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

4. Clinical features favorably influencing survival in pediatric medulloblastoma: univariate analysis
Author Period #pts Gender Age T-stage M-stage
Hershatter et al >T2 NE
Tait et al female - <T3 NE
Evans et al >4 years - M0
Jenkin et al female - <T3 M0-1
Wara et al female >3 years - M0
Miralbell et al female - - M0

5. Clinical features favorably influencing survival in pediatric medulloblastoma: multivariate analysis
Author Period #pts Gender Age T-stage M-stage
Hershatter et al >T2 NE
Evans et al >4 years - M0
Jenkin et al
Wara et al female - - M0
Miralbell et al female - - M0

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

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

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
Set-up of the spinal field

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

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

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. R. Miralbell QARC & Swiss POG Geneva, CH
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. POG Trial 9031 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 cm3
- T3b, T4
- M+ (1-3)

19. Patient material & RT guidelines
Patients: evaluable
CSI (dose):
M0-1 M2-3 dose/fx
WBI & spine Gy Gy 1.6 Gy
PF (boost) Gy Gy 1.8 Gy
Metastases Gy Gy 1.6 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: mm, minor; <0 mm, major
Spine: Inf field abutting the sac, minor
Inf field transsecting the sac, major
PF: < field boundaries, major
Tumor: 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): % (4.1 SE)
OS (5-y): % (3.8 SE)
Relapsed: patients
Progressed: patients
Dead: patients

26. Results: treatment deviations
Fully evaluable: 160 patients
# deviations # patients

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

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

29. Results: outcome & cumulative effect of treatment deviations
5-year
Deviations EFS OS
% %
% (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? Conventional RT frequently associated with severe side effects:
Significant increase in survival in pediatric oncology in the last 25 years
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: Gy
Ovaries: 2-12 Gy

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

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
3D Dose Distribution
Fluence or Intensity Map
field width
field length
Beam-let
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…
There is no advantage to any patient for any irradiation of any normal tissue.
Radiation complications never ocur in unirradiated tissues
That a smaller treatment volume is superior is not a medical research question
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. Dose to the pituitary gland: 25 Gy (high-risk of GH deficiency)
Brainstem glioma
3-D conformal
radiotherapy
Dose to the pituitary gland: 25 Gy (high-risk of GH deficiency)

62. Dose to the pituitary gland: 15 Gy (low-risk of GH deficiency)
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. 3-D conformal RT
IMRT

65. 3-D conformal RT
IMRT
Tumor

66. 3-D conformal RT
IMRT
Pituitary gland

68. Medulloblastoma in a 3-year old boy. Spinal radiotherapy: 36 GyE (100%)
Standard XRT
IMRT (X-rays)
Protons
Thyroid
Ovaries

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

73. 3-D conformal with dynamic mMLC & IMRT
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. 3-D conformal with dynamic mMLC & IMRT
Medulloblastoma, post. fossa boost
3-D conformal with dynamic mMLC & IMRT

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

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

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

83. Secondary cancers - Hodgkin disease: 9.7 (8.0-11.6)
Observed/expected ratios (95% CI):
- Hodgkin disease: 9.7 ( )
- Soft-tissue sarcoma: 7.0 ( )
- Neuroblastoma: 6.6 ( )
- CNS tumors: ( )
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 2nd 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 XRT
IMXT
Protons
IMPT

88. Standard XRT
IMRT (X-rays)
Protons

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

90. ICRP #60: organ-specific probability of fatal 2nd cancer (%) per Sv-1 & lethality
Organ Mt Lt
Oesophagus
Stomach
Colon
Breast
Lung
Bone
Thyroid

91. RMS: Estimated absolute yearly rate (%) of 2nd cancer
X-rays IMXT Protons IMPT
Yearly rate
RR compared
to X-rays

92. MDB: Estimated absolute yearly rate (%) of 2nd cancer
Tumor site X-rays IMXT Protons
Oesoph. & stomach
Colon
Breast
Lung
Thyroid
Bone & soft tissue
Leukemia
All
RR (compared to X-rays)

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