Long‐term outcome evaluation of medium/high risk acute lymphoblastic leukaemia children treated with or without cranial radiotherapy in the EORTC 58832 randomized study

Abstract

We investigated the long-term outcome, the incidence of second neoplasms (SN) and the rate of late adverse effects (LAE) in children with central nervous system (CNS) negative medium/high-risk de novo acute lymphoblastic leukaemia (ALL), in first complete remission (CR1) at end of late intensification, randomized to receive no cranial radiotherapy (No CRT, n = 92) versus CRT (standard arm, n = 84) in the non-inferiority EORTC 58832 study (1983)(1984)(1985)(1986)(1987)(1988)(1989). Median follow-up was 20 years (range 4-32 years). The 25-year disease-free survival rate (AESE) was 67Á4 AE 4Á9% without CRT and 70Á2 AE 5Á0% with CRT. The 25-year incidence of isolated (6Á5 AE 2Á6% vs. 4Á8 AE 2Á3%) and any CNS relapse {8Á7 AE 2Á9% vs. 11Á9 AE 3Á5%; hazard ratio (HR) 0Á71 [95% confidence interval (CI) 0Á28-1Á79]; test of non-inferiority: P = 0Á01} was not increased without CRT. The 25-year SN incidence in CR1 was 7Á9 AE 4Á6% vs. 11Á0 AE 4Á2%. The 25-year event-free and overall survival rates were quite similar in both arms [59Á5 AE 6Á3% vs. 60Á5 AE 5Á9%, HR 0Á94 (95% CI 0Á57-1Á52), and 78Á1 AE 4Á3% vs. 78Á5 AE 4Á5%, HR 1Á00 (95% CI 0Á53-1Á88)]. Omission of CRT was associated with dramatic decrease in CNS and endocrine LAE rates. In conclusion, our data suggest that, with proper systemic and intrathecal CNS prophylaxis, CRT could totally be omitted in CR1 without jeopardizing survival, while decreasing LAE in childhood ALL. hormone; LAE, late adverse effects. *Methotrexate injections at 0.5 g/m 2 during interval therapy. † Intermediate-dose methotrexate injections at 2.5 g/m 2 during interval therapy.

CNS-3 status remains an independent adverse prognosis factor in children with acute lymphoblastic leukemia (ALL) treated without cranial irradiation: Results of EORTC Children Leukemia Group study 58951

“…The use of XRT has become contentious because of its late adverse effects [1]. We have shown previously that cranial XRT failed to provide any benefit to medium-and high-risk patients having received high-dose methotrexate (HD MTX) [2].…”

Quality of life of long‐term childhood acute lymphoblastic leukemia survivors: Comparison with healthy controls

“…The latter finding could partly be explained by the relatively low proportion of patients treated with cranial radiotherapy or bone marrow/hematopoietic stem cell transplantation in EORTC protocols compared to other treatment protocols 12–18,37,38 . Indeed, following the results of the randomized EORTC trial 58,832 (no increase in the incidence of CNS relapse in patients randomized without cranial radiotherapy), the EORTC was the first group to omit cranial radiotherapy as first‐line treatment for all patients with childhood ALL 39,40 . In the same study, the evaluation of long‐term side effects showed that the omission of cranial radiotherapy was associated with a lower incidence of second neoplasms and a lower rate of late CNS and endocrine adverse events 40 .…”

“…Indeed, following the results of the randomized EORTC trial 58,832 (no increase in the incidence of CNS relapse in patients randomized without cranial radiotherapy), the EORTC was the first group to omit cranial radiotherapy as first‐line treatment for all patients with childhood ALL 39,40 . In the same study, the evaluation of long‐term side effects showed that the omission of cranial radiotherapy was associated with a lower incidence of second neoplasms and a lower rate of late CNS and endocrine adverse events 40 . Among the three EORTC studies included in the present QoL evaluation, bone marrow/hematopoietic stem cell transplantation was only indicated for “very high‐risk” patients included in EORTC study 58,881, in first complete remission and with an available donor.…”

Socio‐economic outcomes among long‐term childhood acute lymphoblastic leukaemia survivors enrolled between 1971 and 1998 in EORTC CLG studies: Results of the 58LAE study

“…The likely explanation of this result is the occurrence of neurocognitive sequelae (Krull, Brinkman, & Li, 2013 ). We previously evaluated the long‐term outcomes of the randomised question comparing No CRT versus CRT in medium/high‐risk ALL patients included in study 58832 and reported cognitive disturbance in 18.8% of the patients in the No CRT arm versus 42.1% in the CRT arm (Piette et al, 2020 ).…”