Radiation Oncology/Leukemia

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Small Lymphocytic Lymphoma (SLL) / Chronic Lymphocytic Leukemia (CLL)

Epidemiology

Leukemias are the most common cancer of childhood and the number one cause of cancer related death in children. 32% of cancers in children under 15. This varies by year, with leukemia representing 17% of cancers in the first year of life, peaking at 46% for 2-3 year olds, and 9% for nineteen year olds. Total cases of leukemia is 7.24 per 100,000 for age 0-5, 3.8 per 100,000 for ages 5-9, decreasing to about 2.5 for ages 10-19.

Incidence in Children: (SEER 1975-1995, age-adjusted)

Acute lymphoblastic leukemia - 2.9 per 100,000
- 74% of leukemias in children. Incidence decrease
- Burkitt's lymphoma and lymphoblastic lymphoma are now considered forms of ALL.
Acute myeloid leukemia - 0.52 per 100,000
- about 14% of leukemias in children;
Chronic myeloid leukemia - 0.13 per 100,000 (less than 7% of childhood leukemias)
Chronic lymphocytic leukemia - rare (about 0.02 per million)
Others - rare

ALL and AML have the incidence at younger ages (<5 years) then decrease. AML incidence rises after age 10, causing 36% of leukemias at age 15-19, but ALL is still the most common leukemia in the older age group (50%).

Incidence in Adults: (SEER 1997-2001, age-adjusted)

Chronic lymphocytic leukemia - 3.53 per 100,000
- increases sharply with age - 0.78 (age 20-54), 7.34 (55-64), 15.1 (65-74), 24.9 (75+)
- median age 60 yo
- higher in males by about 2:1. somewhat higher in whites than blacks.
- 5-15% will evolve into a more aggressive lymphoid malignancy
Acute myeloid leukemia - 3.77 per 100,000
- increases sharply with age - 1.66 (age 20-54), 5.9 (55-64), 13.8 (65-74), 21.7 (75+)
- higher in males by about 2:1. somewhat higher in whites than blacks
Acute lymphocytic leukemia - 1.5 per 100,000
- incidence increases slightly with age but highest in childhood
- somewhat higher in males than females, whites than blacks
Chronic myeloid leukemia - 1.6 per 100,000
- increases with age
- higher in males than females (by about 1.5:1). somewhat higher in whites than blacks

Risk of Relapse

Clinical
- Age
- WBC count
Biological
- Histology/immunophenotype
- Cytogenetics
- Gene identification
Response based
- Morphology (BM Bx/aspirate)
- Minimal Residual Disease
Lymphomatous presentation (PMID 1855175)

Risk groups:

Low - age 2-9 inclusive, WBC < 10,000; no L2 morphology and boys with plts < 100,000
Intermediate - all others; includes pts who are low risk but have L2 morphology or boys with plts < 100,000
High - WBC > 50,000; pts who are intermediate risk but have L2 morphology

Adults with ALL:

High risk: age > 35, WBC > 30,000, null cell phenotype, Ph+, remission after more than 4 weeks of intensive chemo
Have a 18-28% chance of continuous CR at 5 yrs
Regular risk
60% 5-yr DFS

CNS disease

CNS 1 - Negative cytology (no blasts)
CNS 2 - +cytology, < 5 WBC/microliter
CNS 3 - +cytology, >=5 WBC/microliter, or any CN lesion

Gilchrist 1994

CNS involvement at diagnosis in 3% of children with ALL.
CNS involvement is more common in ALL, rare in AML (except for the variant acute myelomonocytic leukemia, AMML), and rare in CML and CLL. Risk in AMML is 20%. 5-10% risk in adults with ALL.

Roles for Radiation

CNS prophylaxis
CNS Therapy (active disease)
TBI
Testis prophylaxis(sanctuary sites)
Palliation
Treatment of chloromas

BMT

Indications for allogeneic hematopoietic stem cell transplantation (HSCT):

relapse, unfavorable cytogenetics, induction failure.

High risk patients (relapsed or t(9;22) (Philadelphia) may benefit from BMT

Conditioning regimens prior to HSCT: purpose is to prevent graft rejection and eliminate leukemic cells. Regimen may consist of chemotherapy alone or chemotherapy + TBI. There is a suggestion of improved outcomes with TBI.

