CNS late effects after ALL therapy in childhood. Part II: Conventional EEG recordings in asymptomatic long-term survivors of childhood ALL- An evaluation of the interferences between neurophysiology,neurology, psychology,and CNS morphology

Monitoring of therapy-related late effects after acute lymphoblastic leukemia (ALL) therapy in childhood has become an increasingly important area in posttherapeutic patient surveillance. The usefulness of conventional electroencephalographic (EEG) investigations as part of these attempts is controversially discussed. However, EEG recordings have become a popular approach for judgement on the functional integrity of the central nervous system in this subject group. The present report focuses on this problem and discusses the question whether and to what extent conventional EEG recordings were correlated with further measures of central nervous system (CNS) integrity and therapeutic differences. EEGs were recorded in 110 subjects, asymptomatic long-term survivors of ALL in childhood, during a large retrospective multicenter study evaluating CNS late sequelae following antileukemic therapy in Germany and Austria. EEG findings were correlated with demographic data, illness- and treatment-related parameters, as well as with data on the morphological, neurological and psychological status of the participating subjects. At the time of follow-up the EEG was abnormal in 47 cases (42.7%). The most frequent EEG abnormalities observed were disturbances of the background activity (n=45, 95.8%), followed by hypersynchrone activities (n=10, 21.3%) and interhemispheric differences/focal slowings (n=6, 12.8%). With exception of age at diagnosis, none of the observed EEG abnormalities showed a correlation with any of the aforementioned illness- or treatment-related parameters. Eighty percent of the observed EEG abnormalities were found in children younger than 5 years at diagnosis. Children less than 2 years of age as well as those above 5 years at onset of disease showed a significantly reduced prevalence of EEG disturbances compared to subjects between 2 and 5 years at diagnosis. Neither the degree of illness nor therapy-specific differences showed any relationship to EEG outcome. There was no specific EEG finding for a specific morphological substrate, neurological or psychological deficiency and vice versa. Overall, there was no beneficial effect of routine EEG testing in children following therapy for ALL. According to our data, the evaluation of conventional EEG recordings of otherwise asymptomatic ALL long-term survivors is not a very helpful measure for predicting the degree of behavioral deficiencies, neurological disturbances, or morphological CNS abnormalities, which may be present or will develop in this special subject group. Med. Pediatr. Oncol. 29:121–131, 1997. © 1997 Wiley-Liss, Inc.     

Abnormal visual-evoked potentials in leukemic children after cranial radiation

Visual-evoked potentials (VEPs) were studied in 55 asymptomatic children with leukemia or solid tumors in remission in order to detect subclinical demyelination of the optic pathway after CNS prophylaxis. In group I (11 patients with ALL studied prospectively), VEP latency was increased in ten after cranial radiation (CR) as compared with previous values. Group II (18 patients with ALL in maintenance) and group III (16 patients with ALL off therapy) were studied retrospectively and VEP latency was found above normal limits in 33 and 31%, respectively. In group IV (four patients with solid tumors and six with leukemia, all of whom received no CR), VEP latency was normal despite periodical intrathecal methotrexate administrations to five of them. We conclude that CR determines a slowing of conduction on VEP test, probably due to demyelination of the optic pathway, in a high proportion of patients. The future clinical significance of these findings must be established throughout a prolonged follow-up period.     

High-dose methotrexate in childhood all

An event-free survival is currently achieved in 70-80% of children diagnosed with acute lymphocytic leukemia (ALL). A decline in the long-term sequalae from therapy is a challenge at present. Due to the high incidence of central nervous system (CNS) relapse in ALL patients, cranial irradiation was introduced as a prophylactic measure in the beginning of the 1970s. Cranial irradiation, however, may cause secondary malignancies in the CNS. In recent years neurotoxicities have been demonstrated to follow cranial irradiation in a large proportion of ALL patients. Because of these deleterious effects, most ALL protocols are limited to the combination intrathecal and intravenous methotrexate as the standard for CNS prophylaxis. In the 1970s, an intermediate dose was administered, while from the 1980s a high dose of methotrexate was combined with intrathecal methotrexate. The regular methotrexate dose of later years has been in the range of 5-8 g/m². The intravenous methotrexate dose has actually varied from 2 to 33.6 g/m². The highest dose, 33.6 g/m², has been without intrathecal instillation. In a study from Norway, high-dose methotrexate (6-8 g/m²     

