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Cancer Treatment Reviews (2007) 33, 603– 608
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/ctrv
TUMOUR REVIEW
Participation of adolescents with cancer in clinical
trials
Andrea Ferrari
a,*
, Archie Bleyer
b
a
Pediatric Oncology Unit, Istituto Nazionale Tumori, Via G. Venezian, 1 20133 Milano MI, Italy
Cancer Treatment Center, St. Charles Medical Center, Bend, Oregon, and CureSearch/National Childhood Cancer
Foundation and Children’s Oncology Group, Arcadia, CA, USA
b
Received 30 October 2006; received in revised form 29 November 2006; accepted 30 November 2006
KEYWORDS
Summary Adolescent patients with cancer reside in a ‘‘no-man’s land’’ between the world of
pediatric oncology and that of ‘‘adult’’ medical oncology. As compared to younger and older
patients, adolescents and young adults are under-represented on clinical trials. This relative
lack of participation in clinical protocols has been associated to a lack of progress in survival
improvement over the last years. One of the main reasons for the deficit in protocol enrolment
and the worse outcome of adolescents (when compared in particular to children) is the lack of
awareness by the public, community and healthcare systems that cancer may occur in this age
group. However, physicians – inadequately trained or reluctant to care for adolescents – have
important responsibilities. Most 15- to 19-year-olds diagnosed with cancer are treated at adult
facilities, although two-thirds to three-fourths of their cancers are typical of those that occur in
the pediatric age range. The best choice may be to treat them according to their type of tumor,
not according to their age: ‘‘pediatric’’ tumors treated by pediatric oncologists, ‘‘adult’’
tumors by adult medical oncologists, regardless of the patient’s age. This solution, however,
is probably appropriate for the tumor, but not necessarily for the patient. Adolescents are
neither old children nor young adults, and are very complicated individuals, with unique
socio-psychological problems and needs, that may be addressed only by dedicated professionals, adequately trained and supported. The ultimate challenge is the development of a new discipline, adolescent/teenage and young adult oncology, devoted to the care of these patients.
c 2006 Elsevier Ltd. All rights reserved.
Adolescents with cancer;
Young adults with cancer;
Clinical trials
Introduction
* Corresponding author. Tel.: +39 02 23902588; fax: +39 02
2665642.
E-mail address: [email protected] (A. Ferrari).
By comparison with adults, children and adolescents rarely
suffer from cancer, but it is nonetheless the primary cause
of death due to disease in this age group.
0305-7372/$ - see front matter c 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ctrv.2006.11.005
Author's personal copy
604
For a half century, pediatric oncologists have been striving to develop national and international multicenter research and treatment protocols, and this cooperation has
progressively led to advances in our understanding of pediatric malignancies, with a consequent improvement in the
outcome of their treatment.
Developing clinical protocols is a fundamental part of
cancer research. It is undeniable that clinical trials benefit
the scientific community and subsequent generations of
patients, and cooperative clinical trials involving large numbers of patients, preferably using a randomized design, are
the best way to assess the effectiveness of new treatments
by comparison with the standard therapeutic options. Publishing the results of clinical trials makes the new findings
available to the whole scientific world and provides the input
for more clinical studies and further scientific progress.
Being involved in clinical trials may also benefit participating patients, at least in the quality of their care and life
during participation in the trial. Having the attention of a
broader group of professional and the rigor of the trial provides a quality of care – secondary gain in a positive sense –
and generally enhances the cancer experience. There is also
the possibility of a longer survival and higher cure rate since
the trial provides potentially improved treatment that is not
otherwise available to the patient. The Dana Farber group
attempted to assess the empirical evidence supporting such
a positive effect of participation in clinical trials, using a
conceptual framework and a structured literature review:
the authors concluded that, although most published studies
gave the impression of a favorable fallout for patients, the
available data were not sufficient to conclude that such a
trial effect really existed.1 A retrospective study of 126
randomized trials conducted in 36,567 patients by the
Children’s Oncology Group (COG) between 1955 and 1997
concluded that new experimental treatments for childhood
cancer assessed in phase III randomized trials are just as
likely not to extend survival as they are to be better than
standard treatments (which are usually the best available
at the time) in prolonging survival.2 Whereas this observation may limit the potential for direct patient benefit in
survival prolongation, it verifies the quality of the trials conducted since the principle of equipoise specifies that the
likelihood of survival benefit should be unknown when the
trial is designed.
