Radiation Oncology Synopsis

PEDS: Leukemias

General Information and Demographics

Pediatric Leukemias are the most common cancer type in children, accounting for 30% of all childhood malignancies. There are approximately 3000 cases per year. Childhood cancer is the number 2 cause of pediatric death accounting for 10% of all childhood deaths behind accidents at 40% .

Acute lymphocytic leukemias are the more common accounting for 80%. Acute myelogenous leukemias are more aggressive than ALL and are a common indication for bone marrow transplant. In children undergoing bone marrow transplant, radiation therapy has a significant role.

Acute lymphocytic leukemia was the prototype childhood cancer documenting response and cure with chemotherapy and identifying the importance of covering chemotherapy "sanctuary sites" with alternative (radiation) treatment.

Acute Lymphoblastic Leukemia

ALL results from a dysregulated clonal expansion of immature lymphoid cells. Pre-B cell leukemias account for 85% of ALL in children. Most of these are early pre-B lines. B-cell leukemias typically occurs in young children and is associated with a wide range of clinical manifestations and initial WBC counts.

T-cell precursor (pre-T) leukemias account for 15% of the cases in childhood ALL. T-cell derived leukemias generally occur in older children (age > 10 years), and has been associated with extra-medullary involvement in mediastinal nodes and CNS with a high presenting WBC count.

Clinical Presentation

The median age of clinical presentation is 4 years for ALL with a peak between 2 and 4 years.. Boys are more commonly affected than girls, especially in T-cell presentations. The most common presenting signs include fever, ecchymoses or petechiae, lymphadenopathy and hepatosplenomegaly. The diagnosis is suspect when peripheral blood demonstrates the presences of immature lymphblasts or elevated white count.

White counts are

Less often presentation is asociated with extramedullary involvment including CNS, testis or kidney. ALL usually involves the bone marrow and is associated with lymphoblastic infiltration into multiple organs. CNS leukemia is largely asymptomatic although extensive leptomeningeal disease may be manifest clinically by irritability, headaches, sometimes vomiting and weight gain (hypothalamic syndrome).

Staging

The 1995 NIH Consensus Criterion divided pediatric ALL into high risk and low risk groups. Low risk is children aged 1 - 10 and WBC < 50k/mL. One of the most important predictors is early response to chemotherapy. Patients with ≥ 1% blasts in bone marrow on day 19 of induction chemotherapy or 0.1 - 0.99% blasts on completion of 6 week induction chemotherapy are at high risk for recurrence and are staged as standard risk rather than low risk. Those with ≥  1% blasts residual at the end of the 6 week induction chemotherapy regimen are considered high risk.

High Risk B-cell ALL

Bone marrow (based on bone marrow biopsy)

CNS (based on CSF findings)

Studies at St. Jude demonstrate that a traumatic lumbar puncture early in diagnosis and therapy has the potential to introduce circulating blasts into the CNS and is equivalent to a CNS-2 classification. CNS-2 and CNS-3 are associated with less favorable outcomes.

T-cell ALL has a worse prognosis than B-cell ALL with event free survival of 73% at 5 years. Blast status at 8 days (after one intrathecal methotrexate and one week of oral prednisone is the best predictor of outcome.

Treatment

Chemotherapy

Chemotherapy regimens consist of the following:

  1. Induction-remission chemotherapy
    • Steroids (prednisone or dexamethasone -- dexamethasone has superior CNS penetration
    • vincristine and asparaginase OR daunorubicin
    • Remission induction is successful in 97% - 100%
  2. Consolidation Chemotherapy (intensification)
    • Agents: High dose MTX, 6-MP and asparatinase.
    • Reinduction chemotherapy is also a component of induction and has been shown to improve disease control
    • Patients with BCL-ABL (Ph+) gene deficit and poor initial response appear to benefit from BMT in intensification.
  3. Maintenance or continuation chemotherapy
    • routine therapy for ALL presentations except rare mature B-cell variants
    • administered for ≥ 2 years
    • Agents: weekly MTX and 6-MP
    • Goal is to sufficiently suppress slowly replicatingleukemic blasts to allow apoptosis.

Radiotherapy

Radiotherapy is increasingly used selectively in higher risk populations. These populations are being increasingly refined based on serial studies.

T-cell ALL Radiation Therapy Guidelines

*Testicular relapse with regimens in the 1980s was associated with a significant rate of testicular relapse representing 10-20% of all failures. Testicular relapse was typically a late event occuring at a median of 3 years post-diagnosis and was related to high risk features such as T-cell phonotype and high WBC at diagnosis According to Kun, testicular relapse appears to represnt a sign of inadequate systemic disease control rather than a true sanctuary site. Enhanced disease control with the introduction of high dose MTX into prolonged intensification regimens has largely eliminated testicular relapse since 1990.


B-Cell RT Guidelines

Spinal XRT has been eliminated by COG for all patients with ALL. The present standard of care for T-ALL not on therapy is 12 Gy Cranial RT for CNS-1/2 and 18 Gy crainial for CNS-3

European groups are considering eliminating cranial RT for a large subset of patients. The more recent COG studies did not use cranial RT for most T-ALL patients and 1/3 - 1/2 of all relapses included a CNS component (isolated CNS relapse or combine CNS + marrow relapse. A subset of T-ALL patients that received irradiation because of slow response to chemotherapy had very few CNS events.