Preschool Age

During the preschool years (ages 2–6 years), children are egocentric (a perspective of being at the center of everything) and use associative logic, which means that any 2 unrelated things can be understood in terms of 1 causing the other. The combination of egocentricity and associative logic results in magical thinking and interweaving of reality and fantasy. The use of magical thinking may lead a child to believe that his cancer is a punishment for a bad thought or deed. An example of this might be a 4 year-old boy who thinks he has leukemia because he took his sister’s toy or he ate too many cookies. As a result procedures and treatment side effects may feel like punishments, especially if the child is unable to localize the medical illness to a particular body part, as is the case in leukemia. These feelings are consistent with a perception of whole body vulnerability, that “my whole body is sick,” even though only 1 organ system is involved. Whole body vulnerability is made more real for the child with cancer who endures intravenous lines, hair loss, and nausea and vomiting. For children with leukemia this vulnerability is heightened, as it is difficult to grasp the concept of a hematologic malignancy.

The concept of time develops gradually in this age range. Although parents may be focused on the seriousness of a diagnosis, the expected course of treatment, and probabilities of survival, the child will likely only comprehend what will affect him or her in the moment.

The dominant social sphere of the preschool child, and the area most affected by the illness, is family life. Children aged 3 to 6 years spend most of their time with their immediate family, and their contacts outside the home are usually limited to preschool and day care. Separations from family members and care providers can be anxiety provoking and challenging during the course of treatment.

School Age

School age is characterized by mastery of skills. There is the emergence of logical thinking (causal logic) and more appreciation for another’s point of view. School and peer groups play an increasing role in a child’s life. Therefore, disrupted functioning in school performance and peer relationships are common social sequelae, either from direct effects of cancer (time missed from school and friends) or a regressive loss of coping skills. Offering school tutors and age-appropriate activities (such as board games, video games, computers, puzzles, and arts and crafts) can help children to function closer to their premorbid level and may serve as a counterweight to the regressive pull of dependency, helplessness, and loss of control that often accompanies intensive medical treatment.

When school-age children are diagnosed with cancer, they are able to understand the simple functional explanations of their illness and often pride themselves in mastering the names or procedures and treatments they have received. Innovative programs targeting this developmental level include “My Story in Beads” which allows children to mark off each procedure and treatment with a special bead on a string (Elyse Levin-Russman, MSW, LICSW, personal communication, January 2010). Children create a narrative about how their cancer was diagnosed and the treatment they are receiving, allowing them to be active participants in their care. Rules provide predictability in this age group, but a cancer diagnosis disrupts this way of thinking because there are no identifiable causes for most childhood cancers, unlike some adult cancers (eg, smoking leading to lung cancer). It can be frustrating to a child who plays by the rules and follows the doctors’ orders to then face setbacks in treatment despite their best efforts. Helping this age group feel competent in the midst of medical complications can be challenging.

Adolescence

During normal adolescence, areas of growth include identity and independence, sexual development, and peer group involvement. Cognitively, adolescents are able to think abstractly and can understand the complexity of a chronic illness in the same way as adults. They can appreciate the meaning of a life-threatening or chronic illness, but often are not prepared to manage the changes in their lifestyle and activities that the treatment requires.

The multiple demands of living with cancer (including enduring the diagnosis and treatments, physical discomfort, limitations, pain, effect on appearance, and fears about the present and future) threaten the adolescent’s ability to exercise newly acquired independence. These demands occurs at the same time as the adolescent is striving to individuate from parents and trying to establish an independent identity. An adolescent’s identity usually relies on the peer group to determine what is “in” and what is “out,” and attractiveness within this group plays a significant role in determining one’s self-esteem. Time away from school and other activities may strain friendships and create feelings of isolation at a time when feeling connected to peers is of utmost importance to the development of identity. Often the illness occurs at a time when other tensions between the adolescent and parent make relying on the parents uncomfortable or unacceptable. Logistical and emotional reasons thwart individuation; parents may need to bring the adolescent to appointments or stay at the bedside during a hospitalization, or may experience longing for closeness with the adolescent when faced with the issues of mortality raised by cancer. In the setting of this emotionally complex dilemma, some teens become sullen, aggressive, nonadherent, or withdrawn, whereas others are able to negotiate the discomfort of returning to a more dependent supportive relationship with parents.

