Adolescents and young adults with cancer

The scope of the problem and criticality of clinical trials

Authors

  • Archie Bleyer MD,

    Corresponding author
    1. Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
    2. Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas
    3. Children's Oncology Group, Arcadia, California
    • Cancer Treatment Center, St. Charles Medical Center, 2500 NE Neff Road, Bend, Oregon 97701, USA
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    • Fax: (541) 385-6341.

  • Troy Budd,

    1. Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland
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  • Michael Montello PharmD

    1. Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland
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  • Presented at the Pediatric Oncology Group of Ontario Symposium “Walking Two Worlds—Adolescent and Young Adult Oncology,” Toronto, Ontario, Canada, November 2003.

Abstract

In the U.S., older adolescents and young adults with cancer have benefited less from therapeutic advances than did either younger or older patients. One factor that may explain this deficit is the relative lack of participation of patients in this age group on clinical trials of therapies that could improve their outcome. Comparisons were made of the participation of cancer patients on clinical trials in the U.S., as a function of patient age, with the change in national cancer mortality rate; and Surveillance, Epidemiology, End Results (SEER) cancer survival rate as a function of age. The participation rate in cancer treatment trials has been strikingly lower in 15–34-year-olds than in younger or older patients. The nadir has been apparent for both males and females in all of the major ethnic and racial groups. The national cancer mortality reduction and SEER survival improvement shows a similar age dependence. In the U.S., the age-dependence of cancer treatment trial participation, and of improvement in survival prolongation and cancer death rates, are correlated. Regardless of whether there is a causal relationship, the impact on the older adolescent and young adult U.S. population is substantial, adversely affecting the national cost of healthcare, the person-years of life lost, the loss of young people entering the job market, and the scientific knowledge and social implications of cancer during adolescence and early adulthood. National initiatives are underway to address these issues, with special emphasis on increasing the availability and access to clinical trials designed for older adolescents and young adults. Cancer 2006. © 2006 American Cancer Society.

On the occasion of its 20th anniversary, the Pediatric Oncology Group of Ontario (POGO) left behind its teenage years and entered its third decade of existence. It was therefore more than symbolic that the organizers selected the older teenagers and young adults with cancer as a focus of review and deliberation at the anniversary symposium. The conference summarized POGO's progress and identified the challenges that remain, and have been newly created by its successes, many of which are summarized in this supplement to Cancer.

The theme of the meeting, walking two worlds, was particularly appropriate, because it describes succinctly the experience of the adolescent cancer patient. There is the pediatric world this adolescent cancer patient is expected and trying to leave behind, and there is the adult world ahead that presents inordinate challenges and stresses. Under the best of circumstances, when all is well, this transition is one of the most difficult, if not the most challenging, in life. Having to cope with cancer during this transition adds an array of complexities and conflicts that create inordinate stresses for the patient, family, friends, and caregivers.

Caught between 2 worlds, patients with cancer in this age group are less likely to access optimal cancer services, medical and psychosocial, than either younger or older patients. They are also less likely to find their way to a comprehensive cancer center, at least in the U.S., and to clinical trials that could improve their chances of a better outcome. Indeed, less than 2% of these patients are entered onto treatment trials in comparison with approximately 60% of patients younger than 15 years of age and 3%–5% of older adults.1–3 This review summarizes the status of the participation of older adolescents and young adults on clinical trials in the U.S., and analyzes how this deficit has affected this age group. The deficit appears to occur also in referral to cancer centers, treatments directed specifically at these patients, and an understanding of the biology of the cancers that afflict this age group. It is likely that the experience in the U.S. is occurring also in other countries, although differences in magnitude may exist as a result of different referral patterns, health insurance systems, and cultural attitudes and practices.

Older adolescence and young adulthood is being recognized increasingly as a distinct age group that, like those of pediatric, adult, and geriatric patients, has unique medical and psychosocial needs. Not only are these individuals at an obviously different place in human development, but the spectrum and biology of their malignancies are also unique. Epidemiologically, the public health impact of the 15–44-year age group is substantially greater than the impact of the younger than 15-year age group, in that there are 14-fold more patients with cancer in the former group than in the latter. In the U.S., the 15–44-year age group accounts for 117,000 patients per year, 10% of all persons with cancer. Thus, it is especially appropriate for POGO to have selected the older adolescents and young adults with cancer as the focus of POGO's “coming of age.”

MATERIALS AND METHODS

We analyzed the U.S. national cancer mortality rate and the U.S. SEER 5-year relative survival rate for each 5-year age group (0–4, 5–9, 10–14, 15–19, etc.). To quantitate the change in mortality rate as a function of calendar year of death, the average annual percent change was derived from linear regressions of each of the reported annual rates, from 1975 to 1998. To quantitate the change in survival rate as a function of calendar year of diagnosis, the average annual change was based on linear regressions of the mean values of the 1975–1980, 1981–1986, 1987–1992, and 1993–1997 intervals. The most recent interval was truncated at 1997 so as to allow a 5-year follow-up for most patients in the most recent cohort and to reduce the uncertainty of life-table estimates used for this interval. Accrual data for National Cooperative-Group treatment trials by 5-year age increments since 1990 were obtained from the U.S. National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP). These trials consisted of all treatment trials conducted by all of the NCI-sponsored cooperative groups and those trials at NCI-designated comprehensive cancer centers that submitted accrual data to CTEP.

