Download Review Juvenile cancer: improving care for

Annals of Oncology 16: 181 – 188, 2005
doi:10.1093/annonc/mdi036
Review
Juvenile cancer: improving care for adolescents and young
adults within the frame of medical oncology
G. Pentheroudakis & N. Pavlidis*
Department of Medical Oncology, Ioannina University Hospital, Greece
Received 19 May 2004; revised 21 July 2004; accepted 30 July 2004
Despite unique tumour epidemiology, a higher cancer incidence and modest survival improvement
compared to paediatric patients, adolescents and young adults aged 15 – 30 have not been considered
as a separate, ‘special’ group of patients in the frame of medical oncology. In an effort to emphasise
this need, we review the particular characteristics of diagnosed tumours, a aetiologic associations,
nosologic classification, management, outcome and late toxic effects. Adolescents and young adults
are in need of specialised care for intensive treatment of curable malignancies, skilled nursing care,
interaction with peers, family and physicians as well as continuous psychosocial support. Enrolment
in clinical research trials and close follow-up via the development of a cooperative infrastructure are
imperative for the optimisation of management and avoidance of late effects. Similar to geriatric
and paediatric oncology, we call for the intensification of treatment, support and research multidisciplinary efforts in order to better fulfil the pressing demands of this patient group.
Key words: adolescents, cancer, survival, treatment, young adults
Introduction
Over the last four decades, the need for intensive, specialised
treatment, care and support along with the curability of
childhood cancers have led to the establishment of paediatric
oncology as a separate and well-recognised subspecialty in
paediatrics. This has been the story of a spectacular success:
cure rates have improved from <30% in the 1950s to 75%
in the 1990s [1], owing to financial investment, multidisciplinary research efforts and the development of a unique cooperative infrastructure throughout the world. Meanwhile, the next
oldest age group of cancer patients have enjoyed much less of
this focus for research and improved care than their younger
counterparts. Despite the observation of both higher and accelerated cancer incidence in the 15–30 age group in comparison to children, along with only modest survival improvement
[2], adolescents and young adults have not been considered
any differently from their elderly counterparts. Although their
most common malignancies are curable, 15– 30-year-old cancer patients have seen the development of geriatric oncology
taking place well before the need for recognising their unique
characteristics, as well as optimising their care, has become
evident. In this review, our aim is to emphasise the distinctive
features of both tumours and patients in the 15 –30 age group
*Correspondence to: Dr N. Pavlidis, Department of Medical Oncology,
Ioannina University Hospital, Dourouti 45110, Ioannina, Greece.
Tel/Fax: +30-26510-99394; E-mail: [email protected]
q 2005 European Society for Medical Oncology
as well as the imperative need for specialised management,
support and research by skilled personnel.
Epidemiology
Using a conventional age range of 15–19 for adolescents and
20–30 for young adults, there is ample evidence for an overall
higher cancer incidence than that reported in paediatric populations. In fact, the incidence of cancer in young patients aged
15–30 years (220 –250 cases per million youths) is higher and
rising faster than in children. Data from the National Cancer
Institute’s (NCI) Surveillance, Epidemiology and End Results
(SEER) program and the UK cancer registry indicate that the
incidence of cancer in adolescents 15 –19 years old is 50%
higher that in younger persons, for a rate of 203 new cases per
million persons [3 –5]. Overall, rates in both males and
females were significantly higher at 20 –24 years than at
15–19 years [6].
There is evidence of an increase in the cancer incidence
rate in adolescents and young adults over the last quarter of
the 20th century on both sides of the Atlantic. According to
SEER and UK registry data, the overall rate of cancer incidence in adolescents has been rising at an average of 0.9% per
year. Melanomas, non-Hodgkin lymphomas and testicular carcinoma have shown the greatest annual increases, over 5% for
the former and 2% for the latter two [3, 5]. The most common
tumours among 15– 19-year-old adolescents are testicular
cancer (15%) and Hodgkin’s disease (16%) by far, followed
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Figure 1. Incidence of tumour types in adolescents 15–19 years old [3].