A recent study examined the rates and types of distress experienced by teenagers 4 to 8 weeks after they were diagnosed with cancer. The main areas included physical concerns (eg, mucositis), personal changes (eg, hair loss, fatigue, and weight changes) and treatment-related worries (eg, missing school and missing leisure activities).

Body image and sexuality are tremendously affected by cancer. In adolescence, an extraordinary amount of time is spent on one’s appearance and presentation because it often determines one’s self-esteem. For the adolescent with cancer, physical attractiveness takes on new meaning. Competence and interest in developing interpersonal and intimate relationships depend on having a positive sense of self and body image. Both of these are challenged during treatment because of feelings of being different and physical appearance changes such as hair loss caused by chemotherapy or weight gain caused by corticosteroids. As a result of low self-esteem and body image concerns expressed by adolescents with cancer, they avoid or are less likely to establish intimate relationships. Future fertility, threatened by cancer treatment, is also a prominent issue. Semen cryopreservation is available for boys but there are no definitive preservation methods available for girls.

Mood

One might assume that a severe stressor such as a diagnosis of cancer during childhood would overwhelm an individual’s ability to cope emotionally and most if not all children would experience emotional difficulties. However, studies suggest that most children with cancer do not exhibit significant levels of depression or anxiety, although a significant minority do experience marked levels of psychological distress. Some clinical observations have indicated that a subset of patients exhibit more problems, such as greater difficulty coping. Other studies show the emotional well-being of children with cancer currently receiving chemotherapy to be remarkably similar to case-control classroom peers, and initial studies of cancer survivors similarly failed to find increases in social and emotional problems in children with cancer, although new data on survivors has challenged this view (see later discussion).

The type of cancer may play a role in the psychological effect on the child. Children with brain tumors are likely to experience more psychological distress, in large part because of the neurocognitive sequelae of their disease. Similarly, those with severe medical late effects tend to have more depressive symptoms and poorer self-concept.

The involvement of mental health professionals in addressing the psychosocial needs of patients and their families can mediate the overall distress they experience. Optimal psychosocial care for patients with cancer includes opportunities to assess functioning and separate transient distress from more serious and disruptive emotional difficulties. Identification of those children with mood and behavioral difficulties who will require additional services is essential in providing good oncologic care. In assessing a child’s mood, the clinician must be knowledgeable about the side effects of the treatments, which may include fatigue, decreased appetite, and disturbed sleep. If a child does present with clinically significant depressive symptoms, the treatment follows the same course as it would in the physically well child; that is, with psychotherapy such as cognitive-behavioral therapy (CBT) and antidepressant medication as indicated.

Although no large studies have been conducted in children with cancer, selective serotonin reuptake inhibitor (SSRI) medications are the pharmacologic antidepressant treatment of choice, as they are in the population at large. In an uncontrolled pilot study of 15 children with cancer and depression or anxiety, fluvoxamine was well tolerated and effective. Fifty percent of pediatric oncologists at Children’s Hospital of Philadelphia reported prescribing SSRIs for their patients. In another small study, 7% of children involved in National Institutes of Health (NIH) research trials for cancer were found to have been prescribed antidepressant medication. The investigators of this study noted increasing acceptance for psychopharmacologic treatment of subthreshold psychiatric disorders to improve quality of life, and concluded that in addition to psychological support always being indicated in the setting of anxiety or depression, there is a role for the judicious use of psychotropic medications.

