Anatomy and Physiology

The retina is a thin, transparent structure that functions to convert light energy into electrical stimuli for the brain to interpret. The macula, located temporal to the optic disc, is responsible for central vision and contains the highest concentration of photoreceptors. The blood-retina barrier, which is analogous to the blood-brain barrier, protects the retina. It is very sensitive to changes in vascular permeability that can lead to swelling of the retinal layers (i.e. macular edema). The...

Osteopenia

Osteopenia after cancer therapy may be prevented by maintaining optimal calcium (1500 mg daily) and vitamin D (400 units daily) in the diet. Nutritional supplements may be needed in cases of osteopenia that is unresponsive to behavioral and dietary management. In addition, early diagnosis and replacement of hormone deficiencies will benefit bone min- obesity in individual patients. If the obesity is exogenous, and hyperinsulinemia is a consequence of the obesity and insulin resistance,...

X

- a CM cardiomyopathy b CAD coronary artery disease c CD cardiac death d X associations of specific risk factors with specific presentation e likely unknown but likely association f - No known association - a CM cardiomyopathy b CAD coronary artery disease c CD cardiac death d X associations of specific risk factors with specific presentation e likely unknown but likely association f - No known association fied from Fajardo and Stewart 23 includes acute pericarditis during irradiation (rare and...

Coronary Artery Disease

A cardiologist should follow all patients with known coronary artery disease (CAD). Clinical evaluation includes both the regular workup for CAD and a full evaluation to look for other manifestations of cancer therapy-related cardiotoxicity. In the general work-up for CAD,resting ECG and ECHO are performed, as well as an ECG stress test (with or without an imaging study with exercise). The presence of ischemic changes and exercise-induced arrhythmias can be detected by an ECG stress test....

Bone and Connective Tissue

Irradiation of growing bone causes injury to actively dividing mesenchymal cells, osteoblasts and endo-thelial cells 20 it also causes impairment of the osteoid formation. The long-term injury observed in irradiated growth centers includes atrophy, fibrosis of marrow spaces and a lack of osteocytes. Impaired vascularity and fibrosis of both periosteum and endosteum can occur. The soft tissues may also be affected by radiation. Fibrosis occurs as a consequence of increased fibrob-last...

Detection and Screening

Screening of childhood cancer survivors treated with hepatotoxic chemotherapy and radiation therapy should begin with a thorough physical examination (Table 12.1). Physical findings suggesting liver dysfunction, e. g. spider angioma, palmar erythema, hepatomegaly, splenomegaly, icterus or ascites, may be observed in individuals with long-standing liver dysfunction associated with significant hepatitic fibrosis. Patients transfused with any blood product before implementation of blood donor...

Dysrhythmia Conduction Abnormalities

Life-threatening arrhythmia and conduction disturbances are rare and occur years after radiation exposure. They are different from the frequent, asymptomatic, nonspecific and transient repolarization abnormalities seen shortly after irradiation 50 . Serious abnormalities reported after radiotherapy include atrioventricular nodal bradycardia, all levels of heart block - including complete heart block 103, 104 - and sick sinus syndrome 66,104 .In their case series report and review of the...

Acute Radiation Effects

The corneal epithelium is adversely affected after RT doses of 10-20 Gy. Early effects include epithelial defects, keratitis and decreased corneal sensation. When the tear film production or integrity is reduced, the epithelial cells become fragile and loosely adherent to themselves and the underlying stromal bed, resulting in epithelial defects. Patients with this problem will complain of ocular discomfort, foreign body sensation, excess reflex tearing and blurry vision. Acute keratitis is...

Screening for Preclinical Injury

Because the kidneys have a large functional reserve, clinical renal function usually remains normal until there is serious derangement of glomerular or tubular function. Urinalysis is not very quantitative, but it is the cheapest, simplest and most useful test - along with the assessment of blood pressure - for periodically re-evaluating patients for the development of nephropathy. Elevated serum concentrations of blood urea nitrogen (BUN) and creatinine suggest a need for a more accurate...

Disease Considerations

The late toxicities manifested by the CNS are best considered as a combination of several factors acting in a unique host. Certainly the therapy applied to treat the primary disease can have late manifestations however, the primary disease process will also impact on the late effects. Children with leukemia and brain tumors comprise over 50 of all children with newly- diagnosed cancer 10 and represent the majority of long-term survivors. These children, and children with other neoplasms...

Radiation

The majority of reports describing acute radiation hepatopathy in pediatric patients involve obsolete radiation technology and treatment approaches. Persistent or late-onset radiation hepatopathy after contemporary treatment is uncommon in the absence of other predisposing conditions, for example, viral hepatitis. The low frequency of hepatopathy after contemporary radiation suggests complete resolution of acute hepatic injury, but this has not been confirmed in prospective studies. The liver...

Spinal Sequelae

The evaluation of spinal sequelae should include the region of curvature, the magnitude of the curve, the deviation from vertical, the degree of shoulder asymmetry, the position of any rib humps or rib flare, and the type and degree of any gait abnormality. Usually the best way to examine the back is with the patient bending over with the arms touching the toes and the knees straight. At each visit, measurements should be taken of the standing and sitting heights. The spinal shortening that...