HD, Hodgkin’s disease; GCT, germ cell tumours; CNS, central nervous
system tumours; NHL, non-Hodgkin’s lymphomas; ALL, acute
lymphocytic leukaemia; EFT, Ewing family tumours; AML, acute
myelocytic leukaemia.
by central nervous system (CNS) tumours, non-Hodgkin’s
lymphomas (NHL), thyroid cancer, malignant melanoma and
acute lymphoblastic leukaemia (Figure 1). These tumours
account for more than two-thirds of the total of malignant
cases [5, 7]. Non-seminomatous germ cell tumours outnumber
seminomas and most of the cases of Hodgkin’s disease are of
the nodular sclerosis classical subtype [8]. Young patients
with NHL usually have diffuse large B-cell or T-cell highgrade histology according to the World Health Organization
(WHO) classification, in sharp contrast to the predominance
of lymphoblastic and Burkitt types during early childhood [9].
This distribution is unique for this age group, as the paediatric embryonal tumours such as nephroblastoma, neuroblastoma, medulloblastoma, hepatoblastoma and retinoblastoma
are seldom encountered. Rhabdomyosarcoma accounts for
only a quarter of soft tissue sarcomas, the remainder including
synovial sarcoma, liposarcoma and fibrous histiocytoma.
Acute lymphoblastic leukaemia (ALL) (6%) is certainly less
common than in children (30% of all cancers) [5]. Among
patients in the 20–30 age group, the commonest tumours are
reported to be Hodgkin’s disease, germ cell tumours, melanomas, CNS tumours, bone and soft tissue sarcomas [10, 11]
(Figure 2). The first two tumours peak in incidence in this age
group, whereas declining ALL is being surpassed by acute
myelogenous leukaemia. Ovarian tumours are usually germ
cell malignancies (60% of cases) in the 15 –19-year-olds,
whereas 20–24-year-old adult females have ovarian carcinomas in 70% of cases [12]. Characteristic in the 15 –30 age
group is the rare occurrence of common (for older ages) epithelial tumours of the aerodigestive and genitourinary tract.
The relative frequency of epithelial tumours by age groups
can be seen in Figure 3.
Although it is often stated that 15 –19-year-old adolescents more commonly suffer from paediatric tumours, a closer look at epidemiological and incidence data do not
support this observation. Hodgkin’s disease and germ cell
tumours, the two commonest adolescent malignancies, occur
Figure 2. Incidence of tumour types in young adults 20 –30 years old [3].
HD, Hodgkin’s disease; GCT, germ cell tumours; CNS, central nervous
system tumours; NHL, non-Hodgkin’s lymphomas; ALL, acute
lymphocytic leukaemia; EFT, Ewing family tumours; AML, acute
myelocytic leukaemia.
Figure 3. Epithelial malignancies of aerodigestive, gastrointestinal,
genitourinary tract, head and neck, and skin (non-melanoma).
at an incidence 3– 6 times higher than the paediatric one.
Epithelial carcinomas, thyroid cancer and melanomas are
seldom, if ever, encountered in children, while ALL, NHL,
CNS tumours, and osteosarcoma/Ewing family tumours are
almost as common in adolescence as in childhood. Accordingly, neoplasias affecting teenagers should be better characterised as ‘adolescent-type’ tumours that also occur less
often in childhood or tumours that are common in both age
groups. Rhabdomyosarcoma and other embryonal sarcomas
are a notable exception that represent true ‘paediatric-type
tumours’ occurring in adolescence [13].
Ethnic/racial differences in incidence are apparent between
Caucasian and black youths, with cancer appearing 50% more
often in whites. The overall frequency of adolescent tumours
seems to be equal between sexes in the USA [6] and higher for
males in the UK [5]. Individual tumour types have unequal sex
distributions with ALL, NHL, Ewing sarcomas, osteosarcomas
and brain tumours more common in males. Thyroid
183
carcinomas, melanomas and Hodgkin’s disease are diagnosed
more often in females.