HIGH-DOSE METHOTREXATE IN CHILDHOOD ALL

An event-free survival is currently achieved in 70-80% of children diagnosed with acute lymphocytic leukemia (ALL). A decline in the long-term sequalae from therapy is a challenge at present. Due to the high incidence of central nervous system (CNS) relapse in ALL patients, cranial irradiation was introduced as a prophylactic measure in the beginning of the 1970s. Cranial irradiation, however, may cause secondary malignancies in the CNS. In recent years neurotoxicities have been demonstrated to follow cranial irradiation in a large proportion of ALL patients. Because of these deleterious effects, most ALL protocols are limited to the combination intrathecal and intravenous methotrexate as the standard for CNS prophylaxis. In the 1970s, an intermediate dose was administered, while from the 1980s a high dose of methotrexate was combined with intrathecal methotrexate. The regular methotrexate dose of later years has been in the range of 5-8 g/m². The intravenous methotrexate dose has actually varied from 2 to 33.6 g/m². The highest dose, 33.6 g/m², has been without intrathecal instillation. In a study from Norway, high-dose methotrexate (6-8 g/m²     

Chemotherapy for acute lymphoblastic leukemia may cause subtle changes of the spinal cord detectable by somatosensory evoked potentials

Intrathecal chemotherapy has been determined to cause transient or permanent paraparesis due to myelopathy in patients with leukemia or other malignancies. To systematically evaluate the effect of methotrexate on spinal cord function, somatosensory evoked potentials (SEP) were measured in children with acute lymphoblastic leukemia (ALL). A prospective evaluation was performed in 38 consecutive children aged 1.4–15.3 years with newly diagnosed ALL during treatment. Intrathecal methotrexate therapy was included in the therapy schedule of all patients as central nervous system (CNS) therapy in addition to intravenous chemotherapy in 19 standard risk patients and intravenous chemotherapy with cranial irradiation in 19 intermediate or high-risk patients. The measured conduction times were compared with those of 38 control children matched for age, height, and sex. A significant increase in the conduction time of the tibial nerve SEP was found between the Th12 level and the cortex in children with ALL after receiving intrathecal methotrexate therapy during the induction and CNS therapy phases when compared with their controls. The difference of the mean latencies was 1.45 ms (95% CI 0.39–2.51; P < 0.01). There was no significant delay in the median nerve SEP from the brain stem to the cortex, indicating that the conduction delay was in the area of the spinal cord exposed to intrathecal methotrexate. Moreover, the cortical amplitudes of the median nerve SEPs were significantly reduced when measured immediately after intravenous and intrathecal methotrexate and compared to the amplitudes measured after induction therapy in standard risk patients (P = 0.001). Intrathecal methotrexate with systemic chemotherapy causes a deterioration in the somatosensory pathways within the CNS, suggesting also spinal cord dysfunction in children with ALL in addition to the cerebral dysfunction described earlier. © 1997 Wiley-Liss, Inc.     

