1. “Pediatric radiation oncology” R. Miralbell Hôpitaux Universitaires, Genève

4. AuthorPeriod#ptsGenderAgeT-stage M-stage Hershatter et al1940-83127-->T2NE Tait et al 1975-79286female-<T3NE Evans et al1975-81233->4 years-M0 Jenkin et al1977-8772female-<T3M0-1 Wara et al1970-95109female>3 years-M0 Miralbell et al1972-9186female--M0 Clinical features favorably influencing survival in pediatric medulloblastoma: univariate analysis

5. AuthorPeriod#ptsGenderAgeT-stage M-stage Hershatter et al1940-83127-->T2NE Evans et al1975-81233->4 years-M0 Jenkin et al1977-8772---- Wara et al1970-95109female--M0 Miralbell et al1972-9186female--M0 Clinical features favorably influencing survival in pediatric medulloblastoma: multivariate analysis

6. Virtual simulation for cranio-spinal irradiation of medulloblastoma. Clara Jargy, Philippe Nouet, Raymond Miralbell. Radiation Oncology, Geneva University Hospital

7. Patient set-up Lateral mark Mark on the skin for the spine field

8. Set-up of the left lateral brain field with the different structures.

9. Set-up of the spinal field Mark on the skin shifts

10. Junction (brain-spine) in a sagittal slice

11. Effect of the table rotation on the field ’s matching with without

12. Moving junctions between the brain fields and the spinal field. We use asymetric fields (one isocenter for the same region).

13. Moving junction between the two spinal fields. Fields match on the anterior edge of the spinal cord

14. Boost on the posterior fossa

15. Final dosimetry in a sagittal slice passing through the spinal cord. -Dose at the junction. -Dose at the spinal cord (depth and SSD vary).

16. Radiotherapy in pediatric medulloblastoma: quality assessment of POG Trial 9031 R. Miralbell QARC & Swiss POG Geneva, CH

17. Purpose To evaluate the potential influence of the quality of RT on event-free (EFS) & overall survival (OS) in a group of high-riskpediatric medulloblastoma patients treatedin POG Trial 9031

18. Randomize between: - Arm 1: CDDP+VP16 - CSI - vcr+cycloph. - Arm 2: CSI - CDDP+VP16 - vcr+cycloph. 224 high-risk stage patients randomized : - Post-op residual tumor: >1.5 cm 3 - T3b, T4 - M+ (1-3) POG Trial 9031

19. Patient material & RT guidelines Patients: 197 evaluable CSI (dose): M0-1M2-3dose/fx WBI & spine35.2 Gy40.0 Gy1.6 Gy PF (boost)18.0 Gy14.4 Gy1.8 Gy Metastases 0.0 Gy 4.8 Gy1.6 Gy

20. CSI treatment volume boundaries WBI: inf border 0.5 cm below base of skull Spine: inf border 2 cm below the subdural space PF: tentorium+1 cm; C1-C2 interspace; post clinoids; post convexity Tumor: 2 cm around the primary tumor

21. Method of RT quality assessment WBI: distance between the inf field limit & both the cribiform plate & floor of the middle cranial fossa Spine: distance between the end of the inf field limit & the end of the dural sac (MRI). PF: distance between the boost field limits & the tentorium, C1-C2, post clinoids, post convexity Tumor: distance between the boost field limits & the tumor borders as seen in the pre-op brain MRI/CT

22. Treatment deviation guidelines WBI: 0-4 mm, minor; <0 mm, major Spine: Inf field abutting the sac, minor Inf field transsecting the sac, major PF: < field boundaries, major Tumor:10-18 mm, minor; <10 mm, major

23. RT deviations: total dose Maximum accepted variation: +/- 5% Major deviation: 10% or more below dose prescription Delays >51 & >58 days were conpensated with 1 or 2 additional fractions to the PF

24. Endpoints & statistics Assessment of 1st site of failure 5-year EFS & OS according to treatment correctness Kaplan-Meier & log-rank tests

25. Results: overall outcome EFS (5-y): 69.1% (4.1 SE) OS (5-y): 74.4% (3.8 SE) Relapsed: 35 patients Progressed: 14 patients Dead: 57 patients

26. Results: treatment deviations Fully evaluable:160 patients # deviations# patients 0 69 1 50 2 31 3 09 4 01

27. Results: major deviations by site Site#deviat/total patients WBI:54/208 (26%) Spine: 12/174 (7%) PF:82/210 (39%) Tumor:33/189 (17%)

28. Results: EFS & OS by site and deviation status

29. Results: outcome & cumulative effect of treatment deviations 5-year DeviationsEFSOS 0-172.1%76.3% 2-459.2% (p=0.06) 70.6% (p=0.04)

30. Summary Major treatment deviations were observed in 57% of fully evaluable patients. Underdosage or treatment volume misses did not correlate with a worse EFS or OS. A «trend» for a better EFS and OS was observed among patients with lesser number of major deviations (i.e., 0-1). An involved field to boost the tumor bed may be as effective as, and less toxic than, boosting the whole PF.