In general, the age range for older adolescence refers to 15–19-year-olds and young adults to 20–39-years-olds. Exceptions are noted, particularly to the highest age level, because the upper age limit varies with the parameter being evaluated (e.g., clinical trial participation, mortality reduction, survival prolongation) and the subgroup (male, female, white, Hispanic, other races/ethnicities).

RESULTS

The Cancers of Adolescents and Young Adults

For 15–19-year-olds in the U.S., the most common types of cancer are lymphoma (Hodgkin lymphoma, 15%; non-Hodgkin lymphoma, 7%), sarcomas (soft tissue, 8%; bone, 8%), leukemia (acute lymphoblastic, 7%; acute myeloid, 5%), brain tumors (9%), testis cancer (9%), female genital tumors (7%), thyroid cancer (8%), and malignant melanoma (7%).2 Among 20–29-year-olds, the most frequent malignancies are thyroid cancer (12%), malignant melanoma (12%), testis cancer (12%), lymphoma (Hodgkin lymphoma, 10%; non-Hodgkin lymphoma, 6%), sarcomas (soft-tissue, 9%; bone, 2%), female genital tumors (9%), leukemia (acute myeloid, 3%; acute lymphoblastic, 2%), breast cancer (5%), and brain tumors (5%).4 In 30–39-year-olds, they are breast cancer (20%), malignant melanoma (11%), female genital tumors (11%), sarcomas (soft-tissue, 9%; bone, 1%), lymphoma (non-Hodgkin lymphoma, 6%; Hodgkin lymphoma, 3%), thyroid cancer (8%), brain tumors (3%), and leukemia (acute myeloid, 1%; acute lymphoblastic, 1%).4

Mortality and Survival in Adolescents and Young Adults with Cancer

In the U.S., cancer is the leading cause of nonaccidental death among adolescents and young adults. In 15–19-year-olds, cancer is the fourth leading cause of all deaths, following accidental injuries, suicide, and homicide.3 Among 20–29-year-olds, cancer causes more deaths than either suicide, heart disease, human immunodeficiency virus (HIV) infection, cerebrovascular disease, or cirrhosis.5 In females, deaths due to cancer occur at more than twice the frequency of deaths due to the second leading disease-related cause of death.5

Mortality and survival trends in the U.S. in 15– 39-year-old cancer patients have been disappointing with respect to the gains made in younger and older persons.1–3 The average annual improvement in the 5-year survival rate during the past quarter century exceeded 1.5% per year both in children younger than 15 years of age and in adults >50 years of age (Fig. 1).1 In 15–24-year-olds, however, the improvement averaged less than 0.5%, and in 25–34-year-olds, there was no perceptible improvement at all (Figs. 1 and 2).

Figure 1.

Average annual percent change (AAPC) in the 5-year survival rate of patients with invasive cancer who were in the U.S. Survival, Epidemiology, and End Results (SEER) registry from 1997 to 2001.

Figure 2.

Comparison of average annual percent change from 1975 to 1997 in the 5-year survival rate (U.S. SEER) of patients with invasive cancer (upper graph) and the average annual reduction from 1975 to 1998 in the national cancer mortality rate (lower graph).

The reduction in cancer mortality rate among 15– 39-year-olds has lagged behind the reduction in children and older adults (Fig. 2).1 To compound matters, the affected population increased steadily as the “baby boomers” traversed this age range.

These ominous trends in mortality and survival among 15–39-year-olds are apparent in both males and females, with males showing a greater deficit than females (Fig. 3). These trends are evident in all ethnic groups examined to date, including non-Hispanic whites, Hispanics, African Americans, and Asians. And they show no evidence of being reversed, with 5-year survival rates showing no improvement when evaluated by calendar year for either the 15–29-year age group (Fig. 4) or the 30–39-year group (Fig. 5).

Figure 3.

Comparison in males and females with invasive cancer of the average annual percent change (AAPC) in the 5-year survival rate (U.S. SEER) from 1975 to 1997.

Figure 4.

Annual 5-year survival rates of U.S. patients ages 15–29 years with cancer from 1975 to 1994, by calendar year (U.S. SEER). Ave. indicates average.

Figure 5.

5-year survival rates of patients aged 30–39 years in the U.S. with cancer, from 1975 to 1995, by calendar year (U.S. SEER). A transient decrease in the survival rate in the mid-1980s to late-1980s is attributable to the HIV epidemic.