Acute neurotoxicity in children with B-lineage acute lymphoblastic leukemia (B-ALL) treated with intermediate risk protocols

BACKGROUND: This study describes the incidence of acute neurotoxicity (NT) in children with B-lineage acute lymphoblastic leukemia (ALL) treated with three intermediate risk protocols that differ in the intensity of central nervous system (CNS) "prophylaxis. " PROCEDURE: A total of 122 patients (64 boys; median age 5.3 years) with B-lineage ALL without CNS leukemia diagnosed between February 1987 and December 1997 were enrolled in the intermediate risk (IR) protocols: Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP)-ALL 87 (n = 33), 91 (n = 51), and 95 (n = 38). Presymptomatic CNS therapy consisted of intrathecal methotrexate (six doses) and cranial irradiation (18 Gy) in the IR AIEOP 87 study, and extended triple intrathecal therapy with methotrexate, cytarabine, and prednisone depending on age in the IR AIEOP-ALL 91 and 95 protocols (20 and 17 total doses, respectively). World Health Organization (WHO) grade 4 acute neurotoxicity criteria were employed. Patients with neurologic symptoms, in addition to physical examination, underwent EEG, computed tomography (CT) and/or magnetic resonance imaging (MRI), and lumbar puncture to exclude CNS leukemia and infection. RESULTS: Acute NT was not reported in AIEOP-ALL 87 treated patients, but we observed acute NT in 3 out of 51 (5.8%) AIEOP-ALL 91 patients, and in 7 out of 38 (18.4%) AIEOP-ALL 95 patients. CONCLUSIONS: There was an increased incidence of acute NT in our patients with ALL treated with current intermediate risk protocols. The intensification of treatment, however, bettered event free survival (EFS) to 58%, 72% and 85% in IR AIEOP 87, 91 and 95 studies, respectively.     

CT scans of long-term survivors of various childhood malignancies

Forty-two children with various systemic malignancies in continuous remission for 1 to 3 years after the completion of chemotherapy had CT scans with normal ventricular dimensions, similar to a noncancer “control” population. Seventeen of these patients had acute lymphocytic leukemia (ALL) treated either with prophylactic cranial irradiation and intrathecal methotrexate [7] or intrathecal methotrexate alone [10] and the remaining 25 patients had soft tissue sarcomas. Sixteen other patients with sarcomatous meningitis had enlarged ventricles while on chemotherapy. Nine had ALL. Seven had soft tissue sarcomas, none of whom received any prior CNS irradiation or intrathecal chemotherapy. In this retrospective study no evidence of hydrocephalus or significant white matter hypodensity was detected in long-term survivors of childhood cancer, regardless of whether prophylactic intrathecal chemotherapy and/or cranial irradiation was given. Direct involvement of the CNS with meningeal cancer was the most important association with ventriculomegaly.     

CNS late effects after ALL therapy in childhood. Part I: Neuroradiological findings in long-term survivors of childhood ALL—an evaluation of the interferences between morphology and neuropsychological performance

The effect of cranial irradiation on possible therapy-induced morphological central nervous system (CNS) side effects of children cured from acute lymphoblastic leukemia (ALL) is controversially discussed. In a retrospective multicenter study, 118 former ALL patients in first continous remission were investigated using cranial computerised tomography (CCT) or magnetic resonance imaging (MRI) scans to evaluate CNS related impairments. Corresponding to the different kinds of CNS prophylaxis, the patient sample was divided: group A (n = 39) receiving intrathecal methotrexate (ITMTX) and systemical medium-high-dose methotrexate (SMHDMTX), group B (n = 41) cranial irradiated (in mean 16.8 Gy) and administering ITMTX and SMHDMTX, group C (n = 38) irradiated (in mean 17.1 Gy) and getting ITMTX. Pathologic scans showed atrophy, leukoencephalopathy, calcifications or grey matter changes. These findings were compared with the neuropsychological test results. Abnormal MRI or CCT scans were found in 61/118 patients (51.7%). Fifteen belonged to group A (38.5%), 23 to B (56.1%) and 23 to C (60.5%). Patients with definite CNS changes show reduced neuropsychological test results. The prevalence of brain alterations seems to appear twice increased after lengthening the post-therapeutic interval in irradiated patients as in nonirradiated patients. Irradiated patients with an age younger than 2 years at diagnosis may show a lower prevalence for developing CNS alterations. CNS alterations are not sex-related. Children treated with cranial irradiation in combination with SMHDMTX and/or ITMTX were at greater risk of developing morphological brain alterations than patients with chemotherapy alone. These alterations are partly correlated with reduced neuropsychological performances and seem to stay with a longer post-therapeutic interval. Med. Pediatr. Oncol. 28: 387–400, 1997. © 1997 Wiley-Liss, Inc.     

