Cranial radiation therapy

Patients with T-cell phenotype and high initial WBC count.

Patients with high-risk B-ALL and extremely high presenting leukocyte counts and/or adverse cytogenetic abnormalities.

In a trial conducted between 1990 and 1995, the Berlin-Frankfurt-Münster (BFM) group demonstrated that a reduced dose of prophylactic radiation (12 Gy instead of 18 Gy) provided effective CNS prophylaxis in high-risk patients.[26]

In the follow-up trial conducted by the BFM group between 1995 and 2000 (BFM-95), cranial radiation therapy was administered to approximately 20% of patients (compared with 70% on the previous trial), including patients with T-cell phenotype, a slow early response (as measured by peripheral blood blast count after a 1-week steroid prophase), and/or adverse cytogenetic abnormalities.[18]

In the follow-up trial conducted by the BFM group between 1995 and 2000 (BFM-95), cranial radiation therapy was administered to approximately 20% of patients (compared with 70% on the previous trial), including patients with T-cell phenotype, a slow early response (as measured by peripheral blood blast count after a 1-week steroid prophase), and/or adverse cytogenetic abnormalities.[18]

While the rate of isolated CNS relapses was higher in the nonirradiated higher-risk patients compared with historical (irradiated) cohorts, their overall EFS rates were not significantly different.

Several groups, including the St. Jude Children's Research Hospital (SJCRH), the Dutch Childhood Oncology Group (DCOG), and the European Organization for Research and Treatment of Cancer (EORTC), have published results of trials that omitted cranial radiation therapy for all patients, including high-risk subsets.[12,13,27] Most of these trials have included at least four doses of high-dose methotrexate during postinduction consolidation and an increased frequency of intrathecal chemotherapy. The SJCRH and DCOG studies also included frequent vincristine/dexamethasone pulses and intensified dosing of pegaspargase,[12,13] while the EORTC trials included additional high-dose methotrexate and multiple doses of high-dose cytarabine during postinduction treatment phases for patients with CNS3 status (CSF with ≥5 WBC/µL and cytospin positive for blasts).[27]

Several groups, including the St. Jude Children's Research Hospital (SJCRH), the Dutch Childhood Oncology Group (DCOG), and the European Organization for Research and Treatment of Cancer (EORTC), have published results of trials that omitted cranial radiation therapy for all patients, including high-risk subsets.[12,13,27] Most of these trials have included at least four doses of high-dose methotrexate during postinduction consolidation and an increased frequency of intrathecal chemotherapy. The SJCRH and DCOG studies also included frequent vincristine/dexamethasone pulses and intensified dosing of pegaspargase,[12,13] while the EORTC trials included additional high-dose methotrexate and multiple doses of high-dose cytarabine during postinduction treatment phases for patients with CNS3 status (CSF with ≥5 WBC/µL and cytospin positive for blasts).[27]

The 5-year cumulative incidence of isolated CNS relapse on those trials was between 2% and 4%, although some patient subsets had a significantly higher rate of CNS relapse. On the SJCRH study, clinical features associated with a significantly higher risk of isolated CNS relapse included T-cell phenotype, the t(1;19) translocation, and the presence of blasts in the CSF at diagnosis.[12]

Several groups, including the St. Jude Children's Research Hospital (SJCRH), the Dutch Childhood Oncology Group (DCOG), and the European Organization for Research and Treatment of Cancer (EORTC), have published results of trials that omitted cranial radiation therapy for all patients, including high-risk subsets.[12,13,27] Most of these trials have included at least four doses of high-dose methotrexate during postinduction consolidation and an increased frequency of intrathecal chemotherapy. The SJCRH and DCOG studies also included frequent vincristine/dexamethasone pulses and intensified dosing of pegaspargase,[12,13] while the EORTC trials included additional high-dose methotrexate and multiple doses of high-dose cytarabine during postinduction treatment phases for patients with CNS3 status (CSF with ≥5 WBC/µL and cytospin positive for blasts).[27]

