Special Section: Cancer in Adolescents andYoung Adults

Overview

In 2020, there will be approximately 89,500 new cancer cases and 9,270 cancer deaths in adolescents and young adults (AYAs) ages 15 to 39 years in the United States (Table S1). These patients are often grouped with younger or older patient populations, which masks important differences in cancer distribution, tumor biology, and survivorship. For example, an increasing body ofevidence indicates that several typesof cancer in AYAs are molecularly distinct from those that occur in other age groups, suggesting possible differences in how cancersin this age group develop and are most effectively treated.1, 2 In addition, for some cancertypes, AYAs are more likely to be diagnosed at a late stage because of both delays in diagnosis due to the rarity of cancer in this age groupand higher uninsured rates and higher prevalence of aggressive disease.3, 4 AYA patients also have a high risk of long-term and late effects, including infertility, sexual dysfunction, heart problems, andfuture cancers.5-8

Despite the number of obstacles facing AYA cancer patients, this group was understudied in the US until the mid-2000s, when the National CancerInstitute (NCI), in collaboration with the LIVESTRONG Foundation, convened a group of experts to report on priority areas forAYAs across the cancer continuum.9 Although this landmark report provided the impetus for rapid progress over the past decade, several challenges remain, including research gaps in basic biology, treatment, and survivorship, as well as persistent disparities in healthcare access and survival for some commoncancers.10

In this special section, we provide an overview of trends in cancer incidence, mortality, and survival and discuss some of the unique challenges among AYAs. In order to fully describe the heterogeneity in the diseaseburden within AYAs, cancer occurrence is also described separately by age group.

Leading cancersin AYAs

The most commoncancers among AYAs varysubstantially by age and are shown in Figure S1. Adolescents (15- to 19-year-olds) have a unique cancerprofile that includes childhood cancers (e.g., acute lymphocytic leukemia),adult cancers (e.g., thyroid and melanoma of the skin), and a disproportionately high burden of lymphoma. For example, Hodgkin lymphoma accounts for 13% of cancer cases in adolescentscompared to 9% in ages 20-29 years and 3% in ages 30-39 years.11 Conversely, adults 20-39 years have a higher proportionof solid tumors. In 2020, the most commonly diagnosed cancers willbe thyroid, testicular germ cell tumors (GCTs), and melanoma of the skinin ages 20-29 years and femalebreast, thyroid, and melanoma in ages30-39 years (Figure S2).

Common cancer risk factors in AYAs

Little is known about the causes of many pediatric cancers that occur in AYAs, andestablished risk factors for adult cancers are based on studies conducted amongolder populations. Althoughthe majority of cases in AYAsoccur in the absence of a known hereditary predisposition,12-14 certain genetic syndromes are strongly linked to early-onset cancers,such as:

• Lynch syndrome and colorectal, ovarian, and endometrial cancers15

• Familial adenomatous polyposis and colorectal cancer16

• Li-Fraumeni syndrome and several cancer types, including breast, sarcoma,brain, and leukemia17

• MEN2 familial syndrome and medullarythyroid cancer18

In addition, a history of cancer in a parent or sibling increases the risk of beingdiagnosed with cancer at a younger age, especially if the relativewas diagnosed at a young age.13, 19, 20 For example, men witha first-degree relative with a history of a testicular GCT are four times morelikely to develop the disease compared to those without this medical history.12, 21

Research is still ongoing to describe the complexinteractions between environmental exposures, health behaviors, and/or geneticsusceptibility that likely precipitate the development of cancer in AYAs. For example,melanoma of the skin in AYAs appearsto occur among susceptible individuals through genetic interactions with early-life UVexposure, whereas melanoma in older adults likelyreflects cumulative lifetime UV exposure among those with lesssusceptibility.22 However, someexposures may be linked toearly-onset disease regardless of heredity. In one study, excess body weight was associated with an increased riskof early-onset colorectal cancer among womenregardless of family history of the disease.23

Exposure to infectious agents is another importantrisk factor among AYAs. Infections associated with cancers in AYAs include human papillomavirus,Epstein-Barr virus, human immunodeficiency virus (HIV), and human herpesvirus8. Importantly, although smoking-related cancers other than cervical aregenerally uncommon in AYAs, cigarette smoking increases susceptibility to thesecancer-related infections.24

