Prevention of CNS disease in intermediate-risk acute lymphoblastic leukemia: comparison of cranial radiation and intrathecal methotrexate and the importance of systemic therapy: a Childrens Cancer Group report.

PURPOSE: This study (Childrens Cancer Group [CCG]-105) was designed in part to determine in a prospective randomized trial whether intrathecal methotrexate (IT MTX) administered during induction, consolidation, and maintenance could provide protection from CNS relapse equivalent to that provided by cranial radiation (CXRT) in children with acute lymphoblastic leukemia (ALL) and intermediate-risk features. PATIENTS AND METHODS: We randomized 1,388 children with intermediate-risk ALL to the two CNS regimens. They received either IT MTX at intervals throughout their course of therapy or CXRT (18 Gy) during consolidation with IT MTX during induction, consolidation, and delayed intensification. Systemic therapy was randomized to one of four treatment regimens derived from a regimen used by CCG in recent studies for this patient population and three more intensive regimens based on the Berlin-Frankfurt-Munster trials. RESULTS: Life-table estimates at 7 years show a 93% and 91% CNS relapse-free survival rate for the CXRT and IT MTX groups, respectively. The corresponding event-free survival (EFS) rates are 68% and 64%. The differences are not significant. Patients who received more intensive systemic therapy had a 94% CNS relapse-free survival rate on either CXRT or IT MTX, while patients who received standard systemic therapy had 90% and 80% rates for CXRT and IT MTX, respectively (P < .0001). Patients less than 10 years of age who received CXRT or IT MTX had 72% and 71% EFS rates if they received more intensive systemic therapy. Patients 10 years or older who received CXRT had an improved EFS (61% v 53%) with a more intensive systemic program. This was primarily due to fewer bone marrow relapses (P = .04). CONCLUSIONS: IT MTX during induction, consolidation, and maintenance provides protection from CNS relapse in patients with intermediate-risk ALL equivalent to that provided by CXRT if more intensive systemic therapy is given. The CNS relapse rate with either CXRT or IT MTX is in part dependent on the associated systemic therapy. For intermediate-risk patients less than 10 years of age, IT MTX with an intensified systemic regimen provided CNS prophylaxis comparable to that provided by CXRT, whereas older patients had fewer systemic relapses if they received CXRT.

Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: a Childrens Cancer Group phase III trial.

PURPOSE: The Berlin-Frankfurt-Munster (BFM) 76/79 trial of acute lymphoblastic leukemia (ALL) in children produced impressive disease-free survival (DFS) rates with a protocol that began with 8 weeks of intensive therapy, followed by 8 weeks of maintenance therapy, and then another 6 weeks of intensive treatment. The current study was conducted to determine the relative contributions of each of these periods of intense therapy on the DFS rates of ALL patients with intermediate presenting features. In addition, due to concerns regarding the toxicity of CNS irradiation, we compared cranial irradiation (CXRT) with intrathecal methotrexate (IT MTX) administered during induction and consolidation to IT MTX during all phases of the treatment program. PATIENTS AND METHODS: Between May 1983 and April 1989, more than 1,600 children with ALL and intermediate presenting features, as defined by the Childrens Cancer Group (CCG), were entered into a randomized trial that tested four systemic therapy regimens and two CNS programs. RESULTS: The results with a median follow-up of 57 months show that systemic regimens with a delayed intensification (Delint) phase of therapy had a 5-year event-free survival (EFS) rate of 73% compared with the control regimen EFS rate of 61% (p = .006). For children less than 10 years of age, standard three-drug induction and Delint produced a 77% 5-year EFS. IT MTX during all phases of therapy provided CNS protection comparable to the CXRT regimen in children less than 10 years of age. Children 10 years of age or older appear to have a better EFS rate with intensive induction, Delint, and CXRT. CONCLUSION: Delint improves the EFS rate of children with ALL and intermediate presenting features. Maintenance IT MTX can be safely substituted for CXRT for presymptomatic CNS therapy in children with intermediate-risk characteristics less than 10 years of age.

A comparison of four staging systems for localized and regional neuroblastoma: a report from the Childrens Cancer Study Group.

Four major staging systems have been used to estimate the prognosis for children with local and regional neuroblastoma (NBL). Data obtained at diagnosis for 251 neuroblastoma patients from two Childrens Cancer Study Group (CCSG) studies were analyzed according to staging systems of the CCSG, St Jude Children's Research Hospital, the Pediatric Oncology Group (POG), and the Union Internationale Contre le Cancer (UICC) tumor-nodes-metastasis (TNM) system. The most significant variables were found to be age, tumor stage, extent of tumor removal, transgression of the midline by tumor infiltration, and site of primary tumor. Involvement of lymph nodes per se was not a bad prognostic sign unless associated with extension beyond the midline, the latter being the single most important prognostic variable. All four staging systems had value for prognostication and all identified with accuracy the low stage patient (stage I, stage A) who fares well (greater than or equal to 87% survival). The CCSG definition of stages II and III disease discriminated prognostic groups best among the remaining patients, and was able to identify the child with local-regional NBL with poor survival. The estimated 5-year survival rates for children with regional tumor (stage III, IIIA[N]), according to the four systems were 44%, 74%, 74%, and 74% for the CCSG, St Jude, POG, and UICC methods, respectively. We conclude that all four staging systems effectively define good-prognosis patients with localized disease but that the CCSG staging system most accurately identifies patients with regional tumor who have a poor outcome.

Down syndrome and acute leukemia in children: a 10-year retrospective survey from Childrens Cancer Study Group.

Review of 5406 children with acute lymphoblastic (ALL) or nonlymphoblastic leukemia (ANLL) registered with Childrens Cancer Study Group (CCSG) since 1972 identified 115 patients (2.1%) with Down syndrome. The proportion of patients with Down syndrome was the same for ALL (2.1%) and ANLL (2.1%). Patients with ALL with and without Down syndrome did not differ significantly with respect to age at diagnosis, sex, race, morphology (FAB classification), cell surface markers, initial white blood cell count, pretreatment hemoglobin value, hepatomegaly, lymphadenopathy, presence of mediastinal mass, CNS disease at diagnosis, or prognostic group as defined by age and initial white blood cell count. Patients with ALL-Down syndrome less frequently had splenomegaly, had lower pretreatment platelet counts, and more often had normal or elevated IgG or IgA levels. In addition, they had a significantly lower rate of remission (81% versus 94%), a higher mortality during induction therapy (14% versus 3%), and a poorer overall survival with 5-year life table rates of 50% versus 65% (P less than 0.001). If an initial remission was achieved, there were no significant differences with respect to remission duration, survival, or disease-free survival. Patients with ANLL-Down syndrome were younger at diagnosis than those without Down syndrome. There was no significant difference in the remission rates between these patients. Analysis of findings in patients with ANLL provided results similar to those obtained for patients with ALL with regard to clinical outcome after achievement of an initial remission.