The overall EFS rate was 85.6% for the SJCRH study and 81% for the DCOG study—both in line with outcomes achieved by contemporaneously conducted clinical trials on which some patients received prophylactic radiation therapy—but was lower on the EORTC trial (8-year EFS rate, 69.6%).[27]

Several groups, including the St. Jude Children's Research Hospital (SJCRH), the Dutch Childhood Oncology Group (DCOG), and the European Organization for Research and Treatment of Cancer (EORTC), have published results of trials that omitted cranial radiation therapy for all patients, including high-risk subsets.[12,13,27] Most of these trials have included at least four doses of high-dose methotrexate during postinduction consolidation and an increased frequency of intrathecal chemotherapy. The SJCRH and DCOG studies also included frequent vincristine/dexamethasone pulses and intensified dosing of pegaspargase,[12,13] while the EORTC trials included additional high-dose methotrexate and multiple doses of high-dose cytarabine during postinduction treatment phases for patients with CNS3 status (CSF with ≥5 WBC/µL and cytospin positive for blasts).[27]

On the SJCRH study, 33 of 498 patients (6.6%) in first remission with high-risk features (including 26 patients with high minimal residual disease [MRD], 6 with BCR::ABL1-positive ALL, and 1 with near haploidy) received an allogeneic hematopoietic stem cell transplant, which included total-body irradiation.[12]

In a meta-analysis of aggregated data from more than 16,000 patients treated between 1996 and 2007 by ten cooperative groups, the use of cranial radiation therapy did not appear to impact 5-year OS or cumulative incidence of any event.[14]

In a meta-analysis of aggregated data from more than 16,000 patients treated between 1996 and 2007 by ten cooperative groups, the use of cranial radiation therapy did not appear to impact 5-year OS or cumulative incidence of any event.[14]

In subgroup analyses of high-risk subsets, only those with CNS3 status at diagnosis appeared to benefit from cranial radiation, with a significantly lower rate of CNS relapses (isolated/any) in irradiated patients. However, even within this subgroup, OS rates were similar with or without the use of radiation therapy.

In a meta-analysis of aggregated data from more than 16,000 patients treated between 1996 and 2007 by ten cooperative groups, the use of cranial radiation therapy did not appear to impact 5-year OS or cumulative incidence of any event.[14]

This study suggests that cranial radiation therapy may not be an essential component of treatment, even for high-risk patients. However, interpretation is limited by the considerable variation in treatment administered to patients by the different cooperative groups.

The EORTC-58832 trial that was conducted between 1983 and 1989 included patients with medium-risk and high-risk ALL. Patients were randomly assigned to receive or not to receive cranial radiation after intensification and before maintenance therapy.[28][Level of evidence A1]

The EORTC-58832 trial that was conducted between 1983 and 1989 included patients with medium-risk and high-risk ALL. Patients were randomly assigned to receive or not to receive cranial radiation after intensification and before maintenance therapy.[28][Level of evidence A1]

The 25-year EFS and OS rates in the two arms of the trial were similar: the EFS rate was 59.5% and the OS rate was 78.1% for patients who did not receive cranial radiation; the EFS rate was 60.5% and the OS rate was 78.5% for patients who received cranial radiation.

The EORTC-58832 trial that was conducted between 1983 and 1989 included patients with medium-risk and high-risk ALL. Patients were randomly assigned to receive or not to receive cranial radiation after intensification and before maintenance therapy.[28][Level of evidence A1]

There was a dramatic decrease in the rate of late CNS adverse events in the patients who did not receive cranial radiation therapy.

The EORTC-58832 trial that was conducted between 1983 and 1989 included patients with medium-risk and high-risk ALL. Patients were randomly assigned to receive or not to receive cranial radiation after intensification and before maintenance therapy.[28][Level of evidence A1]

The incidence of second neoplasms was also decreased in patients who did not receive radiation (7.3%) compared with patients who did receive radiation (13%) (HR, 0.43). Meningiomas accounted for the increased incidence of second neoplasms in the cranial radiation group.