Psychosocial Aspects of Radiotherapy for the Child and Family with Cancer

Shulamith Kreitler

Myriam Weyl Ben Arush

Elena Krivoy

Hana Golan

Michal Kreitler

Amos Toren

As cure can be achieved in a large majority of pediatric cancer patients, long-term effects and quality of life of the survivors are nowadays the principal challenges to pediatric oncologists. In recent years, it has become increasingly clear that the psychosocial effects of a treatment are an integral part of the treatment and should be considered when evaluating its overall effect and its impact on the patient’s quality of life.

In this chapter, we will first present a literature review of what is known about the psychosocial effects of pediatric radiotherapy (RT) and then describe the results of an initial survey with children and parents we have conducted in two pediatric oncology centers in Israel about the psychosocial effects of RT.

LITERATURE REVIEW

In recent years there have been an increasing number of pediatric cancer survivors. The rate of survival has reached about 80% and is increasing. Additionally, the health professionals as well as the parents and the children themselves are increasingly becoming aware and conscious of the effects of the treatments, including RT. Hence, there is a growing body of studies of the psychosocial correlates and effects of pediatric cancer treatments in general and of RT specifically. Some of the effects are direct, others indirect and result from a variety of effects of radiation on physical functions.

Cognitive Effects of Radiotherapy

A large number of studies deal with investigating and assessing the cognitive effects of RT. As could be expected, the greatest bulk of the studies focus on the cognitive effects of cranial radiotherapy (CRT), since it is in this domain that cognitive effects are likely to be most easily detectable. Up to 40% of childhood cancer survivors who were exposed to CRT may experience neurocognitive impairment in one or more specific domains (1). Recent years have witnessed a remarkable advancement in the number and quality of studies focusing on cognitive effects following CRT (2). This surge of interest has led to an increase in information about the kind of cognitive effects of RT as well as the relations between these effects and various characteristics of RT. Nevertheless, the findings need to be considered with caution for two main reasons. First, although in the present review special care was taken to include only studies that refer directly to the effects of RT per se, it is likely that many of the children participating in these studies did not undergo exclusively RT but often also surgery and chemotherapy that could have also impacted cognition in unspecified ways. Second, many of the children treated with RT got the treatment as a cure for brain tumors, which could have affected cognition independently of the RT.

The effects of radiation on the brain are usually described in terms of three stages: the acute phase, often associated with a sudden neurological deterioration, the subacute phase (or early delayed, 2-6 weeks after radiotherapy) when the “somnolence syndrome” may occur attended by fatigue and a transient exaggeration of the neurological signs, and finally the late phase in which various gradual neurocognitive deficits show up (3,4). Thus, most of the reported findings refer to the third phase.

Effects of RT on Intelligence

A large number of studies report the effects of RT on intelligence (Table 26.1). The studies vary greatly in the characteristics of the samples and the administered doses of RT. However, the majority support the general conclusion that CRT brings about a decline of about 5-20 points in IQ, which according to many studies, but not all, tends to be more pronounced if the RT dose has been higher and the child who got RT is younger. The decline in IQ persists over time, even to over 10 years after RT. There is evidence that the decline in IQ may be due at least partly to a decreased rate of acquiring new information (23).

Effects of RT on Specific Cognitive Functions

Several studies focused on identifying the effects of CRT on more specific cognitive functions than overall intelligence. Deficits in cognitive functioning following CRT are evident in attention, executive functioning, processing speed, working memory, and memory, all of which contribute to declines in intellectual and academic abilities (10,24). Monje (25) reported that CRT is associated with a progressive decline in cognitive function, prominently memory function, whereby impairment of hippocampal neurogenesis is thought to be an important mechanism. Children with acute lymphoblastic leukemia (ALL), who had been treated with RT, were compared in cognitive functioning with ALL patients who had been treated only with chemotherapy and with healthy controls (8). The comparison showed that the group who got RT had deficits in working memory and processing speed relative to

healthy controls. Further, differences in working memory mediated the observed differences in IQ between the CRT group and controls. However, processing speed did not fully account for the working memory deficit in the CRT group. The data suggest that deficits in processing speed and working memory following CRT may underlie the frequently reported declines in IQ.