Aetiology
The vast majority of cancers of adolescence and adulthood are
sporadic events of unknown aetiology. Genetic conditions that
are associated with an increased frequency of malignancies
such as skin cancer, lymphoma, sarcoma, hepatic tumours and
various carcinomas account for only a small proportion of
malignant cases in these age groups. Indeed, neurofibromatosis,
Li–Fraumeni syndrome, xeroderma pigmentosum, ataxiatelangiectasia, Fanconi pancytopenia, hereditary dysplastic
nevus syndrome, Turner, Beckwith – Wiedemann, Gorlin,
Bloom’s syndrome and multiple endocrine neoplasia (MEN)
syndromes make up <10% of observed adolescent and young
adult tumours [14, 15]. The rare breast/ovarian carcinomas
encountered in young females aged <30 may be related to the
presence of BRCA1/BRCA2 tumour suppressor gene
mutations, similar to colorectal cancer cases associated with
familial adenomatous polyposis or Lynch syndromes
(hMLH1/hMSH2,6 mutations).
Similar to genetic factors, environmental factors have rarely
been incriminated in the pathogenesis of malignancies of adolescents and young adults. Exceptions are clear-cell adenocarcinomas of the vagina–cervix in adolescent females, caused
by prenatal exposure to diethylstilbestrol taken by their
mothers, hepatic tumours caused by early hepatitis B/C infection, contraceptive use, aflatoxin exposure and human papilloma virus infection [16]. Early onset of active sexual life and
multiple sexual partners lead to increased likelihood of
chronic infection from high risk HPV strains and, consequently, increased risk for cervical cancer development at a
young age. The latter could well turn out to be a preventable
or treatable ‘juvenile’ tumour in view of hopes for complementarity of HPV DNA testing to cervical cytologic screening
and effectiveness of HPV vaccination [17]. Adolescents and
young adults exposed to radiation or chemoradiation during
early childhood occasionally experience second tumours. In
fact, a lot of ‘juvenile’ malignant cases that have been linked
to aetiologic factors are antineoplastic treatment-induced
second tumours [18].
Most known carcinogens (tobacco, sunlight, diet and chemicals) cause DNA damage in somatic cells resulting in cancer
after a delay of more than two decades. Accordingly, one
would expect to observe a reduced incidence of such common
carcinomas in the adolescent and young adult population,
which is indeed the case. The emerging concept of accelerated
carcinogenic effects of environmental toxins affecting developing tissues during childhood with resulting early epithelial
tumours in young adulthood is not widely accepted yet. A
notable exception is the frequent occurrence of melanoma in
youths in sunny countries, a finding that lends weight to the
possibility of carcinogenesis after a relatively short latent
period secondary to intermittent, intense sun exposure during
childhood and adolescence [19].
Nosologic classification
Classification of paediatric tumours is based on morphology
(histology) [20], whereas adult tumours are classified according to organ site of the primary (International Classification of
Disease, ICD-O) [21]. As stated before, the epidemiology of
malignancy in adolescents and young adults represents a transitional phase between that of paediatric embryonal tumours
and carcinomas/sarcomas of older adults. In order to develop
services tailored to their needs, it is necessary to define patient
characteristics through precise analyses of relevant population-based data. Since both paediatric and adult classification
schemes seem to be inappropriate for the juvenile group, a
diagnostic classification scheme is needed so as to meet epidemiological and service planning purposes, as well as be
applied to international cancer registration procedures.
Some authors have advocated use of the paediatric classification system, at least for adolescents [22]. However, a number of major childhood cancer groups are irrelevant in
adolescents and young adults. Moreover, cancers of older
patients, especially carcinomas, do occur in adolescents and
youngsters. Carcinomas, as specified in the childhood cancer
classification, are inappropriately subdivided and do not
describe adequately the pattern observed in young adults. On
the other hand, the adult ICD classification cannot differentiate carcinomas, soft tissue sarcomas and germ cell tumours
that arise in many different anatomical sites. On top of this, it
is unable to define the important differences between morphological subtypes of carcinomas, CNS and bone tumours.
Consequently, neither histology nor organ of origin provides an accurate basis on which to classify the cancers of
adolescents and young adults. Some authors have suggested
changes of the paediatric classification, such as separate enumeration of colorectal, salivary, lung and breast carcinomas
from the ‘other carcinoma’ group [22]. In an effort to produce
a separate ‘juvenile’ nosologic system, Birch et al. [5] created
a morphology-based classification scheme with revised tumour
Table 1. Synopsis of cancer classification in persons aged 15–24 years
Tumour group
Definition
Group 1
Leukaemias
Group 2
Lymphomas
Group 3
CNS tumours
Group 4
Bone tumours
Group 5
Soft tissue sarcomas
Group 6
Germ cell tumours
Group 7
Melanoma and skin carcinoma
Group 8
Carcinomas (except of skin)
Group 9
Miscellaneous specified neoplasms
(including embryonal paediatric tumours)
Group 10
Unspecified malignant neoplasms
Data from Birch et al. [5].
