Basic Principles of Nutrition in Patients With Cancer
The average total fat-soluble activator and mineral intake of calcium and phosphorus of these children would far exceed that of the daily intake of the average American child. After TBI conditioning, most male patients retain their ability to produce testosterone but will experience germ cell failure. Individuals with asplenia, regardless of the reason for the asplenic state, have an increased risk of fulminant bacteremia, especially associated with encapsulated bacteria, which is associated with a high mortality rate. Table 5 summarizes digestive tract late effects and the related health screenings. In patients with chronic hepatitis, precautions to reduce viral transmission to household and sexual contacts should also be reviewed.
General Information About Late Effects of Treatment for Childhood Cancer
Improper disposal of Duragesic in the trash has resulted in accidental exposures and deaths. Exposure to Duragesic patches discarded in the trash by children have been reported and have resulted in deaths. Prolonged use of Duragesic during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.
Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations 8. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Duragesic-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions.
When using Duragesic with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Duragesic-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Duragesic until stable drug effects are achieved [see Dosage and Administration 2. When using Duragesic with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions 7 ].
Exposure to heat may increase fentanyl absorption and there have been reports of overdose and death as a result of exposure to heat. A clinical pharmacology study conducted in healthy adult subjects has shown that the application of heat over the Duragesic system increased fentanyl exposure [see Clinical Pharmacology Warn patients to avoid exposing the Duragesic application site and surrounding area to direct external heat sources [see Dosage and Administration 2.
Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions 7 ]. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response.
If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation. Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined.
Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions 7 , Patient Counseling Information 17 ]. Monitor patients wearing Duragesic systems who develop fever closely for sedation and respiratory depression and reduce the Duragesic dose, if necessary.
Warn patients to avoid strenuous exertion that leads to increased core body temperature while wearing Duragesic to avoid the risk of potential overdose and death. The use of Duragesic in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: Duragesic-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Duragesic [see Warnings and Precautions 5.
Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions 5.
Monitor such patients closely, particularly when initiating and titrating Duragesic and when Duragesic is given concomitantly with other drugs that depress respiration [see Warnings and Precautions 5. Alternatively, consider the use of non-opioid analgesics in these patients.
Serotonergic drugs include selective serotonin reuptake inhibitors SSRIs , serotonin and norepinephrine reuptake inhibitors SNRIs , tricyclic antidepressants TCAs , triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system e. This may occur within the recommended dosage range. Serotonin syndrome symptoms may include mental status changes e.
The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that.
Discontinue Duragesic immediately if serotonin syndrome is suspected. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers.
Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs e.
Monitor these patients for signs of hypotension after initiating or titrating the dosage of Duragesic. In patients with circulatory shock, Duragesic may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Duragesic in patients with circulatory shock. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Duragesic. Avoid the use of Duragesic in patients with impaired consciousness or coma.
Duragesic may produce bradycardia. Monitor patients with bradyarrhythmias closely for changes in heart rate, particularly when initiating therapy with Duragesic. A clinical pharmacology study with Duragesic in patients with cirrhosis has shown that systemic fentanyl exposure increased in these patients. Because of the long half-life of fentanyl when administered as Duragesic and hepatic metabolism of fentanyl, avoid use of Duragesic in patients with severe hepatic impairment.
Insufficient information exists to make precise dosing recommendations regarding the use of Duragesic in patients with impaired hepatic function. Therefore, to avoid starting patients with mild to moderate hepatic impairment on too high of a dose, start with one half of the usual dosage of Duragesic. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase.
A clinical pharmacology study with intravenous fentanyl in patients undergoing kidney transplantation has shown that patients with high blood urea nitrogen level had low fentanyl clearance. Because of the long half-life of fentanyl when administered as Duragesic, avoid the use of Duragesic in patients with severe renal impairment.
Insufficient information exists to make precise dosing recommendations regarding the use of Duragesic in patients with impaired renal function. Therefore, to avoid starting patients with mild to moderate renal impairment on too high of a dose, start with one half of the usual dosage of Duragesic. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase [see Dosage and Administration 2.
Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms. Monitor patients with a history of seizure disorders for worsened seizure control during Duragesic therapy. Duragesic may impair the mental or physical abilities required for the performance of potentially dangerous activities, such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of the Duragesic and know how they will react to the medication [see Patient Counseling Information 17 ].
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of Duragesic was evaluated in patients who took at least one dose of Duragesic in a multicenter, double-blind, randomized, placebo-controlled clinical trial of Duragesic.
This trial examined patients over 40 years of age with severe pain induced by osteoarthritis of the hip or knee and who were in need of and waiting for joint replacement. General disorders and administration site conditions: Reproductive system and breast disorders: Respiratory, thoracic and mediastinal disorders: Skin and subcutaneous tissue disorders: The safety of Duragesic was evaluated in three open-label trials in pediatric patients with chronic pain, 2 years of age through 18 years of age.
The following adverse reactions have been identified during post-approval use of Duragesic. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Respiratory, Thoracic, and Mediastinal Disorders: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis, including anaphylactic shock, has been reported with ingredients contained in Duragesic. Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions 5.
Available data with Duragesic in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing.
When administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival and developmental delays at doses within the range of the human recommended dosing. No evidence of malformations were noted in animal studies completed to date [ see Data ]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.
Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions 5. Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Duragesic is not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate.
Opioid analgesics, including Duragesic, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.
Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. There are no adequate and well-controlled studies in pregnant women. Duragesic should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.
In contrast, the intravenous administration of fentanyl 0, 0. There was no clear evidence of teratogenicity noted. Pregnant female New Zealand White rabbits were treated with fentanyl 0, 0. Fentanyl produced a slight decrease in the body weight of the live fetuses at the high dose, which may be attributed to maternal toxicity. Under the conditions of the assay, there was no evidence for fentanyl induced adverse effects on embryo-fetal development at doses up to 0. The potential effects of fentanyl on prenatal and postnatal development were examined in the rat model.
Female Wistar rats were treated with 0, 0. Both the mid-dose and high-dose of fentanyl animals demonstrated alterations in some physical landmarks of development delayed incisor eruption and eye opening and transient behavioral development decreased locomotor activity at Day 28 which recovered by Day The mid-dose and the high-dose are 0.
Fentanyl is excreted in human milk; therefore, Duragesic is not recommended for use in nursing women because of the possibility of effects in their infants. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Duragesic.
Monitor infants exposed to Duragesic through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. Due to effects of androgen deficiency, chronic use of opioids may cause reduced fertility in females and males of reproductive potential.
