Seminars in Radiation Oncology
Volume 20, Issue 1 , Pages 12-20, January 2010

Normal Tissue Development, Homeostasis, Senescence, and the Sensitivity to Radiation Injury Across the Age Spectrum

  • Arnold C. Paulino, MD

      Affiliations

    • Department of Radiation Oncology, The Methodist Hospital, Houston, TX
    • Department of Radiology and Pediatrics, Baylor College of Medicine, Houston, TX
    • ,
  • Louis S. Constine, MD

      Affiliations

    • Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY
    • Department of Pediatrics, University of Rochester Medical Center, Rochester, NY
    • Corresponding Author InformationAddress reprint requests to Louis S. Constine, MD, Department of Radiation Oncology, James P. Wilmot Cancer Center, University of Rochester Medical Center, 601 Elmwood Avenue, Box 647, Rochester, NY 14642
    • ,
  • Philip Rubin, MD

      Affiliations

    • Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY
    • ,
  • Jacqueline P. Williams, PhD

      Affiliations

    • Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY

Article Outline

Late effects in normal tissues following radiotherapy vary across the age spectrum. It seems that sensitivity to radiation injury is a function of the developmental dynamics and status of the organ, its regenerative potential, and ultimately the extent to which it has begun to senesce. For instance, organ maturational processes in children can be impaired or even disabled by radiation therapy, leading to a spectrum of effects that differ from those in adults, in which the capacity and means for tissues to repair damage are the predominant predictor for chronic injury. Thus, radiation-induced impairment of growth and maturation is unique to children, whereas organ damage, with tissue-specific dysfunction in repair processes, is common to both children and adults. Finally, the susceptibility to late effects in the elderly seems to involve not only a decline in their ability to repair damage, but also cell attrition, all intertwined with effects of comorbid illness that are frequent in this age group. The challenge for clinicians is to understand these differences in the sensitivity to radiation damage with respect to age to formulate a basis for modulating therapy that can rationally minimize late effects and maximize a survivor's quality of life.

 

It is intuitive that the risks from cancer therapy would differ between infants, children, adolescents, young adults, older adults, and the elderly people. In fact, the late effects of treatment, which occur months to years after therapy, have driven the evolution of treatment for many curable cancers across these age groups. Unfortunately, malignancies resistant to therapy have demanded an aggressive treatment approach that often resides on the edge of, or even exceeds, normal tissue tolerance. Thus, the potential to ameliorate or prevent such normal tissue damage, or to manage and rehabilitate affected patients, requires an understanding of normal tissue tolerances to therapy across the age spectrum.

The strategies for the treatment of several malignancies clearly reflect the evolutionary changes that have resulted from a demonstrated potential for curability, coincident with the recognition of normal tissue damage. In children, less radiotherapy (treatment volume and/or dose) in conjunction with chemotherapy has proven to be the sensible approach for tumors such as medulloblastoma, Hodgkin's lymphoma, Wilms' tumor, and intracranial germinoma. Similarly, in adults, organ preservation of the larynx, breast, bladder, and anal canal using radiotherapy, with or without chemotherapy to minimize the morbidity of surgery and loss of the affected organ, has been used in an effort to enhance quality of life. Adults with testicular cancer and lymphomas are also treated with lower radiation doses to avoid secondary neoplasms and other late toxicities from radiotherapy, although it is recognized that radiation is not the only cause of late effect induction.

It is the premise of this article that differences in tissue and organ development explain many of the susceptibilities to and manifestations of radiation-induced injury throughout the early years of life, whereas a differential ability to repair injury is the primary determinant of chronic tissue injury in the mature and senescing adult. We recognize the heterogeneity that exists between tissues and among critical cell populations that comprise tissues. Regardless, we have attempted to rationalize the observed similarities and differences to provide a framework for discussion of prevention and amelioration.