Anxiety

Because of the need for frequent procedures and treatments (eg, blood draws and intravenous [IV] placements, as well as chemotherapy), the child with cancer often presents to mental health treatment with anticipatory anxiety and/or nausea and vomiting. Anticipatory anxiety without a nausea/vomiting component is initially addressed with behavioral interventions. Understanding the cause of the anxiety is helpful in determining what modifications will be most helpful. For preschool and school-age children, the worry may be about separation from a caregiver. They may demonstrate a greater resistance to being separated from parents or become more fearful of new people. They will want to know exactly where their parents will be before, during, and after. Distraction is a helpful and easy mechanism to alleviate anxiety. The use of handheld video games and watching videos has been shown to decrease anticipatory anxiety preoperatively for children and can be easily employed in the child’s hospital room or waiting area. Worries about pain are also foremost in a child’s mind. Pain should be controlled or eliminated whenever possible, even when this may mean a delay in a procedure. The application of a topical anesthetic (EMLA cream) is standard practice in most pediatric oncology settings before venipuncture. In 1 recent study, the combination of EMLA with self-hypnosis further decreased the associated anticipatory anxiety. Regularly scheduled lumbar punctures and bone marrow aspirates are part of many childhood cancer protocols. To minimize the pain associated with these procedures they are often done with conscious sedation. Parents and staff should explain procedures in simple terms including where and when a procedure will occur and, if there is pain associated with the procedure, how it will be addressed.

Anticipatory anxiety with nausea/vomiting (ANV) affects many children despite advances in antiemetic medication. The child may feel nauseated or vomit on arriving at the outpatient clinic or hospital. One study reports 59% of children experienced mild to severe anticipatory nausea and vomiting despite the use of ondansetron. As with adults, ANV seems to fit the model of classic conditioning. The children with the most severe cases of ANV are those who experience postchemotherapy nausea and vomiting. However, there is a subset of children who do not experience postchemotherapy nausea and vomiting, but manifest ANV. In mild cases, effective behavioral approaches include thought stopping, hypnosis, distraction, and relaxation. More severe cases of ANV in association with postchemotherapy nausea and vomiting may respond to increased use of antiemetics, including higher doses of ondansetron, corticosteroids, and benzodiazepines. There are also some data to support the use of acupuncture in this population.

Preschool Age

During the preschool years (ages 2–6 years), children are egocentric (a perspective of being at the center of everything) and use associative logic, which means that any 2 unrelated things can be understood in terms of 1 causing the other. The combination of egocentricity and associative logic results in magical thinking and interweaving of reality and fantasy. The use of magical thinking may lead a child to believe that his cancer is a punishment for a bad thought or deed. An example of this might be a 4 year-old boy who thinks he has leukemia because he took his sister’s toy or he ate too many cookies. As a result procedures and treatment side effects may feel like punishments, especially if the child is unable to localize the medical illness to a particular body part, as is the case in leukemia. These feelings are consistent with a perception of whole body vulnerability, that “my whole body is sick,” even though only 1 organ system is involved. Whole body vulnerability is made more real for the child with cancer who endures intravenous lines, hair loss, and nausea and vomiting. For children with leukemia this vulnerability is heightened, as it is difficult to grasp the concept of a hematologic malignancy.

The concept of time develops gradually in this age range. Although parents may be focused on the seriousness of a diagnosis, the expected course of treatment, and probabilities of survival, the child will likely only comprehend what will affect him or her in the moment.

The dominant social sphere of the preschool child, and the area most affected by the illness, is family life. Children aged 3 to 6 years spend most of their time with their immediate family, and their contacts outside the home are usually limited to preschool and day care. Separations from family members and care providers can be anxiety provoking and challenging during the course of treatment.

School Age

School age is characterized by mastery of skills. There is the emergence of logical thinking (causal logic) and more appreciation for another’s point of view. School and peer groups play an increasing role in a child’s life. Therefore, disrupted functioning in school performance and peer relationships are common social sequelae, either from direct effects of cancer (time missed from school and friends) or a regressive loss of coping skills. Offering school tutors and age-appropriate activities (such as board games, video games, computers, puzzles, and arts and crafts) can help children to function closer to their premorbid level and may serve as a counterweight to the regressive pull of dependency, helplessness, and loss of control that often accompanies intensive medical treatment.

