time of diagnosis, AYAs have better survival outcome compared with older adults. 5-years RS was 80.8%, 44% and 17.9% for children age below 15, AYAs and older adults (≥40 years), respectively [56].

Barriers to AYA Cancer Treatment

Across the world, there is significant variation of health care system, degree of socio-economic development, private and public insurance coverage, culture and even social norms which all could potentially influence treatment of AYA with cancer.

However, difficulty for AYA with cancer to access specialized treatment center is not an uncommon problem across the world [4,8]. Centralized and multidisciplinary treatment centers with tailored therapy for AYA cancers are essential components for improving treatment outcome [9]. A report based on Los Angeles cancer registry studied the impact of treatment in designated Compre-hensive Cancer Center (CCC)/Children’s Oncology Group (COG) versus non-CCG/COG sites on survival outcomes of ALL and AML in AYA aged 15-39 years. Proportion of patients being treated at CCC/COG site decreased with age, 50.5% of those age 15-21 received treatment in CCC/COG sites whereas it dropped to 12.3% among age 22-39. Patients treated in non CCG/COG centers had inferior outcome and lack of private insurance and African American/Hispanic race/ethnicity were barriers against seeking treatment in specialized centers [2].

SES and financial issues also affect AYA in accessing specialized centers for treatment and completing therapy. In the US, studies have examined the relationship between SES and insurance coverage. It is estimated that 9% of people in the US did not have insurance coverage [58]. AYA aged 18-24 was the least insured age group with more than 30% not having health insurance [12]. Study in adults in the US revealed that patient having Medicaid coverage/no insurance were more likely to present with metastatic disease, less likely to receive surgery/radiotherapy and having a higher chance of death compared to those with non-Medicaid insurance [59].

AYA with cancer is no exception and insurance status is an independent factor associated with distant metastasis at the time of diagnosis [60]. A study in California shown that, during 1991 to 2014, among AYA with public/no insurance, the chance of having treatment in specialized centers was lower than those with private insurance [61]. Two studies in the US looked into the issue of insurance disparities in 40,000 young adults in the time period 2007-2009 and 66,556 AYA from 2007 through 2014. Among those with public or no insurance, there were higher chance of metastatic disease at the time of presentation, lower proportion received definitive treatment and having poorer survival outcome [22,62].

An analysis of a cohort of AYA patients in the Health Outcome and Patient Experience (HOPE) study found insurance coverage extending beyond AYA cancer diagnosis decreases with time and was lower for the elder age and lower educational level group. A quarter of AYA patients would have certain time period without insurance coverage in the 3 years after cancer diagnosis [63]. Al-though the importance of insurance coverage in seeking medical treatment is not the same across different health care systems, it reflects the potential obstacles for AYA patients in seeking appropriate medical treatments.

Under-representation in clinical trials due to lack of tailored trials for AYA and lack of access to centers participating in AYA clinical trials were postulated to be the cause of lack of improvement in AYA cancer. In the US and Europe, majority of children with cancer age less than 15 are enrolled in clinical trials; whereas the proportion decrease to 10% for those aged 15-19 in the US with a further drop to 1 to 2% for young adults [12].

In 2016, the European Society for Medical Oncology (ESMO)/the European Society for Pediatric Oncology (SIOPE) conducted an online survey on HCP with interest in AYA cancer. Two-third of respondents reported that their patients were not able to access specialized services and the problem was more severe in Eastern and South-Eastern Europe. It was alarming that more than two-third said they were not aware of any research activities on AYA cancer [4].

A similar survey was carried out by the ESMO/SIOPE and the Asian continental branch of International Society of Pediatric Oncology in Asia in 2018. It also identified similar difficulty in accessing specialized AYA cancer services and lack of awareness of research activities among HCP. This survey had additional questions looking into funding of cancer treatment and issue of non-compliance and non-adherence to treatment. In about two-third of the respondents, they acknowledged funding source being government-based social insurance and patient self-financed, at least partially. About half of their patients had private insurance while a quarter of them experienced difficulties in terms of insurance. Seventy percent of respondents reckoned financial and insurance issues being the reasons behind abandoning and non-adherence to treatment, which is worrying; while one-out-of-four respondents replied that religious belief would play a role in non-adherence and an equal proportion of respondents regarded gender inequality a problem affecting decision on treatment [8].