It is not known whether these effects on fertility are reversible [see Adverse Reactions 6. The safety and effectiveness of Duragesic in children under 2 years of age have not been established. To guard against excessive exposure to Duragesic by young children, advise caregivers to strictly adhere to recommended Duragesic application and disposal instructions [see Dosage and Administration 2. Clinical studies of Duragesic did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life.
Moreover, elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the Duragesic patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours [see Clinical Pharmacology Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration.
Titrate the dosage of Duragesic slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions 5. Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. The effect of hepatic impairment on the pharmacokinetics of Duragesic has not been fully evaluated.
Because there is in-vitro and in-vivo evidence of extensive hepatic contribution to the elimination of Duragesic, hepatic impairment would be expected to have significant effects on the pharmacokinetics of Duragesic. Avoid use of Duragesic in patients with severe hepatic impairment [see Dosage and Administration 2. The effect of renal impairment on the pharmacokinetics of Duragesic has not been fully evaluated. Because there is in-vivo evidence of renal contribution to the elimination of Duragesic, renal impairment would be expected to have significant effects on the pharmacokinetics of Duragesic.
Avoid the use of Duragesic in patients with severe renal impairment [see Dosage and Administration 2. Duragesic contains fentanyl, a substance with a high potential for abuse similar to other opioids including hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol.
Duragesic can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions 5. The high drug content in long-acting formulations adds to the risk of adverse outcomes from abuse and misuse. All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare providers.
Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. Duragesic, like other opioids, can be diverted for non-medical use into illicit channels of distribution.
Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Duragesic is intended for transdermal use only.
Abuse of Duragesic poses a risk of overdose and death. This risk is increased with concurrent abuse of Duragesic with alcohol and other central nervous system depressants [see Warnings and Precautions 5. Intentional compromise of the transdermal delivery system may result in the uncontrolled delivery of fentanyl and pose a significant risk to the abuser that could result in overdose and death [see Warnings and Precautions 5.
Abuse may occur by applying the transdermal system in the absence of legitimate purpose, or by swallowing, snorting or injecting fentanyl extracted from the transdermal system. Both tolerance and physical dependence can develop during chronic opioid therapy.
Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia in the absence of disease progression or other external factors. Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug.
Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity e. Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. Duragesic should not be abruptly discontinued [see Dosage and Administration 2. If Duragesic is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur.
Some or all of the following can characterize this syndrome: Other signs and symptoms also may develop, including: Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations 8.
Acute overdose with Duragesic can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death.
Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology Give primary attention to the reestablishment of a patent airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures including oxygen and vasopressors in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.
Once stable, ensure examine the patient and ensure that all Duragesic Transdermal Systems have been removed. The opioid antagonists, such as naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist.
Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to fentanyl overdose. Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in Duragesic, carefully monitor the patient until spontaneous respiration is reliably reestablished.
Therefore, management of an overdose must be monitored accordingly, at least 72 to 96 hours beyond the overdose. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome.
The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.
Duragesic fentanyl transdermal system contains fentanyl, an opioid agonist, available as a patch for transdermal administration. The composition per unit area of all system sizes is identical. The molecular weight of fentanyl base is The pKa is 8.
The chemical name is N-Phenyl-N- 1- 2-phenylethyl piperidinyl propanamide. The structural formula is:. Duragesic is a rectangular transparent unit comprised of a clear siliconized polyethylene terephthalate protective liner and two functional layers. Proceeding from the outer surface toward the surface adhering to skin, these functional layers are:. Before use, a protective liner covering the adhesive layer is removed and discarded.
Fentanyl is an opioid agonist. Fentanyl interacts predominately with the opioid mu-receptor. These mu-binding sites are distributed in the human brain, spinal cord, and other tissues. Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.
Fentanyl causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic e. Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. In clinical trials of non-opioid tolerant subjects treated with Duragesic, 13 subjects experienced hypoventilation. In these studies, the incidence of hypoventilation was higher in nontolerant women 10 than in men 3 and in subjects weighing less than 63 kg 9 of Although subjects with prior impaired respiration were not common in the trials, they had higher rates of hypoventilation.
In addition, post-marketing reports have been received that describe opioid-naive post-operative patients who have experienced clinically significant hypoventilation and death with Duragesic. Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations, especially for patients who have an underlying pulmonary condition or who receive concomitant opioids or other CNS drugs associated with hypoventilation. The use of Duragesic is contraindicated in patients who are not tolerant to opioid therapy.
Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm, resulting in constipation.
Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Fentanyl produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Histamine assays and skin wheal testing in clinical studies indicate that clinically significant histamine release rarely occurs with fentanyl administration. They also stimulate prolactin, growth hormone GH secretion, and pancreatic secretion of insulin and glucagon.
Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions 6.
Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids.
There is a relationship between increasing fentanyl plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration 2.
Duragesic is a drug-in-adhesive matrix designed formulation. Fentanyl is released from the matrix at a nearly constant amount per unit time. The concentration gradient existing between the matrix and the lower concentration in the skin drives drug release.
Fentanyl moves in the direction of the lower concentration at a rate determined by the matrix and the diffusion of fentanyl through the skin layers. While the actual rate of fentanyl delivery to the skin varies over the hour application period, each system is labeled with a nominal flux which represents the average amount of drug delivered to the systemic circulation per hour across average skin.
While there is variation in dose delivered among patients, the nominal flux of the systems Following Duragesic application, the skin under the system absorbs fentanyl, and a depot of fentanyl concentrates in the upper skin layers. Fentanyl then becomes available to the systemic circulation. Serum fentanyl concentrations increase gradually following initial Duragesic application, generally leveling off between 12 and 24 hours and remaining relatively constant, with some fluctuation, for the remainder of the hour application period.
Peak serum concentrations of fentanyl generally occurred between 20 and 72 hours after initial application see Table 7. Serum fentanyl concentrations achieved are proportional to the Duragesic delivery rate. With continuous use, serum fentanyl concentrations continue to rise for the first two system applications. By the end of the second hour application, a steady-state serum concentration is reached and is maintained during subsequent applications of a patch of the same size see Figure 1.
Patients reach and maintain a steady-state serum concentration that is determined by individual variation in skin permeability and body clearance of fentanyl. Continued absorption of fentanyl from the skin accounts for a slower disappearance of the drug from the serum than is seen after an IV infusion, where the apparent half-life is approximately 7 range 3—12 hours. Fentanyl plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system.
Fentanyl accumulates in the skeletal muscle and fat and is released slowly into the blood. Fentanyl is metabolized primarily via human cytochrome P 3A4 isoenzyme system. In humans, the drug appears to be metabolized primarily by oxidative N-dealkylation to norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug. Skin does not appear to metabolize fentanyl delivered transdermally. Moreover elderly patients may be more sensitive to the active substance than younger patients.
A study conducted with the Duragesic fentanyl transdermal patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours.
