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...

Organ Damage Induced by Cytotoxic Therapy

Acute GI toxicity develops frequently following radiation and a variety of chemotherapeutic agents and is characterized by recovery without sequelae in the majority of individuals. The most common gastrointestinal tract complications observed in long-term childhood cancer survivors typically result from chronic mucosal inflammation that interferes with the digestion and absorption of nutrients (enteritis) or predisposes patients to scarring (fibrosis) of the intra-abdominal tissues. Persistent...

Detection and Screening

Long-term survivors of childhood cancer who have received potentially cardiotoxic therapies should undergo regular, repeated evaluations of cardiac status, even if the patient is asymptomatic. Patients at highest risk include (but may not be limited to) those who have received anthracyclines, high-dose cyclophosphamide (typically, only those who received it in preparation for bone marrow transplant), and cardiac irradiation (mediastinal, mantle, and possibly spinal, whole lung and left renal...

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...

Acute Radiation Effects

Madarosis, or loss of eyelashes, and erythema are the first side effects of radiation therapy (RT) involving the eye. Usually, eyelashes will grow back however, permanent loss does occur. Erythema can occur within days of treatment (generally after doses of at least 20-30 Gy) and usually persists for a few days. Dermatitis is the most common acute side effect of RT. Dry dermatitis of irradiated skin can occur with doses greater than 20 Gy and often leads to desquamation. Moist dermatitis, with...

Chronic Radiation Effects

The late effects of RT to the eyelids following doses from 30-60 Gy include madarosis, telangiectasia (dilated, tortuous blood vessels Fig. 6.3), hyperpigmen-tation, depigmentation, ectropion, hyperkeratosis, atrophy, necrosis, ulceration and punctual occlusion. Although rarely seen today, lid deformities, such as ectropion (out-turning of eyelid margin), entropion (in-turning of eyelid margin) and atrophy or contracture, are seen when the tarsus has been included in the radiation field. The...

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...

Skin and Mucous Membranes

Skin and mucosa exhibit early epithelial damage and delayed permanent vascular injury that are dependent on the total radiation dose, the fraction size and the volume of irradiated tissue. Early radiation injury to the skin is directly attributable to the effect of ionizing radiation on the stratum germinativum cells 20 . Release of vasoactive substances results in increased capillary permeability and dilatation that manifest as skin erythema 55 . An increase in melanin- containing cells at 2-3...

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...

Normal Organ Development

Hormonal function and potential for fertility are synchronous in females, as the ovary both produces oocytes and secretes steroid hormones. Prepubertal females possess their lifetime supply of oocytes with no new oogonia formed after birth. Active mitosis of oogonia occurs during fetal life, reaching a peak of 6-7 million by 20 weeks of gestation, and then rapidly declining to 1-2 million at birth. At the onset of puberty, only 300,000 remain 1 . The cortices of the ovaries harbor the follicles...

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...

Bone and Connective Tissue

Clinical manifestations of radiation include hypoplasia, deformities, fracture and necrosis. The craniofacial development of children is affected, resulting in reduced temporomandibular joint mobility, growth retardation and osteoradionecrosis 10 . Impaired growth of the mandible and facial bones can contribute to malocclusion. Chemotherapy may also affect the growing skeleton, although with limited long-term consequences. In the immature rat, the growth plate becomes thicker with methotrexate...

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...

Info

Duggal MS (2003) Root surface areas in long-term survivors of childhood cancer. Oral Oncol 39 178-183 16. Eisbruch A et al. (1999) Dose, volume and function relationships in parotid glands following conformal and intensity modulated irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys 45 577-587 17. Epstein JB et al. (1996) Effects of compliance with fluoride gel application on caries and caries risk in patients after radiation therapy for head and neck cancer. Oral Surg Oral...

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...