Cancer in AYAs by sex andrace/ethnicity

Sex

During 2012-2016, cancer incidence rates for allsites combined were similar in females and males ages 15-19 years (23 versus 24cases per 100,000, respectively) but 30% higher in females compared to malesages 20-29 years (55 versus 42 per 100,000) and nearly double in females ages30-39 years (161 versus 84 per 100,000).11 Higher incidence rates in women ages 20-39 years are primarily driven bybreast cancer, as well as higher rates of thyroidcancer and melanomaof the skin. For example, thyroid cancer incidence ratesamong women in their 20s are more than fivefold those among men (15 versus 3per 100,000 during 2012-2016, respectively).11 Notably, although lung cancer is rare in AYAs, incidence rates in womenin their 30s are higher than those in men, in contrast to higher rates amongmen compared to women 50 years of age and older.25 Higher lung cancer rates in young women are not fully explained bysmoking prevalence.

Despite lower overallrates, incidence is higher in malesthan females for a numberof cancers in AYAs. In particular, gonadalGCTs are substantially more common in males than females acrossall age groups,for reasons that are largelyunknown but may reflect sex-specific interactions between genetic factors andmaternal hormones prior to birth.26 Testicular GCTs are the most commonly diagnosed cancer amongyoung adult men, with ratespeaking in the 30-39 age group (13 per 100,000during 2012-2016).11 Conversely, ovarian GCTs are rareand rates peak during adolescence (0.8 per 100,000).

In contrast to incidence, cancer mortality in malesis slightly higher than in females among adolescents and young adultsin their 20s (Figure S3), primarily reflecting higher incidence rates among males forcancers with lower survival (e.g., brain tumors and soft tissue and bonesarcomas).27 Notably, melanoma and thyroid cancer death rates in females are similar to or lower than those in males despite higher incidence rates because much of the overall case burden is due to overdiagnosis (i.e.,the detectionof cancers that would neverhave progressed or caused harm), and males are slightly more likely tobe diagnosed with distant-stage disease. Leukemia is the leading cause ofcancer death in both males and females ages15-29 years, whereasbrain and breastcancers are the leadingcauses of death in males and females, respectively, ages 30-39 years. Althoughcervical cancer is highly preventable, it is the second-leading cause of cancer death among women ages 20-39 years.

Race/Ethnicity

While AYAs account for 5% of cancer cases in the USoverall, they represent about 1 in 10 cases among Hispanics and Asians/PacificIslanders,11 reflecting the young age structure ofthese populations. AYA cancer incidence rates are highest in non-Hispanicwhites (83 per 100,000), followed by non-Hispanic blacks (63 per 100,000), andare lowest in Asians/Pacific Islanders (54 per100,000) (Figure S4). However,non-Hispanic blacks have thehighest cancer mortality rates (11 per 100,000) despite 25% lower incidencerates than those in non-

Hispanic whites. In women, this largely reflectssubstantial disparities in breast cancer; breast cancer mortality rates in non-Hispanic black women in their 30sare nearly double those in non-Hispanic whites (8.5 versus 4.5 deaths per 100,000, respectively).28

Trends in AYA canceroccurrence

Trends in incidence rates

In contrast to steadier trends among adolescentsand young adult women, cancer incidence among young adult men increasedrapidly in the late 1980s and declinedin the early 1990s in parallelwith the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS)epidemic (Figure S3). This pattern primarily reflects a peak in the occurrence of Kaposisarcoma (Figure S5). The HIV/ AIDS epidemic did not contribute substantially to trends in female AYAsor male adolescents.