Training and education of HCP is also an important issue that should not be over-emphasized. However, surveys in Europe and Asia both revealed that only a minority of HCP were able to access education and training related to AYA cancers [4,8]. This is sub-optimal and efforts should be made to improve the situation.

Long Term Outcome, Survivorship Health and Late Sequelae

Majority of AYA with cancer would be cured and given the relatively young age at diagnosis, there are decades of life ahead for these survivors. Taking good care of the long-term health issues of these survivors should not be neglected.

There is a long-term increase risk of death in survivors of AYA with cancers. In 2020, a report on the long-term outcome of AYA cancer survivors registered in the Uni-versity of Texas MD Anderson Cancer Tumor Registry was published. The cohort was comprised of 16,728 AYA cancer survivors and OS was estimated to be 86%, 74% and 68% at 10-year, 20-year and 25-year after initial diagnosis, respectively. The survival probability was lower than that of matched-cohort of general population at all time points [64].

Long term co-mobilities including cardiovascular and respiratory diseases and second malignant neoplasm (SMN) are potential threats to cancer survivors. A study investigated the risk of SMN among 2-year survivors of AYA cancer in Southern California from 1990 to 2012. The risk of SMN is estimated to be 12.5% at 20 years after initial diagnosis and resulted in 7-fold increase in mortality compared with survivors without SMN [65]. In another large cohort of 200,945 AYA cancer survivors in the Teenage and Young Adult Cancer Survivor Study (TYACSS) in England and Wales, there were 12,321 SMN at a median follow up of 16.8 years. AYA with history of breast cancer, cervical cancer, testicular cancer or Hodgkin lymphoma were particularly at risk of SMN [66].

In regard to cardiovascular and respiratory co-morbidities, AYA cancer survivors are also at increased risk when compared with general population. The Kaiser Permanente Cancer Survivor Study shown that, among 5,671 AYA cancer survivors, the risk of having cardiovascular diseases (CVD) including heart failure, coronary artery disease and stroke is at least 2 times higher than that of matched subjects without cancer. Chance of dying from the CVD is also significantly elevated, estimated at 11 times higher, when compared with general population [67]. In the TYACSS, there were 1,079 respiratory deaths in the cohort of 200,945 AYA cancer survivors with a mean follow up of 19.3 years. It was observed that the risk of dying from respiratory diseases was 70% higher when compared with general population, with standardized mortality ratio highest for pneumonitis and pneumonia. Cancer survivors of lung cancer, leukemia, head and neck cancer and central nervous system tumor carried the greatest excess risk of death [68].

In summary, AYA with cancer is distinct from younger children and older adults in terms of spectrum of disease, biology and treatment outcome even for the same cancer and the incidence is rising. Despite favorable survival outcome is observed for the whole AYA group, survival in AYA is still inferior for many cancer types common to both children and AYA. Treatment in centralized centers and promotion of accrual to clinical trials should be strongly advocated. Risk of long-term co-morbidities, risk of SMN and mortality should be properly addressed.

Supplementary Material
cpho-28-1-1-supple.pdf
 Conflict of Interest Statement

The authors have no conflict of interest to declare.