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The Biology of Late Effects: Cell Proliferation, Maturation, and Senescence 

The premise that the most critical radiation sensitive cell type within a tissue was its parenchymal cell population, and that dysfunction of this population was responsible for the manifestation of late toxicity, was a dogma for decades,1 although there was significant support for radiation-induced dysfunction in the microcirculation also providing a rational explanation.2 These concepts have now been tempered by the recognition that it is the interaction of multiple cell systems, affected through complex communications involving both intra- and extracellular signaling mechanisms, that results in radiation-induced changes.3, 4 Although the induction of radiation pneumonitis was believed to be a consequence of direct injury to the type II pneumocyte, other factors such as the activation and/or infiltration of other cell types,5 acute and chronic production of reactive oxygen species,6 hypoxia, and upregulation of both proinflammatory and profibrotic factors (such as tumor necrosis factor-α, the interleukins, and transforming growth factor-β7), are now believed to play critical roles in normal tissue responses.8, 9

In general, the manifestation of late effects is now observed to be the climax of a complex cell–cell signaling process that is affected by the tissue microenvironment, the competence of the immune system, and genetic factors. In addition, with respect to age span, the effects of radiation therapy are related to not only the developmental stage of the targeted tissue or organ itself, but also that of the other organs affected within the irradiated site. A primary example is the pulmonary consequences of chest irradiation in the child, which may differ significantly from the adult; however both adult and child will be prone to pulmonary consequences, such as inflammation and fibrosis, the child also will be susceptible to a direct restriction of lung compliance from bone hypoplasia and malformation in the developing ribs and spine, as well as indirect effects of compliance due to greater levels of atelectasis and air trapping.10 Such is not the case in the adult, where the bones are fully grown and hypoplasia and malformation are not an issue. However, comedical factors in the adult, such as smoking, will affect the risk of treatment-related pneumonitis,11 whereas in the elderly the capacity for tissue repair may be relatively limited.

In many (but not all) tissues, organ development goes hand in hand with cell growth, and cellular proliferation starts during the prenatal period. During the developmental period of each tissue, stem cells within the embryo will move beyond the pluripotent stage and, under the influence of intrinsic and extrinsic factors, will follow 1 of 2 paths: (a) towards self-renewal, ie, generation of more stem cells (multipotency), or (b) towards differentiation, thereby giving rise to a more specialized cell type or tissue (unipotency).12 Achieving a delicate balance between these 2 processes is critical for an organ to achieve homeostasis. Thus, both pathways are involved in growth as well as the repair and regeneration of tissues. It can be simplistically assumed that the downstream consequences from an injury, such as radiation, may be predicted from the response of the respective stem cell populations because stem cells and their progeny proliferate to ensure both organ growth and regeneration of injured and dying cells. However, as adulthood/full maturation is reached, each organ will be made up of a mosaic of both dividing and nondividing cells, not just within the tissue as a whole, but also within each of the representative cell populations. Non-dividing cells exist in several compartments: for example, some may be found resting in G0 phase, although not all of these are fully quiescent because some populations seem to be capable of reentering the cell cycle if the tissue is challenged or stimulated. After a partial hepatectomy or severe injury, hepatocytes enable liver regeneration through a proliferative process that is not dependent on a reserve of stem cells, but on participation from all mature liver cell types.13 Alternatively, nondividing cells can exist in a terminally differentiated form and will eventually die, without again dividing. Examples of these cells include the upper layers of the epidermis in skin and the tip of villi of the small intestine. Other nondividing cells do not enter G0 phase yet cannot be recalled into cell cycle, although they perform physiological functions, undergo maturation or cellular hypertrophy, and ultimately die; neurons and cardiac myocytes are examples of these cells.

