CNS-directed Chemotherapy Research Articles

Successful Salvage Chemotherapy for Isolated Central Nervous System (CNS) Relapse in Burkitt Lymphoma

Short-term intensive chemotherapy regimens have substantially improved the prognosis of pediatric patients with Burkitt lymphoma (BL), which now has an excellent overall outcome. However, central nervous system (CNS) involvement at diagnosis remains a poor prognostic factor, and progressive or relapsed disease in the CNS is associated with even worse outcomes. We report 3 boys aged 4, 7, and 12 years treated under the French Société Française d'Oncologie Pédiatrique LMB 89/96 protocols who presented, respectively, with CNS-/bone marrow+ stage-IV BL; CNS+ stage-IV BL; and stage-I BL. Each experienced an isolated CNS relapse, which was treated with CNS-directed salvage chemotherapy. All 3 are alive after 11 years of median follow-up, indicating that this chemotherapy regimen can be curative in pediatric BL with isolated CNS relapse.

Lumbar spinal fluid collections in children treated with intrathecal chemotherapy: Elevated CSF protein as a diagnostic clue

Subdural fluid collections can interfere with the effective intrathecal administration of chemotherapy by lumbar puncture (LP). We detected this complication in six children who were treated for acute lymphoblastic leukemia (ALL) and presented with an elevated protein concentration of the cerebrospinal fluid (CSF) during routine LP. Contrary to expectation the lumbar fluid collections persisted in two cases and in one case required the insertion of an Ommaya reservoir to continue intrathecal chemotherapy. Awareness and detection of this complication by imaging is important because of its potential to interfere with effective CNS-directed chemotherapy of ALL.

Prognostic Significance of Blasts with/without Pleiocytosis in the Cerebro-Spinal Fluid (CSF) of Children with Acute Lymphoblastic Leukemia (ALL) Treated without Cranial Irradiation: Results of European Organization for Research and Treatment of Cancer (EORTC) Children Leukemia Group Study 58881.

To evaluate the prognostic significance of blasts in the CSF at diagnosis in children with ALL, 2049 patients (pts) enrolled from 1989 to 1996 in EORTC 58881 trial were retrospectively studied. Treatment design was according to BFM. Central nervous system (CNS)-directed therapy consisted in i.v. methotrexate (MTX) (5 g/sqm over 4 hours) in 4 to 10 courses, according to grade of initial CNS involvement, and intrathecal MTX. No radiotherapy was used. Three randomizations were programmed: Erwinia vs Medac E.coli asparaginase (all pts); addition or not of i.v. Ara-C to i.v. MTX (for increased-risk pts); addition of monthly courses of i.v. 6-MP in maintenance therapy (all pts). According to CNS status, pts were classified in 4 groups: 1) CNS-1: <6 WBC/μl, RBC<100/μl, no blasts; 2) dubious CNS-2: presence of blasts, RBC>100/μl; 3) surreptitious CNS-2: presence of blasts, <6 WBC/μl, RBC<100/μl; 4) CNS-3: presence of blasts, >5 WBC/μl, RBC<100/μl. Only CNS-3 pts were to receive 10 courses of i.v. MTX, but some of dubious (N=21) and surreptitious CNS-2 pts (N=19) did eventually receive 10 courses as well. Dubious CNS-2 (n=53), surreptitious CNS-2 (n=52), and CNS-3 (n=54) contained a higher rate of pts with unfavourable features than CNS-1 pts: WBC > 100000/μl; T-lineage; NCI high risk; very high risk (VHR) features (≥1000 peripheral blasts/μl post prephase, high-risk cytogenetics). Median follow-up was 7.5 years. The 5-yr overall event-free survival (EFS) and overall survival (OS) rates (SE%) were 71.6 % (1.0 %) and 82.6 % (0.8%) respectively. The 5-yr EFS rate (SE%) was 72.1 % (1.0%) for CNS-1, 62.2 % (6.6%) for dubious CNS-2, 64.7 % (6.7%) for surreptitious CNS-2, and 70.3 % (6.2%) for CNS-3 group. Overall, pts with blasts in the CSF (dubious CNS-2, surreptitious CNS-2 or CNS-3) had a significantly (p=0.02) shorter EFS than those in the CNS-1 group: 5-yr EFS rate 65.6% (3.8%) vs 72.1%. Multivariate analysis indicated that low WBC, Medac E-Coli asparaginase, absence of VHR features, middle age group were, together, predictive for longer EFS, whereas CNS involvement (CNS-2/-3 vs CNS-1) lost its prognostic value (p=0.87). Out of 2018 pts who reached CR, a total of 71 isolated and 78 combined CNS relapses were reported. The 5-yr isolated CNS relapse rate was 3.8%: 3.5% in CNS-1, 6.7% in dubious CNS-2, 10.5% in surreptitious CNS-2 and 7.1% in CNS-3 group. The 5-yr isolated or combined CNS relapse rate was 7.9%; in the 4 CNS-groups it was 7.6%, 11.1%, 14.7% and 9.2% respectively. The 5-yr OS rate (SE%) was 83.5% (0.9%) in CNS-1 vs 72.4% (3.9%) in CNS-2/-3: p=0.0003. Prognostic importance was lost (p=0.23) in multivariate analysis. Conclusion: the presence of blasts in the CSF, with or without pleiocytosis, is associated with unfavorable prognostic features and with worse outcome. Intensification of CNS-directed chemotherapy, without CNS radiation, is an effective treatment of initial meningeal leukemic involvement.

Chemotherapy and attentional dysfunction in survivors of childhood acute lymphoblastic leukemia: Effect of treatment intensity

Central nervous system (CNS) directed chemotherapy is replacing prophylactic cranial irradiation in treatment protocols for childhood acute lymphoblastic leukemia (ALL), mainly to reduce long-term neuropsychological sequelae. We evaluated the effects of chemotherapy on attentional function in survivors of ALL and examined whether possible deficits are related to treatment intensity. In a multi-center study, we compared attentional function in 36 children at least 1 year after finishing treatment with chemotherapy only for ALL, with a cancer control group consisting of 39 Wilms tumor patients and with 110 healthy children. We differentiated between standard- and intensified ALL treatment. The role of previously reported risk factors for neuropsychological deficits was also assessed. After chemotherapy, attentional deficits were detected in patients with ALL, but not in Wilms tumor patients. Children treated according to standard ALL protocols performed worse than healthy controls on only 1 of 10 outcome measures (P = 0.004), while those who had received intensified treatment performed worse on four outcome measures (0.0001 < P < 0.004). Higher treatment intensity, young age at diagnosis, and female gender were associated with worse performance. CNS-directed chemotherapy, even in the absence of cranial irradiation, is associated with attentional dysfunction in survivors of childhood ALL, particularly in case of intensified treatment protocols. These sequelae stress the importance of reducing doses of neurotoxic chemotherapy as much as possible in the design of future treatment protocols for ALL.