Although recent improvement has been observed, adolescent and young adult (AYA) patients with cancer do not show equivalent gains in survival to those reported for patients in both the younger and older age groups, according to an article in the November/December 2019 issue of CA: A Cancer Journal for Clinicians.
In the United States (US) alone, approximately 70,000 new cancer diagnoses are made annually in persons aged 15 to 39 years, which accounts for 5% of all new diagnosis of invasive cancer, wrote lead author Dr Allison G. Close of the Division of Hematology/Oncology, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh in Pittsburgh, PA, USA.
In addition to historical reports of poorer survival in this cohort, paediatric and AYA cancer cases show a 30% rise during the most recent time period studied (2011-2015), whereas incidence rates from 2006 to 2015 have declined in adult men and remained stable in women. The magnitude of the issues of increasing cancer incidence coupled with poorer survival in AYAs prompted Dr. Close and colleagues to investigate the demographics of cancer in the AYA groups, as well as the biological, societal and psychological factors that make cancer in AYAs a unique area of concern for clinicians.
The authors first conducted a review of cancer incidence and survival data up to 2015 for AYAs registered in the National Cancer Institute’s Surveillance, Epidemiology, and End Results registry programme and the North American Association of Central Cancer Registries, as well as mortality data from the Centers for Disease Control and Prevention’s National Center for Health Statistics. While they found encouraging data reflecting increases in 5-year survival for AYA cancers since 2000 that have paralleled those of childhood cancers, the investigators also found that an “AYA Gap” remains. This “AYA Gap” refers to the lower percentage of improvement in AYA cancer survival in recent decades compared with that of other age groups. This gap may be attributed to differences within the AYA population, unique cancer biology, and societal factors.
The distribution of different cancers and survival rates varies substantially across AYA age groups and by sex
Within the AYA population, the authors identified 3 separate age categories with individual characteristics: ages 15 to 19 years, 20 to 29 years, and 29 to 39 years. Each age category was affected by different types of cancer. For example, haematologic malignancies most often occurred from 15 to 19 years especially lymphoma, which accounted for 22% of all cases. This group also had a higher incidence (10.4%) of brain tumours. Both haematologic malignancies and brain tumours were less common in the two older groups where the incidence of lymphoma and leukaemia was 7.7% and 3.4%, respectively. Among older AYAs melanoma, breast, and colorectal cancers were more common; while breast and cervical cancer occur at rates of 29.0% and 7.7% in females aged 30 to 39 years, they represent less than 1% of cancers in adolescents. Important differences were seen in the incidence of cancer types that occur in both male and female AYAs but vary by sex; female AYAs have a nearly 5-fold greater incidence rate of thyroid carcinoma than males.
Survival was found to differ according to the age subgroup among AYAs; from 2008 through 2014, the 5-year survival for patients with acute myeloid leukaemia was 81.2% for males aged 15 to 19 years but this rate fell to 60.3% and 62.7% for males aged 20 to 29 years and 30 to 39 years, respectively. The 5-year colorectal cancer survival rate was similar among males across age groups at approximately 66% or 67% but was 90.3% in females, especially in the 15 to 19 year age group.
According to the authors, mortality rates among paediatric, AYA, and adult populations have declined since 1970. Review of mortality rates from 2007 to 2016 in AYAs revealed a 0.8%/year decrease. This decline was similar in males and females for leukaemia, and non-Hodgkin lymphoma, whereas some cancer types varied according to sex. For example, rates for Hodgkin lymphoma declined by 10%/year in female AYAs but by just 5%/year in males. Unfortunately, these advances have been offset by stable or increasing mortality rates in several types of cancer commonly diagnosed in AYAs, including cancer of the colorectum, bones and joints, and uterine corpus.
The biology of some cancers is specific to AYAs
Unique biological and/or genomic characteristics of cancer have been observed in AYAs. Analysis of driver mutations in AYA cancer is ongoing but the data acquired thus far indicate that the mutational burden appears to be higher in AYAs and some tumours, such as breast and colorectal, have less favourable histology. More aggressive types of cancer, such as mucinous colon cancer or triple-negative breast cancer are overrepresented in AYAs. Mutations in the MUC gene seem to be associated with the higher incidence of mucinous colorectal cancer in AYAs. Data suggest that alterations in the mismatch repair genes driving colorectal cancer may be disproportionately more common in AYAs compared with older adults, even when patients harbouring the genetic predisposition for hereditary non-polyposis colon cancer syndrome are excluded. Recent reports also indicate that the rising incidence of colorectal cancer in AYAs may be concomitant with the rise of obesity in younger adults.