Interestingly, for many years, it was thought that at birth the full complement of neurons and cardiac myocytes were present, and that neurons undergo maturation during synaptogenesis whereas cardiac myocytes undergo hypertrophy in response to environmental stimuli. However, we now know that this teaching is not completely true as both the brain and the heart seem to retain a degree of plasticity, and that both neurogenesis and myocyte proliferation have been reported in adults.14, 15, 16

In the final stages of life, nondividing cells may play a greater role in injury response as cells within the proliferative compartment move towards a permanent quiescent or senescent state. This “aging” process becomes critical following injury because, although senescent cells are capable of metabolic functions, they are no longer able to generate a proliferative response to an insult. In addition, we have become aware of accelerated changes that can occur within cell populations due to the induction of stress-induced premature senescence,17 particularly in endothelial cells accelerating the numbers of cells within a tissue and its supportive microvasculature that undergo death through senescence-associated pathways.18 Interestingly, senescent cells also secrete various factors that can inhibit the ability of neighboring cells to function, and can stimulate the proliferation and malignant progression of nearby cells. Hence, an accumulation of senescent cells may both compromise normal tissue function and facilitate cancer occurrence or progression,19 although others have suggested that senescence suppresses tumorigenesis.20 Therefore, late effects in the elderly population may be observed to be the result of an interplay between their declining ability to repair from cell injury together with their natural inclination to be moving towards a senescent state, which itself may be accelerated by irradiation.

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Revising the Classic Concepts of Radiosensitivity 

Classically, it was believed that radiation sensitivity (as measured by cell kill) was dependent on an actively proliferating compartment. Injured cells unsuccessfully attempted to complete division and thus resulted in mitotic cell death, whereas noncycling cells were radiation resistant. The classic laws of the French radiobiologists, Bergonié and Tribondeau (1906), provided the basis for this concept in stating that radiation has its largest affect on cells that are the least differentiated, have the greatest proliferative capacity (longest dividing future), and have the shortest cell cycle time; the least responsive cells are therefore those in which differentiation and function are established or fixed. Such a concept would suggest that most pediatric organs and tissues would demonstrate increased sensitivity relative to those found in adults due to the greater fraction of cells in growth phase and longest potential for mitotic replication.

However, we now understand that the consequence of injury at the cellular level is not only dependent on the above factors,21 but also cell type, age, and internal/external microenvironments.22 Furthermore, each cell's response can range from survival to proliferation to cell death, with the death pathways, including interphase cell death (apoptosis, autophagy), mitotic catastrophe, terminal growth arrest, and senescence. Therefore, any difference that is observed between children and adults is unlikely to be based on a “simple” singular factor, such as mitotic potential, but rather on a plethora of complex mechanisms.

Earlier, we mentioned 1 example of how our understanding of the rules governing radiation sensitivity has been modified, and that is the response of some normal proliferating cells to radiation by transitioning to a quiescent (or senescent) state. This outcome is no longer observed to be an effect on telomerase, as was originally described by Hayflick and Moorehead,23 but through the induction of stress-induced premature senescence, an outcome that itself is dependent on the balance between p53-ARF and pRB-p16 signaling pathways. Of course, an alternative response in proliferating cells is to transition into a postmitotic or differentiated stage, and it is apparent that either of these transitional responses (premature senescence or differentiation) would have an entirely different consequence on tissue integrity and function in an immature, proliferating tissue (in a child) compared with a fully mature tissue, where most cells are differentiated and largely quiescent. Finally, not even the concept of differentiation as a function of radiosensitivity has stood the test of time. We now know that stem cells, the least differentiated cells in the mature organism, are frequently in a quiescent state and exist within a relatively radiation resistant hypoxic niche. This emphasizes the role that microenvironment may play in response to injury.24, 25

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Sensitivity to Radiation Injury According to Developmental Dynamics 

To discuss the differential changes in response to injury across the lifespan, we must first define the principal developmental periods.

Embryo and Fetus 

The period in utero can be divided into 3 phases: preimplantation, prenatal organogenesis, and the fetal period.26 Preimplantation occurs from the time of fertilization to implantation at 2 weeks postconception. This is the most radiosensitive phase, usually resulting in embryonic loss. The irradiated preimplanted embryo that survives until term grows normally in the pre-partum and post-partum periods. Prenatal organogenesis occurs from implantation to about 60 days postconception, during which organ differentiation is active. This is the most sensitive phase for the induction of malformations, particularly in the brain, skeleton, eye, teeth, and genitalia. For example, the incidence of microcephaly was greatest in atomic bomb survivors exposed at 6- to 11-week gestation.27 The fetal period occurs from 60 days after conception through parturition. Body and organ growth problems from radiation exposure are predominant as differentiation becomes more complete. Structural malformations become less common whereas disturbances of growth are more prominent.