These trends have held true also for individual types of cancer, including sarcomas,4 lymphomas, brain tumors (astrocytomas, ependymomas, and other gliomas),5 breast cancer, and leukemia.6 Although 15–29-year-olds with leukemia did not have a nadir in outcome improvement, they did have a worse mortality rate than that of any other age group.7

Reasons for Lack of Progress in Older Adolescent and Young Adult Cancer Patients

Why have older adolescents and young adults fared less well than younger or older patients, as measured by survival improvement and mortality rate reduction? A minor factor is the onset of the HIV epidemic during the 1980s and of the HIV-associated malignancies, primarily non-Hodgkin lymphoma and Kaposi sarcoma, that have a poor prognosis and may have increased the overall national cancer mortality rate and reduced the overall cancer survival rate. The impact of the HIV-related malignancies that occurred in these patients is likely to have made a minor contribution to the overall lack of progress in adolescents and young adults for several reasons. The lack of progress began before the increase in cancer incidence associated with the HIV epidemic. Evaluating the 5-year survival rate on an annual basis reveals no improvement since 1980, whereas the increase in HIV-related lymphomas and Kaposi sarcoma was noted in the late 1980s. The HIV effect was limited primarily to males older than 25–30 years of age. A decrease in overall survival of patients with cancer who were 30–39-years of age in the late 1980s is apparent in Figure 5. In this older age group, this effect appears to have dissipated by the mid 1990s when the HIV epidemic subsided, the disease became treatable, and for those who developed cancer, earlier diagnosis and better therapy became available. As noted in Figure 5, the decrease is transient and slight. Among 15–29-year-olds, there was no apparent decrease in survival (Fig. 4) and also no improvement in survival during the 1990s when the HIV epidemic and associated cancer impact declined. The age-related plateau in cancer survival and mortality improvement is observed in females and in males younger than 25–30 years of age, in whom the HIV-related malignancies are rare. The incidence of Kaposi sarcoma, for example, is negligible before 25 years of age and in females of any age. Also re-analysis of the data without the HIV-related malignancies had a negligible effect on the age-dependent pattern of survival improvement or mortality rate reduction.

Melanoma has increased in incidence also during the last quarter century. The overall good prognosis of melanoma did not decline during these years, however, and could not have explained the lack of overall survival or mortality improvement. It is possible that the incidence of other cancers, with a prognosis worse than the average survival of all cancers in the young adult age group, may have increased in the interval. However, there are no known examples of this possibility.

A more likely explanation is the lack of attention given to the younger adult and older adolescent age group by the cancer professionals, healthcare services, and the research organizations. Children and older adults have been the focus of intense research since the 1940s, when the first cancer therapies were discovered in these age groups. The national clinical trial enterprise was developed along these age-lines, with the pediatric cooperative groups and children's hospitals dedicated to children less than 15 years of age, and the adult cooperative groups and cancer centers targeting the common cancers that occur primarily in persons older than 40 years of age. This relative lack of focus on the age group in between is apparent in the national clinical research agenda, with a host of treatment and nontreatment trials for children and older adults with cancer, and few, if any, discrete national clinical trials for older adolescents and young adults with cancer.

Management Sites of Older Adolescent and Young Adult Cancer Patients

In the U.S. and Canada, more than 90% of children with cancer who are younger than 15 years are managed at institutions that are members of the Children's Oncology Group and participate in NCI-sponsored clinical trials conducted by the Group. In a population-based analysis of cooperative group entries from 1992 to 1997, 71% of children younger than 15 years of age were formally registered with the national pediatric cancer cooperative groups that were in existence at the time and subsequently merged to form the Children's Oncology Group.8 At the same time, only 24% of the 15–19-year-olds who were diagnosed to have cancer were registered with the pediatric cooperative groups.9 The proportion of 15–19-year-olds managed at either a member institution of the Children's Oncology Group, at one of the adult cooperative group member or institutions at a NCI-designated cancer center is estimated to be less than 30%.7, 9 In Utah, a state that has only one children's hospital, there was a strikingly low proportion of 15–19-year-olds with cancer who were seen at the pediatric facility.10 The rate is even lower between 20 and 30 years of age, with fewer than 10% managed at institutions that are academic medical centers or members of cooperative groups, either pediatric or adult. Thus, more than 90% of the nation's 20–29-year-olds with cancer are managed by community physicians. Between 30 and 40 years of age, the proportion managed in the community declines to 85%, and between 40 and 80 years, it is approximately 80%. Thus, some of the failure to improve on the results of treatment outcome in young adults with cancer is due to their referral patterns. At no time in life before 70 years of age are fewer patients seen at, or managed by, comprehensive cancer centers or member institutions of the national cooperative groups.

Clinical Trial Participation Rates among Adolescent and Young Adult Cancer Patients

Since at least 1990, when national clinical trial statistics became available, there has been a steep U- or V-shaped correlation of clinical trial accrual rates as a function of age.7 Geographically, this gap has been observed throughout the U.S. and is in striking contrast to the accrual of a majority of patients younger than 15 years of age to clinical trials in virtually all metropolitan and rural areas across the country.7 Since 1997, the accrual data have been captured in CTEP by automated, electronic methods from all sites conducting national clinical trials. From 1997 to 2003, between 10% and 15% of patients with cancer in the U.S., who were 15–19 years of age, are estimated to have participated in national cancer treatment trials sponsored by the NCI (Fig. 6). This is approximately one-fourth of the rate estimated in children younger than 15 years of age. The corresponding rates may be lower in Canada, but it is likely that more than 40% of all Canadian children with cancer are placed on at least one formal treatment trial and that less than 15% of 15–19-year-olds are treated similarly.