Second Transition Period Young Adulthood

As the survivor enters late adolescence and young adulthood, she and her family embark upon the second critical transition period 7 . This is a develop-mentally important time in the life of the survivor, as she begins exerting her independence and becomes responsible for her own healthcare. How the cancer experience influences the health practices and behaviors of the parent of an adolescent with cancer (e.g. preventive periodic health examination, completion of cancer screening tests, tobacco...

Pericarditis

Historically, pericarditis was the most common sequelae of radiotherapy to the chest, occurring in 20-40 of Hodgkin's disease patients 79-81 . However, reports from one center employing modern techniques - including equally-weighted anterior and posterior fields, daily fraction sizes of 2.0 Gy or less and subcarinal blocking - showed a decrease in the frequency of pericarditis from 20 to 2.5 80 . Pericarditis can remain clinically silent, or it can present with sudden onset of fever, dyspnea,...

Management of Delayed Puberty

Female patients exposed to gonadal toxic therapies during the prepubertal period and who are not progressing appropriately through puberty should be promptly referred to a pediatric endocrinologist for further evaluation and treatment. The use of hormonal replacement therapy for induction and progression of puberty must be closely monitored together with skeletal growth, as the two processes are closely linked. Generally, the recommendation will be to initiate a regimen of hormone replacement...

Growth

The grow of those who have undergone an HSCT is affected by many factors, including genetic, nutritional, hormonal and therapeutic factors. Effects are most commonly attributed to radiation of the hypo-thalamic pituitary axis, which can result in either growth hormone deficiency or abnormal secretion of growth hormone. Direct impairment of bone growth may also occur. The risk of growth failure is enhanced by TBI and by cranial irradiation as a component of prior therapy. Higher risk is also...

Of Normal Gonadal Development

Although the chromosomal and genetic sex of an embryo is determined at fertilization, male and female morphological sexual characteristics do not differ until the seventh week of gestation 51 . This initial period of early genital development is referred to as the indifferent stage of sexual development. During the fifth week, proliferation of the mesothelial cells and of the underlying mesenchyme produces a bulge on the medial side of the mesonephros, known as the gonadal ridge. Next,...

Skin and Mucous Membranes

Mucosal atrophy after conventionally fractionated doses of 60-70 Gy over a period of 6-7 weeks is com-mon,but necrosis, chronic ulceration and bone exposure rarely occur unless the delivery of dose is accelerated or the total dose exceeds 70 Gy in 7 wks 7 . Thrombosis of small blood vessels in the submucosa results in ischemia and the consequent appearance of ulcers and telangiectasias. This condition may become apparent as soon as six months after irradia tion or as late as 1-5 years and is...

Management of Established Problems 16351 Management and Rehabilitation

Although the acute effects of irradiation are less common now, they can be alarming when they occur. It is important to remember that healing will generally occur spontaneously within 2- 4 weeks. There is no clinically accepted way to reverse late radiation skin changes, though celecoxib has been reported to decrease skin damage after radiation in mice 30 .Because of the lack of sebaceous secretions after treatment, it may be helpful to use Vaseline or a moisturizing cream for patient comfort....

Brief Overview of Normal Organ Development

The skin develops from two sources the superficial layer (epidermis) from the surface ectoderm and the deep layer (dermis) from mesoderm. Early in development, the fetus is covered with a single layer of ec-todermal cells. In the beginning of the second month through the fourth month, the four layers of the epidermis form a) the basal layer, which is responsible for the production of new cells and is known as the germinative layer b) a thick, spinous layer, consisting of large polyhedral cells...

Info

Unclear but those at greatest risk received > 35 Gy Pericarditis pericardial effusion, non-specific ECG changes Myocardial Infarction, cardiomyopathy, pericarditis (chronic), conduction abnormalities arrhythmias, valvular defects a The literature suggests a heightened risk of toxicity at or above the mentioned doses. However, damage can occur at lower doses, especially when other risk factors are present and or a patient receives more than one cardiotoxic agent. b Acute < 1 year Chronic >...

Precocious Puberty

GnRH analogs are the most effective treatments for precocious puberty, rapid tempo puberty or normally-timed puberty that is inappropriate for height. GnRH analogs suppress LH and FSH release from the pituitary gland through the provision of a steady, rather than a pulsatile, level of GnRH the pituitary gland stops responding to GnRH when GnRH concentrations are steady or unchanging. The use of GnRH analogs to delay pubertal progression optimizes adult height potential by permitting the child...

Hyperprolactinemia

Hyperprolactinemia has been described in patients who have received doses of radiation to the hypothalamus greater than 50 Gy, as well as in patients who have undergone surgery disrupting the integrity of the pituitary stalk. Hyperprolactinemia may result in delayed puberty. In adult women, hyperprolactine-mia may cause galactorrhea, menstrual irregulari-ties,loss of libido, hot flashes, infertility and osteope-nia. In adult men, impotence and loss of libido can result. Primary hypothyroidism...

How to Challenge a Denied Claim

Cancer treatment often involves numerous bills from different parties hospital, physicians (surgeon, anesthesiologist, oncologist, radiologist, etc.), support services (nurse, social worker, nutritionist, therapist, etc.), radiology group, pharmacy (drugs and medical supplies) and consumer businesses (wigs, breast in-serts,special clothing, etc.). Insurance companies will pay some of these parties directly, in part or in whole. The survivor must pay other bills and submit copies to the company...