Postnatal Period and Childhood 

The postnatal period and childhood occurs from the time of birth to the beginning of the adult stage of life. This period is divided into 3 phases: infancy/early childhood, late childhood, and puberty. Different organs develop at different rates during these phases; hence the effects of irradiation are dependent on the time of exposure.

Infancy/early childhood occurs from the time of birth to approximately 6 years of age. Normal tissues are newly formed and development occurs through cell replication or hypertrophy, depending on the organ.

The late childhood years are between 6 years of age and just before the onset of puberty. Several organs now have their full complement of functional subunits, and growth is less robust during this time. Irradiation at this time will be less deleterious as the mitotic activity is diminished.

Puberty occurs during the time from onset of puberty into adolescence. The functional subunit complement is complete for most organs with the exception of the musculoskeletal system, breast tissue, and genitalia; for these latter organs or organ systems, radiation injury causes more late effects than during the early childhood phase.

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The Predominant Patterns of Tissue/Organ Development and Radiation Sensitivity 

During childhood and adolescence, normal tissues in the body follow 1 of 4 general classic growth patterns (Fig. 1). The rapid growth of normal tissues also seems to coincide with the periods for susceptibility to develop neoplasia as discussed in the previous article. The 4 classic growth curves are as follows: (1) lymphoid, (2) neural (brain), (3) musculoskeletal, and (4) gonadal.

Lymphoid Growth Pattern 

This is characterized by a log phase growth that peaks early and involutes at the time of puberty. The thymus, a lymphoid organ responsible for T-cell differentiation, is a classic example of this pattern of growth. It reaches its greatest relative weight at the time of birth, but its absolute weight continues to increase until the onset of puberty. Thereafter, it begins to undergo an involution and progressively decreases in size throughout adult life.

Neural Growth Pattern 

This is characterized by rapid postnatal growth, which slows in adolescence. The most active phases of synaptogenesis and myelinization are in the first 5 years, but continue for the subsequent 2 to 3 decades without significant volumetric changes. Other organs that develop according to this pattern are the liver, kidney, heart, and lung.

Musculoskeletal Growth Pattern 

Also called the general growth pattern, this is the classic example of this type with 2 growth peaks: 1 during the early postnatal period and the other at the onset of puberty. The gastrointestinal, head and neck, skin, and circulatory systems also follow this general growth pattern.

Gonadal Growth Pattern 

This is characterized by small change during early life, but rapid development just before and coincident with puberty. Examples of organs with this growth pattern are the testicle, ovary, and breast.

These growth curves provide us with a context in which to discuss the incidence and differential responses of children with respect to the normal tissue effects.

Lymphoid 

Age specific late effects related to the lymphoid system are not clearly described. It may be that the inherent radiation sensitivity of lymphoid tissue may outweigh any differential that could be observed due to age.

Neural (Brain) 

Although the brain is most sensitive to the effects of ionizing radiation during the early fetal period, because of early postnatal growth it is extremely sensitive during the first few years of life (Fig. 1). Several studies have shown that age at the time of irradiation has a significant effect on cognitive function in children with brain tumors (Fig. 2). For example, a study from investigators at St. Jude Children's Hospital evaluated 87 children with ependymoma treated with conformal radiotherapy to doses ranging from 54 to 59.4 Gy. Although cognitive testing revealed that math and spelling scores remained stable at a median follow-up time of 59.6 months, the reading scores deteriorated, particularly in children irradiated at <5 years of age.28 Another study from the Children's Cancer Group showed that the non-verbal intelligence quotient (IQ) decline was worse in children receiving craniospinal followed by posterior fossa boost for medulloblastoma when their age was <7 years at time of radiotherapy.29 Investigators from the Children's Hospital of Philadelphia found that children <7 years of age at time of cranial irradiation had a mean full-scale IQ decline of 25 points 2 years after treatment.30

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  • Figure 2. 