Figure 6.

Entries of 51,395 patients age <45 years onto U.S. National Cooperative Group treatment trials sponsored by the Cancer Therapy Evaluation Program of the National Cancer Institute Division of Cancer Treatment and Diagnosis during 1997–2003, inclusive.

In U.S. cancer patients between 20 and 30 years of age, the clinical trial participation rate between 1997 and 2000 is estimated to have been less than 2%, which is less than 5% of the rate in children and less than half of the average rate in adults between 40 and 65 years of age. Again, the absolute rates in Canada may vary, but the general relationship of accrual rates to patient age is probably similar, with a nadir between 15 and 30 years of age.

The ethnicity- and race-specific accrual to U.S. national treatment trials for each 5-year age interval up to 40 years of age is shown in Figure 7. The age-dependent accrual pattern is independent of race and ethnicity, with nadirs occurring between 15 and 30 years of age in all groups and in both males and females. The pattern is similar in non-Hispanic whites, Hispanics, African Americans, Asians, native Indians, Alaskan natives, and Hawaiian and other Pacific Islanders. Also, independent of race and ethnicity is the gender pattern of accrual vs. age, with more boys entered onto trials than girls, and more young adult female patients entered than young adult male patients, and a nadir that is more striking (V-shaped) in females than in males (Fig. 7).

Figure 7.

Accrual of patients less than 40 years of age to cooperative group treatment trials by race/ethnicity as a function of age at entry, during 1997–2001, inclusive.

We have begun investigating the age dependence of clinical trial accruals within specific cancers of older adolescents and young adults. In sarcomas, leukemia, and brain tumors, the accrual pattern was similar to the overall pattern reported here.6, 7 With one exception, the accrual nadir for soft-tissue and bone sarcomas occurred during the same age interval, 25–35-years of age,6 as in the overall cancer experience. Kaposi sarcoma had the inverse trend of treatment trial accrual (a peak of accrual activity in young adults) and national outcome improvement (improved survival among young adults).6 A key observation was that the clinical trial accrual and outcome improvement were again correlated, with the inverse profiles.

Comparison of Knowledge Gained from Treatment Clinical Trials among Older Adult Cancer Patients

Why older Americans have had greater progress in cancer survival prolongation has been presented recently by one of the authors.11 Knowledge gained from treatment clinical trials appears to be less contributary, because screening and early detection are far more available for the cancers of older adults (mammography, prostate-specific antigen blood test, Pap smear, colonoscopy, digital rectal examination, stool occult blood test), and there are more explanations for progress (better health insurance, greater awareness of the cancer problem, medical systems for evaluation and management such as the National Comprehensive Cancer Network guidelines.)

The problem for younger adults (and older adolescents) is different. Nearly all that we have learned in pediatric oncology has been derived from clinical trials and translational research. Screening, prevention, and early detection have contributed much less to the progress in pediatric cancer outcomes than did staging and treatment, including supportive care. Staging and treatment have been learned mainly, if not exclusively, from clinical trials. The current situation in older adolescents and young adults with cancer must be somewhere between the rigorous dependence of improved outcome in pediatric patients on clinical trials and the lower dependence in older adults, as alluded to earlier.

DISCUSSION

Multiple reasons for the gap in the participation of older adolescents and young adults in clinical trials have been proposed (Table 1).12 The responsible factors are undoubtedly multifactorial, with no single explanation accounting for more than a small proportion of the effect. One factor that does not appear to contribute to the deficit is lack of participation by minority adolescent patients in clinical trials. In the U.S., minority children and adolescents with cancer show equal or higher rates of entry onto national clinical trials.11

