%0 Journal Article
%A Hill, RM
%A Richardson, S
%A Schwalbe, EC
%A Hicks, D
%A Lindsey, JC
%A Crosier, S
%A Rafiee, G
%A Grabovska, Y
%A Wharton, SB
%A Jacques, TS
%A Michalski, A
%A Joshi, A
%A Pizer, B
%A Williamson, D
%A Bailey, S
%A Clifford, SC
%D 2020
%F discovery:10116096
%J The Lancet Child & Adolescent Health
%N 12
%P 865-874
%T Time, pattern, and outcome of medulloblastoma relapse and their association with tumour biology at diagnosis and therapy: a multicentre cohort study
%U https://discovery.ucl.ac.uk/id/eprint/10116096/
%V 4
%X Background Disease: relapse occurs in around 30% of children with medulloblastoma, and is almost universally fatal.  We aimed to establish whether the clinical and molecular characteristics of the disease at diagnosis are associated  with the nature of relapse and subsequent disease course, and whether these associations could inform clinical  management.  Methods: In this multicentre cohort study we comprehensively surveyed the clinical features of medulloblastoma  relapse (time to relapse, pattern of relapse, time from relapse to death, and overall outcome) in centrally reviewed  patients who relapsed following standard upfront therapies, from 16 UK Children’s Cancer and Leukaemia Group  institutions and four collaborating centres. We compared these relapse-associated features with clinical and molecular  features at diagnosis, including established and recently described molecular features, prognostic factors, and  treatment at diagnosis and relapse.  Findings: 247 patients (175 [71%] boys and 72 [29%] girls) with medulloblastoma relapse (median year of diagnosis  2000 [IQR 1995–2006]) were included in this study. 17 patients were later excluded from further analyses because they  did not meet the age and treatment criteria for inclusion. Patients who received upfront craniospinal irradiation  (irradiated group; 178 [72%] patients) had a more prolonged time to relapse compared with patients who did not  receive upfront craniospinal irradiation (non-irradiated group; 52 [21%] patients; p<0·0001). In the non-irradiated  group, craniospinal irradiation at relapse (hazard ratio [HR] 0·27, 95% CI 0·11–0·68) and desmoplastic/nodular  histology (0·23, 0·07–0·77) were associated with prolonged time to death after relapse, MYC amplification was  associated with a reduced overall survival (23·52, 4·85–114·05), and re-resection at relapse was associated with longer  overall survival (0·17, 0·05–0·57). In the irradiated group, patients with MBGroup3 tumours relapsed significantly more  quickly than did patients with MBGroup4 tumours (median 1·34 [0·99–1·89] years vs 2·04 [1·39–3·42 years; p=0·0043).  Distant disease was prevalent in patients with MBGroup3 (23 [92%] of 25 patients) and MBGroup4 (56 [90%] of 62 patients)  tumour relapses. Patients with distantly-relapsed MBGroup3 and MBGroup4 displayed both nodular and diffuse patterns of  disease whereas isolated nodular relapses were rare in distantly-relapsed MBSHH (1 [8%] of 12 distantly-relapsed MBSHH  were nodular alone compared with 26 [34%] of 77 distantly-relapsed MBGroup3 and MBGroup4). In MBGroup3 and MBGroup4,  nodular disease was associated with a prolonged survival after relapse (HR 0·42, 0·21–0·81). Investigation of secondgeneration MBGroup3 and MBGroup4 molecular subtypes refined our understanding of heterogeneous relapse  characteristics. Subtype VIII had prolonged time to relapse and subtype II had a rapid time from relapse to death.  Subtypes II, III, and VIII developed a significantly higher incidence of distant disease at relapse whereas  subtypes V and VII did not (equivalent rates to diagnosis).  Interpretation: This study suggests that the nature and outcome of medulloblastoma relapse are biology and therapydependent, providing translational opportunities for improved disease management through biology-directed disease  surveillance, post-relapse prognostication, and risk-stratified selection of second-line treatment strategies
%Z This is an Open Access article under the CC BY 4·0 license  https://creativecommons.org/licenses/by/4.0/