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Epidemiologia cancerului la copil.

Epidemiologia cancerelor la copil; date de bază de epidemiologie descriptivă, analitică şi experimentală

Epidemiologia cancerului la copil

Definitie epidemiologie:
Definitie incidenta:
Definitie prevalenta:
Incidenta: 16/100.000/ an
Există facotri care influențează tiparele de distribuție a cancerelor într-o populație dată.
Epidemiologie descriptivă – catalogarea acestor tipare de distribuție a cancerelor
Factorii sunt multipli, în interacțiune, endogenni și exogeni. Identificarea factorilor, a contribuției
acestora, și a interacțiunii dintre ei – epidemiologie analitică
Epidemiologie experimentală?

EPIDEMIOLOGIE DESCRIPTIVA
0-14 ani:
- LAL - cele mai frecvente (~25%) dintre cazurile nou dg
- LAM (~20%)
- Tumori SNC (~20%)
- Nb ~5%
- LNH ~5%
- Wilms ~5%
- Altele (2-4% fiecare)
o LH
o RMS
o Tumori de tesuturi moi non-RMS
o OS
 o RB

15-19 ani:
- LH 15%
- Tumori cu celule germinale 10%
- Tumori SNC 10%
- LNH 8%
- Cancer tiroidian 8%
- LAL 7%
- Melanom 5%
- LAM 4%
- OS 4%
- Sarcom Ewing 2%

Snc - în total locul 3

Incidenta mai mică în categoria 15-19 decât 0-14

Tumori mai frecvente la copii (SNC, neuroblastom, retinoblastom, hepatoblastom, Wilms) - rare
în segmentul 15-19ani

Sex
- <15a:
o predominanta masculină ÎN incidenta ÎN LAL, LyH, LNH, EWing, RMS,
hepatoblastom, carcinom nasofaringian;
o predominanta feminina în tiroida, wilms, celule germinale, melanom
- 15-19a: incidenta similara cu <15. Excepții:
A. LH - incidenta aprox egala între sexe
B.celule germinale - baieti de 3.5x mai mult
C. Osteosarcom - băieți de 2x mai mult

Rasa și etnicitate

SSE
Incidente mai mari în tari cu sse crescut, deși se estimează că cca 80% dintre cazuri apar în tarile
cu SSE mediu și mic - deficit de raportare

În funcție de zona geografica

0-14 ani
LA - cele mai frecvente
- Africa de N și Africa subsahariana - limfoame sunt mai prevalente decât în alte regiuni
(incidenta mai mare Burkitt)
Sarcoame de.tesuturi moi - mai frecvente în Africa subsahariana (sarcom Kaposi)

15-19 ani
În toate regiunile- cele mai frecvente: limfoame și Tumori epiteliale
Sarcoamele de tesuturi moi sunt mai frecvente în Africa Sub-Sahariana

Incidenta in creștere in toate zonele lumii (exceptie: Africa sub-sahariana - tratamentul HIV a
scazut incidenta sarcomului Kaposi)

Cea mai mare cauză de mortalitate prin boală la copii <15 ani (12%). Peste 15 ani - 5%

Supraviețuire
Improvements in survival rates have continued into the mid-2000s in the United States (Fig. 1.4),
with 3- and 5-year survival rates exceeding 80% for children and adolescents diagnosed during
this period.
Speranta De viata a atins 80%, pentru cei diagnosticati in 2005 to 2006

Supraviețuire la 5 ani
- cele mai bune pentru thyroid cancer, melanoma, Hodgkin lymphoma, germ cell tumors,
and ALL.
- The worst survival in this age group was seen among children diagnosed with AML and
RMS.

Supraviețuire la 5 ani for 15- to 19-year-olds were similar to those for younger children for most
cancer types, including thyroid cancer, melanoma, CNS tumors, Hodgkin lymphoma,
neuroblastoma, non-RMS soft-tissue sarcomas, and germ cell tumors.
Survival rates for 15- to 19-yearolds with ALL were lower than those for younger children,
which could be due in part to a higher proportion of cases with unfavorable biology among 15-
to 19-year-olds. A similar explanation may clarify the lower survival rates for 15- to 19-year-olds
with RMS. Five-year survival rates were also lower among adolescents diagnosed with Ewing
sarcoma, osteosarcoma, and AML.

