Caught in the In-Between: Challenges in Treating Adolescents and Young Adults With Cancer

Adolescents and young adults (AYAs) comprise a unique cohort of patients of age 15-39 years; cancer diagnoses in this population account for roughly 5% of all cancer diagnoses each year.¹ Concerningly, although the 5-year survival rate in the AYA population is around 80% as compared with approximately 67% among all individuals with cancer overall, the 5-year survival rate for AYAs lags behind that of the pediatric (0-19 years of age) population, whose 5-year survival rate is approximately 85%.^2,3 Moreover, AYAs have not benefitted from improvements in survival seen by both the pediatric and older adult populations.² Along with navigating the challenges inherent to the diagnosis and treatment of cancer at any age, AYAs with cancer face issues related to their developmental stage, their presentation and access to care, and their unique cancer biology. An awareness and understanding of the factors uniquely facing AYAs with cancer is paramount to optimizing the oncologic care and health outcomes of this at-risk patient population—the in-between population.

Developmentally, adolescence and young adulthood is a period of significant physical and psychosocial change; this is especially challenging for AYAs who are undergoing cancer treatment. Psychosocially, the achievement of key developmental milestones that typify the AYA developmental stage, such as attending college, gaining financial independence, or the pursuit of romantic relationships is impeded by adjusting to a cancer diagnosis and the associated physical and psychosocial tolls of treatment.¹ The autonomy for which AYAs strive is threatened by a cancer diagnosis, which can impose significant financial burdens on individuals who are often newly financially independent. In addition, the prospect of aging out of their parents' health insurance and significant out-of-pocket costs for fertility preservation also contribute to financial burdens facing AYAs with cancer.¹ Although the emerging autonomy characteristic of the AYA stage can often be compromised in AYAs diagnosed with cancer, this same autonomy can also pose challenges in this patient group, specifically with regard to treatment adherence. Some AYAs may be purposefully nonadherent to therapeutic recommendations as a demonstration of asserting their independence, whereas other AYAs may be overwhelmed in attempting to manage the logistics of their own appointment schedules and treatment regimens.⁴ This can lead to poor follow-up or missed medications and treatments, which can negatively affect outcomes.

Adolescence is also a time of significant physical growth, with physiologic changes in body composition, protein binding, and organ function, all of which can lead to perturbations in drug metabolism.⁵ These alterations in drug metabolism can cause drug toxicity and can, in some cases, result in dose reductions of key drugs in treatment regimens. For example, AYAs undergoing acute lymphoblastic leukemia (ALL) treatment experience increased rates of avascular necrosis as compared with their pediatric counterparts, which can require dose reduction of the steroids that are a critical component of ALL therapy.⁵ Although making these dose reductions in the setting of increased toxicity in AYAs is important to reduce the burden of therapy-related late effects in this population, such adjustments also have the potential to result in suboptimal treatment of the cancer itself. Importantly, although AYAs treated on pediatric protocols may incur more toxicity as the protocols are designed for pediatric drug metabolism, AYAs face a different but related issue when being treated on protocols designed for older adults. AYAs often have overall better organ function than that of older adults and have generally not acquired the comorbidities that exist in older adults; accordingly, they do not require the dose modifications that are built into the protocols for older adults as a result of anticipated underlying organ dysfunction and comorbidities.^5,6 This can subsequently lead to undertreatment of AYAs treated on protocols designed for older adults.

Delays to presentation and diagnosis and, in some cases, suboptimal access to care can also negatively affect outcomes in the AYA population. Emerging autonomy in this population comes with increased demands on time and AYAs may not participate routinely in health maintenance examinations, resulting in missed opportunities to detect cancers at earlier stages. Moreover, both AYAs and physicians may attribute vague constellations of symptoms such as fatigue and weight changes to overexertion and poor dietary habits rather than to an underlying cancer. AYAs face specific challenges not only during the diagnosis of their cancers but also during the decision making surrounding their treatment. One of the first treatment decisions that must be made is location of treatment, specifically with regard to whether treatment occurs at a pediatric or adult institution. This is especially important in leukemia diagnoses as pediatric regimens are overall more frequently used in the treatment of AYAs with leukemia. A recent review identified 23 of 25 publications that compared ALL and lymphoblastic lymphoma outcomes in AYAs and found more favorable outcomes when AYAs were treated on pediatric protocols. The authors recommended that AYAs with newly diagnosed ALL be treated according to pediatric-inspired protocols or on an age-appropriate AYA clinical trial.⁷