In older pediatric patients, the pharmacokinetic parameters were similar to that of adults. However, these findings have been taken into consideration in determining the dosing recommendations for opioid-tolerant pediatric patients 2 years of age and older. For pediatric dosing information, refer to [see Dosage and Administration 2. Information on the effect of hepatic impairment on the pharmacokinetics of Duragesic is limited. Avoid use of Duragesic in patients with severe hepatic impairment [see Dosing and Administration 2.
Information on the effect of renal impairment on the pharmacokinetics of Duragesic is limited. An inverse relationship between blood urea nitrogen level and fentanyl clearance was found. Avoid the use of Duragesic in patients with severe renal impairment [see Dosing and Administration 2.
The interaction between ritonavir, a CPY3A4 inhibitor, and fentanyl was investigated in eleven healthy volunteers in a randomized crossover study. Subjects received oral ritonavir or placebo for 3 days. The ritonavir dose was mg three times a day on Day 1 and mg three times a day on Day 2 followed by one morning dose of mg on Day 3.
Naloxone was administered to counteract the side effects of fentanyl. The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, or grapefruit juice may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression.
This was investigated in children with leukemia who were treated with HSCT. In a series of 36 patients, performance on neurocognitive measures typically associated with white matter was compared with performance on measures thought to correlate with gray matter function. Composite white matter scores were significantly lower than composite gray matter scores, thereby supporting the belief that white matter damage contributes to neurocognitive late effects in this population. In children with CNS tumors, mass effect, tumor infiltration, and increased intracranial pressure may result in motor or sensory deficits, cerebellar dysfunction, and secondary effects such as seizures and cerebrovascular complications.
Numerous reports describe abnormalities of CNS integrity and function, but such studies are typically limited by small sample size, cohort selection and participation bias, cross-sectional ascertainment of outcomes, and variable time of assessment from treatment exposures. In contrast, relatively few studies comprehensively or systematically ascertain outcomes related to peripheral nervous system function.
Neurologic complications that may occur in survivors of childhood cancer include the following:. Among adult survivors of extracranial solid tumors of childhood median time from diagnosis, 25 years , standardized assessment of neuromuscular function disclosed motor impairment in association with vincristine exposure and sensory impairment in association with cisplatin exposure.
These studies underscore the importance of assessment and referral to rehabilitative services to optimize functional outcomes among long-term survivors. In a cross-sectional study that evaluated neurologic morbidity and quality of life in survivors of childhood ALL median age at evaluation, Female sex, ten doses or more of intrathecal chemotherapy, cranial irradiation, CNS leukemia at diagnosis, and history of ALL relapse were associated with neurologic morbidity.
Neuroimaging studies of irradiated and nonirradiated ALL survivors demonstrate a variety of CNS abnormalities, including leukoencephalopathy, cerebral lacunes, cerebral atrophy, and dystrophic calcifications mineralizing microangiopathy.
Among these, abnormalities of cerebral white matter integrity and volume have been correlated with neurocognitive outcomes. Cavernomas have also been observed in ALL survivors treated with cranial irradiation. They have been speculated to result from angiogenic processes as opposed to tumorigenesis. Table 3 summarizes CNS late effects and the related health screenings.
Many childhood cancer survivors report reduced quality of life or other adverse psychosocial outcomes. Evidence for adverse psychosocial adjustment after childhood cancer has been derived from a number of sources, ranging from patient-reported or proxy-reported outcomes to data from population-based registries.
The former may be limited by small sample size, cohort selection and participation bias, and variable methods and venues clinical vs. The latter is often not well correlated with clinical and treatment characteristics that permit the identification of survivors at high risk of psychosocial deficits. Survivors with neurocognitive deficits are particularly vulnerable to adverse psychosocial outcomes that affect achievement of expected social outcomes during adulthood.
Childhood cancer survivors are also at risk of developing symptoms of psychological distress. In a longitudinal study of more than 4, survivors, subgroups of survivors were found to be at risk of developing persistent and increasing symptoms of anxiety and depression during a year period.
Survivors who reported pain and worsening health status were at the greatest risk of developing symptoms of anxiety, depression, and somatization over time. Adult survivors of childhood cancer are also at risk of suicide ideation compared with siblings, with survivors of CNS tumors being most likely to report thoughts of suicide. In a CCSS study that evaluated the prevalence of recurrent suicidal ideation among 9, adult long-term survivors of childhood cancer, survivors were more likely to report late suicidal ideation odds ratio [OR], 1.
History of seizure was associated with a twofold increased likelihood of suicide ideation in survivors. The presence of chronic health conditions can also impact aspects of psychological health. HSCT survivors with severe or life-threatening health conditions and active chronic GVHD had a twofold increased risk of somatic distress.
Incorporation of psychological screening into clinical visits for childhood cancer survivors may be valuable; however, limiting such evaluations to those returning to long-term follow-up clinics may result in a biased subsample of survivors with more difficulties, and precise prevalence rates may be difficult to establish.
On the Symptom Checklist 90 Revised, 32 subjects had a positive screen indicating psychological distress , and 14 subjects reported at least one suicidal symptom. In this study, the instrument was shown to be feasible for use in the clinic visit setting because the psychological screening was completed in less than 30 minutes.
Anxiety and Distress for more information about psychological distress and cancer patients. Despite the many stresses associated with the diagnosis of cancer and its treatment, studies have generally shown low levels of post-traumatic stress symptoms and post-traumatic stress disorder PTSD in children with cancer, typically no higher than those in healthy comparison children.
Because avoidance of places and persons associated with the cancer is part of PTSD, the syndrome may interfere with obtaining appropriate health care. Those with PTSD perceive greater current threats to their lives or the lives of their children. Other risk factors include poor family functioning, decreased social support, and noncancer stressors. Most research on late effects after cancer has focused on individuals with a cancer manifestation during childhood.
Little is known about the specific impact of a cancer diagnosis with an onset in adolescence or the impact of childhood cancer on adolescent and young adult AYA psychosocial outcomes. Overall results support that behavioral, emotional, and social symptoms frequently co-occur in adolescent survivors and are associated with treatment exposures cranial radiation, corticosteroids, and methotrexate and late effects obesity, cancer-related pain, and sensory impairments.
It should be noted that social withdrawal in adolescence has been associated with adult obesity and physical inactivity. Because of the challenges experienced by adolescents and young adults at cancer diagnosis and during long-term follow-up, this group may benefit from access to programs to address the unique psychosocial, educational, and vocational issues that impact their transition to survivorship.
Chemotherapy, radiation therapy, and local surgery can cause multiple cosmetic and functional abnormalities of the oral cavity and dentition. The quality of current evidence regarding this outcome is limited by retrospective data collection, small sample size, cohort selection and participation bias, and heterogeneity in treatment approach, time since treatment, and method of ascertainment. Oral and dental complications reported in childhood cancer survivors include the following:.