References
  1. Adolescents and Young Adults Oncology Review Group. Closing the gap: research and care imperatives for adolescents and young adults with cancer. Bethesda: NIH publication, 2006.
  2. Wolfson J, Sun CL, Wyatt L, Stock W, Bhatia S. Adolescents and young adults with acute lymphoblastic leukemia and acute myeloid leukemia: impact of care at specialized cancer centers on survival outcome. Cancer Epidemiol Biomarkers Prev 2017;26:312-20.
    Pubmed KoreaMed CrossRef
  3. Fidler MM, Gupta S, Soerjomataram I, Ferlay J, Steliarova-Foucher E, Bray F. Cancer incidence and mortality among young adults aged 20-39 years worldwide in 2012: a population-based study. Lancet Oncol 2017;18:1579-89.
    Pubmed CrossRef
  4. Li CK, Dalvi R, Yonemori K, et al. Care of adolescents and young adults with cancer in Asia: results of an ESMO/SIOPE/SIOP Asia survey. ESMO Open 2019;4:e000467.
    Pubmed KoreaMed CrossRef
  5. Barr RD, Ferrari A, Ries L, Whelan J, Bleyer WA. Cancer in adolescents and young adults: a narrative review of the current status and a view of the future. JAMA Pediatr 2016;170:495-501.
    Pubmed CrossRef
  6. Desandes E, Stark DP. Epidemiology of adolescents and young adults with cancer in europe. Prog Tumor Res 2016;43:1-15.
    Pubmed CrossRef
  7. Roder DM, Warr A, Patterson P, Allison KR. Australian adolescents and young adults-trends in cancer incidence, mortality, and survival over three decades. J Adolesc Young Adult Oncol 2018;7:326-38.
    Pubmed CrossRef
  8. Li CK, Dalvi R, Yonemori K, et al. Care of adolescents and young adults with cancer in Asia: results of an ESMO/SIOPE/SIOP Asia survey. ESMO Open 2019;4:e000467.
    Pubmed KoreaMed CrossRef
  9. Trama A, Botta L, Steliarova-Foucher E. Cancer burden in adolescents and young adults: a review of epidemiological evidence. Cancer J 2018;24:256-66.
    Pubmed CrossRef
  10. Moon EK, Park HJ, Oh CM, et al. Cancer incidence and survival among adolescents and young adults in Korea. PLoS One 2014;9:e96088.
    Pubmed KoreaMed CrossRef
  11. Ohara A, Furui T, Shimizu C, et al. Current situation of cancer among adolescents and young adults in Japan. Int J Clin Oncol 2018;23:1201-11.
    Pubmed CrossRef
  12. Burke ME, Albritton K, Marina N. Challenges in the recruitment of adolescents and young adults to cancer clinical trials. Cancer 2007;110:2385-93.
    Pubmed CrossRef
  13. Close AG, Dreyzin A, Miller KD, Seynnaeve BKN, Rapkin LB. Adolescent and young adult oncology-past, present, and future. CA Cancer J Clin 2019;69:485-96.
    Pubmed CrossRef
  14. Gupta S, Harper A, Ruan Y, et al. International trends in the incidence of cancer among adolescents and young adults. J Natl Cancer Inst 2020;112:1105-17.
    Pubmed KoreaMed CrossRef
  15. Nomellini PF, Curado MP, Oliveira MM. Cancer incidence in adolescents and young adults in 24 selected populations of Latin America. J Adolesc Young Adult Oncol 2018;7:164-73.
    Pubmed CrossRef
  16. Bleyer A, Ferrari A, Whelan J, Barr RD. Global assessment of cancer incidence and survival in adolescents and young adults. Pediatr Blood Cancer 2017;64.
    Pubmed CrossRef
  17. Ahn HS, Kim HJ, Welch HG. Korea's thyroid-cancer "epi-demic"--screening and overdiagnosis. N Engl J Med 2014;371:1765-7.
    Pubmed CrossRef
  18. Katanoda K, Shibata A, Matsuda T, et al. Childhood, adolescent and young adult cancer incidence in Japan in 2009-2011. Jpn J Clin Oncol 2017;47:762-71.
    Pubmed KoreaMed CrossRef
  19. Desandes E, Lacour B, Belot A, et al. Cancer incidence and survival in adolescents and young adults in France, 2000-2008. Pediatr Hematol Oncol 2013;30:291-306.