TBI - Socié et al, Blood 2001

CNS prophylaxis

Indications:

CNS involvement at time of diagnosis
High risk disease
- <1 yo, >10 yo
- WBC > 100,000
- T-cell ALL with WBC > 50,000
- bcr-abl translocation (Philadelphia chromosome)
- lymphomatous presentation

PCI for CNS prophylaxis as frontline treatment for patients with ALL led to an increase in survival in the 1960s. Toxicity from PCI is significant. Earlier trials used 24 Gy. Later trials showed that the dose can be reduced to 12-18 Gy or eliminated entirely if appropriate systemic and intrathecal chemotherapy is used.

Treatment of CNS disease

Therapeutic Cranial Irradiation -5% of those on initial presentation -CNS failure

See appropriate protocol for chemotherapy regimen, individual risk-adapted, and response criteria to stratify by risk category.

Dose
- Varies on protocol
- 24 Gy in past, no longer used.
- 18 Gy (standard dose) associated with decreased risk of CNS complications
  - PMID 11443604 - Waber DP, Shapiro BL, Carpentieri SC, et al.: Excellent therapeutic efficacy and minimal late neurotoxicity in children treated with 18 grays of cranial radiation therapy for high-risk acute lymphoblastic leukemia: a 7-year follow-up study of the Dana-Farber Cancer Institute Consortium Protocol 87-01. Cancer 92 (1): 15-22, 2001.
- 12 Gy has been used more recently in European trials
  - PMID 10828010 - Schrappe M, Reiter A, Ludwig WD, et al.: Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 95 (11): 3310-22, 2000.

Fraction size
- Usually 180
- Sometimes 160 (thought to be lower neurocognitive effects)

Volume
- Cranial radiation only (no spinal irradiation)
  - (need ref)
- Areas to watch
  - Cribiform plate (reported site of failure for medulloblastoma)
  - Temporal lobes

Treatments:
CCG trials from 1971-78 used cranial RT + intrathecal MTX but no spinal RT.
CSI was found to be more effective than cranial RT in treating pts with CNS relapse. (Willougby, MRC, PMID 816410, 1976)
CCG trials from 1978-83 used 24 Gy cranial + 12 Gy spinal given during consolidation phase along with systemic and intrathecal chemo.

CNS disease at diagnosis was not an independent prognostic factor, thereby indicating the effectiveness of CNS treatment regimens used.

CCG trials from 1983-89 used more intensive chemotherapy. Reduced spinal dose to 6 Gy in those treated with intensive consolidation phase in order to limit hematopoietic toxicity.

Toxicity

Finnish Cancer Registry; 2007 PMID 17687156 -- "Scholastic achievements of childhood leukemia patients: a nationwide, register-based study." (Harila-Saari AH, J Clin Oncol. 2007 Aug 10;25(23):3518-24.)
- Retrospective. 371 patients with leukemia diagnosis, <16 years old, born 1974-1986. Five matched controls from Population Registry of Finland. Information on 9th grade school analyzed
- If cranial irradiation: lower overall marks (mean -0.24 on scale 4-10), and lower marks for all school subjects
- If chemo alone: females <7 at diagnosis had worse school marks
- Conclusion: Cranial irradiation impairs scholastic achievement; also chemo alone in females before school age

1981 PMID 6948611 -- "Neurologic sequelae of methotrexate and ionizing radiation: a new classification." (Bleyer WA, Cancer Treat Rep. 1981;65 Suppl 1:89-98.)
- Review of data
- Conclusion: concurrent CNS irradiation and chemotherapy most neurotoxic. Single modalities safer, with HD-MTX least neurotoxic

Review articles

CNS treatment: PMID 12525506 — "Toward optimal central nervous system-directed treatment in childhood acute lymphoblastic leukemia." Pui CH et al. J Clin Oncol. 2003 Jan 15;21(2):179-81.
CNS treatment: PMID 16215818, 2005 — "Leukemic and lymphomatous meningitis: incidence, prognosis and treatment." Chamberlain MC et al. J Neurooncol. 2005 Oct;75(1):71-83.
ALL treamtent: PMID 16407512 — "Treatment of Acute Lymphoblastic Leukemia." Pui CH et al. NEJM. 2006 Jan 12;354(2):166-178.

References

SEER publication on pediatric leukemia (PDF)