Abnormalities of dental development reported in childhood cancer survivors include the following: The prevalence of hypodontia has varied widely in series depending on age at diagnosis, treatment modality, and method of ascertainment. Cancer treatments that have been associated with dental maldevelopment include the following: Key findings related to cancer treatment effect on tooth development include the following:. Developing teeth may be irradiated in the course of treating head and neck sarcomas, Hodgkin lymphoma, neuroblastoma, central nervous system leukemia, nasopharyngeal cancer, brain tumors, and as a component of total-body irradiation TBI.
Doses of 10 Gy to 40 Gy can cause root shortening or abnormal curvature, dwarfism, and hypocalcification. Xerostomia, the sensation of dry mouth, is a potential side effect after head and neck irradiation or HSCT that can severely impact quality of life.
Complications of reduced salivary secretion include the following: The prevalence of salivary gland dysfunction after cancer treatment varies based on measurement techniques patient report vs.
In the CCSS, the prevalence of self-reported xerostomia in survivors was 2. Key findings related to cancer treatment effect on salivary gland function include the following:.
The impact of infectious complications and alterations in the microflora during and after therapy is not known. Craniofacial maldevelopment is a common adverse outcome among children treated with high-dose radiation therapy to the head and neck that frequently occurs in association with other oral cavity sequelae such as dental anomalies, xerostomia, and trismus.
Remediation of cosmetic and functional abnormalities often requires multiple surgical interventions. Some studies suggest that fluoride products or chlorhexidine rinses may be beneficial in patients who have undergone radiation therapy.
The use of topical fluoride can dramatically reduce the frequency of caries, and saliva substitutes and sialagogues can ameliorate sequelae such as xerostomia.
It has been reported that the incidence of dental visits for childhood cancer survivors falls below the American Dental Association's recommendation that all adults visit the dentist annually. These findings give health care providers further impetus to encourage routine dental care and dental hygiene evaluations for survivors of childhood treatment. Table 4 summarizes oral and dental late effects and the related health screenings.
The gastrointestinal GI tract is sensitive to the acute toxicities of chemotherapy, radiation therapy, and surgery. However, these important treatment modalities can also result in some long-term issues in a treatment- and dose-dependent manner. Reports published about long-term GI tract outcomes are limited by retrospective data collection, small sample size, cohort selection and participation bias, heterogeneity in treatment approach, time since treatment, and method of ascertainment.
Factors predicting higher risk of specific GI complications include the following:. In general, fractionated radiation doses of 20 Gy to 30 Gy can be delivered to the small bowel without significant long-term morbidity.
Doses greater than 40 Gy are associated with a higher risk of bowel obstruction or chronic enterocolitis. Intra-abdominal tumors represent a relatively common location for several pediatric malignancies, including rhabdomyosarcoma, Wilms tumor, lymphoma, germ cell tumors, and neuroblastoma.
Thus, these tumors would be expected to be particularly prone to long-term digestive tract issues. A limited number of reports describe GI complications in pediatric patients with genitourinary solid tumors treated with radiation therapy: Table 5 summarizes digestive tract late effects and the related health screenings.
Hepatic complications resulting from childhood cancer therapy are observed primarily as acute treatment toxicities. Severe acute hepatic complications rarely occur. Survivors of childhood cancer can occasionally exhibit long-standing hepatic injury. Some general concepts regarding hepatotoxicity related to childhood cancer include the following:.
Asymptomatic elevation of liver enzymes is the most common hepatobiliary complication. Dutch investigators observed hepatobiliary dysfunction in 8. Cases with a history of viral hepatitis and a history of veno-occlusive disease were excluded. Less commonly reported hepatobiliary complications include the following:. These lesions are thought to be iatrogenic benign manifestations of vascular damage and have been associated with veno-occlusive disease, high-dose alkylating agents e. The lesions can mimic metastatic or subsequent tumors, but MRI imaging has a characteristic pattern and is generally diagnostic.
Biopsy or resection is usually unnecessary unless the lesions grow or patients have worrisome symptoms. Biopsy may be necessary to distinguish nodular regenerative hyperplasia from a subsequent malignancy. MRI has emerged as an accurate, noninvasive means for measuring iron in multiple organ systems. In a multivariable analysis, cumulative packed red blood cell volume and older age at diagnosis predicted elevated liver iron concentration.
The type and intensity of previous therapy influences risk for late-occurring hepatobiliary effects. In addition to the risk of treatment-related toxicity, recipients of HSCT frequently experience chronic liver dysfunction related to microvascular, immunologic, infectious, metabolic, and other toxic etiologies. Key findings related to cancer treatment effect on hepatobiliary complications include the following:. Radiation hepatopathy after contemporary treatment appears to be uncommon in long-term survivors without predisposing conditions such as viral hepatitis or iron overload.
The risk of injury in children increases with radiation dose, hepatic volume, younger age at treatment, previous partial hepatectomy, and concomitant use of radiomimetic chemotherapy such as dactinomycin and doxorubicin. Viral hepatitis B and C may complicate the treatment course of childhood cancer and result in chronic hepatic dysfunction.
Hepatitis B tends to have a more aggressive acute clinical course and a lower rate of chronic infection. Hepatitis C is characterized by a mild acute infection and a high rate of chronic infection. Chronic hepatitis predisposes the childhood cancer survivor to cirrhosis, end-stage liver disease, and hepatocellular carcinoma.
Concurrent infection with hepatitis B and C in combination or in co-occurrence with other hepatotrophic viruses accelerates the progression of liver disease. Survivors with liver dysfunction should be counseled regarding risk-reduction methods to prevent hepatic injury. Standard recommendations include maintenance of a healthy body weight, abstinence from alcohol use, and immunization against hepatitis A and B viruses.
In patients with chronic hepatitis, precautions to reduce viral transmission to household and sexual contacts should also be reviewed. Table 6 summarizes hepatobiliary late effects and the related health screenings.
The pancreas has been thought to be relatively radioresistant because of a paucity of information about late pancreatic-related effects. However, children and young adults treated with TBI or abdominal irradiation are known to have an increased risk of insulin resistance and diabetes mellitus. Endocrine dysfunction is very common among childhood cancer survivors, especially those treated with surgery or radiation therapy that involves hormone-producing organs and those receiving alkylating agent chemotherapy.
Prevalence of endocrine disorders at the last follow-up visit, by sex. The prevalence of specific endocrine disorders is affected by the following: The following sections summarize research that characterizes the clinical features of survivors at risk of endocrine dysfunction that impacts pituitary, thyroid, adrenal, and gonadal function. Thyroid dysfunction is a common delayed effect of radiation therapy fields that include the thyroid gland incidental to treating Hodgkin lymphoma HL , brain tumors, head and neck sarcomas, and acute lymphoblastic leukemia ALL.