CNS, central nervous system.
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groups specifically for the 15 –24 age group malignant epidemiology (Table 1). Hopefully this scheme, which also facilitates comparisons of cancer data in children with those
in adolescents, will become a standard format for data presentation. It may also facilitate international comparisons and
encourage research in juvenile oncology.
Special management issues
The majority of juvenile tumours are potentially curable.
Five-year survival rates for ALL, Hodgkin’s disease, NHL,
sarcomas, germ cell and CNS tumours range from 45% to
90% and usually correspond to a cure [23, 24] (Table 2).
Accordingly, treatment given to a youngster with malignancy
often aims for long-term disease control and survival. This is
an aim paediatric oncologists are familiar with, but ‘adult’
medical oncologists are not as only too often palliation of
symptoms and modest prolongation of survival are the only
realistic targets they can hope for. On the other hand, paediatric oncologists may not have the experience to deal with the
different types of lymphomas, soft tissue sarcomas, melanomas, germ cell tumours and carcinomas that affect adolescents
and young adults more often than children.
The curative purpose of treatment in the juvenile patient
group necessitates that it is given in a ‘state of the art’ fashion,
as intensive as it needs to be so as to maximise the chances
for cure. Management often consists of combined-modality
treatment, incorporating multi-agent chemotherapy, high-dose
radiotherapy and aggressive surgery. Chemotherapy is often
dose-intense, dose-dense or high-dose with autologous marrow/stem cell rescue. Differences in outcome as large as cure
or relapse may depend on factors like adequate dosing, avoidance of unnecessary treatment delays or dose reductions,
Table 2. Five-year survival rates by cancer type and period, age 15–19
years, SEER data [6]
Tumour type
1975–1984
1985–1994
ALL
35%
51%
AML
22%
42%
Hodgkin’s disease
88%
90%
NHL
56%
69%
Astrocytoma
62%
75%
Medulloblastoma
63%
75%
Osteosarcoma
49%
59%
Ewing sarcoma
36%
56%
Soft tissue sarcoma
70%
63%
Rhabdomyosarcoma
40%
45%
Germ cell tumours
79%
90%
Thyroid carcinoma
99%
99%
Melanoma
84%
92%
Total
69%
77%
ALL, acute lymphocytic leukaemia; AML, acute myelocytic leukaemia;
NHL, non-Hodgkin’s lymphoma.
skilled and close supportive care for disease- and treatmentrelated symptoms and consequences [25]. Adolescents and
young adults have to be treated by skilled personnel in the
presence of an appropriate infrastructure. There is evidence
from retrospective and cohort studies that the outcome of such
patients is superior when treatment is given in a reference cancer centre [26] or in the context of a high-quality clinical trial
[27]. Moreover, survival seems to correlate with the number
of patients with the malignancy seen annually in each centre
[28]. The above merely reflect the experience of personnel,
quality of treatment and supportive care administered as well
as access to modern facilities, clinical trials and up-to-date
practice.
It is a common experience of young patients and attending
personnel that adolescents and young adults do not ‘fit’ in
either paediatric wards or medical wards with elderly patients.
Dedicated units for patients of the 15 –30 age group within
the context of medical oncology offer an ideal environment
for treatment, interaction with physician, family and peers,
skilled nursing care, individualised psychosocial support and
coordinated clinical research [29]. Educational activities could
also be set up, though quite difficult to organise. Nowadays,
most countries recommend referral of adolescents with cancer
to specialised centres (model of centralised care) for more
effective multidisciplinary treatment along the example of
paediatric oncology [30]. Such units should be developed as a
component of a broader structure of care that includes recognition of local providers, resources available in the community
and awareness of factors that can ensure access to care for
these patients. Some degree of decentralisation may be more
realistic for models of care suitable for sparsely populated or
remote areas. Adolescent oncology units already function successfully in the UK, a country that spearheaded the way for
their development [31].