During the past decade of available data (2007-2016),rates in men ages 20-39 years were largely stable,whereas incidence rates increased byabout 1% annually in adolescents and 0.4% to 1.1% annually in women ages20-39 years. Contemporary trends, especially among women, are driven by rapidincreases in thyroid cancer incidence rates as a result of rising detection of papillary thyroidtumors (Figure S6).29 During 2007-2016, the steepest increases in thyroid cancer incidence rates occurredamong adolescents, 4.9% per year among males and 4.1% per year among females.In adults ages 20-39 years, rates increased for cancers of thecolorectum (3%-6% per year), uterine corpus (3%), kidney (3%), and femalebreast (0.2%-2%), with more rapid increases occurring among those in their 20s. While rates are alsoincreasing in older adults for kidney and uterine corpus cancers, increasesin AYAs are steeper.30 Increasing attentionhas been given to the possible contribution of the obesity epidemicand related factors(e.g., poor diet) to rising incidencerates of many cancers in young adults, suchas colorectal and uterine corpus.23, 30 Increasing kidney cancerrates may partly reflect increased detection via advances in imaging. Ratesalso increased in all AYA age groupsfor leukemia in both sexesand testicular GCTs in men. Increases in leukemia may belinked to increased exposure to radiation and chemotherapy for the treatment of previous cancers,as well as obesity, although it is unclear to what extent each of these factorscontributes.30-32 Little is known about the causes ofrising incidence rates of testicular GCTs, but trends may reflect changes inprenatal hormonal exposures, as well as other environmental exposures.33, 34

In contrast, melanoma incidence rates have rapidlydeclined in adolescents (6% annuallyduring 2007-2016) and adultsin their 20s (3% annually) after peaking in theearly- to mid-2000s. Among adultsin their 30s, melanoma rates remained stable infemales and slightly declined among males. Recentdeclines in younger AYAsmay reflect successful interventionsto increase sun- protective behaviors and reduce indoor tanning.35 Similarly, cervical cancer incidence rates decreased by 2% annually during 2007-2016 among womenin their 20s but appear to have stabilized among women in their 30s. The stable trend in women ages30-39 years largely reflects attenuatingdeclines in squamous cell cervical cancer rates due to recent slight declinesin cervical cancer screening with the Pap test.36, 37 Incidence rates have largely declinedor remained stable for other commonAYA cancers, includingHodgkin lymphoma, non- Hodgkin lymphoma, soft tissuesarcomas, bone and jointtumors, and brain cancer.

Trends in mortality rates

Cancermortality rates in AYAs have been declining in all age/sex groups since at least 1975 (Figure S3).However, these trends do not reflect the impact of the HIV/AIDS- related cancers becausethese deaths are often attributed to the underlying viral infection. In addition, Kaposi sarcoma was not a separatereportable cause of death until 1999. During the most recent 10 years of availabledata (2008-2017), mortality rates for all cancers combined declined on averageby about 1% per year in men butappear to have stabilized in recent yearsamong women. In contrastto declines for many common cancers, death rates in AYAs during2008-2017 increased for colorectaland uterine corpus cancer and were stable for cervical, thyroid, and testicular cancer(Figure S7).27 Female breast cancer deathrates have also stabilized in recent years after more than two decades ofdeclines.

Cancer survival in AYAs

Overall 5-year survival has increased since themid-1970s among AYAs with the exception of a decline during the HIV/AIDSepidemic among young adult men. Five-year relative survival rates for AYApatients diagnosed during 2009-2015 were generally similar across age groups

(83%-86%) and comparable to that in children (84%), butsubstantially higher than that in adults 40 years of age and older (66%).38 High overall survival in AYAs reflects

5-year relative survival rates of 94% or greaterfor many of the most common cancers,such as thyroid and testicular cancer, melanoma, and Hodgkin lymphoma, but masks lower rates for leukemias, braintumors, and bone and soft tissue sarcomas (Table S2).Importantly, overall AYA cancer survival may be artificially inflated as a result of overdetection of thyroidcancer, which has

>99% 5-year survival.39

Notably, there are some cancer types for which survivalprogress in AYAs has lagged behind that in children.39 For example, AYAs have substantially worse 5-year relative survival than children for acute lymphocyticleukemia overall (60% versus 91%, respectively) and inevery AYA age group (Table S2),38which may reflect differences in biology and/or clinical trial participation.40 Similarly, the 5-year survival ratein AYAs for non-Kaposi soft tissue sarcomawas lower than that in children for patients diagnosed during 2009-2015(73% versus 81%) despite a higherrate during 1975-77 (70% versus 58%).41 This is partly due to the higheroccurrence of aggressive clinical characteristics amongnon-Kaposi sarcomas in AYAscompared to those in children, but also reflectslower clinical trial participation among AYAs.42