There is considerable evidence linking radiation exposure to thyroid abnormalities, but the prevalence of specific conditions varies widely because studies are limited by cohort selection and participation bias, heterogeneity in radiation treatment approach, time since radiation exposure, and method of ascertainment e.
Thyroid abnormalities observed in excess in childhood cancer survivors include the following:. Of children treated with radiation therapy, most develop hypothyroidism within the first 2 to 5 years posttreatment, but new cases can occur later. Reports of thyroid dysfunction differ depending on the dose of radiation, the length of follow-up, and the biochemical criteria utilized to make the diagnosis. Compensated hypothyroidism includes an elevated TSH with a normal T 4 and is asymptomatic.
The natural history is unclear, but most endocrinologists support treatment. Uncompensated hypothyroidism includes both an elevated TSH and a depressed T 4. Thyroid hormone replacement is beneficial for correction of the metabolic abnormality, and has clinical benefits for cardiovascular, gastrointestinal, and neurocognitive function.
An increased risk of hypothyroidism has been reported among childhood cancer survivors treated with head and neck radiation exposing the thyroid gland, especially among survivors of HL. Any radiation field that includes the thyroid is associated with an excess risk of thyroid neoplasms, which may be benign usually adenomas or malignant most often differentiated papillary carcinoma. CCSS investigators performed a nested case-control study to evaluate the magnitude of risk for thyroid cancer over the therapeutic radiation dose range of pediatric cancers.
The risk of thyroid cancer increased with radiation doses up to 20 Gy to 29 Gy odds ratio [OR], 9. The following factors are linked to an increased risk of thyroid nodule development:. In a pooled study of two cohorts of 16, survivors that included patients with secondary thyroid cancer, treatments with alkylating agents, anthracyclines, or bleomycin were associated with a significantly increased risk of thyroid cancer in individuals not exposed to radiation therapy.
Several investigations have demonstrated the superiority of ultrasound to clinical exam for detecting thyroid nodules and thyroid cancers and characterized ultrasonographic features of nodules that are more likely to be malignant. In fact, because these lesions tend to be indolent, are rarely life-threatening, and may clinically manifest many years after exposure to radiation, there are significant concerns regarding the costs and harms of overscreening.
A decision aid to facilitate discussion accompanies their recommendations. Refer to the Subsequent Neoplasms section of this summary for information about subsequent thyroid cancers. Non—TBI-containing regimens historically were not associated with an increased risk. TSH deficiency central hypothyroidism is discussed with late effects that affect the pituitary gland.
Table 7 summarizes thyroid late effects and the related health screenings. Survivors of childhood cancer are at risk of developing a spectrum of neuroendocrine abnormalities, primarily because of the effect of radiation therapy on the hypothalamus. Essentially all of the hypothalamic-pituitary axes are at risk.
Although the quality of the literature regarding pituitary endocrinopathy among childhood cancer survivors is often limited by retrospective data collection, small sample size, cohort selection and participation bias, heterogeneity in treatment approach, time since treatment, and method of ascertainment, the evidence linking this outcome with radiation therapy, surgery, and tumor infiltration is quite compelling because affected individuals typically present with metabolic and developmental abnormalities early in follow-up.
Central diabetes insipidus may herald the diagnosis of craniopharyngioma, suprasellar germ cell tumor, or Langerhans cell histiocytosis. More commonly, however, diabetes insipidus occurs in the context of panhypopituitarism caused by the presence of a tumor in close proximity to the sellar region or as a consequence of surgical procedures undertaken for local tumor control.
Central diabetes insipidus has not been reported as a late effect of cranial irradiation in childhood cancer survivors. Deficiencies of anterior pituitary hormones and major hypothalamic regulatory factors are common late effects among survivors treated with cranial irradiation. The six anterior pituitary hormones and their major hypothalamic regulatory factors are outlined in Table 8.
Growth hormone deficiency is the earliest hormonal deficiency associated with cranial radiation therapy in childhood cancer survivors.
The risk increases with radiation dose and time since treatment. Growth hormone deficiency is sensitive to low doses of radiation. Other hormone deficiencies require higher doses, and their time to onset is much longer than for growth hormone deficiency.
Growth hormone deficiency is commonly observed in these long-term survivors because of radiation doses used in the treatment of childhood brain tumors. The dose-response relationship has a threshold of 18 Gy to 20 Gy; the higher the radiation dose, the earlier that growth hormone deficiency will occur after treatment.
Evidence radiation-dose response relationship of growth hormone deficiency:. Peak growth hormone GH according to hypothalamic mean dose and time after start of radiation. Children treated with CNS-directed therapy for leukemia are also at increased risk of growth hormone deficiency. Evidence risk of growth hormone deficiency in childhood ALL survivors:.
Children who undergo HSCT with TBI have a significant risk of both growth hormone deficiency and the direct effects of radiation on skeletal development. The risk is increased with single-dose TBI as opposed to fractionated TBI, pretransplant cranial irradiation, female sex, and posttreatment complications such as graft-versus-host disease GVHD. Growth hormone deficiency replacement therapy provides the benefit of optimizing height outcomes among children who have not reached skeletal maturity.
Treatment with recombinant growth hormone rGH replacement therapy is generally delayed until 12 months after successful completion of cancer or brain tumor treatments and after a multidisciplinary discussion involving the prescribing pediatric endocrinologist, the primary oncologist, and other providers selected by the patient or family.
The following study results have been reported in survivors who did or did not receive treatment with growth hormone. In general, the data addressing subsequent malignancies should be interpreted with caution given the small number of events. Pubertal development can be adversely affected by cranial radiation therapy. Central precocious puberty is defined by the onset of pubertal development before age 8 years in girls and 9 years in boys as a result of the premature activation of the hypothalamic-pituitary-gonadal axis.
Aside from the adjustment and psychosocial challenges associated with early pubertal development, precocious puberty can lead to the rapid closure of the skeletal growth plates and short stature. This deleterious effect can be further potentiated by growth hormone deficiency. It is also important to note that the assessment of puberty cannot be performed using testicular volume measurements in boys exposed to chemotherapy or direct radiation to the testes, given the toxic effect of these treatments on germ cells and repercussions on gonadal size.
The staging of puberty in males within this population relies on the presence of other signs of virilization, such as the presence of pubic hair and the measurement of plasma testosterone levels. When appropriate, delaying the progression of puberty relies on the use of various gonadotropin-releasing hormone agonist preparations, an approach that has been shown to improve growth prospects—especially when other pituitary abnormalities, including growth hormone deficiency, are concurrently treated.