Case Control Study

The case control study is the most common type of epidemiologic study design. It is often used to determine preliminary information about the etiology of a disease. In this type of study, cases and controls are selected on the basis of the outcome status of interest and the frequency and or dosage of the exposure in question is compared between the groups. In late-effect studies, the case-control design is somewhat uncommon because the exposure of interest (specific cancer treatment) is already...

Other Late Hepatobiliary Complications

Less commonly reported hepatobiliary complications include cholelithiasis, focal nodular hyperpla-sia, nodular regenerative hyperplasia and hepatic mi-crovesicular fatty change and siderosis. In a singleinstitution study including 6,050 childhood cancer patients, Mahmoud et al. reported a higher risk of biliary calculi in childhood cancer patients (median age 12.4 years) who did not have underlying chronic hemolytic anemia or a history of gallstones before treatment, compared with rates...

Types of Epidemiologic Study Designs

Two basic types of study design are employed in epidemiologic research of late effects descriptive studies and analytic studies. Features of both the exposure (usually treatment-related) and the outcome will influence the choice of study design, as will the amount of time needed to collect the data and the resources available to conduct the study. Results of previous research and gaps in knowledge that remain to be filled must also be taken into account. A given hypothesis can be, and often is,...

Bone Marrow Transplant

The incidence and the severity of delayed GI tract toxicity following allogeneic hematopoietic stem cell transplantation are related to the cumulative radiation dose used in the conditioning regimen, the presence of GVHD, or, a combination of both. Whereas GI tract toxicity is frequent in the acute transplant setting, chronic late problems affecting GI tissues are relatively uncommon. Xerostomia may result from sclerodermatous changes of the mucous membranes and salivary glands and predispose...

Teeth

RT effects on dentition are influenced by the developmental stage of the tooth, with the most severe disturbances occurring in children younger than six years of age 9, 34, 56 . Prior to morphodifferentia-tion and calcification, irradiation may result in agenesis. Direct irradiation at a later stage may cause microdontia, enamel hypoplasia, incomplete calcification of enamel and arrested root development. Chemotherapeutic agents, such as cyclophos-phamide, vincristine and vinblastine, have also...

Medical and Nursing Management

At the present time, there are no known medical treatments for the reversal of cataracts. Prevention of cataracts is best accomplished by fractionation of the RT dose,lens shielding during treatment and limiting exposure to toxic medications. Once a clinically significant cataract develops, surgical extractions and observation become the only options. Cataract extraction is elective in the vast majority of situations and depends upon the patient's and family's desires. Visual pathways in the...

Family and Medical Leave

The Family and Medical Leave Act requires employers with at least 50 workers to provide employees up to 12 weeks of unpaid leave for serious medical illness, including cancer, to care for themselves or dependents. The statute provides a number of benefits to people with cancer Requires employers to continue to provide benefits, including health insurance coverage, during the leave period. Provides 12 weeks of unpaid leave during any 12 month period. Requires employers to restore employees to...

Wendy Landier Thomas E Merchant

5.2 Pathophysiology 1C9 5.2.1 Normal Anatomy and Physiology 1C9 5.2.2 Ototoxic Effects of Tumor and Therapy Risk Factors and Incidence 111 5.2.2.1 Surgery and Tumor 111 5.2.2.2 Radiation Therapy 112 5.2.2.3 Pharmacologic Therapy 113 5.2.3 Preventive Measures 114 5.3 Clinical Manifestations 111 to Surgery or Tumor 11l of Radiation-Related Ototoxicity . . . 11l 5.3.3 Clinical Manifestations of Ototoxicity Related to Pharmacologic Agents 11l 5.4 Detection and Screening 11S 5.4.1 Auditory Screening...

References

Ahmed SR, Shalet SM, Campbell RH, Deakin DP (1983) Primary gonadal damage following treatment of brain tumors in childhood. J Pediatr 103 562-565 2. Albers-Schonberg HE (1903) ber eine bisher unbekannte Wirkung der Roengenstrahlen auf den Organismus der Tiere. Munch Med Wochenschr 50 1859-1860 3. Andersson AM, Muller J, Skakkeaek NE (1998) Different roles of prepubertal and postpubertal germ cells and Sertoli cells in the regulation of serum inhibin B levels. J Clin Endocrinol Metab 83...

Anatomy of Normal Testis

The adult testis is an oblong organ, approximately 4.5 cm in length and weighing 34-45 grams 82 . The testis is composed of three principal cell types germ cells that develop into sperm Sertoli cells that support and nurture developing germ cells and are also the site of production of the glycoprotein hormone, inhibin and Leydig cells that are responsible for testosterone synthesis 76 . Seminiferous tubules, the sites of spermatogenesis, are formed by germ cells and Sertoli cells. The Leydig...

Development of the Lung

Lung development begins on day 26 of gestation and continues through the toddler years. There are five phases in development. The embryonic period extends from day 26 through 52 of gestation. During this time, the primitive lung bud arises from the foregut, elongates caudally and branches to form the major airways. The pseudoglandular phase encompasses the time from day 52 through the end of 16 weeks gestation. During this phase of development, the process of branching continues and the smaller...

Normal Organ Development

In the third week of gestation, cardiac development begins, and primary morphogenesis is complete by the end of the eighth week. Myocardial cell replication rates are highest in the earlier weeks and decrease as the septum of the heart develops 3 . Cell size remains constant during this period of rapid growth. During most of embryonic development, the heart increases its mass by cell proliferation (hyper-plasia) rather than cell enlargement (hypertrophy) 4 . In the late prenatal and early...

