Pediatric Growth and Development: Impact on Vulnerability to Normal Tissue Damage from Cancer Therapy



Fig. 3.1
Four classic growth curves according to age and organ size (Modified with permission from Tanner [26])




Table 3.1
Anatomy and physiology: relative rate of development























































































 
Age 0–5 years

Age 5–10 years

Age 10–15 years

Age 15 to adult

Brain

4

2

1

1

Thyroid

2

3

3

4

GI

4

3

3

2

Gonadal

1

1

4

4

Lung

3

2

3

4

Urinary system

4

3

3

2

Skin

3

2

4

4

Lymphoid tissues

4

4

Hypoplasia

Hypoplasia

Liver

4

2

3

2

Musculoskeletal

3

2

4

2

Head and neck

4

2

2

1

Circulatory

3

2

4

2


1 static, 2 mild, 3 moderate, 4 significant


In regard to potential late effects from cancer therapy, it is critical to understand that human development is not a linear or homogenous process, but instead that the organs of the body develop and mature at different rates and temporal sequences. Because of this, at any given time during child development, one can expect relative differences in the type and severity of possible late effects, with more pronounced and severe complications occurring if radiation is administered during the periods of increased mitotic activity and relative immaturity. These growth curves provide a context in which to explore and discuss the incidence and differential responses of children with respect to the normal tissue effects. However, it is important to note that these classic measures of growth and development focused primarily on increases in weight. Additional measures of physical size and physiologic function may in many cases provide more meaning metrics in regard to growth and maturity of organ systems and thus relative vulnerability to therapy in regard to subsequent late effects.


3.3.1 Classic Growth Patterns



3.3.1.1 Lymphoid Growth Pattern


This type of growth pattern is characterized by gradual evolution and involution to the time of puberty. An example of an organ that follows this pattern is the thymus. It reaches its greatest relative weight at birth, but its absolute weight continues to increase until the onset of puberty. In fact, in the renewal phase of adulthood, it is estimated that the thymus gland is only about 5–10 % of its original size. No significant late effects from RT occur in the lymphoid system. In particular, there are no age-specific effects, perhaps because the inherent radiation sensitivity of lymphoid tissues outweighs any differential that could be observed due to age.


3.3.1.2 Brain Growth Pattern


This type of growth pattern is characterized by rapid postnatal growth which slows down and is almost complete in adolescence. Naturally, the head and neck also follow this pattern of growth.

The brain is most sensitive to ionizing radiation in the early fetal period but also postnatally during the first few years of life. Brain growth during the first 3 years of life is not secondary to increase in number of neurons but due to axonal growth, dendritic arborization, and synaptogenesis. Myelinization, though well developed at about the second year of life, is not complete until the second to third decade of life [6]. By 6 years of age, the child’s brain has reached adult size. Several studies have shown greater cognitive impairment in younger children compared to older children receiving cranial irradiation [4, 22]. It is for this reason that for many years prior to the era of conformal radiotherapy, in an effort to avoid the deleterious effects of radiotherapy, chemotherapy after surgery was the treatment for children <3 years of age with medulloblastoma, ependymoma, and high-grade gliomas [7]. A report from St. Jude Children’s Research Hospital showed cognitive decline after conformal radiotherapy for children under 12 years of age with low-grade glioma (Fig. 3.2). In fact, age at time of irradiation was more important than radiation dose in predicting cognitive decline. Children <5 years old show the most cognitive decline [15]. Consistent with this, most children who are affected with radiation-induced moyamoya syndrome were irradiated when they were <5 years of age, a time when brain growth is rapid [5].

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Fig. 3.2
Intelligence quotient (IQ) scores after conformal radiotherapy in children with low-grade glioma (Reprinted with permission from Merchant et al. [15])

One study attributed a greater degree of deficient development with loss of white matter, and this was presumptively correlated with the impaired cognitive outcome of younger children [17]. This description of white matter changes is consistent with the classic finding after radiation insult of the normal brain of a focal or diffuse area of white matter necrosis [14]. It is also consistent with the premise that radiotherapy would have more effect during the time when there is greater growth of the brain. Table 3.2 shows the growth and development of the brain according to time of irradiation.


Table 3.2
Growth and development of the brain with respect to time of irradiation
































Phase

Time

Manifestation after radiation therapy

Preimplantation

First 2 weeks postconception

Death of preimplanted embryo

Prenatal organogenesis and fetal period

2 weeks to parturition

Microcephaly, mental retardation (greatest risk at 8–15 weeks postconception)

Neogenesis

Birth to 6 years

Mental retardation, severe cognitive deficits especially in children <3 years of age when myelin formation is still not nearly complete. Hypoplasia of the portion of the skull and soft tissues which receive radiation therapy

Genesis

6 years to puberty

Mild to moderate cognitive deficits. Mild or no hypoplasia of the skull as the brain reaches its adult size at 6 years of age

Pubogenesis

Puberty to 18 years

Mild cognitive deficits. No hypoplasia of the skull


3.3.1.3 General Growth Pattern (Musculoskeletal, Heart, Lungs, GI, GU)


This type of growth pattern is characterized by peak growth rates in the early postnatal period and during puberty. It is perhaps best exemplified by the musculoskeletal system; however, the liver and gastrointestinal tract, kidneys and urinary system, and skin also follow this pattern.

Radiation damage to bone is expressed in the epiphysis by arrested chondrogenesis, in the metaphysis by deficient absorptive processes in the calcified bone and cartilage, and in the diaphysis by an alteration in periosteal activity causing abnormal bone modeling [21]. Doses >20 Gy are usually necessary to arrest endochondral bone formation. In a classic study of spinal growth after radiotherapy, the greatest retardation of growth was seen during the periods of most active growth in children <6 years of age and those undergoing puberty [21]. In another study of slipped epiphysis secondary to radiation therapy, doses of >2,500 cGy and young age at time of irradiation were the main risk factors for this complication [24], which occurred in 50 % of children <4 years and 5 % of children 5–15 years of age. In contrast to children and adolescents, adult bone is much more tolerant to radiation damage; doses of 6,000 cGy or more are needed to cause osteoradionecrosis.

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Feb 18, 2017 | Posted by in ONCOLOGY | Comments Off on Pediatric Growth and Development: Impact on Vulnerability to Normal Tissue Damage from Cancer Therapy
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