TSH deficiency also referred to as central hypothyroidism in survivors of childhood cancer can have profound clinical consequences and be underappreciated. Symptoms of central hypothyroidism e. In addition to delayed puberty and slow growth, hypothyroidism may cause fatigue, dry skin, constipation, increased sleep requirement, and cold intolerance.
The risk of TSH deficiency is highest among patients treated with cranial radiation at doses greater than or equal to 30 Gy; TSH deficiency following the exposure to lower doses can occur at delayed time points.
Mixed primary and central hypothyroidism can also occur and reflects separate injuries to the thyroid gland and the hypothalamus e. Thyroid hormone replacement therapy using levothyroxine represents the mainstay of treatment of TSH deficiency.
The dose of levothyroxine needs to be adjusted solely using plasma free T 4 levels; the levels of TSH are expected to remain low during therapy, given the central nature of this deficiency. ACTH deficiency is less common than other neuroendocrine deficits but should be suspected in patients who have a history of brain tumor regardless of therapy modality , cranial radiation therapy, growth hormone deficiency, or central hypothyroidism.
The diagnosis should be suspected when low plasma levels of morning cortisol are measured a screening cortisol level collected at 8 a. Confirmation is necessary using dynamic testing such as the low-dose ACTH stimulation test.
Patients with partial ACTH deficiency may have only subtle symptoms unless they become ill. Hyperprolactinemia has been described in patients who received radiation therapy to the hypothalamus in doses higher than 50 Gy or who underwent surgery that disrupted the integrity of the pituitary stalk.
Primary hypothyroidism may lead to hyperprolactinemia as a result of hyperplasia of thyrotrophs and lactotrophs, presumably due to TRH hypersecretion. The prolactin response to TRH is usually exaggerated in these patients. In general, hyperprolactinemia may result in delayed puberty, galactorrhea, menstrual irregularities, loss of libido, hot flashes, infertility, and osteopenia.
However, hyperprolactinemia resulting from cranial radiation therapy is rarely symptomatic and, given its frequent associations with hypogonadism both central and primary. Table 9 summarizes pituitary gland late effects and the related health screenings.
Testicular and ovarian hormonal functions are discussed in the Late Effects of the Reproductive System section of this summary. An increased risk of metabolic syndrome or its components has been observed among cancer survivors. The evidence for this outcome ranges from clinically manifested conditions that are self-reported by survivors to retrospectively assessed data in medical records and hospital registries to systematic clinical evaluations of clinically well-characterized cohorts.
Studies have been limited by cohort selection and participation bias, heterogeneity in treatment approach, time since treatment, and method of ascertainment. Despite these limitations, compelling evidence indicates that metabolic syndrome is highly associated with cardiovascular events and mortality.
Definitions of metabolic syndrome are evolving but generally include a combination of central abdominal obesity with at least two of the following features:. Evidence prevalence of and risk factors for metabolic syndrome in childhood cancer survivors:.
Long-term survivors of ALL, especially those treated with cranial radiation therapy, may have a higher prevalence of some potentially modifiable risk factors for cardiovascular disease such as impaired glucose tolerance or overt diabetes mellitus, dyslipidemia, hypertension, and obesity. Several studies have provided support for the potential benefits of lifestyle modifications in reducing cardiovascular disease risk.
Evidence lifestyle modifications to reduce cardiovascular risk in childhood cancer survivors:. Abdominal radiation therapy and TBI are increasingly recognized as independent risk factors for diabetes mellitus in childhood cancer survivors.
Evidence risk factors for diabetes mellitus in childhood cancer survivors:. Table 10 summarizes metabolic syndrome late effects and the related health screenings. BMI at diagnosis has been identified as a significant predictor of being underweight or overweight at follow-up, suggesting that genetic or environmental factors contribute to the development or persistence of abnormal body composition. CCSS investigators identified treatment-related risk factors for being underweight, including TBI females or abdominal irradiation males , use of alkylating agents, and use of anthracyclines.
To date, cancer patients with an increased incidence of being overweight and obese are primarily ALL [ 90 , 92 - 98 ] and CNS tumor [ 4 , 23 ] survivors who were treated with cranial radiation therapy. Also, craniopharyngioma survivors have a substantially increased risk of extreme obesity because of the tumor location and the hypothalamic damage resulting from surgical resection.
In addition to treatment factors, lifestyle factors and medication use can also contribute to the risk of obesity. CCSS investigators reported the following independent risk factors for obesity in childhood cancer survivors: Survivors who adhered to the U.
Moderate-dose cranial radiation therapy 18—24 Gy among ALL survivors is associated with obesity, particularly in females treated at a young age. These outcomes are attenuated in males. However, a study of long-term male survivors of ALL mean age, 29 years observed significantly higher body adiposity than in age-matched controls, despite normal weight and BMI.
Potential indicators of increased adiposity included high leptin and low sex hormone—binding globulin levels. Serum testicular endocrine markers testosterone, FSH, or inhibin B did not correlate with body adiposity. ALL therapy regimens are associated with increases in BMI shortly after completion of therapy, and possibly with a higher risk of obesity in the long term.
Evidence body composition changes in adult survivors of childhood ALL:. Results from the CCSS, however, were based on self-reported height and weight measurements. Again, these variable outcomes likely relate to the use of BMI as the metric for abnormal body composition, which does not adequately assess visceral adiposity that can contribute to metabolic risk in this population.
Among brain tumor survivors treated with higher doses of cranial radiation therapy, only females treated at a younger age appear to be at increased risk for obesity. Young adult childhood cancer survivors have a higher-than-expected prevalence of frailty, a phenotype characterized by low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness.
Individuals are termed prefrail if they have two of these five characteristics and frail if they have three or more of these characteristics. The frailty phenotype increases in prevalence with aging, and has been associated with excess risk of mortality and onset of chronic conditions.
Table 11 summarizes body composition late effects and the related health screenings. Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for endocrine and metabolic syndrome late effects information, including risk factors, evaluation, and health counseling.
Late effects of the immune system have not been well studied, especially in survivors treated with contemporary therapies. Reports published about long-term immune system outcomes are limited by retrospective data collection, small sample size, cohort selection and participation bias, heterogeneity in treatment approach, time since treatment, and method of ascertainment. Surgical or functional splenectomy increases the risk of life-threatening invasive bacterial infection: Individuals with asplenia, regardless of the reason for the asplenic state, have an increased risk of fulminant bacteremia, especially associated with encapsulated bacteria, which is associated with a high mortality rate.
The risk of bacteremia is higher in younger children than in older children, and this risk may be higher during the years immediately after splenectomy. Fulminant septicemia, however, has been reported in adults up to 25 years after splenectomy.
