Prophylactic Cranial Irradiation in Acute Lymphoblastic Leukemia: Is there still an indication? Celine Bicquart, MD Radiation Medicine May 5, 2010
Outline Epidemiology Risk-groups Background & Rationale for PCI Radiotherapy Technique Future Directions?
Epidemiology Leukemias represent 30% of childhood cancers in North America. ALL accounts for 80% of childhood leukemias. 3000 children presents annually in US Median age of presentation is 4y; peak occurrence from 2-4y Boys>girls Association with trisomy 21 B precursors account for 80-85% of ALL cases, tend to occur in younger children T precursors account for 15% of ALL cases, tend to occur in children >10y, frequent extramedullary involvement CNS disease at presentation occurs in <5% of cases. 1
Risk Categories for ALL Common risk assessment determined at NCI consensus conference in 1995 LOW RISK: age 1-9, WBC<50K HIGH Risk: age<1 or >10, WBC>50K CNS 1: absence of blasts on CSF CNS 2: + blasts, but <5/µL CNS 3: + blasts, >5/µL
Advancement in Treatment of ALL Development of combination chemotherapy Need for maintenance chemotherapy
Improvement in leukemic control is due to introduction of CNS irradiation in the 1960 s. Simone JV NEJM 2003; 349: 627-28
Rationale for CNS preventive Irradiation Animal experiments from mouse L1210 model at St. Jude s suggested that leukemia control possible only with CNS irradiation added to intraperitoneal chemotherapy. St. Jude s: used induction (vincristine, prednisone), then maintenance (MTX and 6-MP), then 5-12Gy CSI. Found that CNS relapse was dominant event limiting remission once chemotherapy could prolong hematologic remission.
Early Studies St. Jude s Total IV (1973) 2 : benefit of combination chemotherapy Combination chemotherapy is superior to sequential administration of single agents. Full dose is superior to half-dose chemotherapy NO CNS XRT given CNS failures:
St. Jude s Total VI (1978) 3 : benefit of CSI of 24Gy Randomized to +/- CSI 24Gy in 15/16 fxs Isolated CNS relapsed decreased from 67% to 4% No change in OS due to BM failures Those who developed isolated CNS relapse received 24Gy with maintenance chemo 23-35% cured.
St. Jude s Total VII 1981 4 : Randomized CrI 24Gy + IT-MTX vs. CSI 24Gy Equivalent outcomes Establishes effective CNS control with approach of CrI + IT-MTX rather than CSI
Children s Cancer Study Group 1981 5 478 patients with marrow remission 299 179 24Gy CSI 24Gy CrI + IT MTX 18Gy CSI 18Gy CrI + IT MTX
No increased CNS relapse with 18Gy No increased BM relapse with 18Gy No increased death with 18Gy
PCI dose effects on late cognitive function in children treated for ALL 6 1992 Children that received 18Gy (n=16), 24Gy (n=19), were compared to controls (Wilms) (n=12). Mean age at diagnosis: 49m Mean age at testing: 142m
Wechsler Intelligence Scale for Children- IQ Wide Range Achievement Testing- reading, spelling, arithmetic 18Gy performed much better than 24Gy (12 points better), and at same level as controls. 24Gy patients had SS worse IQ and academic performance
Dana Farber Protocol 87-01 7 201 high risk ALL received 18Gy PCI Evaluate long-term survival and late neuropsychologic effects. Wechsler Intelligence Scale for Children Vocabulary & Block Design permit IQ estimation
Rey-Osterrieth Complex Figure Test, Copy, & Immediate Memory used to assess executive function, memory, visuospatial reasoning, motor output. (novel, complex information) Visual & Verbal Learning subtest from Wide Range Assessment of Memory and Learning used to assess declarative memory
Only 2/201 (1.0%) patients developed CNS recurrence
<36m at diagnosis Lower performance on WISC-III Vocabulary (OR= 34.1, p<0.01) Lower performance on WISC-III Digit Span (OR= 5.2, p<0.03) So despite normal IQs, may have cognitive processing deficits
ALL-BFM 90-12Gy 10 ALL-BFM 90 2178 patients stratified into standard-risk, medium-risk (adequate early response) or high-risk (inadequate response, Phr chr Goal to reduce toxicity 1) Dose intensification in induction followed by more rapid drug sequence 2) L-asparaginase during consolidation in MRG 3) Enforced consolidation in HRG 4) Reduction in anthracyclines and 12Gy PCI in MRG and HRG
6y EFS: 78% 6y EFS in SRG: 85% 6y EFS in MRG: 82% 6y EFS in HRG: 34% due to systemic relapses CNS relapses in MRG: 0.8% CNS relapses in HRG: 1.6% Suggesting that 12Gy is enough.
Radiotherapy Technique
Acute: Hair loss, N/V, fatigue, HA, skin reaction Long-term: Neurocognitive Effects Endocrinologic Effects Secondary Malignancy: Tokyo Children s Cancer Study Group 8 L84-11, L89-12, L92-13, L95-14. 1846 children with ALL between 1984-1999. PCI assigned to 100%, 80%, 44%, and 44% of patients in studies respectively. 2 nd brain tumors developed in 12 patients, at 8-22 years after CrI out of 1233 patients that received CrI. Cumulative incidence of brain tumors: 2.8 +/- 0.9% at 20 years. Hijiya et al 9 reported 3.00 +/- 0.59% at 30 years (excluding meningiomas).
St. Jude s XV 11 : elimination of PCI 498 ALL pts at high risk for CNS relapse Treatment intensity based on presenting features & level of residual disease after remission-induction treatment Low risk ALL: pre-b cell between 1-10y.o. with WBC <50k; DNA index >1.16; t(12;21) High risk ALL: t(9;22) or minimal residual disease >1% Standard risk: >1% minimal residual disease on day 19, or.10 or.99% after completion of 6 weeks induction
Compared duration of continuous remission in the 71 pts that would have received PCI in past vs. 56 historical controls who did receive it
CNS directed therapy: IT cytarabine immediately after LP, and triple IT (MTX, cytarabine, hydrocortisone) chemo used in all treatment. LR received 13-18 IT txs SR received 16-25 IT txs
Of all 498 patients 33 relapses in total 17 hematologic 11 isolated CNS 4 combined CNS & hematologic 1 testicular
Among 71 pts meeting PCI criteria 2 BM relapses 1 CNS relapse 1 died in remission
Unemployed?
References 1 Bleyer WA. Pediatr Clin North Am. 1988 (35): 789-814. 2 Simone J, Cancer. 1972 Dec;30(6):1488-94 3 Dahl GV. Cancer 1978 Nov; 42(5): 2187-91 4 Simone JV, Lancet. 1981 Sep 5;2(8245):531 5 Nesbit ME. Lancet 1981 Feb 28; (8218): 461-6 6 Halberg FE. IJROBP 1992; 22 (1): 13-6 7Waber DP. Cancer. 2001 Jul 1;92(1):15-22 8 Tsuchida M. Leukemia 2010 (24): 383-96 9 Hijiya N. JAMA 2007 (297): 1207-1215 10 Schrappe M. Blood. 2000 (95): 3310-3322 11 Pui CH. NEJM 2009 360 (26): 2730-41