Studies performed in the 1970s and early 1980s suggested
a directed benefit for patients treated in organized pediatric oncology setting (for acute lymphoblastic leukemia,3
non-Hodgkin’s lymphoma,4 Wilms’ tumor5 and medulloblastoma6). In North America, an analysis concerning adolescent
patients with acute leukemia also showed better survival results for patients treated in cooperative group trials.7
While it is difficult to assert that taking part in clinical
trials affords a personal benefit in terms of a better chance
of cure, there is direct benefit of clinical participation in the
breadth and quality of care, and associated quality of
survival.
Clinical trial participation rates
Pediatric oncologists tend to assume that enlisting their
patients in clinical trials is the way to offer them the best
A. Ferrari, A. Bleyer
chance of survival and one of the fundamentals of quality
treatment. Despite their conviction, patient enrolment
rates are high for younger children, but disappointing for
adolescents.
It has been estimated that around 80% of 0–14 year-olds
with cancer in Italy are included in national cooperative
protocols (coordinated by the Associazione Italiana Ematologia Oncologia Pediatrica – AIEOP), as opposed to just
25–30% of patients over 15 years old (Fig. 1) (G. Pastore,
personal communication). In the United States, the participation for 15–19 year-olds in treatment protocols sponsored by the National Cancer Institute (NCI) between 1997
and 2003 was between 10% and 15%, that means about
one-fourth of the corresponding rate among younger children.8–10 A population-based analysis (cooperative group
entries from 1992 to 1997) reported that 71% of children
under 15 were formally registered with current national
pediatric cancer cooperative groups (which subsequently
merged to form the COG), while this was true of only 24%
of the 15–19 year-olds.11 The situation is even worse when
adults are considered: with the exception of the very
elderly (over 85), the 20–29 year-old age group has the
lowest rate of participation in clinical trials (less than 2%)
(Fig. 2).8–10
Figure 1 Percentage of Italian patients (younger and older
than 15 years) enrolled in clinical trials of the Associazione
Italiana Ematologia Oncologia Pediatrica – AIEOP (courtesy:
Guido Pastore and Andrea Pession, data base modello 1.01
AIEOP).
Figure 2 Entries of 51,395 patients age < 45 years onto US
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 (from: Bleyer A, Budd T, Montello M.
Adolescents and young adults with cancer: the scope of the
problem and criticality of clinical trials. Cancer. 2006;
107(S7):1645–1655. Walking two worlds – Adolescent and
young adult oncology. Proceedings of a symposium held by the
pediatric Oncology Group of Ontario. Authorized by the author
and by the journal).
Author's personal copy
Participation of adolescents with cancer in clinical trials
The accrual pattern in the United States is much the
same for all racial and ethnic groups, gender (though the nadir in the participation rate is even more striking in males),
place of residence (metropolitan or rural areas) and type of
cancer.8
Survival
The age-related rate of involvement in clinical trials
strongly reflects the steep V-shaped figures for the mean
annual improvement in survival rates in the last 25 years.
The Survival, Epidemiology and End Results (SEER) analysis
found an average annual improvement in survival of more
than 1.5% a year among children under 15 and adults over
50, but it dropped to less than 0.5% in the 15–24 year-olds
(and in the 25–34 year-olds there was no perceptible
improvement at all) (Fig. 3).8–10,12–14 Thus, the poor rate
of accrual in clinical protocols coincides with a worse rate
of progress in improving the survival of older adolescents
and young adults by comparison with all the other age
groups – and this may be probably applied not only to the
United States, but to the rest of the world too.