31. RT in children: a unique treatment paradigm

32. Why? 1. Significant increase in survival in pediatric oncology in the last 25 years 2. Conventional RT frequently associated with severe side effects: Growth & musculoskeletal Endocrine & fertility Neuropsychologic Secondary cancers

34. Bone growth and radiation damage Radiation kills dividing chondroblasts Arrested chondrogenesis in the epiphysis Stop endochondral bone formation: >20 Gy

35. Changes in skeletal growth: the height A consequence of treating the spinal axis: reduced sitting heights Age dependant: <12 years Dose dependent: >20 Gy

38. Craniospinal RT for medulloblatoma/PNET

39. Pituitary gland: 36 Gy

40. Thyroid: 25-30 Gy Ovaries: 2-12 Gy

43. 44 Gy Hodgkin’s Lymphoma in 1950’s-1980’s: «mantle» field irradiation

44. Hodgkin’s Lymphoma in the 1990’s-2000’s: involved field irradiation 20 Gy

51. …is further optimization possible? New treatment technologies such as intensity modulated X-ray beams and proton beams can provide an even superior dose distribution compared to conventional 3-D conformal RT

52. Intensity Modulated X-ray Beams

53. Intensity Modulated Radiation Therapy Beam-let 3D Dose Distribution Fluence or Intensity Map IMRT is a highly conformal RT technique whereby many beamlets of varying radiation intensity within one treatment field can be delivered

54. Proton Beams

56. Photon: No mass, uncharged Proton: Large mass, charged « + »

57. Proton Beams

58. Four truisms… 1.There is no advantage to any patient for any irradiation of any normal tissue. 2.Radiation complications never ocur in unirradiated tissues 3.That a smaller treatment volume is superior is not a medical research question 4.One may investigate the magnitude of the gain or the cost of achieving that gain (Suit, IJROBP 53; 2002)

59. Brainstem (pilocytic) glioma in a 8 y-old girl: 50 Gy (100%). Pituitary gland Optic chiasm Brainstem Target volume

61. 3-D conformal radiotherapy Brainstem glioma Dose to the pituitary gland: 25 Gy (high-risk of GH deficiency)

62. Brainstem glioma IMRT Dose to the pituitary gland: 15 Gy (low-risk of GH deficiency)

63. Cancer of the nasopharynx in a 16 y-old boy: 70 Gy (100%)

64. IMRT3-D conformal RT

65. IMRT3-D conformal RT Tumor

66. 3-D conformal RTIMRT Pituitary gland

68. Standard XRTIMRT (X-rays)Protons Medulloblastoma in a 3-year old boy. Spinal radiotherapy: 36 GyE (100%) ThyroidOvaries

72. Brainstem glioma 3-D conformal radiotherapy (CRT)

73. Brainstem glioma 3-D conformal with dynamic mMLC & IMRT

74. Comparative planning 3-D mMLC (CRT)3-D mMLC (dynamic IMRT)

75. Medulloblastoma, post. fossa boost 3-D conformal radiotherapy (CRT)

76. Medulloblastoma, post. fossa boost 3-D conformal with dynamic mMLC & IMRT

77. Axial view: cochlear level 3-D CRT IMRT

78. Comparative planning 3-D mMLC (CRT) 3 -D mMLC (dynamic IMRT) PTV Rt cochlea Lt cochlea O. chiasm

79. Nonperoperative strokes in children with CNS tumors Incidence: 13/807 patients (1.6%) Ocurrence:2.3 years from diagnosis Increased risk: - treatment with RT - optic pathway gliomas (Bowers et al, Cancer 94;2002)

80. Oligo-astrocytoma G-II of the mesencephalus in a 12-year old girl

81. PTV Brainstem O. chiasm Rt & Lt Cochleae O. nerves

82. Protons Pylocitic astrocytoma of the right optic pathway in a 8 year old girl (type-I NF):

83. Secondary cancers Observed/expected ratios (95% CI): - Hodgkin disease:9.7 (8.0-11.6) - Soft-tissue sarcoma:7.0 (4.9-9.7) - Neuroblastoma:6.6 (3.3-11.8) - CNS tumors:4.4 (1.8-5.4) Increased risk: female & young age. (JNCI, 93;2001)

85. Purpose  To assess the potential influence of improved dose distribution with proton beams compared to conventional or IM X- ray beams on the incidence of treatment- induced 2 nd cancers in pediatric oncology.

86. Material A 7-y old boy with a rhabdomyosarcoma (RMS) of the left paranasal sinus: 50.4 Gy (28 x 1.8 Gy, qd) to the tumor bed. (IJROBP, 47;2000) A 3-y old boy with a medulloblastoma (MDB): 36 Gy (20 x 1.8 Gy, qd) to the spine. (IJROBP, 38;1997)

87. Conformal XRTIMXT ProtonsIMPT

88. Standard XRTIMRT (X-rays) Protons

89. Estimation of 2 nd cancer incidence Based on ICRP #60 guidelines M = S t M t H t /L t M ; probability in % of 2 nd cancer incidence (Sv -1 ) (total) M t ; probability in % of fatal 2 nd cancer (Sv -1 ) (organ-specific) H t ; average dose (Sv) in the outlined organs L t ; organ-specific cancer lethality

90. ICRP #60: organ-specific probability of fatal 2 nd cancer (%) per Sv -1 & lethality OrganM t L t Oesophagus0.550.95 Stomach2.180.90 Colon1.650.55 Breast0.390.50 Lung1.600.95 Bone0.030.70 Thyroid0.070.10

91. RMS: Estimated absolute yearly rate (%) of 2 nd cancer X-raysIMXTProtonsIMPT Yearly rate 0.060.050.040.02 RR compared to X-rays10.80.70.4

92. MDB: Estimated absolute yearly rate (%) of 2 nd cancer Tumor siteX-raysIMXTProtons Oesoph. & stomach0.150.110.00 Colon0.150.070.00 Breast0.000.000.00 Lung0.070.070.01 Thyroid0.180.060.00 Bone & soft tissue0.030.020.01 Leukemia0.070.050.03 All0.750.430.05 RR (compared to X-rays)10.60.07

93. Conclusions Proton beams may reduce the expected incidence of radiation-induced 2 nd cancers by a factor of >2 (RMS) or >8 (MDB) With a lower risk of 2 nd cancers the cost per life saved may be significantly reduced