AYAs have better 5-year relativesurvival for most cancerscompared to older adults, with the exception of female breast (86% in AYAs versus 91% in ages 45-64 years).38 AYA female breast cancer patients are less likely than older adults to be diagnosed with early-stage disease (47% versus 60% in ages 45-54years, 65% in ages 55-64 years, and 68% in ages 65+ respectively),11 which likely reflects diagnostic delays, aswell as a higher prevalence of aggressive molecular subtypes.43,44 (See Breast Cancer Facts & Figures 2019-2020, available on cancer.org, for more information.) In contrast, 5-yearrelative colorectal cancer survivalin AYAs is higher than that in screening-age adults ages 50+ (68% versus 64%, respectively) despite a greater likelihood of beingdiagnosed with distant-stage disease(24% versus 20% during 2012-2016, respectively).38

Compared to non-Hispanic whites, 5-year cause-specific survival in AYAs forall cancer types combined is lower in racial/ethnicminorities, especially non-Hispanic blacks (75% versus 88%,respectively) (Figure S8).38By cancer type, some of the largest black-white racial disparities occur for acute lymphocyticleukemia (57% versus 71%, respectively), melanoma (90% versus 95%), and femalebreast cancer (78% versus 88%). These disparities are largely driven

by delays in diagnosis and treatment as a result ofdifferences in insurance status and accessto care, but also by differences in tumorcharacteristics, such as estrogen-receptor status for female breastcancer.3, 45

Prevention and early detection of cancer in AYAs

Stage distribution for selected commoncancers in AYAs isshown in Figure S9. Compared to screening-age adults, AYAs are more likely to bediagnosed at a distant stage for female breast and colorectal cancers.3, 4 Although routine cancer screening in individuals younger than 40 years ofage is only recommended for cervical cancer (beginning at age 21; see page 70),increased awareness through self-examination could alert AYAs to changes in the skin, breasts, and testicles. In2018, 74% of adults ages 21-29 years and 90% of those ages 30-39 years were up-to-date with cervical cancerscreening, compared to 86% of adults ages 40-65 years.46

Several cancers in AYAs couldpotentially be prevented. For example, almostall cervical cancerscan be prevented through screening, which allows for the removal of precancerous lesions, as well as humanpapillomavirus (HPV) vaccination, whichis recommended for females up to age 26 and, depending on risk,males up to age 21.47 Although studies havebeen primarily limited to the effectiveness of the HPV vaccine in preventingcervical cancer, the vaccine will likely prevent most other HPV- related cancers.From 2011-2012 to 2015-2016, HPV vaccination prevalence (receipt of ≥2doses) increased among AYAs ages 18-26 years but remained low overall,especially in males (32% in ages 18-21 years and 17% in ages 22-26 years,compared to 54% in females).48 This, combined withthe comparatively low use of screening in women ages 20-29 years, highlightsimportant targets for decreasing the burden of cervical and other HPV-associated cancers in AYAs. Finally, cervical and other tobacco-related cancerscould be prevented through reducing cigarette smoking prevalence in AYAs. In2018, cigarette smoking prevalence was similar between AYAs and older adults(15% and 16%, respectively).46

Reducing exposure to excess UV radiation throughsun protective behaviors and not sunbathing orusing indoor tanning are important for preventing melanoma andother skin cancers. The risk of melanomais about 60% higher for people who beginusing indoor tanning before the age of 35, and riskincreases with duration and intensity of use.49, 50 Although indoor tanning has decreased inthe US,35 in 2015, indoortanning prevalence in women was 10% in ages 18-29 years and 7% in ages 30-39 years, comparedto 4% in ages 40+; indoor tanning use among men was low (1-2%).46

Many additional cancerscould be prevented in AYAs by reducing obesity prevalence.Increasing incidence rates for many solid tumors have been linked to risingexcess bodyweight. Although trends may have leveled off in children and youngadults in the past decade,51in 2015- 2016, theprevalence of excess body weight (body mass index [BMI] ≥25 kg/m2) among young adults ages 20-39years was 65% (68% in men; 62% in women).52