The recent report on the European situation from the
Automated Childhood Cancer Information System (ACCIS)
project described a very similar global survival rate for all
cancers in Europe among children and adolescents, but this
was influenced by the higher proportion of ‘‘favorable’’
tumors (i.e. Hodgkin’s disease, thyroid and testis cancer)
in the adolescent group. When the different types of cancer
were considered separately, significant differences in outcome became apparent, with adolescents revealing a worse
survival than children for leukemia, sarcomas and cerebral
tumors.15
605
Possible explanations for adolescents having
a worse outcome
This a complex issue and there may be several reasons why
adolescents fare less well than children with the same disease, and why in the last 25 years we have failed to reduce
the mortality rates among adolescent and young adult cancer patients to the same degree that has occurred for other
age groups.9,16,17
First, there may be a greater incidence of adverse prognostic variables in older patients and age may itself be an
independent negative prognostic factor in some pediatric
tumors (i.e. rhabdomyosarcoma).18,19 Other factors relating
to the patients and their families, the society or community
in which they live, or the health professionals who take care
of them may also be involved, however.8–10
One of the main concerns is that adolescents, their families, the community and the healthcare system seem scarcely aware that cancer can affect this age group.8–10,13,16
Adolescents tend to have a age-specific strong sense of
independence and invincibility; they may be reluctant to
trust the medical establishment and to have a known primary physician; they may delay speaking about their symptoms to parents and physicians, and even when they see the
physician, they may give poor information.
The lack of awareness that cancer can arise in adolescents
might be understandable in the young patients involved, but
it is more difficult to explain in other members of the community and amongst health operators. Since it is assumed that
adolescents do not get cancer, clinical attention to telltale
signs may be low and symptoms are often attributed to physical exertion, fatigue, trauma, and stress. This means that
the diagnosis comes late: the interval between the onset of
Figure 3 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 1975 to 1997 (courtesy from: Bleyer A, O’Leary M, Barr R, Ries LAG
(eds): Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, Including SEER Incidence and Survival:
1975–2000. National Cancer Institute, NIH Pub. No. 06-5767. Bethesda, MD 2006).
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606
the early symptoms and the diagnosis of cancer is longer in
adolescents than in children, with obvious effects on the
stage of the disease and the final outcome.20–22
Another factor limiting their recourse to medical care
(particularly in the United States) is that adolescents (and
young adults) are no longer covered by their parents’ health
insurance policies: nearly half of the adolescents lose the
insurance provided by their parents and do not acquire adequate coverage at their next destination in life. The 18- 24year age group has the lowest rate of health insurance
among all ages in the United States.23
Nonetheless, an important factor behind the worse outcome of cancer in adolescents than in children could well
have to do with their more limited participation in clinical
trials: adolescents are less likely to gain access to optimal
cancer services at comprehensive cancer centers and consequently are not offered participation in clinical trials. And
even when referred to a tertiary center, there are fewer
clinical trials open to patients in the age group that for
other ages.8–10,12,13 The healthcare system – and physicians – are the responsible for this situation.
Physicians (and other professionals) may be poorly
trained, or unwilling, to care for adolescents; moreover,
they may even be reluctant to recommend enrolling adolescents and young adults in clinical trials, because they could
perceive these patients as likely to be non-adherent with
the trial requirement, or because of the time, cost and effort involved, not only for themselves but also for the patients and their families.
Another main problem is that sometimes there are no
clinical trials available: adult cooperative groups and cancer
centers may lack treatment protocols designed for younger
patients, while pediatric cooperative groups and hospitals
may lack treatment protocols for older ones. Children’s hospitals often have upper age limits and consequently reject
older patients, and the same applies vice versa to patients
too young to join protocols at oncology units intended
primarily for adult patients.8–10,12,13 The clinical trial itself
may sometimes establish age limits that exclude otherwise
eligible patients.
