Equivalence of intrathecal chemotherapy and radiotherapy as central nervous system prophylaxis in children with acute lymphatic leukemia: a pediatric oncology group study

Abstract

The efficacy of intrathecal (i.t.) chemoprophylaxis was compared with cranial radiotherapy plus i.t. methotrexate (MTX) in a Southwest Oncology Group (SWOG) study accessing 408 patients from September 10, 1974, to October 29, 1976. Randomization was stratified by prognostic groups (PGs) based on age and white blood cell count at diagnosis. All received induction therapy with vincristine and prednisone (Pred); maintenance therapy consisted of daily 6-mercaptopurine and weekly MTX. Consolidation for arm 1 employed cyclophosphamide and L-asparaginase followed by biweekly 5-day courses of parenteral MTX. The first dose of each course of MTX was given i.t. in triple chemoprophylaxis (MTX, hydrocortisone, and cytosine arabinoside). During maintenance, i.t. chemoprophylaxis was bimonthly and 28-day Pred “pulses” were given every 3 mo. Arm 2 i.t. chemoprophylaxis was initiated on achievement of remission, and arm 3 i.t. on treatment day 1; both continued 1 yr. Arm 4 induction included two doses of L-asparaginase. On achievement of remission, CNS prophylaxis (radiotherapy, 2400 rad plus i.t. MTX) was given. For all, therapy was discontinued after 3 yr of continuous complete remission. Survival and the incidence of extramedullary relapse were similar for the treatments employing either i.t. chemoprophylaxis or radiotherapy plus i.t. MTX upon achievement of remission. Among poor prognosis patients, the duration of complete remission was significantly better with the regimen using i.t. chemoprophylaxis as a component of consolidation therapy than with the regimen employing i.t. chemoprophylaxis early in induction or with the treatment using radiotherapy plus i.t. MTX for CNS prophylaxis. In poor prognosis patients, the initiation of i.t. chemoprophylaxis during consolidation was also associated with hematologic remissions that were significantly better than those achieved with the treatment employing early CNS chemoprophylaxis or with the regimen using radiotherapy plus i.t. MTX. Among average prognosis patients, therapy with CNS chemoprophylaxis during consolidation, as well as the regimen employing radiotherapy and i.t. MTX for CNS prophylaxis, produced hematologic remissions that were significantly longer than those obtained with the regimen using early CNS chemoprophylaxis. Hematologic remissions of good prognosis patients who received treatment with the regimen employing i.t. chemoprophylaxis during consolidation were statistically superior when compared to the regimen employing CNS radiotherapy plus i.t. MTX. This study indicates that i.t. chemoprophylaxis may be substituted for cranial radiotherapy when utilizing effective systemic regimens. Additionally, chemoprophylaxis may be reduced from 3 to 1 yr in patients with good prognostic factors.

Impact of the timing of triple intrathecal therapy on remission induction in childhood acute lymphoblastic leukemia: A pediatric oncology group study

“…CNS chemoprophylaxis for ALL is now considered preferable to cranial radiation with IT methotrexate because of equal effectiveness [4] and decreased potential for long-term neurologic changes [ 10, Ill. The question of timing of CNS chemoprophylaxis remains open-the introduction of triple IT therapy on the first day of induction treatment as used in this study was associated with significant increase in morbidity and mortality from infection in high risk patients and especially in infants less than 2 years of age.…”

“…laxis was initiated on the first day of therapy, a study of the Pediatric Oncology (POG)' was activated on September 10,1974, and closed to entries on October 29, 1976 [4]. All newly diagnosed patients with ALL, who were less than 18 years of age and under the care of POG investigators, were eligible for this study.…”

“…Eva Hvizdala, MD chemotherapy (methotrexate, hydrocortisone, cytosine arabinoside) starting on day 1 of treatment were added to systemic induction therapy in a regimen (Arm 3) that was compared to three other regimens (Arms 1,2, and 4) in which central nervous system (CNS) prophylaxis was initiated after complete marrow remission (CR) was attained. The CR rate for Arm 3 was only 83% as compared to 91-92% for other Arms.…”

“…If central nervous system (CNS) preventive treatment could be introduced with safety at an earlier point, there might be an advantage for those patients with actual or incipient meningeal disease at the time of diagnosis. This secondary question of the influence of scheduling was incorporated into a cooperative study of the effectiveness of CNS chemoprophylaxis alone versus prophylaxis employing radiation therapy and intrathecal methorexate [4]. The purpose of this paper is to report the remission induction clinical course of patients given immediate triple intrathecal chemotherapy in comparison with those in whom CNS therapy was delayed until marrow remission was established.…”

Improvement in CNS protective treatment in non-high-risk childhood acute lymphoblastic leukemia: report from the Japanese Children's Cancer and Leukemia Study Group

“…However, the obvious therapeutic benefit of this approach has been tempered by the recognition of long-term neurotoxicity, particu-larly associated with CRT [3][4][5]. Although the alternative approach omitting cranial irradiation for the non-highrisk patients has been evaluated as effective as CRT regimens [6][7][8][9][10][11][12][13][14][15], the optimal form of preventive CNS therapy remains debatable [8][9][10]12,[16][17][18][19]. To address this issue, we surveyed the incidence of CNS relapse through a series of protocols that had been conducted for children with ALL between 1987 and 1993 in Children's Cancer and Leukemia Study Group (CCLSG).…”