    Intelligence quotient of 10 patients age <5 years at diagnosis, 8 of 10 whom were irradiated at age <5 years. Circles are patients age >5 years at diagnosis, and squares are patients age <5 years at diagnosis. Regression line also indicated (r = 0.22; P = 0.3). (Modified from BMC Cancer 8:15, 2008.)

In older children with intracranial germinoma receiving cranial irradiation, Merchant et al31 did not find a significant decline in full-scale verbal and performance IQs between pre- and post-irradiation. It is not surprising that many strategies have omitted or deferred radiotherapy in young children (<3 years of age) with brain tumors because of clinicians' fear of neurocognitive toxicity.32 The circle of Willis is also most affected when the radiotherapy insult occurs during the most rapid period of brain growth. Finally, a report has shown that radiation-induced Moyamoya syndrome is most common in children irradiated to the parasellar region at <5 years of age.33

The kidney also follows the same neural growth pattern as the brain. There are differences in the incidence of radiation nephropathy according to age at the time of irradiation, particularly during the first few years of life.34 Peschel et al35 have previously demonstrated the possibility of lower tolerance doses for renal preservation in very young children with stage IVS neuroblastoma treated for hepatomegaly. Children aged <5 years undergoing total body irradiation have been found to be more susceptible to renal dysfunction compared with children ≥5 years.36

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Musculoskeletal 

The vulnerability of this tissue to radiation injury reflects its developmental dynamics; greater sensitivity exists during periods of rapid growth. As can be observed in the musculoskeletal growth curve (Fig. 1), bone growth does not occur at a gradual rate. There is accelerated growth from birth to about 5 years old, steady slow growth from 5 to 10 years old, and accelerated growth during the pubertal years. The various bones grow in parallel to the muscles, and their potential for volumetric change directly mirrors their potential for growth retardation (Fig. 3). 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 modeling37; doses >20 Gy are necessary to arrest endochondral bone formation. In a classic study of spinal growth after radiotherapy, the greatest retardation of growth was observed during the periods of most active growth in children <6 years and those undergoing puberty.38 The only exception may be in young children where doses <20 Gy have been shown to be capable of retarding bone growth, and in particular causing scoliotic changes in irradiated spine. For instance, in a study of 58 children with a median age of 6 months, the dose delivered to the spine was predictive of risk of scoliosis with the 15 year scoliosis-free rates for children treated with <17.5 Gy, 17.6 to 23 Gy, and >23 Gy being 87.5%, 51.4% and 44.4%, respectively.37 In another study of slipped epiphysis secondary to radiation therapy, doses >25 Gy and young age at the time of irradiation were the main risk factors for this complication, occurring in 50% of children <4 years and 5% of children 5 to 15 years of age. Vulnerability for slippage was also seen just before puberty.39 Muscular growth parallels bone growth and is bimodal, again occurring during the early postnatal and pubertal periods. Muscular hypoplasia and atrophy have been reported in young children receiving radiotherapy to the spine and extremities.38, 40

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  • Figure 3. 

    Polarity and amplification of skeletal bone growth and modeling. Different bones have different growth potentials, and their directional growth varies according to the location and orientation of the growth center. (Modified from Dynamic Classification of Bone Dysplasias, 1969.)