Anual mor ~100.000 de copii (75% sub 15 ani)

Rata mortalității a scăzut în mare parte a lumii (Europa, America de N, Oceania, Japonia)
Mortalitatea - mai mică în tarile cu SSE mare - acces la tratament avansat
ANALITIC
Identificarea factorilor de risc, mai degraba decat descrierea distributiei bolii

Studii de tipul RCT nu au aplicare în etiologia cancerului (probleme etice/practicalitate)

Se utilizează studii observaționale pentru evaluarea factorilor de risc

Studiile observaționale – influențele cauzale ale factori de risc potențiali și pentru a le cuantifica
impactul
Inncorporarea caracteristicilor biologice si genetice care ar putea influenta susceptibilitatea la
cancer. – epidemiologie moleculară
Furthermore, there is a growing movement to integrate these data into a more comprehensive
approach in characterizing cancer risk (i.e., integrative molecular epidemiology). Such studies
aim to determine the roles of environmental and biologic factors in the initiation and
progression of the carcinogenic process. The approach of incorporating molecular markers in
epidemiologic studies of childhood cancer etiology shows promise for reducing cancer risk and
providing strategies for prevention. However, all subdisciplines of analytic epidemiology
(e.g., molecular epidemiology, environmental epidemiology) rely on well-designed
observational studies.

Tipuri de studii
Design Avantaje
Populaționale
1. Rapid de efectuat
1. Transversale =
cross-sectionale = de 2. Putin costisitoare
prevalenta 3. Eficiente in studii cu
supraviețuitori de
cancer
2. Caz-control (cel mai 1. Studiul a unei game
frecvent utilizate largi de expuneri
pentru depistarea (genetice/mediu) și a
factorilor de risc – rezultatelor (outcome)
de mediu/genetici) 2. Potrivit pentru studiul
rezultatelor rare
3. Cohorta 1. Potrivit pentru
studiul
expunerilor rare
2. Claritate pentru 2. Scumpe
relatie temprala
intre expunere si
rezultat
Dezavantaje
1. Relatie temporal greu de
stabilit
2. Analiza expunerilor
anterioare poate fi greu de
analizat
1. Dificultăți în
identificarea unui grup
de control valid
2. Recall-bias
1. Dificultati pentru
rezultate rare (cancere
pediatrice)
3. Cronofage
Familaile
Triada caz-părinâi (trio) 1. Potrivit pentru studiul 1. Nu poate studia efectul
bolilor genetice principal al expunerii la
moștenite factorii de mediu
2. Robust la stratificarea 2. Costisitor (genotipare)
populationala in studiul
bolilor genetice
moștenite

Transversale
In a cross-sectional study (or prevalence study), a sample of a reference population is assessed at
a given point in time, providing a “snapshot” of the population. In this way, demographic
characteristics, geographic patterns, and temporal trends can be determined.
Caz-control
A case–control study of childhood cancer identifies and recruits children (or their parents) who
are diagnosed within a defined population and time period. A similar group of children without
the disease, but from the same defined population (in time, location, and eligibility criteria) that
gave rise to the cases, are recruited to serve as controls. The investigator, as completely and
accurately as possible, uses self-report, health records, environmental measures, and biologic
specimens to reconstruct the cases’ prediagnosis exposure experience. Similarly, a “reference”
date substituting for a diagnosis date is assigned to each control child, whose exposure
experience before that date is reconstructed. The exposure frequency among the case group is
then compared statistically to the exposure frequency among the control group. The resultant
statistic, known as an odds ratio (OR), can approximate a relative risk (RR) and is a measure of
the strength of the association between the exposure and the disease.
The case–control design is also commonly used in genetic association studies of childhood
cancers, including genome-wide association studies (GWAS)
*Case–control studies of genetic risk factors are, however, vulnerable to a
type of confounding referred to as “population stratification bias,” in which a
false association between a genotype and disease, or the masking of a
genotypic effect, is induced by the existence of subgroups within a population
(e.g., different racial or ethnic groups) that have different genetic profiles
(i.e., genotypes) and frequencies of disease. However, the use of certain
statistical techniques (e.g., genotype-derived principal components analysis)
can be used to account for genetic ancestry in these assessments.
**A variation of the case–control design, referred to as the case-only study,
has also been useful in the study of childhood cancer. In a case-only
design, the entire sample consists of those with disease (i.e., cases).
Specifically, this design has been used extensively to evaluate gene–
environment interactions and gene–gene interactions because it offers better
precision than do traditional case–control approaches. Although the “main
effects” of individual genes or exposures cannot be evaluated in a case-only
study, this design is informative, because the assessment of interacting factors
(e.g., gene–environment and gene–gene interactions) is likely to be important
in determining susceptibility to childhood cancer.
Cohorta
Cohort studies evaluate subjects initially free of a specific disease of interest
and whose exposure status can be classified. Subjects are followed up for a
defined time period to ascertain differences in rates of end points attributable
to exposure, such as new events in or death from a specific disease. The
disease rate in the exposed group is then compared statistically to the rate in
the unexposed group. A prospective cohort study resembles a clinical trial,
but subjects are not randomly allocated to an exposure arm. Rather, exposure
(or lack of exposure) occurs “naturally” and the investigator uses variations
in natural exposure levels to evaluate differences in the risk of subsequent
disease occurrence during some follow-up period.
Typically, cohort studies of childhood cancer etiology are assembled by
record linkage rather than by active participation.
However, an important use of cohort studies is the assessment of late effects among childhood
cancer
survivors. Cohort studies can be prospective or retrospective in nature.
Prospective cohort studies involve active follow-up of subjects in real time,
as in clinical trials. Retrospective cohort studies use historical records to
identify the study population and to reconstruct their exposure and subsequent
disease experience.