Central nervous system complications in childhood leukemia. Correlation between clinical and computed tomographic findings

We used cranial computed tomography (CT) to evaluate 51 leukemic patients with or without central nervous system (CNS) symptoms. Among 17 symptomatic patients, nine had gross abnormalities on CT scans; leukemic infiltrations, infections (CNS aspergillosis), hemorrhages, and therapy-related complications were all evident. One with a leukemic infiltration showed a periventricular low density on the CT scans. The differential diagnosis of CT findings and the correlation between clinical and CT findings is described. The significance of a low-density area observed in an asymptomatic patient on long-term intrathecal methotrexate therapy for CNS leukemia is also discussed.     

Systematic review and meta‐analysis of randomized trials of central nervous system directed therapy for childhood acute lymphoblastic leukemia

Treatment of the central nervous system (CNS) is an essential therapy component for childhood acute lymphoblastic leukemia (ALL). Individual patient data from 47 trials addressing 16 CNS treatment comparisons were analyzed. Event‐free survival (EFS) was similar for radiotherapy versus intrathecal (IT), and radiotherapy plus IT versus IV methotrexate (IV MTX) plus IT. Triple intrathecal therapy (TIT) gave similar EFS but poorer survival than intrathecal methotrexate (IT MTX), but additional IV MTX improved both outcomes. One trial resulted in similar EFS and survival with IV MTX plus IT MTX versus TIT alone. Radiotherapy can generally be replaced by IT therapy. TIT should be used with effective systemic therapy such as IV MTX. Pediatr Blood Cancer 2013;60:185–195. © 2012 Wiley Periodicals, Inc.     

CRANIAL COMPUTED TOMOGRAPHY DURING TREATMENT OF CHILDHOOD LYMPHOCYTIC LEUKEMIA

ABSTRACT. Twenty-three children with acute lymphocytic leukemia (ALL) were examined by computed tomography (CT) of the head on two occasions more than 11 months apart. The first CT was performed at the time of diagnosis in 11 children, who were re-examined while still in their first complete remission. They had received prophylactic central nervous system (CNS) treatment consisting of intrathecal methotrexate supplemented by irradiation in 7 cases and intermediate dose methotrexate in 4 cases. Twelve children were receiving treatment for CNS relapse. This included therapeutic irradiation and intrathecal methotrexate. Abnormal CT developed in 7 children. Three CT scans demonstrated areas of decreased attenuation coefficient, one with intracerebral calcifications. In 5 patients, dilatation of the ventricles and cortical sulci had developed. AU CT abnormalities occurred in children in remission after CNS relapse. These results indicate that prophylactic treatment including cranial irradiation with 24 Gy and low cumulative doses of methotrexate is a safe procedure. Patients with CNS leukemia are at risk of developing CNS abnormalities, when they receive treatment with cranial irradiation and methotrexate. The risk is not correlated with age or sex of the child, the duration of the disease, the dose of irradiation or the cumulative dose of methotrexate.     

Lower incidence of meningeal leukemia when prednisone is replaced by dexamethasone in the treatment of acute lymphocytic leukemia