Table 1. Potential Barriers to Participation of Older Adolescents and Young Adults in Clinical Trials: Conclusions of Adolescent and Young Adult Initiative
Continuity of Care and Philosophy
• Older adolescents and young adults have the lowest rate of primary care use of any age group.
• Adolescents and young adults are more likely than children to lack a usual source of care. Without a known primary physician, the patient may be reluctant to trust the medical establishment and the clinical trial enterprise.
• Physicians and other healthcare professionals are poorly trained, or unwilling, to care for adolescents.
• Adolescents and young adults are not “supposed to” have cancer. As a result, clinical suspicion is low and symptoms are often attributed to physical exertion, fatigue, trauma, and stress.
• Adolescents and young adults have a strong sense of invincibility. Out of denial, they may delay seeing a physician about symptoms. Even when seen, they may give poor historical information, especially to a physician untrained to “read between the lines” of a young person's history.
Economic and Insurance-based Factors
• In the U.S., young adults are the most uninsured and under-insured age group. Nearly half of all 15–19-year-olds lose the healthcare insurance provided by their parents and do not acquire adequate coverage at their next destination in life, whether at an institution of higher learning or through an employer.
• Treating physicians may be reluctant to promote the enrollment of adolescents or young adults onto clinical trials because of the time, cost and effort involved, not only on their part (and that of their team) but also on the part of the patient and family.
• Health insurance organizations may deter the referral of adolescents and young adults to a cancer center or cooperative group or entry onto clinical trials, although there is little direct evidence of this factor.
Provider Bias
• Coping with older adolescents and young adults with cancer is difficult in general. The additional burden of clinical trial participation is therefore heavier with adolescents than with younger or older patients.
• Treating physicians may be reluctant to refer adolescent and young adult patients to clinical trials because they perceive these patients as likely to be noncompliant (or nonadherent) with the protocol requirements. These patients are perceived to have enough difficulty complying with a treatment plan and keeping up their lives, without the additional burden of protocol obligations.
• Oncologists (surgeons, radiotherapists, medical oncologists, gynecologists) in private practice may retain these patients rather than refer them to a tertiary-care facility or cooperative group member institution.
• Providers may be biased against clinical trials in adolescents and young adults. Reasons may include the historically better results of standard treatments in adolescents and young adults than in older and younger patients, and the additional effort of entering someone in the age group onto a clinical trial, including having to explain and obtain consent to study entry from both the patient and family.
• Family practitioners, gynecologists, and internists may not judge multimodality therapy to be as important in older adolescents and young adults as in younger and older patients. Reasons may include the greater use of single-modality therapy in patients in this age range. The additional burden of coordinating multidisciplinary care in this age group may be a factor.
• Providers may be unaware of opportunities for clinical trial participation for adolescents and young adults with cancer.
Patient/Family Preferences
• Adolescent and young adult patients and/or their parents are more inclined to refuse referral to a cooperative group member institution or to be entered onto a clinical trial.
• Patients and/or their parents may be unaware of opportunities for clinical trial participation for adolescents and young adults with cancer.
Provider Age Policies
• The age policies of hospitals may prevent patient access to clinical trials that are under way at the institution. Children's hospitals may have upper age limits that deny the admission of older patients or deny clinical privileges to the treating physician. The reverse may be true for younger patients accessing clinical trials intended primarily for adult patients.
• The clinical trial itself may have age limits that prohibit the entry of an otherwise eligible patient.
Cooperative Group and Cancer Center Limitations
• Pediatric and adult cooperative groups and cancer centers may not allow the enrollment of adolescents and young adults onto clinical trials because of restrictive eligibility criteria.
• A clinical trial may not be available.
• Adult cooperative groups and cancer centers may lack treatment protocols for younger patients.
• Pediatric cooperative groups and hospitals may lack treatment protocols for older patients.
• Clinical trials for the types of cancer that predominate among adolescents and young adults may not be a priority of the cooperative group enterprise.

One explanation is the under-utilization of healthcare services by adolescents in general.13 Among 18–39-year-olds in the U.S., lack of health insurance is a likely contributing factor. No other age group has less coverage. That lack of health insurance or under insurance appears to result in delays in time to cancer diagnosis was observed recently in a study of 15–29-year-olds. The lag time from the onset of the initial cancer symptom to diagnosis was significantly longer in 5 of the 6 most common cancers in the age group among patients with public insurance than in those with private insurance policies. The additional mean time associated with less insurance ranged from 1 month for acute lymphoblastic leukemia to 5 months for osteosarcoma.

A corollary reason is the place of treatment, as fewer patients in the 15–29-year age group are referred to dedicated, comprehensive cancer centers than patients in any other age group, with the possible exception of patients in the most elderly age group (>85 years). In particular, in the U.S., more than 90% of children with cancer who are younger than 15 years of age are treated at institutions that participate in NCI-sponsored clinical trials. In contrast, only about 20% of 15–19-year-olds with cancer are treated at such institutions, and only about 10% are entered onto a clinical trial. Among 20–29-year-olds, the inclusion rate is even lower, with fewer than 10% treated at institutions that are members of cooperative groups, either pediatric or adult, and only about 1% of 20–25-year-olds are entered onto clinical trials conducted by either pediatric or adult cooperative groups. Conversely, a population-based study of 15–29-year-olds with acute leukemia in England and Wales showed no difference in outcome between patients treated and not treated on national clinical trials or between patients treated at teaching hospitals and those not treated at teaching hospitals.14 This observation appears to be an exception, however, in that subsequent national trials in acute myelogenous leukemia patients conducted in the United Kingdom showed some of the best results reported to date.15

Another reason for the deficit in clinical trial participation is a lack of appropriate treatment regimens for older adolescent and young adult patients who have a pediatric type of cancer that is managed with an adult-based therapy instead of a pediatric approach. Acute lymphoblastic leukemia, Ewing sarcoma, and rhabdomyosarcoma are examples. In France, the U.S., and the Netherlands, a pediatric regimen for acute lymphoblastic leukemia resulted in superior outcomes—nearly twice the event-free and overall survival rates—to those in patients in the same age group (16–21 years) treated for the same disease on adult treatment trials extant at the time.16–18 Similar differences have been reported for Ewing sarcoma and rhabdomyosarcoma.19, 20 The lower clinical trial participation rate for older adolescents and young adults in the U.S. helps explain the lower-than-expected improvement in the subsequent outcomes in this age group, relative to younger and older patients.