Gonadal 

In contrast to the musculoskeletal growth curve, gonadal growth is characterized by small change during early life. Instead, there is rapid development just before and coincident with puberty. This may explain why, unlike in other sites where children are more vulnerable to the late effects of radiotherapy compared with their adult counterparts, the ovary is different with respect to sterility (Fig. 4). The ovary contains a fixed pool of primordial oocytes, maximal at 5 months of gestational age, declining with increasing age in an exponential fashion, culminating at menopause. In contrast to other organs that are able to maintain homeostasis, the ovary does not replenish oocytes, similar to other organs in cellular senescence during the past years. A classic study by Wallace et al41 showed that the effective sterilizing dose to the ovary after fractionated radiotherapy decreased at increasing age of irradiation: 20.3 Gy at birth, 18.4 Gy at 10 years, 16.5 Gy at 20 years, and 14.3 Gy at 30 years of age. This finding is also supported by the Childhood Cancer Survivor Study, which showed that cyclophosphamide exposure was a risk factor for sterility only in older (13-20 years), but not younger (<13 years) children.42 Finally, data exist showing that ovarian dysfunction may be less in children receiving total body irradiation at an age before menarche, compared with those who were older and received radiotherapy after menarche,43 although this difference is temporary as longer follow-up of patients reveal the same incidence of permanent ovarian dysfunction.

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  • Figure 4. 

    Ovarian failure. The number of oocytes progressively diminishes throughout human maturation, and radiation-induced sterility seems to be correlated with oocyte number. (Modified from Cyclic histology and cytology of the genital tract, Novak's Textbook of Gynecology, 1988.)

The uterus develops in parallel to other gonadal tissues and, again, radiation effects are dependent on the time of irradiation. In a report by Larsen et al,44 100 childhood cancer survivors were evaluated using transvaginal sonography. Uterine volume decreased from 47 mL in unirradiated patients to 13 mL in young children who were irradiated. In addition, there was a significant increase in midtrimester abortions in patients who had higher uterine radiation exposure compared with those who did not. Thus, uterine irradiation in childhood may reduce adult uterine volume, which could lead to adverse pregnancy outcomes.

Children and adults have different manifestations of late radiation injury in the breast, with breast hypoplasia being the most common type of late toxicity in children. In 129 children, <4 years of age receiving a mean dose of 2.3 Gy for hemangioma, breast hypoplasia was observed in 53%.45 Others have also observed breast hypoplasia after relatively low doses of radiation, such as for pulmonary metastases from Wilms' tumor where children receive bilateral lung irradiation to doses of 10 to 12 Gy.46 Although the dose was quite low, the breast in the young has not fully developed, with hyperplasia of the breast not occurring till puberty.

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Adulthood 

In the animal kingdom, biological adulthood starts once the capacity to reproduce has been attained with physical maturation typically occurring between the ages of 15 to 25 years. Therefore, the exact age when one can be called a biological adult will differ from person to person. In the adult, complete normal tissue development has been largely attained and regeneration through homeostasis becomes the predominant mechanism for self-renewal or maintenance of the organs.

Radiotherapy during adulthood will lead to tissue reactions that are usually inflammatory and fibrogenic in nature, although the individual cells' responses to radiation or other toxic events can vary significantly. The overwhelming significance of both the inflammatory and fibrotic processes in adult patients has been recognized by several investigators who have demonstrated that individuals' responses can be predicted from their pre-and/or post-treatment expression of critical signaling factors.47, 48 At the cellular level, the response to radiation-induced damage can be summarized as complete repair, restoring the cell and tissue to its basal state; or if irreparable, can result in cell death (apoptosis), senescence, or even an oncogenic mutation. Division by a neighboring cell, stem cell, or progenitor cell may replace cells lost to apoptosis. However, senescent cells may not be readily replaced, and their number will increase with age. In addition, if there is a sufficient level of damage, the amount of cell death through mitotic catastrophe or apoptotic pathways may overwhelm the tissue's ability to mount a complete response, leading to a microenvironment that will support tissue remodeling and inflammation rather than healing.

In general, 3 phases during adulthood have been described in relation to the ability to repair and regenerate: regeneration, degeneration, and senescence:

The regenerative phase starts from the beginning of adulthood to about 45 years of age. This is a time when functional subunits may be replaced, and repair of tissues is rapid. Normal tissues seem largely regenerative and capable of preserving organ function. A homeostatic state is achieved to ensure survival of the species.