    Pubmed CrossRef
  20. Bleyer A, Barr R, Hayes-Lattin B, et al. The distinctive biology of cancer in adolescents and young adults. Nat Rev Cancer 2008;8:288-98.
    Pubmed CrossRef
  21. Rytting ME, Jabbour EJ, O'Brien SM, Kantarjian HM. Acute lymphoblastic leukemia in adolescents and young adults. Cancer 2017;123:2398-403.
    Pubmed CrossRef
  22. Colton MD, Goulding D, Beltrami A, et al. A U. S. population-based study of insurance disparities in cancer survival among adolescents and young adults. Cancer Med 2019;8:4867-74.
    Pubmed KoreaMed CrossRef
  23. Barr RD, Holowaty EJ, Birch JM. Classification schemes for tumors diagnosed in adolescents and young adults. Cancer 2006;106:1425-30.
    Pubmed CrossRef
  24. Birch JM, Alston RD, Kelsey AM, Quinn MJ, Babb P, McNally RJ. Classification and incidence of cancers in adolescents and young adults in England 1979-1997. Br J Cancer 2002;87:1267-74.
    Pubmed KoreaMed CrossRef
  25. Trama A, Bernasconi A, McCabe MG, et al. Is the cancer survival improvement in European and American adolescent and young adults still lagging behind that in children? Pediatr Blood Cancer 2019;66:e27407.
    Pubmed CrossRef
  26. Ramanujachar R, Richards S, Hann I, et al. Adolescents with acute lymphoblastic leukaemia: outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatr Blood Cancer 2007;48:254-61.
    Pubmed CrossRef
  27. Ram R, Wolach O, Vidal L, Gafter-Gvili A, Shpilberg O, Raanani P. Adolescents and young adults with acute lymphoblastic leukemia have a better outcome when treated with pediatric-inspired regimens: systematic review and meta-analysis. Am J Hematol 2012;87:472-8.
    Pubmed CrossRef
  28. Pole JD, Alibhai SM, Ethier MC, et al. Adolescents with acute lymphoblastic leukemia treated at pediatric versus adult hospitals. Ann Oncol 2013;24:801-6.
    Pubmed CrossRef
  29. Stock W, La M, Sanford B, et al. What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children's Cancer Group and Cancer and Leukemia Group B studies. Blood 2008;112:1646-54.
    Pubmed KoreaMed CrossRef
  30. Hayakawa F, Sakara T, Yujiri T, et al. Markedly improved outcomes and acceptable toxicity in adolescents and young adults with acute lymphoblastic leukemia following treatment with a pediatric protocol: a phase II study by the Japan Adult Leukemia Study Group. Blood Cancer J 2014;4:e252.
    Pubmed KoreaMed CrossRef
  31. Alvarnas JC, Brown PA, Aoun P, et al. Acute lymphoblastic leukemia, version 2.2015. J Natl Compr Canc Netw 2015;13:1240-79.
    Pubmed CrossRef
  32. Stock W, Luger SM, Advani AS, et al. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood 2019;133:1548-59.
    Pubmed KoreaMed CrossRef
  33. Papworth KE, Arroyo VM, Styring E, Zaikova O, Melin BS, Lupo PJ. Soft-tissue sarcoma in adolescents and young adults compared with older adults: a report among 5000 patients from the Scandinavian Sarcoma Group Central Register. Cancer 2019;125:3595-602.
    Pubmed CrossRef
  34. Herzog CE. Overview of sarcomas in the adolescent and young adult population. J Pediatr Hematol Oncol 2005;27:215-8.
    Pubmed CrossRef
  35. Kasper B, Ouali M, van Glabbeke M, et al. Prognostic factors in adolescents and young adults (AYA) with high risk soft tissue sarcoma (STS) treated by adjuvant chemotherapy: a study based on pooled European Organisation for Research and Treatment of Cancer (EORTC) clinical trials 62771 and 62931. Eur J Cancer 2013;49:449-56.
    Pubmed CrossRef