Trial enrollment itself is another challenge facing AYAs; it is well-established that this population has lower clinical trial enrollment than pediatric patients.^2,6 In a retrospective cohort study at a tertiary children's hospital, clinical trial enrollment for 865 patients was analyzed and a significant difference was seen between the number of younger (< 15 years) and older (15-22 years) patients on clinical trials, with 34% of younger children treated on a trial as compared with 24% of older individuals.⁸ Lack of an open trial was cited as the most common reason for this discrepancy in enrollment.⁸ Arbitrary age cutoffs for trial eligibility often mean AYAs are excluded both from pediatric trials and from trials designed for older adults.

Treatment center type also contributes to differential clinical trial enrollment rates; Close et al² note that 20%-38% of children were enrolled on a clinical trial at pediatric institutions—significantly higher than the 5% of adults enrolled on a clinical trial in adult institutions—and that AYAs treated at pediatric institutions still had enrollment rates up to 20% lower than children. Reduced enrollment not only means fewer AYAs have access to cutting-edge treatment options but also prevents the development of AYA-specific biorepositories or the creation of treatment protocols designed specifically to fit the unique biology of AYA cancers, as discussed below. Information delivery may also be a barrier to AYA enrollment in clinical trials; strategies such as using social media for recruitment of AYAs and inclusion of AYAs in trial design have been proposed as possible solutions.^6,7

In addition to challenges related to their developmental stage and treatment decisions, AYAs with cancer must also navigate the ramifications of their unique cancer biology. It has been posited that AYA cancers have unique biology, as evidenced by multiple factors including the specific common types of cancers seen in this cohort and types of genetic changes seen in tumors in the AYA population.⁵ The range of cancers seen in the AYA population is specific to this cohort and includes leukemias and lymphomas, carcinomas (breast, genitourinary, colon, and thyroid), sarcomas, and brain tumors.^5,6 It is also notable that these cancers, when presenting in AYAs, often harbor unfavorable genetic changes that portend a worse prognosis. For example, Rytting et al⁹ report that 60% of children younger than 10 years diagnosed with ALL have favorable cytogenetics, including hyperdiploidy or the TEL-AML translocation. AYA leukemias have a significantly lower likelihood of harboring these favorable cytogenetic changes and, unfortunately, a higher rate of unfavorable features, including BCR-ABL-like features or the presence of an MLL/KMT2A translocation.⁹ Breast cancers in the AYA age group are often triple-negative, meaning they lack hormone receptors and as such targeted therapies cannot be used.¹⁰ These patients face high relapse rates.¹⁰ Additionally, breast cancers arising in young women in the AYA population may result from mutations that are associated with the development of breast cancer at a young age, such as BRCA1, which are inherently more aggressive.

AYAs with cancer face unique challenges during their cancer diagnoses and treatment because of their developmental stage, their presentation and access to care, and their specific cancer biology. Accordingly, the improvements that have been seen in pediatric and older adult cancers have not been observed in this population.² Improving oncologic care in the AYA population requires a multipronged approach that accounts for AYAs' emerging independence and physiologic changes, addresses the inequities in clinical trial enrollment opportunities and the need for age-appropriate information delivery, and investigates the unique biology that is thought to underlie cancers in this population. Through a thoughtful, tailored, and comprehensive approach to diagnosing and treating patients with AYA oncology, the health outcomes of this in-between population can be optimized.

AUTHOR CONTRIBUTIONS

Conception and design: All authors

Data analysis and interpretation: All authors

Collection and assembly of data: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Caught in the In-Between: Challenges in Treating Adolescents and Young Adults With Cancer

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