Pediatric radiation oncology R Miralbell Hpitaux Universitaires Genve

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

Clinical features favorably influencing survival in pediatric medulloblastoma: univariate analysis Author Period #pts Gender Age T-stage M-stage Hershatter et al 1940 -83 127 - - >T 2 NE Tait et al 1975 -79 286 female - <T 3 NE Evans et al 1975 -81 233 - >4 years - M 0 Jenkin et al 1977 -87 72 female - <T 3 M 0 -1 Wara et al 1970 -95 109 female >3 years - M 0 Miralbell et al 1972 -91 86 female - M 0 -

Clinical features favorably influencing survival in pediatric medulloblastoma: multivariate analysis Author Period #pts Gender Age T-stage M-stage Hershatter et al 1940 -83 127 - - >T 2 NE Evans et al 1975 -81 233 - >4 years - M 0 Jenkin et al 1977 -87 72 - - Wara et al 1970 -95 109 female - - M 0 Miralbell et al 1972 -91 86 female - - M 0

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

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

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

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

Junction (brain-spine) in a sagittal slice

without Effect of the table rotation on the field ’s matching

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

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

Boost on the posterior fossa

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

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

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

POG Trial 9031 • Randomize between: - Arm 1: CDDP+VP 16 - CSI - vcr+cycloph. - Arm 2: CSI - CDDP+VP 16 - vcr+cycloph. • 224 high-risk stage patients randomized : - Post-op residual tumor: >1. 5 cm 3 - T 3 b, T 4 - M+ (1 -3)

Patient material & RT guidelines • Patients: 197 evaluable • CSI (dose): M 0 -1 WBI & spine 1. 6 Gy PF (boost) 1. 8 Gy Metastases 1. 6 Gy M 2 -3 dose/fx 35. 2 Gy 40. 0 Gy 18. 0 Gy 14. 4 Gy 0. 0 Gy 4. 8 Gy

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; C 1 -C 2 interspace; post clinoids; post convexity • Tumor: 2 cm around the primary tumor

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, C 1 -C 2, post clinoids, post convexity • Tumor: distance between the boost field limits & the tumor borders as seen in the pre-op brain MRI/CT

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

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

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

Results: overall outcome • EFS (5 -y): (4. 1 SE) • OS (5 -y): 69. 1% 74. 4% (3. 8 SE) • Relapsed: 35 patients • Progressed: 14 patients • Dead: 57 patients

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

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

Results: EFS & OS by site and deviation status

Results: outcome & cumulative effect of treatment deviations Deviations EFS 5 -year OS 0 -1 72. 1% 76. 3% 2 -4 59. 2% (p=0. 06) 70. 6% (p=0. 04)

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.

RT in children: a unique treatment paradigm

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

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

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

Craniospinal RT for medulloblatoma/PNET

Pituitary gland: 36 Gy

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

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

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

…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

Intensity Modulated X-ray Beams

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

Proton Beams

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

Proton Beams

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)

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

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

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

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

3 -D conformal RT IMRT

3 -D conformal RT IMRT Tumor

3 -D conformal RT Pituitary gland IMRT

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

Brainstem glioma 3 -D conformal radiotherapy (CRT)

Brainstem glioma 3 -D conformal with dynamic m. MLC & IMRT

Comparative planning 3 -D m. MLC (CRT) 3 -D m. MLC (dynamic IMRT)

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

Medulloblastoma, post. fossa boost 3 -D conformal with dynamic m. MLC & IMRT

Axial view: cochlear level IMRT 3 -D CRT

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

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)

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

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

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

Secondary cancers • Observed/expected ratios (95% CI): - Hodgkin disease: - Soft-tissue sarcoma: - Neuroblastoma: - CNS tumors: • 9. 7 (8. 0 -11. 6) 7. 0 (4. 9 -9. 7) 6. 6 (3. 3 -11. 8) 4. 4 (1. 8 -5. 4) Increased risk: female & young age. (JNCI, 93; 2001)

Purpose *To assess the potential influence of improved dose distribution with proton beams compared to conventional or IM Xray beams on the incidence of treatmentinduced 2 nd cancers in pediatric oncology.

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)

Conformal XRT IMXT Protons IMPT

Standard XRT IMRT (X-rays) Protons

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

ICRP #60: organ-specific probability of fatal 2 nd cancer (%) per Sv-1 & lethality Organ Mt Oesophagus 0. 55 Stomach 2. 18 Colon 1. 65 0. 55 Breast 0. 39 Lung 1. 60 0. 95 Bone 0. 03 0. 70 Thyroid 0. 07 Lt 0. 95 0. 90 0. 50 0. 10

RMS: Estimated absolute yearly rate (%) of 2 nd cancer X-rays IMXT Protons Yearly rate 0. 06 0. 05 0. 04 0. 02 RR compared to X-rays 1 0. 8 0. 7 0. 4 IMPT

MDB: Estimated absolute yearly rate (%) of 2 nd cancer Tumor site X-rays Oesoph. & stomach Colon 0. 15 0. 07 0. 00 Breast 0. 00 Lung 0. 07 0. 01 Thyroid 0. 18 0. 06 Bone & soft tissue 0. 03 Leukemia 0. 07 0. 05 All 0. 75 0. 43 0. 05 IMXT Protons 0. 15 0. 11 0. 00 0. 02 0. 01 0. 03 RR (compared to X-rays) 1 0. 6 0. 07

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