Psychologic and social support is another pivotal issue for
15–30-year-old patients. These youths face several challenges,
such as independence, education, sexual maturation, employment, marriage, reproduction, parenting on top of a struggle
for reconciliation with cancer diagnosis, for cure and survival
[32]. Isolation from peers and society, carrying the ‘stigma’ of
cancer is often devastating [33]. The adverse effects of
therapy such as mutilating surgery, alopecia, acne, weight
gain, stunted growth, disruption of normal sexual function
may be overwhelming to individuals at a time in their life
when they would normally try to define and accept their selfimage. Time away from school is hard to accept [34, 35]. At
the same time, the youth going through these hardships has to
rely on the family’s help at a period when his/her important
target would be financial and emotional independence from it.
Skilled, individualised psychosocial support of these young
patients is imperative for unhindered management and smooth
re-incorporation into active socioeconomic life [36]. Evidence
suggests that it should be long-term, continuing for years after
successful treatment [37]. It is also pivotal for the patient with
relapsed disease or the terminally ill youngster. Support
should also encompass the family, friends, educational
185
and work environment. Psychiatrists, psychologists, social
workers and medical personnel should be actively involved
with it, working as a team.
Long-term follow-up of youngsters treated for malignant
diseases, their education and adherence to health promotional
measures are crucial for both timely diagnosis of relapse as
well as prevention of related or unrelated comorbidity. Transition of care and identification of the long-term follow-up
provider are critical issues: lifelong follow-up in the treating
specialised unit, the use of joint clinics staffed by juvenile
and medical oncologists, implementation of a ‘transition programme’ to transfer the patient’s care to either the medical
oncologist or the general practitioner have been provided in
various parts of the world. At present no gold standard can be
identified, as each model has to take into consideration the
resources available, the quality, interest and geographical
location of juvenile, adult oncologic and primary health
services [38].
Outcome and clinical research
The overall 5-year survival for adolescents with cancer has
been reported to be 77%, with similar outcome data existing
for the young adult age group (19 –24 year-olds) [6]. The
survival gains that have been accomplished for most of the
adolescent tumour types during the 1980s and 1990s are
encouraging (Table 2). The worse outcomes are seen in AML,
ALL and sarcomas (bone and soft-tissue), with data on carcinomas being scant. Each of the above tumours is associated
with a lower mean 5-year survival rate than that in younger
patients [2]. Cancer mortality burden in adolescents is mainly
due to leukaemias, followed by lymphomas, CNS tumours,
sarcomas and, to a lesser extent, germ cell tumours [39]. This
parameter is a function of both survival and incidence rates.
Most embryonal paediatric tumours (neuroblastoma,
nephroblastoma, rhabdomyosarcoma) have a worsening outcome with increasing age, a fact that probably reflects differing tumour biology and host factors [40]. Children with CNS
tumours fare better than adolescents, with the exception of
those of very young age (<4 years). At this age, inability to
administer full doses of radiation therapy because of vulnerability of the developing brain adversely affects outcome [41].
In contrast, the prognosis of children and adolescents with
osteosarcoma seems to improve with age. Adolescents and
adults with germ cell tumours seem to fare as well as children,
with young adult patients tolerating bleomycin better than
older adults who may experience pulmonary toxicity. Of note,
mediastinal teratomas may behave in a more benign manner
in children and young teenagers but are more aggressive and
often fatal in older patients [42].
Adolescents and young adults with Hodgkin’s disease have
a more favourable prognosis than older adults (>45 years) but
an inferior prognosis when compared to children, who fare
better because of higher frequency of lymphocyte predominant
histology, stage I disease, lower frequency of B symptoms and
more common use of combined modality therapy [43].
Children with lymphoblastic lymphoma and Burkitt’s lymphoma have a superior outcome when compared to the juvenile patient group, probably due to more intensive therapy [44].
Acute lymphoblastic leukaemia exhibits an age-related prognosis with children faring better than adolescents, who, in
turn, fare better than adults. This differential prognosis is
mainly due to differing biology of the malignancy with
adverse karyotypic and molecular markers appearing more
often in adolescents and adults, although the higher doseintensity of paediatric chemotherapy protocols may also contribute to the favourable prognosis of children, as shown by
recent clinical trials [45, 46].