In 1971, Cancer and Leukemia Group B (CALGB) mounted a study of acute lymphocytic leukemia (ALL) that compared the effects of the two steroid hormones dexa-methasome and prednisone. Six-hundred-forty-six children and adolescents with ALL were randomized to receive either prednisone or dexamethasone as part of their remission induction therapy. The 493 evaluable patients who achieved complete remission received the same steroid as pulses throughout remission. Specific central nervous system (CNS) therapy was randomized to either six injections of intrathecal methotrexate (IT MTX) alone or to six injections of IT MTX with cranial radiation (2,400 cGy). Both cranial radiation and dexamethasone offered increased protection against CNS relapse as the first site of failure over IT MTX alone. There were 30 CNS relapses among 238 patients (12.6%) receiving cranial radiation plus IT MTX, whereas there were 70 CNS relapses among 225 (P < 0.001) (22.5%) in those who received IT MTX alone. Similarly, there were 33 CNS relapses among 231 (14.3%) children treated with dexamethasone, whereas there were 67 CNS relapses among 262 (25.6%) treated with prednisone (P = 0.017). Both steroids appeared equal in protecting the bone marrow. Recent national studies have shown significant improvements in preventing CNS relapse over the results in the present report. However, this finding warrants further investigation and, with further documentation, could lead to the substitution of prednisone by dexamethasone to aid further in preventing CNS relapse. This may be particularly important in patients at higher risk for CNS relapse.     

Medulloblastoma as a secondary malignancy after radiotherapy-free treatment for acute lymphoblastic leukemia

Malignant brain tumors have been reported to occur in survivors of childhood acute lymphoblastic leukemia (ALL) more frequently than in the noncancer control population. The strongest risk factor seems to be cranial radiotherapy, used as central nervous system (CNS) prophylaxis. We report the case of a 9-year-old girl affected with metastatic medulloblastoma that developed 6 years after a diagnosis of acute lymphoblastic leukemia. CNS prophylaxis for ALL consisted of intrathecal methotrexate plus cytarabine (20 administrations) and 4 courses of high-dose methotrexate (5g/m2). No prophylactic cranial radiotherapy was administered. The child, in first complete remission, was well until the occurrence of a second tumor. She was treated for medulloblastoma with craniospinal radiotherapy and chemotherapy. At present, she is alive but with disease. As the unusual association of these 2 malignancies in this patient, the p53 status was investigated using FISH analysis by specific DNA probe; no p53 mutation was detected.     

Prolonged intrathecal chemotherapy replacing cranial irradiation in high-risk acute lymphatic leukaemia: Long-term follow up with cerebral computed tomography scans and endocrinological studies

Cranial irradiation in children with acute lymphatic leukaemia (ALL) decreases the risk of CNS relapse but is associated with serious long-term side-effects. We present the long-term outcome of 21 children with high-risk ALL who received prolonged intrathecal chemotherapy instead of the recommended cranial irradiation. Intrathecal triple therapy (methotrexate, hydrocortisone, and cytarabine) was administered every 2nd month throughout the maintenance phase. The average number of courses of intrathecal methotrexate was 8.7 and of triple 9.0. The 5-year event-free survival was 79%. No CNS relapses occurred. CT scan was performed at diagnosis, at cessation of therapy, and 3 years thereafter. No density abnormalities, pathological contrast enhancement, ventricular dilatation, or calcifications were found. One child showed cortical atrophy both at diagnosis and at cessation of therapy. There was a slight decrease in height SDS with time but no change in weight SDS. Delayed bone age was found in 5 children. No abnormalities of growth hormone, thyroid, adrenal, or gonadal function were observed.Conclusion The study indicates that extended intrathecal chemotherapy in children with high-risk ALL may provide an effective protection from CNS relapses and is associated with a low risk of long-term side-effects.     

Isolated central nervous system relapse in acute lymphocytic leukemia (ALL) in children. Experiences of the Swiss Pediatric Oncology Group (SPOG/SAKK) 1976-1986

The incidence of isolated CNS-relapse in the SPOG ALL studies 1976-1986 was analyzed and the prophylaxis of meningosis leucaemica of the different studies was compared. In the SPOG ALL high-risk study 1979-1983, the incidence of isolated CNS-relapse was significantly higher (17/71, 24%) than in the other studies. In this period, radiotherapy was omitted and the prophylactic treatment consisted only of moderately high doses of intravenous methotrexate and intrathecal methotrexate. In other studies, it was shown that the prophylactic combination of CNS-radiotherapy and intrathecal methotrexate, or the periodic administration of combined intrathecal chemotherapy alone, during the whole therapy of 2 1/2 years, produced comparably good results. The prophylaxis with the combined intrathecal chemotherapy was less neurotoxic and allowed the use of a curative radiotherapy in case of a CNS-relapse.     