Organ Damage Induced by Cytotoxic Therapy

Radiotherapy and chemotherapy each may cause transitory or permanent effects on hormonal function, reproductive capacity and sexual function. Primary ovarian failure, impaired development of secondary sexual characteristics, menstrual irregularities, including oligomenorrhea and amenorrhea, or premature menopause may occur. The menopausal state, when it occurs prematurely, is associated with the same physical symptoms as are seen with normal aging,including hot flashes,loss oflibido and...

Prevention of Testicular Damage

The cytotoxic effect of chemotherapy on germinal epithelia function launched a search for possible fertility preservation strategies in men undergoing therapy. Cryopreservation of sperm has become standard practice, and it should be offered to all newly diagnosed, postpubertal males at risk for potential infertility. Many improvements have been made in the techniques used to store sperm. There have also been advancements in assisted reproductive technology using intracytoplasmic sperm injection...

Americans with Disabilities

Students who are older than 21, and thus no longer protected by the IDEA, can turn to the Americans with Disabilities Act for protection from discrimination in higher education. The ADA mandates that no individual with a disability shall be excluded from participation in public services or programs, such as higher education. Educational institutions are required to provide disabled students who can meet the academic standards of the school with reasonable accommodations. For example, a...

Of Risk Based Healthcare During Childhood

Although there is general agreement that risk-based healthcare provided through LTFU programs is important to the health and well-being of survivors, there is a paucity of such programs in North America. In 1997, only 53 of the centers that treat children and adolescents for cancer had an LTFU program 13 . Since that time, this number has slowly increased. However, because of the limited resources and available trained personnel, a significant percent of centers still lack a LTFU program....

Case Cohort Design

The case-cohort study 20 is a relatively new study design that is similar to the nested case-control design, except that the selection of controls is performed without any reference to the specific time of the occurrence of each case's outcome of interest. Case-cohort studies share many of the advantages and disadvantages of nested case-control studies. A key additional advantage of the case-cohort design, compared with the nested case-control design, is the ability to use the same controls for...

Neuropsychologic

Conditioning regimens contain high drug doses and radiation that may be neurotoxic and result in neuropsychologic sequelae. Agents that are associated with neurotoxicity include busulfan, thiotepa and melphalan. Although much is known about the neuropsychologic effects of cranial irradiation for leukemias and brain tumors, there is relatively little known about the outcomes of children post HSCT. Doses of radiation used for central nervous system leukemia are between 1800-2400 cGy, and for...

Conclusion

Current knowledge regarding late effects in childhood cancer survivors can be attributed to the diligence of investigators who performed the initial studies and to the wisdom of succeeding researchers in building on work previously completed. The establishment of large, well-characterized cohorts of long-term survivors, such as the CCSS and others (including the National Wilms' Tumor Study and the Late Effects Study Group), has created a framework that allows for both the continued surveillance...

Cohort Study

The cohort study is perhaps the most effective study design for late-effect research. A cohort study compares a group of subjects who share a common characteristic (such as being treated for childhood cancer) within a defined time period. Subjects within the cohort are categorized according to exposures of interest. The groups are followed over time and their outcomes are compared. Cohort studies typically enroll large numbers of individuals and follow them for many years. Because of the study...

Summary

Although childhood and adolescent cancers comprise only 2-3 of all cancers, as survival rates continue to increase, now approaching approximately 70-80 , the number of individuals at risk for new neoplasms over an extended lifetime continues to grow. With approximately 12,400 children and adolescents or one in 300 persons under the age of 20 years diagnosed with cancer each year in the U.S.,it is estimated that 1 in 450 young adults is a survivor of childhood cancer. One of the most...

Exposure Assessment

In assessing the risk of late effects by therapeutic exposure, one must obtain accurate and detailed information on all cancer therapies received by the patients. The assessment process must be unbiased with respect to patients' characteristics, including the types of cancer, the treating institution, whether the patient has experienced any late effects and the length of follow-up. Specifically, the information must be equally available and of equal quality across all institutions participating...

LH or FSH Deficiency

High doses of cranial radiation (> 30 Gy) are more likely to cause hypothalamic GnRH deficiency and, as a result, gonadotropin deficiency. In some patients, high doses of cranial radiation leads to the precocious onset of puberty, due to the damage of GABA secretory neurons, andlater progresses to gonado-tropin deficiency due to the loss of GnRH secretory cells. Lower doses of cranial radiation (18-24 Gy) are more likely to cause damage only to the neurons secreting gamma-aminobutyric-acid...

Introduction

Chemotherapy, radiation and surgery all may affect the testes, exerting a profound effect on future reproductive function. The differential sensitivity of spermatozoa-producing Sertoli cells, in contrast to testosterone-producing Leydig cells, results in more significant effects on reproductive capacity than on sexual function. Since the testes are more sensitive than the ovary to cytotoxic therapies, ensuing injuries from identical treatment regimens are more damaging to male fertility than to...

Chronic Radiation Effects

The posterior subcapsular cataract is the characteristic late complication of RT (Fig. 6.4). The lens is the most radiosensitive structure within the eye because of its perpetual mitotic activity and inability to remove injured cells or disperse heat efficiently. The report on cataracts following radiation therapy in 1957 by Merriam and Focht yielded results that remain clinically relevant today. They found the threshold for cataract development to be a single exposure to 200 rads, fractionated...