When school-age children are diagnosed with cancer, they are able to understand the simple functional explanations of their illness and often pride themselves in mastering the names or procedures and treatments they have received. Innovative programs targeting this developmental level include “My Story in Beads” which allows children to mark off each procedure and treatment with a special bead on a string (Elyse Levin-Russman, MSW, LICSW, personal communication, January 2010). Children create a narrative about how their cancer was diagnosed and the treatment they are receiving, allowing them to be active participants in their care. Rules provide predictability in this age group, but a cancer diagnosis disrupts this way of thinking because there are no identifiable causes for most childhood cancers, unlike some adult cancers (eg, smoking leading to lung cancer). It can be frustrating to a child who plays by the rules and follows the doctors’ orders to then face setbacks in treatment despite their best efforts. Helping this age group feel competent in the midst of medical complications can be challenging.

Adolescence

During normal adolescence, areas of growth include identity and independence, sexual development, and peer group involvement. Cognitively, adolescents are able to think abstractly and can understand the complexity of a chronic illness in the same way as adults. They can appreciate the meaning of a life-threatening or chronic illness, but often are not prepared to manage the changes in their lifestyle and activities that the treatment requires.

The multiple demands of living with cancer (including enduring the diagnosis and treatments, physical discomfort, limitations, pain, effect on appearance, and fears about the present and future) threaten the adolescent’s ability to exercise newly acquired independence. These demands occurs at the same time as the adolescent is striving to individuate from parents and trying to establish an independent identity. An adolescent’s identity usually relies on the peer group to determine what is “in” and what is “out,” and attractiveness within this group plays a significant role in determining one’s self-esteem. Time away from school and other activities may strain friendships and create feelings of isolation at a time when feeling connected to peers is of utmost importance to the development of identity. Often the illness occurs at a time when other tensions between the adolescent and parent make relying on the parents uncomfortable or unacceptable. Logistical and emotional reasons thwart individuation; parents may need to bring the adolescent to appointments or stay at the bedside during a hospitalization, or may experience longing for closeness with the adolescent when faced with the issues of mortality raised by cancer. In the setting of this emotionally complex dilemma, some teens become sullen, aggressive, nonadherent, or withdrawn, whereas others are able to negotiate the discomfort of returning to a more dependent supportive relationship with parents.

A recent study examined the rates and types of distress experienced by teenagers 4 to 8 weeks after they were diagnosed with cancer. The main areas included physical concerns (eg, mucositis), personal changes (eg, hair loss, fatigue, and weight changes) and treatment-related worries (eg, missing school and missing leisure activities).

Body image and sexuality are tremendously affected by cancer. In adolescence, an extraordinary amount of time is spent on one’s appearance and presentation because it often determines one’s self-esteem. For the adolescent with cancer, physical attractiveness takes on new meaning. Competence and interest in developing interpersonal and intimate relationships depend on having a positive sense of self and body image. Both of these are challenged during treatment because of feelings of being different and physical appearance changes such as hair loss caused by chemotherapy or weight gain caused by corticosteroids. As a result of low self-esteem and body image concerns expressed by adolescents with cancer, they avoid or are less likely to establish intimate relationships. Future fertility, threatened by cancer treatment, is also a prominent issue. Semen cryopreservation is available for boys but there are no definitive preservation methods available for girls.

Mood

One might assume that a severe stressor such as a diagnosis of cancer during childhood would overwhelm an individual’s ability to cope emotionally and most if not all children would experience emotional difficulties. However, studies suggest that most children with cancer do not exhibit significant levels of depression or anxiety, although a significant minority do experience marked levels of psychological distress. Some clinical observations have indicated that a subset of patients exhibit more problems, such as greater difficulty coping. Other studies show the emotional well-being of children with cancer currently receiving chemotherapy to be remarkably similar to case-control classroom peers, and initial studies of cancer survivors similarly failed to find increases in social and emotional problems in children with cancer, although new data on survivors has challenged this view (see later discussion).