There is a lack of epidemiological data on particular characteristics of the natural history and survival of very young
patients with epithelial carcinomas. Young women aged <25
are diagnosed with localised ovarian carcinoma in 60% of
cases, the reason for early diagnosis being heightened screening of the ovary among girls with delayed menarche or amenorrhea. Little is known of the biology and prognosis of very
young women with breast carcinoma. An inferior prognosis
has been suggested for women aged <35 when compared to
older women, due to a combination of factors such as
increased frequency of hormone-receptor negative disease,
aggressive malignant phenotype and germline mutations
(BRCA1, BRCA2) [47]. Anecdotal evidence indicates aggressive clinical course of lung and gastrointestinal carcinomas in
young patients. Generally young patients with ‘adult’ common
carcinomas are more likely to carry acquired or germline genetic lesions responsible for early carcinogenesis, a genetic bias
that may confer inferior survival.
Although the improvements in outcome of youngsters with
cancer seem to be satisfactory at first glance, they are inferior
to what has been achieved in paediatric oncologic patients.
The relative improvement in 5-year survival rates from 1974
to 1995 has been in excess of 30% for children and only 19%
for adolescents aged 15 –19. In the recently published EUROCARE-3 study, the annual improvement rate of survival in
patients aged 15–24 was shown to be inferior to those
observed both in children and in adults over the age of 40. In
fact, young patient mortality rates were increasing for some
tumour types (soft tissue sarcomas) in the last quarter of the
20th century. In 1974, 5-year adolescent survival rates were
superior when compared to paediatric patients (64% versus
55%) [3]. In sharp contrast, respective figures for the year
2000 are 80% for adolescents versus 85% for children, a
reversal in the survival order from a 10% advantage to a 5%
deficit.
The spectacular success of paediatric oncology is mainly
due to timely diagnosis, optimisation of multi-agent chemotherapy regimens, combined-modality treatment and supportive care. Most of these achievements have been the result of
painstaking, large-scale enrolment and treatment of children
with cancer in cooperative multicentric clinical trials. This
was made possible through the creation of an extensive sociomedical infrastructure via cooperative groups in the USA and
Europe. More than 95% of children with cancer in the USA
186
Figure 4. Participation of children, adolescents and young adults with
cancer in clinical trials and cooperative treatment protocols in the
USA [48]. White area: neither protocol nor trial. Mid-shading: only
cooperative group protocol. Darkest shading: entered into both protocol
and trial.
are treated at institutions that are participating in clinical trials
sponsored by the National Cancer Institute (NCI). In contrast,
only 10% of adolescents and 2% of young adults are entered
on to clinical trials of the paediatric or adult cooperative
groups (Figure 4). The ‘adolescent and young adult gap’
spares no geographic or ethnic regions and probably has many
causes [2, 48]. A perception of poor adolescent compliance to
complex protocols, avoidance of adding the burden of a trial
to a teenager struggling to cope with cancer, false belief that a
trial is not needed because of excellent prognosis, lack of
information about trial participation possibilities, lack of
access to trials and exclusion criteria commonly seen in paediatric or adult trials are some of these causes [49]. Accrual is
the lifeblood of clinical trials and lack of it will hinder the
development of more effective or less toxic treatment strategies. The more common occurrence of carcinomas, tumours
refractory to treatment once spread beyond the primary site,
and more aggressive course of a number of malignancies with
increasing age (ALL, embryonal tumours, CNS tumours, sarcomas) may be secondary factors contributing to the widening
gap in outcome improvement rates.
Late toxicity
Late toxic effects of aggressive treatment are dreaded and
have been well described in the medical literature. Surgery,
chemotherapy and radiotherapy have all been incriminated for
severe late effects, the frequency of which increases exponentially upon combination of the above [50, 51]. They are probably not as important anywhere as in the 15 –30 age group,
where most patients have an excellent outcome and delayed
normal tissue injury has ample opportunity to manifest itself
after several decades. The threat for toxic effects is often combined with risk-taking behaviour and unhealthy lifestyle of
cancer survivors, which augments normal tissue injury [52].
