Table 4.

Effect of Cancer Treatment on Neurobiobehavioral Status in Children

Study	Origin of Specimen(s)	Treatment	Effect on Neurons/Cognition	Comments/Limitations
Barrera et al,57 2005	800 childhood cancer survivors (average age at diagnosis: 2 years, average age at study: 12 y). 36.6% leukemia, 15.2% CNS tumor, 48% other cancers. 923 age-, gender-matched controls	21.3% IT MTX only 15.6% CRT and IT MTX 9% CRT only	Those with BT, leukemia: highest odds ratios of repeated/failed grade in schoola; attending learning disabled programa; academic problems.a Those who received CRT had higher odds ratiosb of above categories	Limitations:mailed questionnaires without objective measurement, survivors had wide range of diagnoses and treatment. An imperfect downstream indicator of neurocognitive deficits
Benesch et al,58 2009	23 children with MBl (78%) or ependymoma (22%) at median 56 mo after diagnosis; 8 children with glioma diagnosed with surgery only were controls	No treatment information, only that itwas multimodality	No significant difference in quality-of-life scores in relation to neurocognitive testing results, no significant difference between groups on KINDL	Limitations: small n; 74% were male; no treatment info
Fouladi et al,50 2004	127 children with MBl or supratentorial PNET	36% HR: 36 Gy CSRT, 55.8 Gy boost; 59% AR: 23.4 Gy CSRT, 55.8 Gy boost; all received HD chemo: CDDP 75 mg/m2 × 4 CPM 4g/m2 × 4 VCR 3mg/m2 × 4; some also received topotecan	17% had WML: 32% grade I, 68% grade II; most common locations pons, cerebellum. 14% of patients with WML had neurologic symptoms. Cumulative index of patients with WML at 1 y: 15%, at 2 y: 17.5%. No difference by risk group, diagnosis, cumulative dose of CPM. IQ ↓c in those with WMLs, but not in those without; decline in mathb for those with WMLs but not without	Those with WMLs had significant cognitive decline over time as compared with those without WMLs. Limitation: cannot determine whether WMLs due to CRT, HD chemo, or combination
Khong et al,59 2003	9 MBl survivors (mean age at diagnosis 7.8 y, mean age at study 10.8 y) 12 healthy age-matched controls	CRT (30.6- to 40-Gy WBRT with 50.4–54 Gy boost to PF) and chemotherapy (VCR, CDDP, and/or etoposide, CPM)	FA ↓ by 12.4%–19% in all areas in subjects as compared with controls. In children <5 y at treatment, 26.7% ↓ in supratentorial FA compared with controls, 23.2% ↓ in those >5 y at treatment. Severe deterioration in academic performance correlated with 46.2% ↓ in supratentorial FA	First study to show DTI sensitivity to neurotoxicity, may be correlated to academic performance. Limitations: small sample size, subjects treated with range of radiation doses and chemotherapy agents
Khong et al,60 2006	12 MBl, 18 leukemia survivors, 55 healthy age-matched controls; mean age at study 13.1 y	BT treated with CSRT (23.4–40 Gy), WBRT (23.4–40 Gy), PF CRT (50–55.8 Gy) and chemo (VCR, CPM, CDDP, etoposide or CCNU, CDDP, VCR). Leukemia treated with chemo (including IT and HD-MTX); 50% received CSRT (12–24 Gy)	Test scores among brain tumor survivors < ALL survivors who received CRT < ALL without CRT < controls but not statistically significant. Difference in WM FA between subjects and controls significantly correlated with FSIQ,a VIQ,b PIQa	Follow-up of previous study. Wide variability in range of radiation doses and chemo agents but demonstrated differences in neurocognitive outcome related to treatment modality
Mabbott et al,61 2005	53 survivors of PF tumors, mean age at diagnosis 6.6 y	26%: reduced-dose CRT (23.4–30.2 Gy), 64%: standard-dose CRT (34–41.4 Gy), 8%: dose unknown. All received boost to PF of 45–55.8 Gy; 74% received chemotherapy	Older age at diagnosis correlated with better reading,b school performance scores by parents.b Longitudinal analysis: decline in math,c spelling,c reading.c Parents’/teachers’ school functioning ratings ↓ over time, with ↑ social,c attentionb problems	Longitudinal data demonstrate continued academic declines over time. Limitation: mixed therapies
