Introduction: The Ageless Quest to Understand Aging, but with a Malignant Twist

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“Youth is a gift of nature, Age is a work of art.”

Helen M. Carrall

For those of us who care for patients with cancer, and struggle to understand its nature, the myriad of issues complicating that quest requires dissection. The biological imperative of aging is one such issue. In this edition of Seminars in Radiation Oncology, more than 20 scientists and clinicians discuss the vagaries of cancer across the age spectrum. Although we provide evidence where it exists, we also speculate on that which is incompletely understood. Some of the questions we address include:

Rubin and Williams et al, pages 3-11, spearhead the quest by speculating on explanations for the varying incidence of cancers throughout the age spectrum. Cell division and differentiation occur in different temporal patterns according to the tissue type and host age. Mutational events leading to cancer may be random (and genetic) or due to exogenous toxins. Thus, the relationship between human age, tissue development, the body's attempt to maintain homeostasis, and the failure of these mechanisms (cell repair and senescence) on the observed distribution of cancers across the age spectrum, are explored. Children are afflicted by cancers that are associated with embryogenesis (eg, Wilms' tumor) or rapid organ growth (eg, osteosarcoma). However, in adults the art of aging can be derailed by exposure to alcohol and tobacco. Vulnerable tissues fail to repair the ensuing injury, resulting in lung and head and neck (H&N) cancers.

Paulino et al, pages 12-20, take a parallel approach to discerning the varying types of late effects that occur in different tissues across the age spectrum. Again, tissue developmental dynamics, the ability for cells to achieve homeostasis through cell repair, and the failure of these adaptations with senescence all influence the evolution of radiation-associated injury. Clear examples of this are impaired bone growth in children irradiated during their maturational spurts, in contrast to osteonecrosis from high doses in adults. Young children are more sensitive to neurocognitive sequelae from any radiation dose than are adults, presumably due to their more actively occurring synaptogenesis and myelinization. Even uterine development is impaired by radiation therapy, and thus aborted or premature births are more common in childhood cancer survivors who retain fertility after direct or scattered pelvic irradiation.

Krasin et al, pages 21-29, also contrast latent normal tissue injury in children compared with adults. With greater depth, they discuss the skeletal and pulmonary systems regarding the underlying biology and manifestation of tissue injury. They argue that pulmonary injury is an example of a normal tissue effect that shares a similar pathogenesis in children and adults, but notable differences due to complicating factors, such as impaired chest wall development in children, and exogenous toxins or comedical disabilities in adults. The authors also address systematic differences in discerning and describing late effects in these age groups. For example, different endpoints, risk intervals, and statistical considerations all affect the identifiable late effects.

Punnett et al, pages 30-44, discuss Hodgkin lymphoma (HL) across the age spectrum. Differences exist, according to age, in the likelihood of developing HL, the gender ratio, the most common histologic subtype, the underlying biology (eg, the role of Epstein–Barr virus), and the potential for cure. Why is HL among children more curable than among adults even when the therapeutic approaches are similar? Is this due to subtle differences in therapeutic aggressiveness, treatment tolerance, or something else? Certainly, differences in treatment strategy have evolved over the years, and this is primarily due to the vulnerability of children to the adverse effects of therapy, particularly radiation, when used with similar volumes or doses. In fact, the pediatric groups use somewhat different risk categorizations as well as treatment approaches, and this is outlined in the article.

Wolden and Alektiar, pages 45-51, discuss the different sarcomas that occur in children compared with adults. Of course, children more commonly develop chemotherapy-sensitive sarcomas, such as rhabdomyosarcoma and Ewing's family tumors, in contrast to adults who tend to develop other soft tissue sarcomas. These cancers vary in metastatic patterns and lymph node involvement. Higher radiation doses are used in adults for soft tissue sarcomas as compared with children, in part due to the different histologic types, but also tissue vulnerabilities to damage. More provocative are the similarities and differences in children vs adults when they are affected by and treated for an identical cancer type. Why do adults with rhabdomyosarcomas more commonly have higher risk features and a poorer outcome with similar therapies? These issues are explored but the answers are not necessarily clear.

H&N cancers are clearly different in adults compared with children. Epithelial H&N cancers are much more common in adults due the influence of toxins. When select H&N cancers occur in children (eg, nasopharyngeal carcinoma), is it the same cancer as in the adult? Marcus and Tishler, pages 52-54 discuss this and make observations relating to the differences in biology (such as associations with Epstein–Barr virus and genetics), geographic epidemiology (endemic vs epidemic), histologic subtype (undifferentiated vs well differentiated), and treatment outcome despite similar treatment approaches.

Brain tumors are a fascinating example of a group of tumors that occur with a whole spectrum of differences in children vs adults, as discussed by Merchant et al, pages 58-66. Glial tumors occur in all age groups, but the subtypes vary according to age, as do the locations (and this is even true for infants vs older children). Ependymomas and medulloblastomas are common in children but rare in adults, and the histologic variants of these tumors vary in different age groups. The likelihood of central nervous system dissemination also differs, though an explanation for this does not exist. Clearly, the therapy-associated toxicities are different, and this has had an enormous effect on the treatment approaches through-out the human lifespan. Most remarkable is the potential for cure, which seems to be superior in children vs adults for apparently identical tumor types.

Secondary cancers are the most agonizing late effect of cancer therapy, but also occur due to nontherapy related inherent tissue proclivities, genetics, and exogenous toxic exposures, as explored by Ng et al, pages 67-78. Tissue maturation and microenvironment, and patient lifestyles, all influence the development of second malignancies. Certain primary cancers that occur at any age, such as HL, are associated with different risks for select secondary cancers. Moreover, the risk for a secondary cancer is influenced by both the age at diagnosis of the primary cancer, and the attained age at diagnosis of the secondary cancer. Ng et al discuss the entire spectrum of these malignancies, and then focus on secondary breast, thyroid, and lung cancer, in their incidence, evolution, and outcome. The authors also address implications for surveillance.

In the classical art of antiquity, children were often depicted as small versions of adults. When we first identified cancer as a distinct disease and began to develop therapeutic strategies for its eradication, we treated afflicted children with approaches adapted from that suitable for adults. The treatment of pediatric HL in the 1960s is illustrative of this. As our understanding of cancer and the consequences of therapy (both good and bad) evolved, so did the treatment paradigms for children vs adults. It is gratifying that we are no longer in our own infancy regarding our appreciation of cancer as it affects patients of different ages. Yet we also recognize that age is a continuum, and categorizing humankind as children vs adults, not to mention the additional subdivisions of infancy, early and late childhood, adolescence, young and older adulthood, and the elderly, is somewhat artificial and arbitrary. What defines the transition from one phase to another? As is clear from the discussions in this issue of Seminars in Radiation Oncology, different cancers predominate at different ages, and the risks and types of normal tissue damage are also associated with developmental age and the capacity for cellular repair. But, have we answered the following question: “when the same cancer occurs at different ages, is it in fact “the same”?” For some cancers this is clearly not the case, whereas for others this may well be true. Unraveling the biological basis for cancer should clarify the effect of age on malignancy. The obverse may also be true: a greater understanding of the effect of age on malignancy may also enhance our quest to unravel its biology.

In closing, I would like to dedicate this issue of Seminars in Radiation Oncology to all of our patients, pausing to appreciate those children fortunate enough to have become adults, and those adults who retain a childlike enthusiasm for living despite the burden of malignancy. I also want to acknowledge Ms Laura Brumbaugh for her dedication and excellence in the preparation of this publication.