Bacteremia may be caused by the following organisms in asplenic survivors:. Individuals with functional or surgical asplenia are also at increased risk of fatal malaria and severe babesiosis. Clinicians should consider and encourage the administration of inactivated vaccines e. Two primary doses of quadrivalent meningococcal conjugate vaccine should be administered 2 months apart to children with asplenia, from age 2 years through adolescence, and a booster dose should be administered every 5 years.
However, the efficacy of meningococcal vaccines in children with asplenia has not been established. Refer to the Meningococcal Infections section of the Red Book for more information. No known contraindication exists to giving these vaccines at the same time as other required vaccines, in separate syringes, at different sites. Pneumococcal conjugate vaccine PCV and pneumococcal polysaccharide vaccine PPSV are indicated at the recommended age for all children with asplenia.
A second dose should be administered 5 years later. For asplenic individuals aged 6 to 18 years who have not received a dose of PCV13, a supplemental dose of PCV13 should be considered. Hib immunization should be initiated at age 2 months, as recommended for otherwise healthy young children and for previously unimmunized children with asplenia. Daily antimicrobial prophylaxis against pneumococcal infections is recommended for young children with asplenia, regardless of their immunization status.
Although the efficacy of daily antimicrobial prophylaxis has been proven only in patients with sickle cell anemia, this experience has been extended to other high-risk children, including asplenic children with a history of malignant neoplasms or thalassemia. In general, antimicrobial prophylaxis in addition to immunization should be considered for all children with asplenia younger than 5 years and for at least 1 year after splenectomy.
The age at which antimicrobial prophylaxis is discontinued is an empiric decision. On the basis of a multicenter study in sickle cell disease, prophylactic penicillin can be discontinued at age 5 years among those who are receiving regular medical attention and who have not had a severe pneumococcal infection or surgical splenectomy.
The appropriate duration of prophylaxis is unknown for children with asplenia attributable to other causes. Some experts continue prophylaxis throughout childhood and into adulthood for particularly high-risk patients with asplenia. Table 12 summarizes spleen late effects and the related health screenings. Although the immune system appears to recover from the effects of active chemotherapy and radiation therapy, there is some evidence that lymphoid subsets do not normalize in all survivors.
Innate immunity, thymopoiesis, and DNA damage responses to radiation were shown to be abnormal in survivors of childhood leukemia.
Survivors of childhood cancer may remain susceptible to vaccine-preventable infections. Treatment intensity, age at diagnosis, and time from treatment are associated with the risk of losing pre-existing immunity. While there is a paucity of data regarding the benefits of administering active immunizations in this population, reimmunization is necessary to provide protective antibodies.
The recommended reimmunization schedule will depend on previously received vaccinations and on the intensity of therapy. Refer to the Immunization Schedules for section of the Red Book for more information. However, responses to pertussis Factors associated with vaccine failure include older age at immunization; lower CD3, CD4, or CD19 count; higher immunoglobulin M concentration; positive recipient cytomegalovirus serology; negative titer before immunization; history of acute or chronic GVHD; and radiation conditioning.
Follow-up recommendations for transplant recipients have been published by the major North American and European transplant groups, the CDC, and the Infectious Diseases Society of America. The musculoskeletal system of growing children and adolescents is vulnerable to the cytotoxic effects of cancer therapies, including surgery, chemotherapy, and radiation therapy.
Documented late effects include the following:. While these late effects are discussed individually, it is important to remember that the components of the musculoskeletal system are interrelated. For example, hypoplasia to a muscle group can negatively affect the function of the long bones and the resultant dysfunction can subsequently lead to disuse and osteoporosis.
The major strength of the published literature documenting musculoskeletal late effects among children and adolescents treated for cancer is that most studies have clearly defined outcomes and exposures. However, many studies are observational and cross-sectional or retrospective in design.
Single-institution studies are common, and for some outcomes, only small convenience cohorts have been described. Thus, it is possible that studies either excluded patients with the most severe musculoskeletal effects because of death or inability to participate in follow-up testing, or oversampled those with the most severe musculoskeletal late effects because these patients were accessible as they returned for complication-related follow-up.
Additionally, some of the results reported in adult survivors of childhood cancer may not be relevant to patients currently being treated because the delivery of anticancer modalities, particularly radiation therapy, has changed over the years in response to documented toxicities. The effect of radiation on bone growth depends on the sites irradiated, as follows:. In an age- and dose-dependent fashion, radiation can inhibit normal bone and muscle maturation and development. Radiation to the head e.
Often, in addition to the cosmetic impact of the craniofacial abnormalities, there can be related dental and sinus problems. Cranial radiation therapy damages the hypothalamic-pituitary axis in an age- and dose-response fashion and can result in growth hormone deficiency. Patients with a central nervous system CNS tumor [ 10 , 14 ] or acute lymphoblastic leukemia ALL [ 15 - 17 ] treated with 18 Gy or higher of cranial radiation therapy are at highest risk.
Patients treated with total-body irradiation TBI , particularly single-fraction TBI,[ 18 - 21 ] and those treated with cranial radiation for non-CNS solid tumors [ 22 ] are also at risk of growth hormone deficiency. If the spine is also irradiated e.
Radiation therapy can also directly affect the growth of the spine and long bones and associated muscle groups and can cause premature closure of the epiphyses, leading to the following: Orthovoltage radiation therapy, commonly used before , delivered high doses of radiation to bone and was commonly associated with subsequent abnormalities in bone growth.
However, even with contemporary radiation therapy, if a solid tumor is located near an epiphysis or the spine, alterations in normal bone development can be difficult to avoid. The effects of radiation therapy administered to the spine on stature in survivors of Wilms tumor have been assessed.
Although increased rates of fracture are not reported among long-term survivors of childhood cancer,[ 33 ] maximal peak bone mass is an important factor influencing the risk of osteoporosis and fracture among older patients. Treatment-related factors that affect bone mineral loss include the following:.
Most of our knowledge about cancer and treatment effects on bone mineralization has been derived from studies of children with ALL. The development of osteonecrosis during treatment for ALL also predicts higher risk of low bone density. Clinical assessment of bone mineral density in adults treated for childhood ALL indicates that most bone mineral deficits normalize over time after discontinuing osteotoxic therapy.
The prefrail phenotype is characterized by having two of five characteristics low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness and the frail phenotype is characterized by having three or more of these characteristics. Modifiable factors such as growth hormone deficiency, smoking, and alcohol consumption were significant predictors for these outcomes, with varying impact on the basis of sex. These data underscore the importance of lifestyle counseling and screening for hormonal deficits during long-term survivors' follow-up evaluations.