The degenerative phase refers to the period from 45 to 70 years of age in which cellular senescence starts and normal tissue regeneration starts losing its capacity to restore cells. The balance during younger age periods, when repair and maintenance exceeds loss, slowly shifts after full reproductive capacity has been achieved to a state where cell loss begins to exceed repair capacity. As a result, some parenchymal atrophy begins.

The senescent phase refers to the period from 70 years to death of the adult. In this phase, homeostasis is disrupted by the inability of the organ to keep up with cell loss. Cellular senescence is the phenomenon where normal diploid differentiated cells lose their ability to divide, normally after about 50 cell divisions in vitro.49 In general, the number of senescent cells increases with age.50 Comorbidities, such as hypertension, diabetes, and other chronic diseases confound this phase. As a result, normal tissue atrophy occurs because hypertrophy or hyperplasia fail to compensate for functional subunit loss. It is noteworthy, though obvious that different organs do not senesce at the same rate within the same individual.51

Although the predominant type of late effects in children result from disturbances in the maturation of an organ, the corresponding late reactions in adults are more pathologic in nature and are typified by inflammatory, atrophic, or fibrotic reactions. Inflammation is frequently present in the delayed radiation injury response in the adult, although a consistent feature is the lack or paucity of cellular response with stromal reactions often devoid of granulocytes and demonstrating only a few macrophages and lymphocytes.52 Fibrinous exudate in the stroma is highly characteristic of radiation-related late toxicity. Atrophic changes can occur throughout the lining epithelium of the alimentary, respiratory, and urinary tracts, as well as salivary, pancreatic, mammary, and cutaneous tissues. These can also be observed in the parenchyma of organs, such as the kidney and lung. Examples of fibrotic type of late radiation effects include pharyngeal, esophageal, bronchial, and intestinal stricture as well as pulmonary fibrosis. These changes can lead to organ dysfunction, including dysphagia, dyspnea, and bowel obstruction. Submucosal fibrosis is the major cause of bowel stricture, although serosal and perirectal fibrosis contributes to its degree of severity.

Neural (Brain) 

Although cognitive dysfunction has been of major concern in children in the past, deficits in neurocognitive function after brain irradiation are now of increasing concern in adults.53, 54 Although the brain loses neurons throughout life, it is now believed to have some capacity for neurogenesis, as described earlier. Neurogenesis in humans is significantly impaired after treatment of malignant brain tumors with radiation therapy and has previously been observed in both adults and children.55 Advancements also have shown that inhibition of hippocampal neurogenesis is involved in the pathogenesis of memory decline after cranial irradiation, and is mediated by perturbation of the neurogenic microenvironment by microglial inflammation.55

In adult patients with limited stage small cell lung cancer, prophylactic cranial irradiation has been used to lower the chance of developing brain metastases. Although neurocognitive testing before radiotherapy indicates that a substantial portion of patients have neurocognitive impairment at baseline, discerning the true neurocognitive effect of radiation has proven difficult.56, 57 An extension of this is that neurocognitive decline in adults has been observed in patients with progression of brain metastases. In fact, disease progression may be the greatest instigator of cognitive decline in adults treated with whole brain radiotherapy for brain metastases. Two hundred eight patients with brain metastases treated with whole brain radiotherapy were assessed with neurocognitive testing (memory, executive function, and fine motor coordination); tumor shrinkage correlated with preservation of executive function and fine motor coordination.58 A study from Aoyama et al59 showed that the average duration before neurocognitive decline as measured by a mini-mental status examination was 16.5 months in those receiving whole brain radiotherapy and stereotactic radiosurgery (SRS), vs 7.6 months for those receiving SRS alone because of more recurrences in the SRS group.

However, observations of brain late effects in adults must be assessed in the context of the changes in the brain that occur with age; these are manifold, complicating interpretations following irradiation. For example, loss of brain weight is accelerated after age 60 years due to factors including cell loss, loss of myelin that surrounds nerve-fibers, and shrinkage of dendrites. In addition, several confounding factors related to decreased integrity and function of cells are present in adults, secondary to aging and other diseases that result in a loss of neurons and a decreased ability to repair damage and maintain homeostasis. A final complication is the development of atherosclerosis, resulting in diminished blood flow. Therefore, in adults, the mechanism for neurocognitive decline is highly complex and related to multiple confounding factors, such as impairment of neurogenesis, aging with loss of neurons, myelin and synaptic density, and medical comorbidities.