Yet another explanation for the deficit in the enrollment of adolescents and young adults with cancer onto clinical trials is that the spectrum of cancers in them differs from that of any other age group. There is no organized body of research that is dedicated to the spectrum of cancers that affect this age group. Adding to this problem is the fact that there is no discipline in medicine devoted to this group. Neither pediatric oncologists nor oncologists who care for adult patients are trained, certainly not optimally, for this set of diseases. Moreover, even those diseases that appear to be the same often have biologic differences. For example, adolescents have different forms of leukemia than either younger or older persons. In particular, the biologic characteristics of acute lymphoblastic leukemia change in postpubertal patients toward worse prognostic subtypes. The proportions of young adults with T-cell disease and with Philadelphia chromosome positive leukemia (bcr-abl translocations) are greater in adults with acute lymphoblastic leukemia than in children. Knowing what the common subtypes are in young adults and having clinical trials for them is another matter.

The Adolescent and Young Adult Initiative of the Children's Oncology Group has been established as a means to increase the enrollment of adolescents and young adults in cancer clinical trials. The Initiative aims to bring advances in cancer education, prevention, and treatment—including educational, social, and emotional development—to this segment of the North American population whose progress in cancer outcome has decreased when compared with that achieved in younger and older patients. Publications by the Children's Oncology Group since the Initiative began are listed in Table 2. The initiative includes several strategies. In all of the pediatric group protocols for malignancies that substantively overlap young adult patients (such as leukemia, Hodgkin lymphoma, and the sarcomas), the upper age limit has been raised to 30, 40, or 50 years, depending on the disease. The pediatric group has also opened adult cooperative group trials in melanoma. Reciprocally, an adult cooperative group has opened the pediatric cooperative group trial in Ewing sarcoma. Plans are underway for the pediatric and adult groups to develop and open trials together in synovial cell sarcoma, malignant peripheral nerve sheath tumors, and giant cell tumor of bone. Other targets for mutual development include Hodgkin and non-Hodgkin lymphomas, hepatic cancer, colon cancer, and Wilms tumor.