On the origin of EEG-slowing and encephalopathy during induction treatment of acute lymphoblastic leukemia

BACKGROUND: Neurological complications and EEG slowing frequently occur in children undergoing induction treatment for acute lymphoblastic leukemia (ALL). Disease-related factors and treatment-related toxicity are believed to play causative roles. We wanted to elucidate the etiology further by serial EEG examinations and parallel CSF amino acid analyses. PROCEDURE: Twenty-nine children participated in the study. EEG examinations with quantitative computerized analysis were scheduled on day 1, 10, 29, and 59 of protocol I of BFM-ALL 90 and 95 Study Protocols. CSF analysis for amino acids was carried out on day 1, 15, 29, 45, and 59. RESULTS: A total of 21 of 25 available EEGs showed slight-to-moderate slowing already at diagnosis. The abundance of slow waves was significantly correlated to the white blood count and the CSF glutamine concentration. The EEGs significantly worsened during the first 10 days of treatment with prednisone, VCR, daunorubicin, and intrathecal methotrexate. The following treatment including asparaginase (ASP) gave rise to depletion of CSF from asparagine and a rise of aspartate; glutamine, and glutamate did not follow this pattern. The EEGs remained abnormal, but did not worsen further; the CSF amino acid changes were not related to the EEG. During the subsequent consolidation treatment, the EEGs normalized despite administration of cyclophosphamide, cytara bine, intrathecal methotrexate, and mercaptopurin. CONCLUSIONS: The greater part of EEG changes observed in the early treatment of ALL is due to disease-related factors. Treatment with prednisone, vincristine, and to a much lesser degree asparaginase aggravates the pre-existing encephalopathy. Depletion of CSF from asparagine does not give rise to additional changes. In the second month, the EEG normalizes despite ongoing treatment with different cytotoxic drugs.     

Eosinophilic Meningitis Preceding Meningeal Relapse in a Child with Acute Lymphoblastic Leukemia: Abnormal Nucleotide Content of Eosinophils

A case of eosinophilk meningitis 2 months before the appearance of lymphoblasts in the cerebrospinal fluid is described in a child with acute lymphoblastic leukemia (ALL). The peripheral blood showed no simultaneous eosinophilia. The child was successfully treated for her CNS relapse, and complete remission was easily obtained. The eosinophils and lymphoblasts disappeared quickly after the administration of intrathecal methotrexate. However, 3¹/₂ years later hypereosinophilia developed in the blood and bone marrow, heralding bone marrow relapse. Simultaneously, meningeal relapse was diagnosed and this time the cerebrospinal fluid showed a mixture of lymphoblasts and eosinophils. Treatment was reinstituted and complete remission was again obtained. Analysis of the blood eosinophils showed abnormal nucleotide patterns. Similar patterns were previously found in the lymphoblasts from other ALL patients.     

Neuropsychological abnormalities following CNS prophylaxis in children with acute lymphatic leukemia