The type of cancer may play a role in the psychological effect on the child. Children with brain tumors are likely to experience more psychological distress, in large part because of the neurocognitive sequelae of their disease. Similarly, those with severe medical late effects tend to have more depressive symptoms and poorer self-concept.

The involvement of mental health professionals in addressing the psychosocial needs of patients and their families can mediate the overall distress they experience. Optimal psychosocial care for patients with cancer includes opportunities to assess functioning and separate transient distress from more serious and disruptive emotional difficulties. Identification of those children with mood and behavioral difficulties who will require additional services is essential in providing good oncologic care. In assessing a child’s mood, the clinician must be knowledgeable about the side effects of the treatments, which may include fatigue, decreased appetite, and disturbed sleep. If a child does present with clinically significant depressive symptoms, the treatment follows the same course as it would in the physically well child; that is, with psychotherapy such as cognitive-behavioral therapy (CBT) and antidepressant medication as indicated.

Although no large studies have been conducted in children with cancer, selective serotonin reuptake inhibitor (SSRI) medications are the pharmacologic antidepressant treatment of choice, as they are in the population at large. In an uncontrolled pilot study of 15 children with cancer and depression or anxiety, fluvoxamine was well tolerated and effective. Fifty percent of pediatric oncologists at Children’s Hospital of Philadelphia reported prescribing SSRIs for their patients. In another small study, 7% of children involved in National Institutes of Health (NIH) research trials for cancer were found to have been prescribed antidepressant medication. The investigators of this study noted increasing acceptance for psychopharmacologic treatment of subthreshold psychiatric disorders to improve quality of life, and concluded that in addition to psychological support always being indicated in the setting of anxiety or depression, there is a role for the judicious use of psychotropic medications.

Anxiety

Because of the need for frequent procedures and treatments (eg, blood draws and intravenous [IV] placements, as well as chemotherapy), the child with cancer often presents to mental health treatment with anticipatory anxiety and/or nausea and vomiting. Anticipatory anxiety without a nausea/vomiting component is initially addressed with behavioral interventions. Understanding the cause of the anxiety is helpful in determining what modifications will be most helpful. For preschool and school-age children, the worry may be about separation from a caregiver. They may demonstrate a greater resistance to being separated from parents or become more fearful of new people. They will want to know exactly where their parents will be before, during, and after. Distraction is a helpful and easy mechanism to alleviate anxiety. The use of handheld video games and watching videos has been shown to decrease anticipatory anxiety preoperatively for children and can be easily employed in the child’s hospital room or waiting area. Worries about pain are also foremost in a child’s mind. Pain should be controlled or eliminated whenever possible, even when this may mean a delay in a procedure. The application of a topical anesthetic (EMLA cream) is standard practice in most pediatric oncology settings before venipuncture. In 1 recent study, the combination of EMLA with self-hypnosis further decreased the associated anticipatory anxiety. Regularly scheduled lumbar punctures and bone marrow aspirates are part of many childhood cancer protocols. To minimize the pain associated with these procedures they are often done with conscious sedation. Parents and staff should explain procedures in simple terms including where and when a procedure will occur and, if there is pain associated with the procedure, how it will be addressed.

Anticipatory anxiety with nausea/vomiting (ANV) affects many children despite advances in antiemetic medication. The child may feel nauseated or vomit on arriving at the outpatient clinic or hospital. One study reports 59% of children experienced mild to severe anticipatory nausea and vomiting despite the use of ondansetron. As with adults, ANV seems to fit the model of classic conditioning. The children with the most severe cases of ANV are those who experience postchemotherapy nausea and vomiting. However, there is a subset of children who do not experience postchemotherapy nausea and vomiting, but manifest ANV. In mild cases, effective behavioral approaches include thought stopping, hypnosis, distraction, and relaxation. More severe cases of ANV in association with postchemotherapy nausea and vomiting may respond to increased use of antiemetics, including higher doses of ondansetron, corticosteroids, and benzodiazepines. There are also some data to support the use of acupuncture in this population.