Familiale
Family-based studies can be used to estimate familial recurrence risks,
assess inheritance patterns of disease, and identify genes that are linked to or
associated with a disease. Linkage-based approaches, many of which rely on
genomic sequencing, can be difficult and expensive to conduct for studies of
childhood cancer because of the rarity of families with multiple, available
affected relatives. In contrast, family-based genetic association studies,
which do not require the presence of multiple affected family members, are
well suited to the study of childhood cancer.
Trio caz-părinți – This design is particular useful for studies of childhood
cancer and conditions with early onset, because parents are generally
available. In addition, this design can be used to assess maternal genetic effects without
incurring additional genotyping expenses (i.e., in the case–control design,
evaluation of the maternal and case genotype would require genotyping cases
and controls as well as the mothers of these individuals).
*Variations on the
case-parent triad design include so-called hybrid-designs, which incorporate
aspects of both case–control and family-based designs.39,40 Also, despite the
name, incomplete trios can be included in analysis using techniques to infer
the probably genotype of missing individuals in the trio.

Aspecte metodologice ale studiilor epidemiologice în cancerele pediatrice

1. Mărimea eșantionului
Cancerele sunt rare
Poate fi dificil de studiat importanta factorilor de risc cu impact mediu/mic
 2. Definiția cazului
Currently, however, it is not completely understood whether these subgroups
of cancers should be “lumped” or “split” for analysis. Use of composite end
points (lumping) has the advantage of increasing statistical power, relative to
analyses based on the individual components (splitting), when the exposure
of interest has a similar effect on each of the component outcomes. However,
if the exposure effects are variable across end points, power can be reduced
and differences between the component end points, which might help clarify
disease mechanisms, can be obscured. The use of polytomous logistic
regression, which can be used to formally assess heterogeneity of the
exposure effect across the different components of a composite end point,55
may help resolve the lumping versus splitting issues in studies of childhood
cancer.

3. Analiza efectelor genetice materne (în studii de susceptibilitate genetic)

In general, epidemiologic studies of adult-onset cancers consider the
genotype, characteristics, and exposure histories of case individuals.
However, for childhood cancer, the exposure history of interest is often that
of the mother of the case and the effect of such exposures may be influenced
by the maternal genotype and other maternal characteristics

Factori de risc
1. Factori de mediu – influenta minima
a. Radiatii ionizante (10%)
b. Poluare – suspectat
c. Pesticide – suspectat
2. Sindroame genetice – 5-10%
a. Li-Fraumeni – osteosarcom, sarcoame de tesuturi moi, tumori
cerebrale
b. Sindroame cu imunodeficiență – leucemii, limfoame
c. Trisomii (13, 18, Klinefelter) – leucemii, tumori cu cellule
germinale, Wilms
3. Malformații congenitale – unul dintre cei mai puternici factori
 Malformatii congenital cu aberatii cromozomiale – 11.6 x pb%
de a dezvolta malignitate
 Malformatii congenital fara aberatii cromozomiale – 2.6 x pb%
de a dezvolta malignitate – hepatoblastom, neuroblastom
4. Variatie genetic comuna
GWAS – cnancere rare și commune.
An important concept in GWAS is the “common disease common variant” hypothesis whereby
common diseases are attributable, in part, to allelic variants present in more than 5% of the
population
GWAS of susceptibility to childhood cancers have been successful in spite of relatively small
sample sizes, primarily because effects seen are larger than for those identified in GWAS of
adult cancers
GWAS a fost efectuat pe
- LAL
- NB
- Ewing
- Wilms
- Osteosarcom
- HLH

GWAS for specific pediatric brain tumors have been especially difficult to conduct because of
the rarity of these tumors and the molecular heterogeneity discussed previously. In addition
GWAS are increasingly being used to determine factors such as response totherapy and relapse,
as well as late effects that are a consequence of
treatment.

Factori de risc pentru diferse forme de malignitate

- LAL
o Iradiere
o Rasa
o Boli genetice
o Greutate la nastere
- LAM
o Chimioterapie
o Boli genetice
- Tumori SNC
o Iradiere a capului
o Boli genetice
- LH
o AHC
o Infectii
- LNH
o Imunodeficiente
o Infectii
- OS
o Iradiere
o Chimio
o Boli genetice
- Sarcom Ewing – rasa
- Neuroblastom – necunoscut
- RB – necunoscut non-ereditar
- WT
o Anomali icongenitale
 o Rasa
- RMS
o Boli genetice
o Anomaii congenitale
- HB – boli genetice
- TCG - criptorhidie