  36. Blay JY, Soibinet P, Penel N, et al. Improved survival using specialized multidisciplinary board in sarcoma patients. Ann Oncol 2017;28:2852-9.
    Pubmed KoreaMed CrossRef
  37. Loong HH, Blay JY, Munhoz RR. International collaborations and regional challenges in providing specialist multidiscipli-nary sarcoma care. Am Soc Clin Oncol Educ Book:616-23.
    Pubmed CrossRef
  38. Johnson RH, Anders CK, Litton JK, Ruddy KJ, Bleyer A. Breast cancer in adolescents and young adults. Pediatr Blood Cancer 2018;65:e27397.
    Pubmed KoreaMed CrossRef
  39. Gondos A, Hiripi E, Holleczek B, et al. Survival among adolescents and young adults with cancer in Germany and the United States: an international comparison. Int J Cancer 2013;133:2207-15.
    Pubmed CrossRef
  40. O'Connell JB, Maggard MA, Liu JH, Etzioni DA, Livingston EH, Ko CY. Rates of colon and rectal cancers are increasing in young adults. Am Surg 2003;69:866-72.
    Pubmed
  41. Troeung L, Sodhi-Berry N, Martini A, et al. Increasing incidence of colorectal cancer in adolescents and young adults aged 15-39 years in Western Australia 1982-2007: examination of colonoscopy history. Front Public Health 2017;5:179.
    Pubmed KoreaMed CrossRef
  42. Quah HM, Joseph R, Schrag D, et al. Young age influences treatment but not outcome of colon cancer. Ann Surg Oncol 2007;14:2759-65.
    Pubmed CrossRef
  43. Levine O, Zbuk K. Colorectal cancer in adolescents and young adults: defining a growing threat. Pediatr Blood Cancer 2019;66:e27941.
    Pubmed CrossRef
  44. Nakayama Y, Kobayashi H, Kawamura H, et al. The long-term outcomes in adolescent and young adult patients with colorectal cancer -a multicenter large-scale cohort study. J Cancer 2020;11:3180-5.
    Pubmed KoreaMed CrossRef
  45. Kusler KA, Poynter JN. International testicular cancer incidence rates in children, adolescents and young adults. Cancer Epidemiol 2018;56:106-11.
    Pubmed CrossRef
  46. Stoneham S, Murray M, Thomas B, Williamson M, Sweeney C, Frazier L. AYA testis cancer: the unmet challenge. Pediatr Blood Cancer 2019;66:e27796.
    Pubmed CrossRef
  47. Amini A, Waxweiler TV, Maroni PD, et al. Survival outcomes of adolescent and adult patients with non-seminomatous testicular germ-cell tumors: a population-based study. J Pediatr Urol 2016;12:405.e1-e9.
    Pubmed CrossRef
  48. Musa J, Achenbach CJ, O'Dwyer LC, et al. Effect of cervical cancer education and provider recommendation for screening on screening rates: a systematic review and meta-analysis. PLoS One 2017;12:e0183924.
    Pubmed KoreaMed CrossRef
  49. Olusola P, Banerjee HN, Philley JV, Dasgupta S. Human papilloma virus-associated cervical cancer and health disparities. Cells 2019;8:622.
    Pubmed KoreaMed CrossRef
  50. Sawaya GF, Smith-McCune K, Kuppermann M. Cervical cancer screening: more choices in 2019. JAMA 2019;321:2018-9.
    Pubmed KoreaMed CrossRef
  51. Lin YJ, Fan LW, Tu YC. Perceived risk of human papillomavirus infection and cervical cancer among adolescent women in Taiwan. Asian Nurs Res (Korean Soc Nurs Sci) 2016;10:45-50.
    Pubmed CrossRef
  52. Vriens MR, Moses W, Weng J, et al. Clinical and molecular features of papillary thyroid cancer in adolescents and young adults. Cancer 2011;117:259-67.
    Pubmed KoreaMed CrossRef
  53. Keegan THM, Grogan RH, Parsons HM, et al. Sociodemographic disparities in differentiated thyroid cancer survival among adolescents and young adults in California. Thyroid 2015;25:635-48.
    Pubmed KoreaMed CrossRef