Radiation and Chemotherapy Combinations Interaction and Tolerance

Many antineoplastic agents potentiate the damaging effects of radiation on the lung. Phillips 102 and Wara 146 demonstrated that dactinomycin administration lowered the radiation dose threshold for pneumonitis. Testing the effects of commonly used chem other ape utic agents, Phillips and colleagues 103 reported that the administration of dactinomycin, cyclophosphamide and, to a lesser extent, vincristine enhanced the lethal potential of thoracic irradiation. The effect of dactinomycin was seen...

Chondronecrosis Of The

Children who present with primary tumors of the head and neck area or brain frequently encounter radiation to the external, internal and middle ear during the course of their treatment 45 . There can be effects on the otic structures, both during the treatment sessions and months to years following therapy. The immediate effect on the ear is desquamation of the columnar epithelium, which lines the ears and covers the ossicles, leading to edema of the mucosa within the ear. Altered production of...

Prolactin

Prolactin (PRL) is a 198-amino acid polypeptide hormone synthesized and secreted from the lactotrophs of the anterior pituitary. A precursor molecule is also secreted and can constitute as much as 10 -20 of the PRL immunoreactivity in the plasma of healthy persons. Hypothalamic control of PRL secretion (primarily through dopamine release) is different from that of the other pituitary hormones in that the hypothalamus inhibits, rather than stimulates, secretion of PRL. Thus, elevated PRL levels...

Pre and Post Natal Brain Development

Normal development of the central nervous system begins at conception and includes numerous overlapping processes, thought to be orchestrated by genetic and epigenetic events that are amenable to external influence 1, 2 . The two main periods of development can be divided into (1) the major histo-genetic events of neurulation (i.e.,the embryonic formation of the neural tube by closure of the neural plate), and (2) reorganization of the human cortex through dendritic and axonal growth, synapse...

Cindy LSchwartz Wendy LHobbie Louis S Constine

This chapter provides charts by organ system that mr 18 cover the late effects of various cancer treatments. The healthcare provider for a patient with cardiac symptomatology, for example, can review the cardiac chart to find the common late side effects, causative treatments (chemo, radiation or surgery), signs and symptoms,screening and diagnostic tests and appropriate intervention and management procedures. If further information is needed, the reader can refer to the chapter that covers the...

Adrenocorticotropin

Adrenocorticotropin (ACTH) is a 39-amino acid pep-tide hormone processed in the corticotrophs from a large precursor molecule, pro-opiomelanocortin. In healthy individuals, hypothalamic corticotrophin-re-leasing hormone and vasopressin are released in two or three synchronous pulses per hour synergisti-cally and stimulate the secretion of ACTH from the pituitary 9 . ACTH secretion is pulsatile and varies throughout the day it peaks before the person awakens in the morning (Fig. 5.2 a),...

Wing Leung Susan R Rose Thomas E Merchant

5.1 Pathophysiology 5.1.1 Normal Hypothalamic-Pituitary Axis 52 5.1.1.1 Growth Hormone 53 5.1.1.5 Prolactin 54 5.1.2 Injury of the Hypothalamic-Pituitary Axis in Patients with Cancer 56 5.1.3 Contribution of Radiation to Hypothalamic-Pituitary Axis Injury 56 5.2 Clinical 5.2.1 GH 5.2.2 LH or FSH or Rapid Tempo Puberty 63 5.2.4 TSH Deficiency 64 5.2.5 ACTH Deficiency 66 5.2.6 Hyperprolactinemia 66 5.2.7 Diabetes 5.2.9 Hypothalamic Obesity 66 5.3 Detection and Screening 67 5.3.1 Signs and...

Pharmacologic Therapy

The primary pharmacologic agents implicated in ototoxicity include platinum chemotherapy, aminoglyco-side antibiotics and loop diuretics. These agents are all capable of causing sensorineural hearing loss. The mechanism of aminoglycoside and platinum-related ototoxicity is destruction of cochlear sensory hair cells. These specialized hair cells are arranged tono-topically (in order of pitch) in four rows (one inner and three outer rows) along the organ of Corti, and each hair cell is sensitive...

Cytotoxic Effects of Chemotherapy

The effects of chemotherapy on ovarian function are both agent and dose-dependent, and this effect may be additive to that resulting from abdominopelvic radiotherapy. Alkylating agents affect the resting oocyte in a dose-dependent, cell cycle-independent manner. Thecal cells and ova are depleted, as are the primordial follicles, resulting in arrest of follicular maturation and decreased estrogen secretion. Again, as was the case with radiotherapy, the effects are more pronounced in...

Effects of Chemotherapy on Ovarian Function

The dose-response relationship of alkylating agents, and the effect of age, is a recurring theme in studies of fertility following chemotherapy. Amenorrhea and ovarian failure occur more commonly in adult women treated with cyclophosphamide and other alkylating agents than with adolescents, with pre-pubertal females tolerating cumulative cyclophos-phamide doses as high as 25 gm m2 11,23 .In examining protocols with common chemotherapy, 86 of women > 24-30 years have been shown to have ovarian...