Corticosteroids

Corticosteroids are routinely used for the treatment of childhood cancers and their sequelae. In many chemotherapy protocols, including leukemias and lymphomas, corticosteroids play a central role. The appearance of adverse psychiatric symptoms is common in children who are receiving high-dose corticosteroids. These symptoms include changes in mood, sleep, and appetite.

Research in the area of psychiatric adverse effects to corticosteroids is much more extensive in adults than in children. The adult literature supports the role of corticosteroids in causing behavioral changes including depression, mood elevation, irritability, anger, insomnia, and excess talkativeness. Psychiatric sequelae are usually dose-dependent and studies have reported increased severity of psychiatric symptoms with higher doses of corticosteroids. Patients can become severely depressed, manic, psychotic and/or delirious. In the largest study of its type, severe psychiatric reactions were seen in 1.3% of patients receiving prednisone 40 mg per day or less; in 4% to 6% of patients receiving 41 to 80 mg per day; and in 18.4% of patient receiving more than 80 mg per day.

The use of corticosteroids in children has been studied in children with renal, pulmonary, and gastrointestinal diseases more commonly than in children with cancer. Effects seen in children with cancer are consistent with the behavioral changes seen in children with other illnesses and in the adult population. In children receiving prednisone at a dosage of 60 mg/m ² /d for leukemia and lymphoma, increased irritability, argumentativeness, tearfulness, reports of “talking too much,” tiredness, low energy, and night waking were common symptoms, with a trend toward more symptoms in younger children. In children with ALL, groups receiving prednisone 40 mg/m ² /d and 120 mg/m ² /d showed adverse changes in attention/hyperactivity, emotionality, sleep disturbance, depressed mood, listlessness, and peer relations, although there was no significant difference between the 2 steroid groups.

Sleep is also significantly affected by the use of corticosteroids. In an unblinded study of children receiving dexamethasone as part of their treatment of ALL, fatigue was worsened, and total sleep, nighttime awakenings, and restlessness were increased. Each child served as their own control by comparing 5-day periods on and off dexamethasone.

The child psychiatrist plays an important role in evaluating and managing corticosteroid-related psychiatric side effects during cancer. In mild cases, children may experience some sleep disturbance and irritability. Psychoeducation about the transient nature of symptoms and support of positive coping skills to adapt to these changes in the patient and family can be helpful. For more moderate cases in which the child’s sleep is more impaired or their behavior and mood are more significantly changed, medication interventions can be extremely helpful. There are numerous case reports of symptom-targeted pharmacotherapy or attempts at prophylaxis with mood stabilizers, antidepressants, and antipsychotics, with varying results. A small open-label trial of olanzapine in adults with manic or mixed symptoms secondary to corticosteroids showed benefit, lending support to the role of atypical antipsychotics. In our clinical practice, symptom-targeted medication interventions have been helpful in managing acute sleep difficulties, extreme irritability and sensitivity, and mood lability. Usually small doses of benzodiazepines or atypical antipsychotics for the duration of the corticosteroid dosing and a few days following are sufficient to manage the psychiatric sequelae of the corticosteroids. In a few cases, the severity of a child’s depression or mania or the development of psychosis requires a reduction or discontinuation of the corticosteroids as well as acute psychopharmacologic intervention.