Regarding melanoma, mutations in genes driving melanoma have been estimated to occur at similar rates in AYAs and older adults; however, a different distribution of non-ultraviolet-associated DNA damage has been reported in AYAs that may be linked to mismatch gene repair and contribute to enhanced melanoma development. Another example is thyroid carcinoma, where similar driver mutations are seen in older and younger patients but differences in secondary gene mutations have been reported. In contrast, genetic analysis of acute lymphoblastic leukaemia shows significant heterogeneity in driver mutations with a greater prevalence of high-risk mutations, such as Philadelphia chromosome-like leukaemia, that increases proportionally as the age of diagnosis increases.
Obstacles to the optimal care of AYAs include less AYA-directed research and clinical trial enrollment, decreased access to care and insurance coverage, and the lack of AYA-specific psychosocial support
Cancer care moves from the paediatrician to a wider set of primary care delivery options between the ages of 15 to 19. The investigators determined that clinical trials enrollment of AYA patients in adult centres may be less than adult enrollment, and in paediatric institutions, AYA trials enrolment is about 10% to 20% lower than paediatric enrolment.
Clinical trials enrollment for AYAs is impacted by the treatment facility and by insurance in a 2-fold manner: uninsured patients, older AYAs, and AYAs who were not treated at a paediatric facility were less likely to be included in clinical trials. Moreover, the highest percentage of uninsured in the US was in young adults particularly those aged ≥ 26 years; in 2016 the uninsured rates were 14% and 16% in persons aged 19 to 25 years and 26 to 34 years compared to rates of 9% and 2% in persons aged 45 to 64 and ≥ 65 years, respectively. The uninsured rate among children and adolescents was 5% but rose sharply in late adolescence to nearly 10% by age 18.
Having either public or no insurance was determined to associate with a greater risk of death in each of 12 most common cancer types affecting AYAs, since those with public or no insurance tend to present at diagnosis with later stage disease. Lack of insurance has been identified as an independent risk factor for mortality even among patients who present at the same disease stage.
This article points out that the age of legal independence is 18 years, but physiologic development of the brain continues until age 30 and psychological development of coping skills continues throughout life. AYA patients reported decreased ability to hold a job, complete education, and maintain mature relationships both during and after cancer diagnosis, indicating that psychological development may slow, stop, or even regress due to diagnosis and treatment. Having unmet psychosocial needs has been associated with worse health-related quality of life, fatigue, and poor work/school functioning.
Patients with cancer in the AYA age groups require support that is different between each group and from older and younger patients. All patients must emotionally deal with a cancer diagnosis and the effects of treatment, but young AYAs are impacted by additional age-specific issues, such as interruption of education and possible delays in living independently. Patients in the older AYA groups deal with interruptions in career development, which also may affect financial independence, as well as the inability to obtain adequate health insurance. These factors are heightened in the older age category of AYAs and are joined by concerns about sexual and relationship issues, including fertility preservation. Improved mental health and support group services are needed to improve depressive symptoms that have been identified in almost one-third of AYA patients with cancer.
The authors concluded that disparities between AYAs and patients with cancer in other age groups may be lessened by increasing research and clinical trials enrollment that are directed toward AYA cancers. Societal measures include improved access to care and insurance coverage, as well as providing AYA-specific psychosocial support. They noted that several organisations have been initiated with these goals, including the Research Efforts Directed Toward AYA Cancers, The Global AYA Cancer Congress, Teen Cancer America in the US, Teenage Cancer Trust in the United Kingdom, and CanTeen Australia.
Although it was not equal across all groups, the authors found that clinical trials enrollment of AYAs increased from 14.8% in 2006 to 17.9% in 2012 and 2013. The Southwest Oncology Group and the Children’s Oncology Group (COG), among other organisations, have attempted to bridge disparities between age groups in research protocols; COG leukaemia and sarcoma research protocols extended the age of eligibility to ≥ 30 years and the Sarcoma Alliance for Research through Collaboration has lowered the minimum ages on clinical trial protocols to 12 years. Another example is the large cohort study, BRIGHTLIGHT that incorporated into the protocol specific committees dedicated to the AYA population.
The authors suggest that individuals advocate for AYA patients by seeking opportunities for trials enrollment, building collaborations with psychology colleagues, and ensuring that all patients are made aware of all financial resources available to them.
Close AG, Dreyzin A, Miller KD, et al. Adolescent and young adult oncology—past, present, and future. CA: A Cancer Journal for Clinicians 2019; 69(6):485-496. doi: 10.3322/caac.21585.