Table 26.1 Studies about the Effects of RT on IQ Scores

Descriptive Characteristics of Study	Findings Concerning IQ
A Japanese sample of 30 children aged 3-16 at diagnosis (5)	IQ level was almost 20 points lower than in healthy controls. The decline increases with time since diagnosis even when there is no tumor recurrence or hydrocephalus
A review of 18 studies (6)	In 12 of the 18 studies, patients who got RT had IQ levels 12-14 points lower than those who did not get RT (see also Ref. 7)
Children diagnosed with ALL who had been treated with RT were compared with two groups: ALL patients who had been treated only with chemotherapy and healthy controls (8)	The group who got RT showed deficits in IQ that were at least partly independent of other cognitive impairments
A comparison of children diagnosed with medulloblastoma who were treated with CRT and those treated only with surgery (9)	The decline in IQ is more severe in those treated with CRT than in those who got only surgery
Verbal intelligence quotient (VIQ) and performance intelligence quotient (PIQ) were assessed in 64 survivors diagnosed with ALL, about 20 years after diagnosis. 44 survivors got CRT, 20 only chemotherapy. The control group consisted of 45 healthy young adults. Earlier neuropsychological test results of 45 of the survivors were available (10)	Mean VIQ test scores were 91, 100, and 109 (p < 0.001), and the mean PIQ test scores 100, 111, and 118 (p < 0.001) for the irradiated survivors, nonirradiated survivors, and controls, respectively. There was a significant decline in PIQ and VIQ test scores in the irradiated group during the follow-up period, but only in VIQ in the nonirradiated group
Study dealt with trend in IQ as a function of time since diagnosis. Fifty children diagnosed with medulloblastoma completed 188 psychological evaluations using the Wechsler Intelligence Scales for Children over a 7-year study period following 35-40 Gy postoperative CRT (11)	Decrease in IQ in children treated with CRT. There was a delay prior to decline in performance for older patients, whereas in younger patients the decline starts earlier (already in the first year), reaches a plateau at approximately 6 years postdiagnosis, and increases more as time from treatment increases. A steeper decline was found for those with higher baseline performance
Children with malignant brain tumors who had been treated from 1986 to 1993 in Finland and were alive and tumor free 5 years later (12)	The mean full scale IQ was 85 (range 45-138), 24% had an IQ value less than 70, and only 36% more than 90
64 patients with posterior fossa tumors, including those treated with either surgery and CRT (n = 32) or surgery without RT (n = 32). Ten patients treated for non-CNS solid tumors were included for comparison (13)	Patients treated with CRT had lowered short-form IQ. Poorest performance was in those treated with CRT and who had postsurgical complications
53 children treated according to the AML-BFM-87 protocol (median age at diagnosis: 8.5 years, range 0.3-17.5; median time since diagnosis: 5.7 years, 3.8-10.7 years), who got CNS prophylaxis that consisted of ARA-C intrathecal, high-dose ARA-C intravenous and either no CRT (n = 15) or CRT (n = 38) at a dose of 12-18 Gy depending on age. Patients with relapse or initial CNS involvement and transplanted patients were excluded (14)	In the total group, no significant differences in IQ (assessed by Raven’s Matrices) were observed between irradiated and nonirradiated patients
The study investigated if the IQ (assessed by the Hamburg Weschsler Intelligence Test for Adults) in 27 children treated for leukemia decreases in the years after whole brain RT. Mean time between RT and IQ measurement was 9 years (15)	IQ results did not differ significantly from the IQs of the general population. Age and dose were not predictors of a decrease in IQ. The only predictor was time lapse between RT and IQ measurement, which was indicative of an IQ decrease even after 9 years
16 children with brain tumor, treated with CRT or local RT, were compared with 15 nonirradiated children with ALL (16)	On the Wechsler Intelligence Scale for Children—Revised Full Scale, the mean standard scores were significantly decreased in the brain tumor group
A review of studies of children treated with CRT (17)	CRT-treated children manifest significant drops in IQ scores especially when they are in the younger age groups
31 patients (with medulloblastoma or ependymoma) treated with standard dose or reduced dose of RT (18)	There was a 2- to 4-point decline per year in IQ. In the younger patients IQ declined quickly in the first few years after treatment, and then more gradually
138 survivors (73 with ALL and 65 with solid tumors), diagnosed before the age of 15 years, with therapy duration over 2 years, had been evaluated at least 10 years after diagnosis (19)	IQ scores of solid tumor survivors were higher than in leukemia survivors who had CRT at dosages ≥24 Gy (108 vs. 98; p = 0.03), and resembled those of leukemia survivors with CRT at lower dosages (102) or who got no CRT (109). Normal IQ correlated positively with age at diagnosis and negatively with CRT. Survivors of ALL who relapsed scored 14 points less than those who had not relapsed. Decline in IQ following RT persists over time
Comparing the IQ of children with pediatric cancer diagnoses who got different doses of CRT (20,21)	There was less decline in those who got reduced-dose CRT (23.4 Gy vs. 36 Gy) and were older (above 8.8 years) at the time of treatment
Study of the effects of low doses of CRT in 22 children with varied diagnoses undergoing BMT. Fifteen got CRT (range 350-1200 cGy), and seven did not. IQ was tested before BMT and 1 year later in children 2.5 to 6 years with Stanford-Binet IV and those 6 years or older the Wechsler Intelligence Scale for Children-Revised (22)	There were no decrements in IQ in the children who got CRT, regardless of the dose and the child’s age. There were also no significant differences compared to baseline in a subgroup who were followed up to 3 years. But there was great variability. There were decrements of 10 points or more in 7 children after 1 year