Interferon

Interferon-α (IFN-α), an immunomodulator, is used to treat some pediatric malignancies including chronic myelogenous leukemia, giant cell tumors, and malignant melanoma. There is a paucity of data about IFN and depression in the pediatric population, and the assessment and treatment of children is based on the adult experience. Studies of interferons in adult patients, and particularly those with viral hepatitis, have shown evidence of psychiatric syndromes associated with treatment. Presentations include acute confusional states (delirium), depressive syndromes, and maniclike symptoms of irritability and agitation, and occasionally euphoria. A depressive syndrome similar to major depression is the most common psychiatric sequela of IFN and has been described in adults being treated for hepatitis C and cancer. Psychiatrists consulted to evaluate patients who are receiving IFN need to be aware that the treatment may be causing the depression. It is also important to recognize that making the diagnosis of depression in a patient receiving IFN can be challenging as fatigue and decreased appetite are 2 of the most common side effects associated with IFN. In addition, thyroid function should be monitored with high-dose IFN, because autoimmune thyroiditis secondary to IFN can lead to hypothyroidism and complicate the clinical picture.

Reports in the literature suggest that SSRI treatment of IFN-induced depression may be effective, and may be considered as a prophylactic treatment in patients with severe premorbid psychopathology, or a history of depression during past IFN treatment. Although some studies have suggested wider prophylactic use in high-dose IFN patients, it is more common to treat depression in patients who become symptomatic during treatment. In our clinical experience, children diagnosed with depression while on IFN have benefited from the use of SSRIs. For mild forms of depression, psychotherapeutic strategies can be beneficial. Psychoeducation for patients and families that symptoms may be transient and biochemically mediated rather than the result of a sudden giving up or self-pity is essential.

Neurocognitive Effects

Given the increased survival rates, a greater focus is being placed on the long-term sequelae of cancer treatment and in particular on the neurocognitive effects. More than 50% of children treated for a childhood malignancy are at risk for developing neurocognitive deficits. Cranial radiation causes the most striking effects on the neurocognitive capabilities of the developing brain, as measured in long-term survivors; however, multiple aspects of treatment can contribute to neurocognitive decline including primary CNS tumor effects, neurosurgical sequelae, and systemic and CNS-focused chemotherapies. Damage to developing cortical and subcortical white matter has been implicated as a key mechanism in the neurocognitive changes. In addition to the types of tumors and treatments, the following patient factors also play a role in who is at greatest risk of neurocognitive decline: female sex, younger age at treatment, genetic polymorphisms, and population and social risk factors. The largest body of research focuses on children who were treated for CNS malignancies and leukemia.

Cranial radiation therapy (CRT) causes the greatest damage to developing white matter and as a result has been shown to cause the greatest negative sequelae for the developing brain. Studies have shown a decrease in IQ of between 15 and 25 points in children with brain tumors who are treated with CRT. Children with ALL who have CNS involvement are also treated with CRT, and this population also shows significant cognitive decline over time. New protocols have been implemented to maintain the improved cure rates, but minimize the exposure to cranial radiation given the significant effect on cognition. Protocols are using lower doses of cranial radiation, decreasing the tissue target volume, and postponing radiation in the highest risk groups or using early focal radiotherapy to minimize the cognitive effects. Newer forms and techniques for delivering radiation are also being used. For example, proton beam radiotherapy, as opposed to standard photon radiotherapy, may decrease the likelihood of significant neurocognitive decline, because there is no exit radiation dose thereby decreasing the volume of white matter involved.

Although cranial radiation is probably the most important single factor, brain tumors can also affect vital brain structures by direct mass effect or through sequelae of neurosurgery. A recent follow-up analysis of 24 patients who only required surgical resection of cerebellar tumors showed that although IQ was normal, neuropsychological testing showed deficits in attention, memory, processing speed, and visuospatial processing, and a variety of behavioral problems. An investigation of patients treated for medulloblastoma showed that adverse factors such as neurologic deficits, meningitis, shunt infections, or the need for repeat surgery increased the risk for IQ deterioration after treatment, indicating that radiation and chemotherapy are not the only relevant considerations. Furthermore, children who develop posterior fossa syndrome, a triad of mutism, ataxia, and behavioral changes postoperatively, are at greater risk for neuropsychological and psychosocial sequelae.