Mabbott et al,62 2006	8 children with MBl (7 males, 1 female), mean age at diagnosis 7.5 y, mean time to study 2.5 y; 8 healthy controls	50% received 36–36.6 Gy CSRT; 50% received 23.4 Gy CSRT; 100% received PF boost to 55.4 Gy. All received either etoposide/CDDP/CPM/VCR or CCNU/VCR/CDDP	Initial mean IQ 17.5 points < controls; mean decline over 2.5 y: 8 patients.a ↓ IQ related to ↑ ADC.b Correlation of low IQ, low FA.b FA in all ROIs lower in subjects than controls	Deficits in IQ outcome related to CRT may be result of tissue compromise. FA, ADC sensitive measures of tissue damage related to loss of progenitor cells, loss of myelin. Limitations: small sample size, only 1 female included, higher mean IQ at baseline of control group may have skewed results
Maddrey et al,63 2005	16 MBl survivors, mean age at diagnosis 7.2 y, mean age at study 22.2 y	All received CRT. 56% received unspecified chemotherapy	Mean IQ = 75, mean vocabulary score extremely low average, mean Block Design within mental retardation range. 67%: impairment in global intellectual functioning, 92%: impairment on 1 test of attention, 79%–86%: impaired on executive function tests	Limitations: small sample size, cross-sectional design, multimodal therapy without specific agents defined
Mulhern et al,7 2001	42 children with MBl, mean age at diagnosis 8.2 y, mean age at study 13.4 y	All received 23.4–36-Gy CRT with PF boost 49–54 Gy. 69% received chemo with 1 or more of: CDDP, etoposide, CPM, CBDCA, VCR, PCB, PDN	70% of correlationc between IQ, age at CRT explained by NAWM volume; 90% for that between factual knowledge, age at CRT; 78% for verbal abstract thinking; 48% for nonverbal abstract thinking; model not significant for NAWM related to verbal memory, sustained attention	Limitations: small sample size, inconsistent number of studies done among subjects
Mulhern et al,51 2004	37 BT survivors; median age at diagnosis 6.5 y, median time since treatment 5.7 y	18 received chemo: CDDP, CBDCA, CPM, VCR, nitrogen mustard, PCB, PDN. All received varying doses of focal CRT to tumor (49.2–70.2 Gy) and/or WBRT (23.4–44 Gy)	Subjects: lower norms on CCPT Overall index,a and 7/10 component indicesa relative to norms. Decreased NAWM volume associated with lower CCPT scores	First study to describe relationship between NAWM, attention; may be due to loss of NAWM over time after treatment or failure to develop NAWM age-appropriately. Limitations: cross-sectional, CCPT not comprehensive in assessment, ROIs did not include some areas involved in attention
Mulhern et al,64 2005	111 children with MBl, median age at diagnosis 7.4 y. 67% AR, 33% HR (with metastatic disease or residual tumor after surgery)	AR: 23.4 Gy CSRT, 36 Gy to PF, 55.8 Gy to tumor bed. HR: 36–39.6 Gy CSRT, 55.8 Gy to PF; all received HD CPM, CDDP, VCR	Tested postoperatively and at 1, 2, and 5 y after diagnosis. AR: mean loss of −0.4 patients/y compared with HR with mean loss of −8.2 patients/y.c Those ≥7 y at diagnosis declined in reading,b spelling.c Those <7 y declined in IQ,b reading,a spelling,a and mathc	Multi-institutional longitudinal study, models suggest AR subjects had better overall neurocognitive function. Limitations: some missing values, more young children had complication of PF syndrome
Penn et al,65 2008	37 children with BT (parents of 37 children, 27 children themselves completed tool). Median age at timepoint 1–9.4 y. Matched to healthy controls	No information about type of treatment	Differences in parent report of health-related QOL at 1, 6, 12 mo after diagnosis compared with controls.b For self-report at time 1, difference in all summary scores, school domain compared with controls.c At 6 mo, difference for total score, physical summary, school domainc	Longitudinal study showed discrepancy between child and parent report. Limitations: small sample size, no treatment-specific information
Reddick et al,52 2003	40 BT survivors, median age at study 12.8 y	CRT with or without chemotherapy	Correlations between WM volume and attentiona and IQ.c Memory not significantly correlated to WM volume	Developed model of therapy where ↓ NAWM correlates to attention deficits, which result in ↓ FSIQ, academic achievement. Limitations: mixed therapy, chemo agents not specified