And Chemotherapy on Reproductive Outcomes

Many survivors of childhood cancer previously treated with cytotoxic therapy will remain fertile, and, therefore, pregnancy outcomes and the risk of cancer or genetic disease in offspring must be addressed. Young women who have been exposed to radiotherapy below the diaphragm are also at risk of impaired uterine development, which can adversely affect pregnancy outcomes, often resulting in premature labor and low birth-weight infants. The magnitude of the risk is related to the radiotherapy...

Organ Damage and Developmental Effects of Cytotoxic Therapy

The head and neck comprise a complex region with multiple tissue types, including mucosa, skin, subcutaneous tissue, salivary gland tissue, teeth, bone and cartilage. Each has a unique response to cytotoxic therapy. In general, two types of effects are seen. Acute effects that occur during or shortly after the course of treatment usually involve tissues that divide rapidly, resulting in erythema and pseudomembrane vs. ulceration of mucosa, erythema and desquamation of skin, reduced serous...

Detection Screening

It is usually not difficult to predict the extent of the acute changes during treatment based on the dose and fractionation schedule of the course of radiotherapy, and on the chemotherapy regimen used. The patient (and parents) can therefore anticipate the severity of the reaction. This will usually diminish some of the anxiety that inevitably accompanies the reaction. Late effects progress with time, and may be subtle at first. Careful physical exams are necessary in order to detect any...

Intrathecal Chemotherapy

Chemotherapy exposures are associated with neu-robehavioral consequences, although the effects may not be as devastating as those produced by CRT. Chemotherapeutic agents for the treatment of childhood ALL administered by the intrathecal route include methotrexate, cytarabine, and hydrocortisone, often in combination. Acute toxicity as a result of in-trathecal methotrexate and intrathecal cytarabine can include chemical arachnoiditis, hallucinations, somnolence, seizures, and neurological...

Chemotherapy Clinical Manifestations

As increasing numbers of patients are cured with chemotherapy, reports of agents responsible for acute, and possibly chronic, pulmonary toxicity are expanding. Drug-related lung injury is most commonly an acute phenomenon, occurring during or shortly after the chemotherapeutic agent(s) are administered 25 . Three typical patterns of pulmonary toxicity have been described pneumonitis or fibro-sis, acute hypersensitivity (or inflammatory interstitial pneumonitis) and noncardiogenic pulmonary...

Chemotherapy and Secondary Leukemia

For more than two decades, secondary leukemia has been linked to alkylating agent therapy 13 . The risk of developing secondary leukemia following treatment with alkylating agents appears to be dose and agent-dependent. MOPP chemotherapy (mechlor-ethamine, vincristine, prednisone and procarbazine) has resulted in cumulative frequencies of secondary leukemia ranging from 3-5 at 7 years, and reaching a plateau of 8 at about 10 years 45 . Substituting cyclophosphamide for mechlorethamine has...

Prevention Primary and Secondary

The primary prevention of adverse CNS outcomes largely consists of seeking alternative therapies that are less toxic but do not compromise cure. Childhood cancer researchers have been successful in implementing this strategy in many instances. In response to the severity of long-term side effects observed after radiation therapy,intrathecal chemotherapy has replaced CRT for CNS leukemia prophylaxis for most types of ALL 43 . Children with ALL who have poor prognosis features or who have...

Systemic Chemotherapy

Systemic administration of methotrexate may enhance both the acute and late toxicities of other CNS-directed therapies. Among children with ALL treated on a non-radiation containing protocol, acute neurotoxic events occurred significantly more often in those children who received IV methotrexate (1,000 mg m2) in addition to IT methotrexate during consolidation therapy 45 . The presenting acute event consisted most often (in 80 of cases) of seizures. Other observed neurotoxicities included...

For Survivors of NonCNS Malignancies

While childhood cancer survivors do show some social developmental differences, it is not clear that these differences represent deficits. Overall, survivors of childhood cancer are rated as more socially isolated and they have fewer best friends than do other children 60 .Survivors participate in fewer than half as many normative peer activities (e.g. going to a friend's house, going out with friends, playing sports) as their never-ill peers 46 . Children whose physical appearance and athletic...

Effects of Radiation

The data for gonadal function following fractionated radiotherapy in humans comes from a) patients with cancers who have been treated with either fields near the testes in which there is scatter dose or b) patients with diseases such as testicular cancers or ALL in which the testes are thought to be at risk of harboring disease and therefore irradiated directly. One of the potentially confounding issues is that some of these cancers may themselves be associated with decreased gonadal function...

Age years

A Complete catch-up growth in a boy after cancer therapy. b Growth in a girl after cancer therapy, without catch-up growth. Normal percentiles (5th, 50th, and 95th, as shown) are obtained from the National Center for Chronic Disease Prevention and Health Promotion 38 precocious puberty 39,40,58 . In girls, the first signs of puberty are a growth spurt and breast development (palpable breast buds or thelarche), followed by pubic hair growth and, after about 2 years, by menar-che. In boys, the...

Effects of Chemotherapy

The extent and reversibility of cytotoxic damage generally depends on the agent and cumulative dose received, although significant individual variation has been observed. The effects of alkylating agents on testicular function have been studied extensively. Cyclophosphamide, either alone or in combination with other agents, is known to damage the germinal epithelium. In a meta-analysis of 30 studies that examined gonadal function following various chemotherapy regimens, gonadal dysfunction...