It is possible to say that adolescent patients are left in a
‘‘no-man’s (also no woman’s) land’’ somewhere between
the worlds of pediatric oncology and of ‘‘adult’’ medical
oncology. To make matters worse, pediatric oncologists
and medical oncologists may be reluctant to co-operate
with one another (though they are dealing with very similar
diseases), and a 15-year-old with a given type of cancer is
often treated quite differently from a 22-year-old with the
same disease, even when they are both seen at the same
experienced institution.24,25
Another explanation for the deficit in the enrollment of
adolescents suffering from cancer onto clinical trials may
be the peculiar spectrum of cancers that affect this agegroup. It is a fact that there is no a discipline, in medicine,
dedicated to this group of tumor. However, while it is true
that adolescents may have a combination of tumor types unique to their age, it is evident that the majority are types of
tumors typical of pediatric age (i.e. brain tumors, leukemia
and lymphoma, sarcomas and germ cell tumors), while the
remainder are tumors of adulthood (i.e. melanoma, thyroid
carcinoma and other carcinomas) (Fig. 4).9 Of course, it is
hard to say, on the other hand, whether a given type of
A. Ferrari, A. Bleyer
Figure 4 Cancers in 15- to 19-year-olds, U.S. Survival,
Epidemiology, and End Results (SEER) registry, 1975-2001.Segments in color represent ‘‘pediatric malignancies’’. (courtesy
from: Bleyer A, O’Leary M, Barr R, Ries LAG (eds): Cancer
Epidemiology in Older Adolescents and Young Adults 15 to 29
Years of Age, Including SEER Incidence and Survival: 1975–
2000. National Cancer Institute, NIH Pub. No. 06-5767.
Bethesda, MD 2006).
cancer would have a different biological behavior when it
occurs in adults as opposed to children. These considerations make the referral of adolescent patients even more
difficult. It is often the first physician to see the patient
who refers the case to an adult or pediatric oncologist,
which may mean a number of things (an internist, family
physician, emergency room physician, neurologist, and so
on) and the pattern of referral can be very different. At
the end, though the majority of tumor of adolescents are
‘‘pediatric’’ cancers, most 15- to 19-year-olds are primarily
sent and then treated at adult facilities (that often lack
treatment protocols designed for ‘‘pediatric’’ cancers),
because the age cut-off for managing them as pediatric or
adult cases is often considered by most physicians as setting
not at 18, but at 15 years of age. As a result, only about 30%
of adolescents are usually treated at pediatric oncology
centers.16,26,27
Pediatric oncologists (and pediatric oncology units) may
be considered naturally more appropriate for managing adolescents with ‘‘pediatric’’ malignancies, and the same principle applies to young adults with ‘‘pediatric’’ cancers. In
North-American28 and European studies,29–33 older adolescents with acute lymphoblastic leukemia fared considerably
better when treated as part of pediatric clinical trials than
using adult leukemia protocols. An analysis from the United
States National Cancer Data Base reported that 15- to 19year-olds with leukemia, lymphoma, liver tumors, and bone
sarcomas had a better outcome when treated at an NCI
pediatric center.7
A German study showed that 15–20 year-old patients
with Ewing sarcoma treated at pediatric cancer centers
survived better than those treated at other institutions,
although the same clinical protocol was adopted.34 The
study also confirmed that the overall outcome was better
for children than for adolescents and young adults, possibly
due to differences in clinical presentation (larger tumors and
a more axial location in older patients) and treatment tolerance. That adolescents treated at pediatric centers should
Author's personal copy
Participation of adolescents with cancer in clinical trials
do better than those treated with the same protocol at adult
oncology centers may have to do with the former centers
having more experience of this particular disease and a different approach to patient care (a pediatric oncologist may
be more expert in delivering intensive chemotherapy).
Studies on adult patients with rhabdomyosarcoma,19
medulloblastoma35 and Wilms’ tumor36 have been conducted by the Istituto Nazionale Tumori (INT) of Milan, Italy
(where the pediatric oncology unit is part of a cancer institute and not of a pediatric department, as is generally the
case, so the INT pediatric oncologists can treat adolescent
and young adult patients with ‘‘pediatric’’ tumors disregarding the age cut-off). The INT studies emphasized that
adult patients with rhabdomyosarcoma19 and medulloblastoma35 had a better outcome when directly enrolled in pediatric trials, or at least when treated ‘‘according to’’ the
protocols for children, and similar findings emerged for patients with synovial sarcoma.24,25 Conversely, adult patients
with Wilms’ tumor had a worse prognosis than is usually reported for the children (whose treatment strictly followed
the rules of the clinical trial), and this seemed to be a matter of undertreatment or erroneous treatment, or poor
compliance with the proposed therapeutic guidelines.36
Possible solutions
Finding a solution to the deficit in clinical trial enrolment
and outcome for adolescents with cancer is no easy matter.