Sands et al,66 1998	10 BT survivors, mean age 5 y 8 mo, mean time off-therapy 37.8 mo	5 cycles of VCR CDDP VP-16 For bone marrow ablation: CBDCA, thiotepa, etoposide	Overall mean IQ 87.1 (19th percentile compared with peers). VIQ mean 88.6; PIQ mean 87.7, both low-average to borderline; 83%: high average to average on reading; 83%: impaired range on confrontational naming, expressive picture vocabulary; 77.8% within normal limits per behavioral checklist	Encouraging but overall mixed results in this early study of outcomes after HD chemo without CRT. Limitation: small sample size
Sands et al,67 2001	43 children with CNS germ cell tumors; average age at diagnosis 14.4 y, mean age at study 21 y	All received CBDCA, etoposide, bleomycin ± CPM; 67% received cranial CRT (G25–55.8 Gy)	Age at diagnosis correlated with FSIQ,b VIQ,c PIQ,c mathc	This study of therapy in older children demonstrated average results in most IQ scales. Limitations: two-thirds of subjects received mixed therapy, small sample size
Sands et al,18 2010	24 BT survivors, mean age at diagnosis 3 y	Received either VCR/CDDP/etoposide/CPM; or those agents plus HD-MTX; or VCR/CBDCA/temozolomide; and HD CBDCA, HD thiotepa, HD etoposide 33% received CRT	Time since diagnosis inversely related to FSIQ,c VIQ,c PIQ,c reading,c delayed verbal memory,b delayed verbal recognitionc	Limitation: those treated with CRT not separated from those who were not
Sands et al,68 2011	25 BT survivors; mean age at study timepoint 1: 8.1 y, at T2 (n = 19): 13.5 y	CDDP VCR VP-16 CPM, CBDCA, thiotepa, 28% received CRT	General Health mean scores “at risk” at T2, high percentage of children at-risk for withdrawal, social skills, leadership, somatization subscales. Younger age at diagnosis correlated with poor adaptability,c leadership skills.b Longer time at follow-up correlated with increased hyperactivity,b attention problemsc	Generally positive findings of quality of life in those treated on more current protocols. Limitations: small sample size, some received CRT, no baseline assessment done prior to therapy for comparison
Stargatt et al,69 2007	35 children with PF tumors, mean age at diagnosis 9.5 y; 43% MBl, 37% pilocytic astrocytoma, 14% ependymoma, 6% other; 23 completed entire study	34% had surgery only; 6% had surgery, CRT; 57% had surgery, CRT, chemo; 54% received 50–59.6 Gy to tumor site; 3% received 39.6 Gy	CRT group had ↓ IQ points from diagnosis to 3 y later,b with no significant ↓ IQ in 1st y, ↑ in 2nd y,b ↓ in 3rd yb; Loss of attention spanb over time in CRT group	Longitudinal study providing data up to 3 y after treatment. Limitation: mixed therapy modalities
Ward et al,47 2009	31 children diagnosed with BT at < 3 y of age. Mean age at diagnosis 1.69 y, mean age at study 11 y	Surgery and/or chemotherapy, agents not specified	Those with > 1 surgical procedure had ↓ PIQ,c executive functioning.a Younger age at treatment correlated with ↓ FSIQ,c VIQ,c executive functioning.c Chemotherapy not related to cognitive outcome	Limitations: chemo agents not specified, no description of numbers of those treated with surgery vs chemo and surgery

Abbreviations: ADC, apparent diffusion coefficient; ALL, acute lymphoblastic leukemia; AR, average risk; BT, brain tumor; CBDCA, carboplatin; CCNU, lomustine; CCPT, Connors Continuous Performance Test; CDDP, cisplatin; CNS, central nervous system; CPM, cyclophosphamide; CRT, cranial radiation therapy; CSRT, craniospinal radiation therapy; DTI, diffusion tensor imaging; FA, fractionated anisotropy; FSIQ, full-scale IQ; HD, high-dose; HR, high-risk; IQ, intelligence quotient; IT, intrathecal; KINDL, German QOL assessment tool; MBl, medulloblastoma; MTX, methotrexate; NAWM, normal-appearing white matter; PCB, procarbazine; PDN, prednisone; PF, posterior fossa; PIQ, performance IQ; PNET, primitive neuroectodermal tumor; ROI, region of interest; T2, timepoint 2; VCR, vincristine; VIQ, verbal IQ; WBRT, whole-brain radiation therapy; WM, white matter; WML, white matter lesions.

^aP < .001.

^bP < .01.

^cP < .05.