Bone mineral density deficits that are likely multifactorial in etiology have been reported in allogeneic hematopoietic stem cell transplantation HSCT recipients conditioned with TBI.
Despite disease-related and treatment-related risks of bone mineral density deficits, the prevalence of self-reported fractures among Childhood Cancer Survivor Study CCSS participants was lower than that reported by sibling controls.
Predictors of increased prevalence of fracture by multivariable analyses included the following: Radiation-induced fractures can occur with doses of radiation of 50 Gy or higher, as is often used in the treatment of Ewing sarcoma of the extremity.
Osteonecrosis also known as aseptic or avascular necrosis is a rare, but well-recognized skeletal complication observed predominantly in survivors of pediatric hematological malignancies treated with corticosteroids. The condition is characterized by death of one or more segments of bone that most often affects weight-bearing joints, especially the hips and knees. Longitudinal cohort studies have identified a spectrum of clinical manifestations of osteonecrosis, ranging from asymptomatic, spontaneously-resolving imaging changes to painful progressive articular collapse requiring joint replacement.
These symptoms may improve over time, persist, or progress in the years after completion of therapy. Osteonecrosis risk may be related to type of corticosteroid, with some studies in patients with ALL indicating increased risk with the use of dexamethasone compared with prednisone.
Corticosteroid dosing schedule also appears to impact the risk of developing osteonecrosis. In addition to corticosteroids, exposure to methotrexate and concurrent asparaginase may contribute to the development of osteonecrosis.
Studies evaluating the influence of sex on the risk of osteonecrosis have yielded conflicting results, with some suggesting a higher incidence in females [ 67 , 70 , 78 ] that has not been confirmed by others. Osteochondromas are benign boney protrusions that can be spontaneous or associated with radiation therapy. They generally occur as a single lesion; however, multiple lesions may develop in the context of hereditary multiple osteochondromatosis. Growth hormone therapy may influence the onset and pace of growth of osteochondromas.
Because malignant degeneration of these lesions is exceptionally rare, clinical rather than radiological follow-up is most appropriate. Amputation and limb-sparing surgery prevent local recurrence of bone tumors by removal of all gross and microscopic disease. If optimally executed, both procedures accomplish an en bloc excision of tumor with a margin of normal uninvolved tissue.
The type of surgical procedure, the primary tumor site, and the age of the patient affect the risk of postsurgical complications. Complications after limb-sparing surgery include non-union, pathologic fracture, aseptic loosening, limb-length discrepancy, endoprosthetic fracture, and limited joint range of motion.
A number of studies have compared functional outcomes after amputation and limb-sparing surgery, but results have been limited by inconsistent methods of functional assessment and small cohort sizes.
Overall, data suggest that limb-sparing surgery results in better function than amputation, but differences are relatively modest. Table 13 summarizes bone and joint late effects and the related health screenings.
Surgery, radiation therapy, or chemotherapy that negatively affects any component of the hypothalamic-pituitary axis or gonads may compromise reproductive outcomes in childhood cancer survivors.
Evidence for this outcome in childhood cancer survivors is limited by studies characterized by small sample size, cohort selection and participation bias, cross-sectional assessment, heterogeneity in treatment approach, time since treatment, and method of ascertainment.
In particular, the literature is deficient regarding hard outcomes of reproductive potential e. The risk of infertility is generally related to the tissues or organs involved by the cancer and the specific type, dose, and combination of cytotoxic therapy. In addition to anticancer therapy, age at treatment, and sex, it is likely that genetic factors influence the risk of permanent infertility.
It should be noted that pediatric cancer treatment protocols often prescribe combined-modality therapy; thus, the additive effects of gonadotoxic exposures may need to be considered in assessing reproductive potential. Detailed information about the specific cancer treatment modalities including specific surgical procedures, the type and cumulative doses of chemotherapeutic agents, and radiation treatment volumes and doses are needed to estimate risks for gonadal dysfunction and infertility.
Cancer treatments that may impair testicular and reproductive function include the following:. Patients who undergo unilateral orchiectomy for testicular torsion may have subnormal sperm counts at long-term follow-up. Among men treated for childhood cancer, the potential for gonadal injury exists if radiation treatment fields include the pelvis, gonads, or total body. The germinal epithelium is more sensitive to radiation injury than are the androgen-producing Leydig cells.
A decrease in sperm counts can be seen 3 to 6 weeks after such irradiation, and depending on the dosage, recovery may take 1 to 3 years. Irreversible germ cell failure may occur with fractionated radiation doses of greater than 2 Gy to 4 Gy.
Radiation injury to Leydig cells is related to the dose delivered and age at treatment. Testosterone production may be normal in prepubertal boys treated with less than 12 Gy fractionated testicular irradiation, but elevated plasma concentrations of luteinizing hormone observed in this group suggest subclinical injury. Gonadal failure typically results when prepubertal boys are treated with more than 20 Gy of radiation to the testes; androgen therapy is required for masculinization.
Leydig cell function is usually preserved in sexually mature male patients if radiation doses do not exceed 30 Gy. Although available data suggest that Leydig cells are more vulnerable when exposed to radiation before puberty, confounding factors, such as the age at testing and the effects of both orchiectomy and chemotherapy, limit the reliability of this observation.
Cumulative alkylating agent e. Most studies suggest that prepubertal males are not at lower risk for chemotherapy-induced testicular damage than are postpubertal patients. Studies of testicular germ cell injury, as evidenced by oligospermia or azoospermia, after alkylating agent administration with or without radiation therapy, have reported the following:.
The risk of gonadal dysfunction and infertility related to conditioning with total-body irradiation TBI , high-dose alkylating agent chemotherapy, or both is substantial. Because transplantation is often undertaken for relapsed or refractory cancer, previous treatment with alkylating agent chemotherapy or hypothalamic-pituitary axis or gonadal radiation therapy may confer additional risks. Age at treatment also influences the risk of gonadal injury.
After TBI conditioning, most male patients retain their ability to produce testosterone but will experience germ cell failure.
Recovery of gonadal function after cytotoxic chemotherapy and radiation therapy is possible. Dutch investigators used inhibin B as a surrogate marker of gonadal function in a cross-sectional, retrospective study of male survivors of childhood cancer, with a median follow-up of The median inhibin B level among the cohort increased based on serial measurements performed over a median of 3.
The probability of recovery of the serum inhibin B level was significantly influenced by baseline inhibin B level, but not age at diagnosis, age at study evaluation, interval between discontinuation of treatment and study evaluation, gonadal irradiation, and alkylating agent dose score. These results suggest that recovery can occur but not if inhibin B is already at a critically low level.
Inhibin B and FSH levels are correlated with sperm concentration and often used to estimate the presence of spermatogenesis; however, limitations in the specificity and positive predictive value of these tests have been reported.