It is true that adolescents with cancer seem, on the
whole, to benefit from being managed by the multidisciplinary team typical of the pediatric oncology unit, which
includes the pediatric oncologist, surgeon, radiotherapist,
nutritionist, infectious disease expert, neurologist and endocrinologist, and also the psychologist and social worker.
Choosing the right specialist for adolescents with
‘‘adult’’ cancers may prove more difficult, however.
Patients with melanoma or colorectal carcinoma should fare
better in the care of an adult medical oncologist, who will
have more expertise on the treatment of such neoplasms.37
In short, the best choice may be to treat adolescent (and
young adult) patients according to their type of tumor, not
according to their age: ‘‘pediatric’’ tumors should be treated by pediatric oncologists, ‘‘adult’’ tumors by adult medical oncologists, regardless of the patient’s age.
This solution is not ideal, however. It is probably ideal for
the tumor, but not for the patient.
Adolescents with cancer are neither old children nor
young adults. They are very complicated individuals, with
unique emotional, spiritual, social and psychological problems to cope with, and particular needs. A 20-year-old young
man with medulloblastoma or rhabdomyosarcoma is going to
feel ill at ease with the cartoons on the walls of a pediatric
center, a motherly style of care and little recognition of his
concerns regarding fertility, absence from work, damage to
his social (and sexual) life, while a 15-year-old with colorectal cancer may well feel intimidated in an adult hospital
ward and may need the parental involvement that adult
medical oncologists are less likely to be able to deal with.
Adolescents may be individuals with very diverse levels
of maturity, different temperaments and different needs.
Specific communication skills are needed to relate with ado-
607
lescents, and neither pediatric nor adult oncologists have
the necessary training to talk about such problem topics
as sexuality or fertility. The needs of adolescents with
cancer can only be addressed by specifically trained and
focused people, with the support of specialized clinics
and inpatient units and, moreover, dedicated research
strategies that are not a part of pediatric or adult care
programs.
Multiple organizations need to be involved for this challenge, including national and local governments, the health
insurance industry (at least in the United States), cooperative
groups running the clinical trials, and healthcare providers.
Improving awareness of the problem at various levels
(patient, community, healthcare system) is a primary goal,
requiring a major effort in public information and education
programs. A more fruitful cooperation is also needed between pediatric and medical oncologists. The ultimate challenge, however, lies in developing oncologists (and oncology
centers) dedicated to the care of adolescent patients. The
best answer would be to create a new discipline, adolescent
and young adult oncology, with its own training programs,
clinical and translational research and national and international organizations.8–10
Few cancer centers have special units for adolescents
and young adults, but specific programs have been established in the United Kingdom,38,39 Australia and North America (e.g. at the Dana Farber Cancer Institute in Boston).9 In
2000, the COG, in conjunction with the NCI and NCI-sponsored adult cooperative groups, formed the Adolescent
and Young Adult (AYA) Committee, whose main aim is to
facilitate the access to clinical trials of adolescents and
young adults with cancer.9 The Committee’s first steps
focused on sarcoma patients and led to the intergroup
sarcoma committees and clinical protocols including both
pediatric and adult cases. Similar strategies were recommended for other malignancies spanning the adolescent–
young adult age bracket (i.e. leukemia and Hodgkin’s
disease), for which the upper age limit for pediatric oncology clinical trials has been raised to 30 or 40.9
The proportion of adolescents and young adults entering
clinical trials has thus increased in the United States, especially as concerns sarcomas, and this improvement has occurred despite a general decline in the protocol enrolment
figures for younger and older patients. Over the next few
years, we would naturally expect to see a further increase
in this positive trend.8
The relatively poor participation of adolescents in clinical trials in the past has certainly affected their chances
of achieving an outcome as good as in children. The chances
of reversing this situation depend largely on the efficacy of
action to educate the public, health professionals, insurers
and cancer policy administrators.
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