Changes Induced by Cytotoxic Therapy

Fibrosis,which is generally periportal and concentric (Fig. 12.4), is the most frequently described complication of antineoplastic therapy observed in the liver 63 . Hepatic fibrosis may be associated with fatty infiltration, focal necrosis and nodular regeneration of cirrhosis, as well as portal hypertension. Chronic hepatitis, regardless of its etiology, is characterized by portal-periportal lymphoplasmacytic infiltration with varying degrees of fibrosis and piecemeal necro Hepatic portal...

Reproductive

Gonadal dysfunction is common following HSCT, a finding attributable to the use of alkylating agents, such as cyclophosphamide, and radiation therapy. Busulfan, as a radiation substitute, also causes a high incidence of gonadal failure 2, 46 . Gonadal dysfunction results in infertility in most affected patients, with some patients also having difficulties with pubertal development. In males, the Sertoli and germ cells are more vulnerable to radiation and chemotherapy than the Leydig cells. FSH...

Upper and Lower Gastrointestinal Tract 12211 Normal Anatomy and Physiology

The upper GI tract extends from the oropharynx to the ileocecal valve and includes the esophagus, stomach and small intestine. The esophagus is a distensible tube lined by an inner mucosa of squamous epithelium, surrounded by a submucosa, a muscularis externa (composed of both striated and smooth muscle) and an outermost connective tissue layer. The neurovascular supply and mucous glands, which are located primarily in submucosa, open into the lumen of the esophagus. The lower esophageal...

Barbara Anne Hieb Susan KOgle Anna T Meadows

18.2.1 Breast Cancer 285 18.2.2 Other Radiation-Associated SMNs 286 18.2.2.1 Skin Cancer 286 18.2.2.2 Thyroid Cancer 286 18.2.2.3 Sarcomas of Bone 286 18.2.2.4 Secondary CNS Tumors 287 18.3 Chemotherapy and Secondary Leukemia 287 18.4 Bone Marrow Transplant 288 18.5 Genetic Predisposition 288 18.5.1 Retinoblastoma 288 18.5.3 Li-Fraumeni Syndrome 290 18.5.4 Other Predisposing Conditions 291 References

Prevention Strategies

Reduction in the dose or use of alkylating agents and abdominopelvic radiotherapy is the most effective means of preserving ovarian function and promoting positive reproductive outcomes. This has been done for pediatric Hodgkin disease, where cooperative group and consortium studies conducted in the mid-1980s through the present have utilized low-dose involved field radiotherapy, or no radiotherapy, in those with a complete response to chemotherapy these studies have also reduced the number,...

ACTH Deficiency

For patients at risk for ACTH deficiency (e.g. those who received > 30 Gy irradiation to HPA), surveillance should include an annual measurement of plasma cortisol concentration at 0800 hours. If the cortisol level is below 18 pg dl (497 nmol l) at 0800 hours, then further evaluation is needed and should be directed by an endocrinologist. The optimal evaluation for ACTH deficiency is controversial 55 . Measurement of the basal plasma ACTH concentration usually can distinguish primary adrenal...

Treatment Induced Leydig Cell Failure from Chemotherapy

Leydig cells are much less vulnerable to damage from cancer therapy than germ cells. This is likely due to their slow rate of turnover 73 . For example, chemotherapy-induced Leydig cell failure resulting in androgen insufficiency and requiring testosterone replacement therapy is rare. However, studies suggest that Leydig cell dysfunction may be observed following treatment with alkylator-based regiments. In fact, raised plasma concentrations of LH, combined with low levels of testosterone, are...

Pulmonary

The assessment of the effects of HSCT conditioning on pulmonary function is usually limited by the age of the patient, as very young children cannot perform pulmonary function tests. The spectrum of long-term pulmonary complications differs among patients who received allogeneic vs autologous HSCT. This is due to the effects of chronic GVHD, which may result in changes called bronchiolitis obliterans. Other factors that may impact pulmonary function post HSCT include prior chemotherapies such...

Leydig Cell Function Following Radiotherapy

Leydig cells in the testes are more resistant to radiation than germ cells. In the study cited previously of patients with Hodgkin's disease who received 6-70 cGy of scatter dose to the testes, no patient showed any elevation in LH levels or decrease in testosterone levels 41 . In the study of men treated for sarcomas by Shapiro et al. discussed above 74 , maximal increases in LH levels relative to baseline were seen at six months following radiation,but these elevations were statistically...

Clinical Manifestations 1021 Anthracyclines

Anthracyclines are the most common class of chemo-therapeutic agents associated with adverse effects on the heart. They were first introduced in the late 1960s and early 1970s 33 and are critical in the treatment of many pediatric malignancies 34 . Krischer et al., in their review of the Pediatric Oncology Group (POG) protocols, demonstrated that more than 50 of 12,680 patients treated between 1974 and 1990 received anthracycline chemotherapy 35 . The most commonly used drugs in this class are...

The Numbers of Cancer Survivors Who Encounter Employment Problems

Unlike many years ago, when cancer was a literal death sentence, today, most working-age survivors return to work 6 . Helen Crothers' summary of several studies from the 1970s and 1980s concluded that 80 of employees returned to work after being diagnosed with cancer 6 . Physicians are now more aware of cancer survivors' employment problems 16 and offer more flexible outpatient treatment programs to accommodate survivors' work schedules 5 .They also have an improved medical arsenal with which...