Treatment considerations for AYAs with cancer

AYA patientscan be treated at pediatricor adult cancer centers depending on cancer type.53 It is important that the treatment team has experience in AYA oncology,as there are several special considerations for this age group. For example, it may be possible to adjust the treatment regimen to help limit the risk of late effects, such as sexual dysfunction and organ damage,given the long life expectancy of AYA patients. The typeof treatment received should consider the patient’shealth and functional status; cognitive and physical development; and preferences and needs.54 The possibility of adverseside effects, coupled with the financial and psychosocialchallenges of undergoing treatment during several important early-life transitions, may contribute todelays in treatment and gaps inadherence.55 The National Comprehensive CancerNetwork (NCCN) guidelines for AYA oncology recommend that AYA patients be encouragedto enroll in clinical trials as appropriate because of the substantialknowledge gaps in AYA cancer treatment.54

Fertility preservation and sexual function Fertility counseling and preservationare crucial componentsin the management of AYA cancer because

many cancer treatments directly or indirectly affect

fertility.56,57 The American Societyfor Clinical Oncology (ACSO) clinical practice guidelines recommend thatfertility preservation be discussed with all new patients at the time of diagnosis becauseefforts such as spermbanking and embryo/oocyte cryopreservation (the freezing of fertilized or unfertilized eggs) should be started in advance of treatment.58 In one study of AYA cancer survivors, 18% of males and 38% of femaleshad not made such fertilitypreservation arrangements because they were not aware of these options.59 Other reasons for not making arrangements included cost; concerns regarding the impact of fertility preservation on outcomes (e.g., delaying cancer treatment, effectson offspring); and physician recommendation against delaying treatment,especially among females.59

Semen cryopreservation (sperm banking) is theestablished method for fertility preservation in men, includingthose with low sperm counts, and may also bepossible in younger adolescents.60-62 Research is ongoing with regard to cryopreservation (freezing) of stem cells from the testis, which may bean option in the future for prepubescent males.62

The established strategy for female fertilitypreservation in AYA women is egg (oocyte)cryopreservation.63 Embryo cryopreservation is also anoption, but requires that patients either have a partner or donor sperm forfertilization. Oocyte cryopreservation can take 2-3 weeks; the patient’sovaries are first stimulated with injectable hormones to produce mature eggs(oocytes), which are then retrieved in a procedure under anesthesia andcryopreserved in the lab the same day. When the patient desires to use the eggsin the future, they are thawed and fertilized with sperm to create embryos (via invitro fertilization), and are then transferred into the woman’s uterus.When cancer treatment cannot be delayed and/or the patient hasnot reached puberty, ovarian tissue cryopreservation may be an option for fertilitypreservation at some institutions.58, 64, 65

When female patients are planning to receiveradiation therapy to the pelvic or groin area,ovarian transposition (a surgical repositioning of the ovaries) is an option. The procedure helps topreserve ovarian function by surgically positioning the ovaries away from the site of radiation. Typically, one or both ovariesare separated from theuterus and attached to the abdominal wall. Patients who undergo ovarian transposition may wantto consider combining it with other fertility preservation options because the ovaries may not be completely protected from radiation exposure. In addition, the ovaries often cannot be reconnected in adultsafter they have been separated from the uterus, so these patients require referral to a reproductive endocrinologist when they wish to conceive.

Many cancer treatments can also interfere withsexual functioning both during and after treatment; in one study, nearly50% of pelvic and breastcancer survivors experiencedsevere, long-term sexual dysfunction.66However, cancer patients often receive insufficient counseling and treatment for these concerns.67 The American Society for Clinical Oncologyrecommends that problems with sexual health and dysfunctionresulting from cancer or its treatment be discussed with all patients.68 Patients may experience problems such as negative body image, low libido, and/orpain during intercourse,which can be addressed through a combinationof psychosocial and/or psychosexualcounseling, over-the-counter treatments (e.g., vaginal lubricants), or other medications (e.g., low-dose vaginal estrogen in women or phosphodiesterase type 5inhibitors in men).

Cancer treatment during pregnancy

Althoughcancer during pregnancy is extremely rare (1 per 1,000 live births),69 all women of childbearing potential should receive a pregnancy testbefore beginning treatment.54 Cancerduring pregnancy poses significant treatment challenges and should be managed by amultidisciplinary team that includes obstetricians, gynecologic oncologists, and perinatologists in addition to medical, surgical, and radiation oncologists,70 ideally with expertise in cancer during pregnancy.