Aggressive surgery is frequently a cause of late effects interfering with a patient’s quality of life. Retroperitoneal lymphadenectomy causes ejaculatory dysfunction in up to 20 –30% of
youths with metastatic germ cell tumours, despite the improvement seen with application of nerve-sparing techniques [53].
Mutilating surgery in the limbs, head and neck or torso causes
disfigurement with resultant functional disabilities. Remarkable
progress has been made in the field with the advent of limbsparing surgery and adjustable endoprostheses.
Loss of fertility is frequently a dreaded consequence of chemotherapy in adolescents and young adults. The frequency,
degree and duration of infertility depend on the dose and type
of drugs administered, the patient’s age and the existing
malignancy. Infertility rates range from 20% to 90% for men
and 15% to 75% for females [54, 55]. Testicular, ovarian and
hypothalamic–pituitary irradiation are likely to cause permanent sterility, whereas Leydig cell function is more variably
affected [56]. Sperm banking, female germ cell banking and
hormone replacement are therapy issues as important as those
of antineoplastic treatment of the patient’s quality of life [57].
Despite lack of evidence supporting latent germ cell damage
[58], fears for teratogenesis or cancer in offspring of longterm survivors of adolescent cancer are common and parents
have to be reassured.
Doxorubicin-induced cardiac injury is more common with
cumulative administered doses in excess of 550 mg/m2 or
combination of anthracycline-containing chemotherapy with
mediastinal radiotherapy, in which case an increased risk of
4–10-fold has been described in the literature [59]. Radiation
therapy and chemotherapeutic agents such as bleomycin, highdose cyclophosphamide, nitrosoureas, busulphan may damage
the lungs, causing pulmonary fibrosis [60, 61]. CNS radiation
causes cerebral atrophy, demyelinisation, leucoencephalopathy
and neurocognitive defects with a frequency of 30 –70%
depending on young age, dose and combination with neurotoxic agents (ifosfamide, methotrexate, cytarabine) [62, 63].
Less common toxic effects include peripheral neuropathy, ototoxicity, Raynaud’s phenomenon, bladder constriction, intestinal fibrosis/obstruction, hepatotoxicity, xerostomia/dental
problems, post-radiotherapy neuropathic pain, femoral head
necrosis.
Undoubtedly the most dreaded complication of antineoplastic treatment is the occurrence of a second tumour. The occurrence of a second tumour in a patient cured from his primary
malignancy may be due to several factors. A chance occurrence, host susceptibility factors, genomic lesions and common environmental influences may all contribute. Still, there
is irrefutable evidence from case –control and prospective
studies that antineoplastic treatment increases the relative risk
of secondary malignancies. Adult survivors of Hodgkin’s disease treated with MOPP-like regimens with or without radiotherapy have a relative risk of 16 –66 for leukaemia, 3–35
for non-Hodgkin’s lymphoma and 3–13 for solid tumours
[64, 65]. An overall cumulative risk of 20% for any second
cancer has been reported at 25 years post-treatment. Causal
links have been established for radiation therapy with
187
sarcomas, thyroid cancer, breast cancer, lung cancer and
leukemias. Cytotoxic agents commonly incriminated for
carcinogenesis are alkylators and nitrosoureas [18, 50]. Cumulative drug dose, treatment duration, radiotherapy dose and
field volume as well as combined/sequential chemoradiotherapy are determinants of the risk. Minimising late toxicity
and carcinogenicity while maximising efficacy is one of the
toughest challenges that juvenile oncology has to meet so as
to offer teenagers and youths a safe prospect for cure.
Conclusions
In conclusion, a renewed focus on clinical research, coordinated support, safe and effective management of youngsters
with juvenile cancer is called on by many aspects of adolescent and young adulthood malignancies and its patients. Even
if medical aspects of individual diseases do not differ across
age groups, distinct tumour biology and epidemiology, need
for skilled intensive treatment, lack of clinical research, lack
of survival improvement comparable to paediatric patients,
requirement for intensive psychosocial-supportive care and
occurrence of late toxic effects are there. They are more than
good enough reasons for the oncologic community to take up
the call and lead the way for a multidisciplinary effort on optimising care and outcome for young patients full of hope and
expectations.
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