Table 2. Publications Resulting from the Children's Oncology Group Adolescents and Young Adult Initiative
1999
Barr RD. On cancer control and the adolescent. Med Pediatr Oncol. 1999;32:404–410.
Haase J, Heiney S, Ruccione K, Stutzer C. Research triangulation to derive meaning-based quality of life theory: Adolescent Resilience Model and instrument development. Int J Cancer. 1999;(Suppl 12):125–131.
2000
Bleyer A. Cancer in children, teenagers, and young adults. Candlelighter Childhood Cancer Family Alliance, Vol. 8, Nov 2000.
Stock W Sather H, Dodge RK, Bloomfield CD, Larson A, Nachman J. Outcome of adolescents and young adults with ALL: A comparison of Children's Cancer Group (CCG) and Cancer and Leukemia Group G (CALGB) Regimens. Blood. 2000;96:467a.
2001
Murray JC, Koss J, Bengston M, et al. Adolescent cancer patients and their special needs: The creation of a “Teen Cancer Clinic” at a pediatric oncology center. J Adolesc Health. 2001;28:140.
Murray JC, Richie-Gillespie M, Koss J. Adolescents with osteogenic sarcoma: Fostering an informed choice between limb sparing surgery versus amputation. J Adolesc Health. 2001;28:141.
Albritton K, Wiggins C. Adolescents with cancer in Utah are not referred to Utah's pediatric tertiary care center. J Clin Oncol ASCO Poster, May 12–15, 2001.
Shochat SJ, Fremgen AM, Murphy SB, et al. Childhood cancer: Patterns of protocol participation in a national survey. CA Cancer J Clin. 2001;51:119–130.
Bleyer A, Stock W, Coppes M, Anderson B. Clinical trial inequality: Where are the teens. Hematol Oncol Today. 2001;2:29.
Boxer L, Newberger P. The lost generation: In clinical trials where are the teenagers? Hematol Oncol Today. 2001;2:1,6–9.
Keohan MK. Adolescents and young adults with cancer: What will it take to improve outcome. ASCO 2001 Educational Book. 138–140.
Barr RD. Cancer control in the adolescent and young adult population: Special Needs, ASCO 2001 Educational Book. 133–137.
Bleyer WA. United States pediatric cancer mortality—An ominous trend? Med Pediatr Oncol. 2001;36:337–339.
Bleyer A. Adolescents and young adults with cancer: A neglected population. ASCO 2001 Educational Book. 125–132.
2002
Bleyer WA. Cancer in adolescents and young adults: Epidemiology, diagnosis, treatment, survival, and importance of clinical trials. Overview. Med Pediatr Oncol. 2002;38:1–10.
Reaman GH, Bleyer A. Infants and adolescents with cancer: Special considerations. In: Pizzo PA, Poplack DG, editors. Principles and Practice of Pediatric Oncology. 4th ed. Philadelphia: J.B. Lippincott; 2002. 409–428.
Bleyer WA. Cancer brings distinct challenges to young adults and older adolescent patients. Hematol Oncol Today. 2002;3:40–42.
Bleyer A, Ries L. U.S. cancer incidence, mortality and survival: Young adults are lagging further behind. Proc Am Soc Clin Oncol. 2002;21:389a.
Bleyer A, Montello M, Budd T, Kelahan A, Ries L. U.S. cancer incidence, mortality and survival: Young adults are lagging further behind. Available at URL: http://virtualmeeting.asco.org/vm2002
Bleyer A. Older adolescents with cancer in North America: Deficits in outcome and research. Pediatr Clin N Am. 2002;49:1027–1042.
Bleyer A, Budd T, Montello M. Cancer in older adolescents and young adults: A new frontier. POGO News, Fall 2002:8–11.
2003
Bleyer A, Albritton K. Special considerations for the young adult and adolescent. In: Kufe DW, Pollock RE, Weichselbaum RR, Bast RC, Holland JF, Frei E, editors. Holland-Frei: Cancer Medicine. 6th ed. New York: BC Dekker; 2003. 2414–2422.
Searle NS, Askins M, Bleyer WA. Homebound schooling is the least favorable option for continued education of adolescent cancer patients: A preliminary report. Med Pediatr Oncol. 2003;40:380–384.
Bleyer A, Montello M, Budd T, Saxman S. Young adults with sarcoma: Lack of clinical trial participation and lack of survival prolongation. Proc Am Soc Clin Oncol. 2003;22:816a.
Jeha S. Who should be treating adolescents and young adults with acute lymphoblastic leukemia? Eur J Cancer. 2003;39:2579–2583.
Pappo A. Melanoma in children and adolescents. Eur J Cancer. 2003;39:2651–2661.
Albritton K, Bleyer A. Management of cancer in the older adolescent. Eur J Cancer. 2003;39:2548–2599.
2004
Bleyer A, Montello M, Budd T. Young adults with leukemia in the United States: Lack of clinical trial participation and mortality reduction during the last decade. Proc Am Soc Clin Oncol. 2004;23:586.
Pappo A, Ries L, Herzog C, Bleyer A. Malignant melanoma in the first three decades of life: A report from the US Surveillance, Epidemiology and End Results (SEER) Program. Proc Am Soc Clin Oncol. 2004;23:721a.
Termuhlen A, Tersak J, Hudson M, et al. Health status, medical care, preventive screening, and risk behaviors of adult survivors of cancer diagnosed during adolescence. A report from the Childhood Cancer Survivor Study. Proc Am Soc Clin Oncol. 2004;23:555a.
Bendel A, Ries L, Beaty O, Bottom K, Bleyer A. CNS tumor epidemiology & outcome in adolescents and young adults in the United States, 1975–1998. Proc Int Symp Pediatr Neuro-Oncol. 2004;51.
Bleyer A, Hag-Alshiekh M, Montello M, et al. Older adolescents and young adults with brain tumors in the United States: Lack of clinical trial participation and of survival prolongation and mortality reduction. Proc Int Symp Pediatr Neuro-Oncol. 2004;52.
Albritton K, Stock W, Paulessen M. Cancer at the interface of pediatric and medical oncology: Striving to understand and improve outcome. ASCO 2004 Educational Book, 2004. 587–564.
Bleyer A. Teenagers, cancer, clinical trials: Still neglected. The Next Step. Fall 2004. 1–4. Children's Cause Cancer Advocacy. Available at URL: www.childrenscause.org/library/pdf/Newsletter_2004_Fall.pdf Accessed November 10, 2005.
Bleyer A. Young adults, cancer, clinical trials: Breakthrough? Reaching Out The Ulman Cancer Fund for Young Adults. Fall 2004. Newsletter, p. 2. Available at URL: http://www.ulmanfund.org/Education/Articles/bleyer-ReachingOut.pdf Accessed March 21, 2005.
2005
Bleyer A, Montello M, Budd T, Saxman S. National survival trends of young adults with sarcoma: Lack of progress is associated with lack of clinical trial participation. Cancer. 2005;103:1891–1897.
Bleyer A. The adolescent and young adult gap in cancer care and outcome. Curr Probl Pediatr Adolesc Health Care. 2005;35:182–217.
Bleyer A, Ulrich C, Martin S, Munsell M, Lange G, Taylor S. Status of health insurance predicts time from symptom onset to cancer diagnosis in young adults. Proc Am Soc Clin Oncol. 2005;23:547a.
Murray JC. Cancer in older adolescents and young adults. Curr Probl Pediatr Adolesc Health Care. 2005;35:186–188.
Bleyer A, Budd T, Montello M. Lack of clinical trial participation and of progress in older adolescents and young adults with cancer. Curr Probl Pediatr Adolesc Health Care. 2005;35:188–195.
Zebrack B, Katz E. Psychosocial issues in adolescent and young adult patients and survivors. Curr Probl Pediatr Adolesc Health Care. 2005;35:195–201.
Oeffinger K. The survivor transition challenge from childhood to adult life. Curr Probl Pediatr Adolesc Health Care. 2005;35:201–203.
Kinahan K, Nelson M. Caring for adult survivors of childhood cancer: North American survey of needs and best practice models. Curr Probl Pediatr Adolesc Health Care. 2005;35:203–207.
Ryan B, Kinahan K. Models of care for childhood cancer survivors including an overview of transition of care for young adults with special health care needs. Curr Probl Pediatr Adolesc Health Care. 2005;35:207–209.
Freyer D. Preparing the adolescent cancer survivor for transition of follow-up care: Role of the pediatrician. Curr Probl Pediatr Adolesc Health Care. 2005;35:209–212.
Albritton K. Age matters: The problem with teen cancer care. Candlelighters Quarterly Journal. Spring 2005:1–5.
Cancer in adolescents and young adults. The Cancer Council of Tasmania Cancer News. 2005;31:1–2.
Ulrich C, Martin S, Munsell M, Lange G, Taylor S, Bleyer A. Time to cancer diagnosis in older adolescents and young adults depends on type of cancer and health insurance coverage. Proc Assoc Ped Oncol Nurses. September 15, 2005.
Freyer DR, Kibrick-Lazear R. In Sickness and In Health: Transition of care for older adolescent and young adult oncology patients. Cancer (accepted for publication).