While surgery for cancer is usually safe during pregnancy, some treatment options,such as radiotherapy, should generally be avoided,and chemotherapy shouldbe avoided during the first trimester.71 Limited research suggests chemotherapy during the second and thirdtrimester may be associated with low birth weight and preterm labor,72 but a multicenter prospective study found no significant adversecognitive or cardiaceffects among children.73 The safety of hormonal therapiesand targeted treatments duringpregnancy has not been fully evaluated in humans.54

Survivorship concerns in AYA cancer

As of January1, 2019, there were 678,420adolescents and young adults(47,760 adolescents ages 15-19 years and 630,660 young adults ages 20-39 years)living in the United States with a history of a cancer diagnosis, some of whomwere diagnosed as children.74AYA cancer survivorsmust cope with psychosocial, physical, and financial effects of cancer and itstreatment, which range from mild to severe. A high proportion of AYA survivors report a variety of unmet needswithin a year after diagnosis, such as access to a mental health professional(56%), cancer rehabilitation (58%), or pain management services (63%).75

Unfortunately, little is known about the long-termsurvivorship experience among AYAs compared to those who were diagnosed aschildren, and much continues to be extrapolated from childhood cancer cohorts.54 Prospective studies of AYA cancer survivors in the US arestill relatively nascent in comparison to decades-long cohort studies inchildren and older adults. The first national prospective cohort study of AYAcancer survivors in the US, the AYA Health Outcomes and Patient Experience (AYA HOPE) study,was conducted among thosediagnosed during 2007-2008.76

Long-term and late effects

AYA cancer survivors are at risk of a number of late and long-termeffects that can influence cognitive and physical functioning.77,78 In particular, they report worseoverall psychosocial functioning than other cancersurvivors as well as their cancer-free peers, which may reflect difficultly in coping with treatment and recovery duringearly-life transitions.79-81 Problems with fertility, sexual dysfunction, and body image,particularly among women, are also common among AYA cancer survivors.8, 82 Cancer and its treatment can causesubstantial disruptions in school and work, as well as changes in functioning and appearance,leading to feelings of shameand isolation that can create further challenges in resumingdaily life activities.83Cancerrehabilitation or other types of physical therapy may be helpful in someinstances.

Certaintypes of chemotherapy used for common AYA cancers,such as anthracyclines for lymphomas, sarcomas, and brain tumors,have been associated with a long-term increasedrisk of heart problems in AYAcancer survivors.84, 85 Testicularcancer survivors who were treated with cisplatin-based chemotherapy are at increased riskof heart and neurologic complications, such as numbness and hearing impairment.86

Risk of subsequent cancers

The risk of subsequent cancers among AYA survivors can be approximated by comparing the number of newcancers in this population to the number expected in thegeneral population, which is referredto as the observed-to-expected (O/E) ratio. Risk varies by originalcancer type and sex and is highest for soft tissuesarcoma (males); Hodgkin lymphoma; and female breastcancer and lowest for thyroid and cervical cancer (Figure S10).

The risk of subsequent cancers is related to manyfactors, including underlying genetic predisposition, adverse health behaviors, and type of initialtreatment received. For example, a recent study showed that AYAs had a higherrisk of subsequent tobacco-related cancers compared to the general population,likely reflecting their higher historical smokingprevalence compared to the general AYA population.87 Depending on the type of treatment received and underlying familial risk,some AYA cancer survivors are recommended to initiatescreening for colorectal and female breast cancersat a younger age than those ataverage risk.54

Financial concerns

Young adults continue to be the least likely to have health insurance comparedto other age groups. In 2017,uninsured rates in 20 to 25 year olds and 26 to 39 year olds were 15%, compared to 10% among 40 to 64 year olds.88 Lack of health insurance is associated with diagnosis delays, leading tomore extensive treatment and poorer outcomes.89 Not surprisingly, AYA cancer survivors have more financial hardship and out-of-pocket medicalcosts than the general population.90 As a result, youngadult survivors have higher rates of bankruptcy and more frequently forgoneeded medical care due to cost compared to older survivors.91 Financial distress among AYA survivors is oftencompounded by nonmedical costs, such as student loans and raising children.