Among other organs that conform to the neural growth curve is the kidney. Its weight and volume actually decreases by 20% to 30% during adult life, mainly in the outer portion of the kidney, where entire nephrons disappear and are replaced by scar tissue. The number of scarred glomeruli increases with age, being approximately 5% of the total at age 40, but 35% to 40% at age 90.60 Coupled with other typical medical comorbidities, such as hypertension, diabetes, and atherosclerosis, the kidney tolerance of an elderly person to radiotherapy is likely to be lower than a young adult.

Musculoskeletal 

Moving on to those organs associated with the musculoskeletal growth curve, from 18 to 20 years of age bone density is at its maximum, and there is uniform compact appearance to the shafts of long bones in x-rays.60 Bone is continuously remodeled by resorption of older or damaged sections and secretion of new bone by osteoblasts. In early adult life, about 10% of bone is remodeled annually; however with age, the activity of osteoclasts increases and that of osteoblast decreases, leading to overall resorption of bone. Damage to the adult bone does not usually occur after doses of 20 to 30 Gy, such as was observed in children where there is stunting and/or inhibition of bone growth. Instead, radiation-induced effects are not observed until doses ≥60 Gy are reached, at which point there will be development of osteonecrosis and fracture61 presumably due to an effect on the vasculature, although these observations are somewhat confounded in some patient populations due to the use of bisphosphonates.62 Like the adult brain, several confounding factors in elderly adults can influence bone late effects, such as aging, osteoporosis, and trauma.

In the adult patient, muscular hypoplasia is not the main problem following irradiation as is observed in children, but instead it is soft tissue fibrosis and atrophy.63 Collagen stiffening and loss of elasticity occurs in the connective tissue as 1 ages, leading to decreased integrity and function. Radiotherapy can further potentiate connective tissue damage by destroying vasculature. As muscle cells die, muscular hypertrophy to maintain homeostasis becomes less common, resulting in atrophy of tissue. Lack of exercise and use of a particular muscle, denervation, and malnutrition can be confounding factors in the elderly people and are likely to potentiate atrophy in irradiated muscular tissue.64

Gonadal 

As previously discussed, the propensity to radiation-induced infertility may be greater in older women due to the decreased number of oocytes. The breast, being fully developed, is at risk for different manifestations of late radiation injury compared with children. For example, in adults telangiectasia and fibrosis can occur, as well as lymphedema and fat necrosis.65 These effects are frequently observed in women who received higher doses of radiation, such as for breast conservation patients who have received 45 to 50 Gy to the entire breast followed by another 10 to 20 Gy to the tumor bed.66 Because the uterus is fully developed in adulthood, its development and ultimate volume would not be limited by radiation exposure, although its vasculature could be affected by high doses, increasing the potential for uterine insufficiency and premature delivery. However, because most patients treated with doses capable of causing this complication would also experience ovarian-associated infertility, uterine insufficiency has not been well studied in adults.

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Conclusions 

Normal tissue late effects from radiotherapy vary across the age spectrum. Differences in organ development and tissue repair in children and adults have a significant effect on the expression of radiation injury. Although the susceptibility of children to radiation injury involves normal tissues that are not fully developed or matured, the susceptibility of adults includes a declining ability to repair damage that is further complicated by cell loss, senescence, and associated comorbid illness. The resulting manifestation of injury in the child includes changes in growth patterns and delays (or even cessation) in maturation of the irradiated organ or tissue, whereas in adults and the elderly people the resulting late effects are usually fibrogenic and/or inflammatory and contribute to loss of function.

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PII: S1053-4296(09)00062-9

doi:10.1016/j.semradonc.2009.08.003

Seminars in Radiation Oncology
Volume 20, Issue 1 , Pages 12-20, January 2010

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