The pattern and prevalence of neuropsychological abnormalities in children receiving combination CNS prophylaxis (2000 rads cranial irradiation and intrathecal methotrexate) during therapy for acute lymphoblastic leukemia (ALL) were studied. Thirty five children (25 boys) in the age group 5–15 years (mean 9.3) with no evidence of CNS leukemia were included and 20 age matched normal siblings served as controls. Neuropsychological parameters of general intelligence (Malin's modification of WISC test); attention and concentration (colour cancellation test); memory (modified PGI memory test) and visuomotor perception (Bender Gestalt test) were evaluated at least 6 months after CNS prophylaxis. Six (17.1%) patients had mean intelligence quotients (IQ) less than 85, while all controls had IQ>85 (p<0.05). The mean IQ of the patient population (93.4±11.9) was significantly lower than the control group (107±8.4) (p<0.001). Scores on the colour cancellation test were lower in the patients as compared to controls (148.7±27.7 versus 184.9±23.9; p<0.01). The mean memory quotient in the patient population was also lower than in controls (74.5±12 versus 93.6±9.2; p<0.001). Scores on the Bender-Gestalt test did not show a significant difference. The presence of significant neuropsychological abnormalities in patients of ALL indicates the need for modification of the schedule of CNS prophylaxis. A comprehensive psychometric evaluation at regular intervals is essential for longterm rehabilitation.     

Neurophysiological findings in a case of carbohydrate-deficient glycoprotein (CDG) syndrome type I with phosphomannomutase deficiency.

The carbohydrate-deficient glycoprotein (CDG) syndromes are multisystemic disorders involving the glycosylation pathway. The most common subtype is CDG syndrome type I (CDG I). In most CDG I patients a phosphomannomutase (PMM) deficiency has been recognized as the basic defect. We made a neurophysiological evaluation in an 8-year-old boy affected by CDG I with PMM deficiency. The evaluation included central and peripheral nervous system assessment [electroencephalogram (EEG), multimodal evoked potentials (MEP), somatosensory evoked potentials (SEP), visual evoked potentials (VEP), auditory brainstem response (ABR), electroretinogram (ERG) and motor and sensory nervous conduction velocity (NCV)]. We found a peculiar electrophysiological pattern characterized by slowly and mildly progressive motor NCV reduction; progressive impairment of ERG and VEP; slowing of background activity and sharp waves at the EEGs; late sensorineural abnormality of ABR; decreased amplitude and increased latency of SEP. To our knowledge this is the first report involving the neurophysiological aspects both at onset and during follow-up of a case of CDG I with proven PMM deficiency.     

High-dose methotrexate improves clinical outcome in children with acute lymphoblastic leukemia: St. Jude Total Therapy Study X

High-dose methotrexate (HDMTX, 1,000 mg/m2) and cranial irradiation/sequential chemotherapy (RTSC) were compared for ability to extend complete remission durations in children with acute lymphoblastic leukemia (ALL). Three hundred thirty patients were enrolled in the study, according to our criteria for standard-risk ALL: a leukocyte count less than 100 X 10(9)/L, no mediastinal mass, no leukemic involvement of the central nervous system (CNS), and blast cells lacking sheep erythrocyte receptors and surface immunoglobulin. Prednisone-vincristine-asparaginase induced complete remissions in 95% of the patients, who were then randomized to receive either HDMTX (n = 154) or RTSC (n = 155). HDMTX was administered with intrathecal MTX for the first 3 weeks following remission induction, and then every 6 weeks with daily mercaptopurine (MP) and weekly oral MTX for a total of 18 months. The RTSC regimen consisted of 1,800 cGy cranial irradiation and intrathecal MTX for 3 weeks, followed by MP/MTX, cyclophosphamide/doxorubicin, and teniposide/cytarabine administered sequentially over 18 months. The final 12 months of treatment for both groups was MP and oral MTX; all patients received intrathecal MTX every 12 weeks. With a median follow-up of 5 years, complete remission durations have been significantly longer among children treated with HDMTX, compared with RTSC (P = .049) or historical institutional control regimens (P = .002). Approximately 67% of the patients receiving HDMTX and 56% of those receiving RTSC are expected to be in continuous complete remission at 4 years. Overall, isolated CNS relapse rates were similar (P = .17) in the two treatment groups, although by newer risk criteria cranial irradiation could be expected to provide better protection in patients with an unfavorable prognosis. These findings indicate that addition of intermittent HDMTX infusions to conventional chemotherapy is an effective method for extending complete remissions in children with ALL.