Normal Hypothalamic Pituitary Axis

Diagrammatic Representation Pituitary

The hypothalamic-pituitary axis (HPA) is the primary interface between the nervous system and the endocrine system. The actions and interactions of the endocrine and nervous systems constitute the major regulatory mechanisms for virtually all physiologic functions. The hypothalamus has extensive neural communications with other brain regions and regulates brain functions, including temperature, appetite, thirst, sexual behavior, and fear. The hypothalamus also contains two types of...

Salivary Glands and Taste Buds

Salivary gland dysfunction may occur when one or more of the major salivary glands are irradiated. Permanent damage can lead to xerostomia, predisposing to dental caries, decay and osteoradionecrosis. Studies of salivary function in children after RT are limited. Fromm found that 8 of 11 parotid glands that had received > 45 Gy to greater than 50 of the volume failed to secrete saliva, whereas all parotid glands receiving < 40 Gy retained the ability to secrete 23 . More recent studies in...

Evaluation of Overt Sequelae

The structure and function of the GU tract can be assessed by a variety of techniques. Simple screening methodologies include the history, with particular attention to urinary incontinence, urine volumes and urine character (bloody or foamy), as well as, the urinalysis. Creatinine clearance is a simple, cost-effective screen of kidney function. Structural abnormalities can be investigated by several tests, including ultrasound, IVP, CT scan and MRI. Retrograde studies may be useful for...

Cardiomyopathy Congestive Heart Failure and Ventricular Arrhythmia

As signs and symptoms of congestive heart failure become evident, therapy clearly becomes necessary. The need to treat survivors with abnormal afterload, contractility and or fractional shortening, but without symptoms, is less clear. While theoretically advisable to prevent progression, one of the most useful medication classes, angiotensin-converting enzyme (ACE) inhibitors, also appear to decrease the heart's normal growth 127 . Additionally, little is known about most of the medications in...

Clinical Manifestations

Damage to skin can be divided into acute effects and late effects. During a course of high-dose irradiation to the skin, the first sign of a skin reaction is faint erythema around the hair follicles. If the radiation is fractionated conventionally (less than 2 Gy per fraction), a dose of 20 Gy will usually produce erythema. Higher doses cause a progression to a generalized erythema, epilation and a decrease in sweating, as well as diminished sebaceous gland secretion. The skin next becomes...

Fighting Back Against Discrimination

Survivors who suspect that they are being treated differently at work because of their cancer history should consider an informal solution before filing a lawsuit. Survivors who face discrimination may consider the following suggestions Consider using your employer's policies and procedures for resolving employment issues informally. First, let your employer know that you are aware of your legal rights and would rather resolve the issues openly and honestly than file a lawsuit. Be careful of...

Hepatobiliary Tree 1231 Pathophysiology 12311 Normal Anatomy and Physiology

The liver is the largest organ in the body and consists of right and left lobes joined posteroinferiorly at the porta hepatis. The gall bladder lies under the visceral surface of the liver. The hepatic lobule, which contains a central vein that is a tributary of the hepatic vein, is the basic ultrastructural unit of the liver. The central vein of each hepatic lobule drains into the inferior vena cava. Columns of hepatocytes radiate from the center of each lobule and are separated by sinusoids....

Subacute Radiation Pneumonitis

Subacute pneumonitis is a pneumonopathy that usually occurs 1-3 months after the completion of radiation. It is well described in the adult literature after the treatment of lung cancer 5, 6,109 , but little of the data from such studies are relevant to modern pediatric cancer therapies. Pneumonitis can occur unexpectedly, with little or no warning. Because of this, many attempts have been made to identify clinical risk factors. The factors that influence risk include total lung radiation dose,...

Assessment of Testicular Function

The male reproductive tract is very susceptible to the toxic effects of chemotherapy and radiation, which may disrupt the endocrine axis or damage the testes directly. Assessment of testicular maturation and function involves pubertal staging, plasma hormone analysis and semen analysis. Pubertal staging provides clinical information about both of these testic-ular functions (i.e. the production of hormones and the production of semen). The development of normal secondary sexual characteristics...

For Anthracycline Induced Cardiotoxicity

There are many risk factors that influence anthra-cycline-induced cardiotoxicity (Table 10.4). Some of the risk factors can be altered. Examples include the type of anthracycline administered, the cumulative dose, the use of cardio-protectants and concomitant mantle radiation 36 .However,patient characteristics, which are not modifiable, also affect the risk of developing cardiomyopathy. These include age at time of treatment, gender, race and length of follow-up. Preexisting or concomitant...

Vagina

Fibrosis and diminished growth secondary to surgical procedures or RT have been described 49-51 . Vaginal mucositis can occur acutely during RT or following chemotherapy, notably with methotrexate, actinomycin-D and doxorubicin. In patients who have received prior RT, the administration of actino-mycin-D or doxorubicin can result in a radiation recall reaction with vaginal mucositis. Significant fibrosis of the vagina can occur after high-dose RT, or after more modest doses of radiation, when...

Radiation Tolerance Doses and Tolerance Volumes

It must be noted that these phenomenon are dose and fraction-dependent, as well as volume dependent. Scattered changes can be seen at 5.0 Gy, but lesions become widespread at lethal doses of irradiation. The effects of lethal radiation doses on the lung parenchyma may not become evident until weeks to months after exposure. With high doses exceeding clinical thresholds 8.0-12.0 Gy, single dose , pulmonary reactions clinically express themselves as a pneumonitic process 1-3 months after the...