Long-term cognitive effects from chemotherapeutic agents are most closely associated with methotrexate, whereas cytarabine and corticosteroids are implicated less strongly. CNS-directed therapy with methotrexate (administered intrathecally), a mainstay of leukemia treatment, has neurocognitive effects. These effects are hypothesized to be mediated by methotrexate interfering with the folate metabolic pathway, and may result in demyelination and other toxic effects. Several studies have examined the cognitive sequelae of CNS-directed chemotherapy. Children with ALL (who received CNS-directed therapy with methotrexate, but not cranial radiation) were compared with children with Wilms tumor (who experienced cancer but received no CNS-directed therapy) and sibling controls (who did not experience cancer but experienced the emotional distress of cancer in the family). Children with ALL showed problems with sustained attention, which correlated with teacher reports of poorer academic performance, particularly in mathematics. They also had increased internalizing behaviors on the Child Behavior Checklist, a parent report measure of social competence and behavior problems. In this and other studies, the impairments are milder than are usually seen from cranial radiation, although intellectual and academic functioning is affected. The most common neurocognitive deficits from chemotherapy are found in visual processing, visual-motor functioning, and attention and executive functioning, with female gender and young age (particularly less than age 3 years) as risk factors. Other findings include problems with academic performance, verbal abilities, and memory. Platinum-based chemotherapies (such as carboplatinum) affect hearing, and therefore can affect learning and academic performance.

In addition to morbidity-limiting strategies to minimize the neurotoxic effects (particularly cranial radiation), some investigators have examined interventions for neurocognitive effects after they have occurred. These have focused on cognitive remediation and psychopharmacologic interventions.

Cognitive remediation has been studied as a specific program combining techniques from the fields of brain injury rehabilitation, special education/educational psychology, and clinical psychology. This program involves activities to strengthen attentional skills and information processing speed; metacognitive strategies to prepare for, approach, complete, and generalize tasks; and cognitive-behavioral strategies to target attention. A multisite, randomized, clinical trial of this program resulted in improved academic achievement and improved attention by parental report. An alternative model of cognitive rehabilitation for patients who had stem cell transplantations failed to show a major effect compared with a control group.

Studies of pharmacologic interventions to treat attentional problems resulting from cancer treatment have focused on methylphenidate, with some promising results. Although stimulants are probably less efficacious in the childhood cancer survivor population than in the general attention-deficit hyperactivity disorder population (75% response rate), a recent randomized, double-blind, placebo-controlled, crossover trial of childhood survivors of ALL and brain tumors showed a response rate of 45.28%. Controlled studies, including 1 specifically geared to evaluate side effects, suggest that patients generally tolerate the medication well, with a subgroup who tolerate the medication less well demonstrating increased side effects.

COG recommends that a neuropsychological evaluation be done as part of entry into long-term follow-up and as clinically indicated for all childhood cancer survivors who received neurotoxic therapies. A complete list of recommendations by COG is available at http://www.survivorshipguidelines.org . As in any child with academic difficulties and cognitive impairments, mental health professionals working with survivors of cancer have a role in educating family members and schools about deficits seen in this population, and advocating for appropriate accommodations and services. Studies show that the decline in IQ may not be apparent initially and can be progressive over time, highlighting the importance of following children longitudinally.

Adherence

Adherence to treatment regimens is a prominent issue with adolescents. Adolescents consistently show higher rates of nonadherence compared with children and adults in the treatment of cancer and other life-threatening illnesses. Risk factors for poor adherence with cancer treatment in adolescents have been identified, including low socioeconomic status of the family, barriers to communication such as cultural and linguistic differences, and mental illness, including depression in a parent and behavioral disturbances during the patient’s childhood. Clinically, poor communication between adolescents and their parents around treatment seems to be a significant contributor to poor adherence. It is important to identify nonadherence issues early in treatment. Blood levels of a drug or its metabolites have been used to monitor adherence with oral medication regimens, such as 6-mercaptopurine in the treatment of ALL. A nonjudgmental inquiry about the patient’s consistency in taking the medication may be just as effective. Confusion about appropriate doses or about who is responsible for administering the medication may contribute to unintentional nonadherence.