Unfortunately, a downward trend in the accrual of patients 15–29-years of age onto U.S. National Cooperative Group treatment trials sponsored by the NCI was apparent from 1997 to 2003 (Fig. 8). The proportion of all patients entered onto the national phase I, II, and III treatment trials declined from 5.5% to 2.5% over this interval. This ominous trend may have been reversed in 2003 as a result, at least in part, of the Children's Oncology Group Initiative described earlier.

Figure 8.

Accrual of patients ages 15–29 years onto U.S. National Cooperative Group treatment trials sponsored by the Cancer Therapy Evaluation Program of the National Cancer Institute Division of Cancer Treatment and Diagnosis during 1997–2003, inclusive. The upper panel depicts the number of patient entries; the lower panel depicts the proportion of entries in the 15–29-years age group relative to all entries (of all ages).

Summary

Cancer in adolescents and young adults has unique features; this is in addition to the special medical, physical, psychological, and social needs of patients in this age group. The spectrum of malignant diseases is also different from that in other age groups, and it is strikingly different from that in older persons. At the same time, more young people between 15 and 29 years of age are diagnosed with cancer than are children less than 15 years of age and during the past 25 years, the incidence of cancer in 15–29-year-olds has increased faster and the reduction in cancer mortality has been lower than that in younger or older patients. Although it was once a relative advantage to have cancer during the adolescent and young adult years, patients in this age group are now behind patients in other age groups—orphaned in the world of cancer care delivery.

The single factor that correlates most highly with the deficit in outcome is lack of participation in clinical treatment trials. Thus, increased availability of and participation in clinical trials is of paramount importance if the current deficits in outcome in young adults and older adolescents are to be eliminated. Eliminating the survival deficit will require a broad initiative to increase clinical trial participation. We are not claiming that patients who participate in clinical trials benefit from them directly in terms of survival prolongation. We correlated the lack of progress as a societal effect with lack of clinical trial activity as a societal deficit. In the age groups in which we have conducted clinical trials, we have learned better how to treat cancer. In age groups that have had few clinical trials, we have learned less. Survival improvement and mortality reduction have followed accordingly. We are claiming that the science of medicine and future patients benefit from what is learned from clinical trials.

Ultimately, a new discipline is probably in order to meet the needs of these young patients: adolescent and young adult oncology. These patients deserve well-trained care providers, specialized clinics and inpatient units, and, probably most importantly, dedicated research strategies that are not available through either pediatric or adult care programs. The NCI has taken note of this challenge and will evaluate, during 2005–2006, its research portfolio in adolescent and young adult oncology. The Institute is setting up a Progress Review Group of experts to assess the strengths, weaknesses, and opportunities of the current national approach to the problem, and will develop short- and long-term recommendations to overcome the obstacles to improve the outcome for these patients, not only in overall and disease-free survival but also in the quality of survival. Regardless of the obstacles and possible solutions, the net result of the deficits is a burden on the U.S. population. Affected are the national cost of healthcare, a substantial number of person-years of life, the number of young people entering the job market, and our scientific knowledge of cancer during adolescence and early adulthood. The deficit deserves attention and research.

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