A review by Bhatia and Landler (17) showed that affected children are particularly prone to problems with receptive and expressive language, attention span, and visual and perceptual motor skills. They most often experience academic difficulties in the areas of reading, language, and mathematics. In another study a follow-up of 59.6 months after termination of therapy showed a modest but significant decline in reading scores, while mathematics and spelling performance remained stable (26). Mulhern et al. (27) showed that the decline in the reading, decoding, and spelling skills is independent of the risk level of the disease. The deficits in the cognitive skills required in academic setups account for the frequently reported school problems and poor academic performance of children who have undergone CRT (28).

Accordingly, many long-term survivors of medulloblastoma treated with RT had significant school problems (72%), impairments of attention and processing speed (79%), learning and memory difficulties (88%), language disabilities (56%), and deficits in visual perception (50%), or executive functions (64%) (29). Similarly, in 31 patients (with medulloblastoma or ependymoma) treated with standard dose or reduced dose of RT, there were significant declines in visual-motor integration, visual memory, verbal fluency, and executive functioning. But there was no evidence for decline in verbal memory and receptive vocabulary (18,30).

An earlier study with pediatric cancer survivors from a large variety of diagnostic groups showed that CRT was associated with deficits in several, primarily nondominant hemispheric neuropsychological functions, most likely to be reflected in nonverbal intelligence, perceptual abilities, and distractibility (31). Further evidence about the effects of CRT on cognition comes from a study which showed that academic achievement, verbal knowledge and reasoning, and perceptual-motor abilities were significantly lower among CRT-treated groups of patients and that there were significant negative associations between CRT dose estimates for cortical regions and perceptual-motor abilities (7). Again, in a group of 138 survivors (73 with acute leukemia and 65 with solid tumors), who had been diagnosed before the age of 15 years, had been treated over 2 years, and were evaluated at least 10 years after diagnosis, assessment of cognitive functioning showed that the most affected cognitive areas were comprehension, arithmetic ability, attention, visual and verbal memory, causative reasoning, and visual-motor coordination. No relationship was found between sensory sequelae (that were mostly mild) and cognitive capacities (19).

In a group of pediatric patients with malignant posterior fossa tumors, some of whom were treated with reduced-dose CRT and some with standard dose, tested 1 year after treatment and at several points later, no significant differences in cognitive performance were found between the groups. Their performance declined for spelling, mathematics, and reading according to achievement tests and ratings by parents and teachers. However, data analyses revealed that there was no loss of skills but a reduced rate of skill acquisition (28). Further, comparing 16 children with brain tumor, who had been treated with CRT or local RT, with a group of children diagnosed with ALL who did not get RT, showed that the former group was assessed by mothers and teachers as functioning with a significantly decreased tempo on a visual analog scale. Low speed and hypoactivity seemed to limit the majority of these children in school and daily life activities (16).

A special emphasis has been placed on two distinct cognitive functions: memory and attention, both because deficits in these functions showed up in a great number of studies and because they may be responsible for further cognitive difficulties and hence also for lower academic achievements in
general. Memory deficits following CRT are a recurrent finding. Thus, Massimo et al. (32) reported a study with 60 children diagnosed with ALL, treated between 1974 and 1978 with or without CRT, who were in complete remission. A psychological investigation performed at least 2 years after terminating therapy showed one clear finding: All those who underwent CRT had memory impairment. Another study showed that children treated with CRT for medulloblastoma had verbal memory deficits in retrieval and recognition verbal memory following RT (33,34).

Concerning attention, deficits following RT were reported by Mulhern et al. (20).

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