  54. Bleyer A, O'Leary M, Barr R, Ries LAG. Cancer epidemiology in older adolescents and young adults 15 to 29 years of age, including SEER incidence and survival: 1975-2000. Bethesda, MD; National Cancer Institute, 2006. (Accessed September 13, 2020, at https://seer.cancer.gov/archive/publications/aya/).
  55. Liu L, Moke DJ, Tsai KY, et al. A reappraisal of sex-specific cancer survival trends among adolescents and young adults in the United States. J Natl Cancer Inst 2019;111:509-18.
    Pubmed KoreaMed CrossRef
  56. Keegan THM, Ries LAG, Barr RD, et al. Comparison of cancer survival trends in the United States of adolescents and young adults with those in children and older adults. Cancer 2016;122:1009-16.
    Pubmed CrossRef
  57. Trama A, Botta L, Foschi R, et al. Survival of European adolescents and young adults diagnosed with cancer in 2000-07: population-based data from EUROCARE-5. Lancet Oncol 2016;17:896-906.
    Pubmed CrossRef
  58. Kehl KL, Keating NL, Giordano SH, Schrag D. Insurance networks and access to affordable cancer care. J Clin Oncol 2020;38:310-5.
    Pubmed KoreaMed CrossRef
  59. Walker GV, Grant SR, Guadagnolo BA, et al. Disparities in stage at diagnosis, treatment, and survival in nonelderly adult patients with cancer according to insurance status. J Clin Oncol 2014;32:3118-25.
    Pubmed KoreaMed CrossRef
  60. Robbins AS, Lerro CC, Barr RD. Insurance status and distant-stage disease at diagnosis among adolescent and young adult patients with cancer aged 15 to 39 years: National Cancer Data Base, 2004 through 2010. Cancer 2014;120:1212-9.
    Pubmed CrossRef
  61. Alvarez E, Keegan T, Johnston EE, et al. Adolescent and young adult oncology patients: disparities in access to specialized cancer centers. Cancer 2017;123:2516-23.
    Pubmed CrossRef
  62. Aizer AA, Falit B, Mendu ML, et al. Cancer-specific outcomes among young adults without health insurance. J Clin Oncol 2014;32:2025-30.
    Pubmed KoreaMed CrossRef
  63. Parsons HM, Schmidt S, Harlan LC, et al. Young and uninsured: insurance patterns of recently diagnosed adolescent and young adult cancer survivors in the AYA HOPE study. Cancer 2014;120:2352-60.
    Pubmed KoreaMed CrossRef
  64. Berkman AM, Livingston JA, Merriman K, et al. Long-term survival among 5-year survivors of adolescent and young adult cancer. Cancer 2020;126:3708-18.
    Pubmed CrossRef
  65. Chao C, Bhatia S, Xu L, et al. Incidence, risk factors, and mortality associated with second malignant neoplasms among survivors of adolescent and young adult cancer. JAMA Netw Open 2019;2:e195536.
    Pubmed KoreaMed CrossRef
  66. Bright CJ, Reulen RC, Winter DL, et al. Risk of subsequent primary neoplasms in survivors of adolescent and young adult cancer (Teenage and Young Adult Cancer Survivor Study): a population-based, cohort study. Lancet Oncol 2019;20:531-45.
    Pubmed KoreaMed CrossRef
  67. Chao C, Xu L, Bhatia S, et al. Cardiovascular disease risk profiles in survivors of adolescent and young adult (AYA) cancer: the Kaiser Permanente AYA Cancer Survivors Study. J Clin Oncol 2016;34:1626-33.
    Pubmed CrossRef
  68. Fidler MM, Reulen RC, Bright CJ, et al. Respiratory mortality of childhood, adolescent and young adult cancer survivors. Thorax 2018;73:959-68.
    Pubmed KoreaMed CrossRef
  69. Aben KK, van Gaal C, van Gils NA, van der Graaf WT, Zielhuis GA. Cancer in adolescents and young adults (15-29 years): a population-based study in the Netherlands 1989-2009. Acta Oncol 2012;51:922-33.
    Pubmed CrossRef


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  • Chi-kong Li