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Caˆmara-Costa et al.

International Journal of Radiation Oncology Biology Physics

(25) assessed quality of survival through use of question- naires of executive function, health status, behavior, health- related quality of life (HRQoL), and growth. That study indicated significantly better executive functioning for chil- dren and young adults treated with HFRT than those treated with STRT, in accordance with the reports by Carrie et al (22) and Gupta et al (23) . No other significant advantage of HFRT was observed for health status, behavior, or HRQoL, and patients receiving HFRT had significantly greater deficit in height gain from diagnosis. Differences between treat- ment arms regarding executive functioning and growth impairment were significantly greater in patients less than 8 years of age at diagnosis (25) . The present study aimed to complement these findings by examining effects of HFRT and STRT on cognitive outcomes in PNET4 survivors as assessed directly using age-appropriate measurements of intellectual ability. A population of 338 participants (4-21 years of age) from 10 countries was randomly assigned to either HFRT or STRT for M0 MB between 2001 and 2006. STRT consisted of 23.4 Gy to the craniospinal axis and 54 Gy to the posterior fossa given over 42 days in 30 daily fractions of 1.8 Gy for 5 days per week. HFRT was given in 68 fractions: 1.0 Gy twice per day with an 8-hour interval between fractions, given over 48 days. In the HFRT arm, the total craniospinal dose was 36 Gy, and the whole pos- terior fossa dose was 60 Gy, with a further focused boost of 8 Gy to the tumor bed. In both arms, a maximum of 8 doses of vincristine, 1.5 mg/m 2 (maximum 2 mg), was given once per week during RT, followed by adjuvant chemotherapy. Eight cycles of cisplatin, 70 mg/m 2 intravenously, lomus- tine, 75 mg/m 2 on day 1, and vincristine, 1.5 mg/m 2 intravenously, on days 1, 8, and 15, began 6 weeks after the end of RT, with a 6-week interval between each cycle (24) . Neuropsychological assessment was not part of the original PNET4 protocol, which consisted of question- naire assessments alone. Four of the original 10 partici- pating countries had collected prospective or cross-sectional data regarding cognitive outcomes be- tween 2004 and 2013. The 216 event-free patients from France, Germany, Italy, and Sweden who remained in remission during the 9-month period of the cross-sectional follow-up study conducted by Kennedy et al (25) were eligible for the present analyses, and of these subjects, 137 (63.4%) had data regarding cognitive outcomes (71 of 107 [66.4%] HFRT; 66 of 109 [60.6%] STRT). A subgroup of 35 of 137 participants (25.6%) had had at least 2 assess- ments of the same cognitive outcomes (mean delay be- tween evaluations was 2.9 years). For this subgroup, the results of the last assessment were considered for the cross-sectional analyses. Methods and Materials Patients

Procedure

The present study conformed to ethical requirements of all participating countries. Written consent was obtained by the treating clinician to conduct cognitive assessments.

Measurements

Cognitive measurements differed according to participants’ ages and countries. Patients were generally evaluated with age-appropriate Wechsler Intelligence Scales (26-29) . In Germany, age-appropriate Raven’s Coloured Matrices (30) and Standard Progressive Matrices (31) , the vocabulary subtests of the Wechsler Scales or Kaufmann Assessment Battery for Children (K-ABC I-II, Riddles subtest), and the Number Recall test of the K-ABC I-II were used to assess children’s performance and verbal and working memory abilities, respectively (32) . Five measurements of cognitive ability were derived from these assessments: Full Scale IQ (FSIQ), VIQ, PIQ, WMI, and PSI (for France, Italy, and Sweden only). In addition, an adapted version of the Medical Exami- nation form (33) addressed to the clinicians and informa- tion from the Medical Educational Employment and Social (MEES) questionnaire addressed to parents and adult par- ticipants (33) provided information on participant’s base- line demographics and secondary outcomes. Effects of treatment allocation on cognitive measurements were evaluated through regression models: first for the whole group and, second, by age category at diagnosis ( < 8 or 8 years of age), similar to those in the study by Kennedy et al (25) . At each step, sex, interval between diagnosis and assessment, presence of postoperative com- plications (or, alternatively, presence of cerebellar mutism) were introduced in the regression models, together with treatment allocation. Statistical significance testing was 2-tailed with a .003 significance level to adjust for multiple testing (Bonferroni correction). However, results with a P value of < .05 and a P value of > .003 were categorized as marginally signifi- cant. For longitudinal analyses, mean differences between first and second assessments were compared to zero using paired Student t tests. Statistical analysis

Results

Group comparisons between participants and nonparticipants

Participants with cognitive outcomes and nonparticipants were similar regarding sex, treatment allocation, and in- terval between diagnosis and cognitive assessment.