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

AuthorPeriod#ptsGenderAgeT-stage M-stage Hershatter et al >T2NE Tait et al female-<T3NE Evans et al >4 years-M0 Jenkin et al female-<T3M0-1 Wara et al female>3 years-M0 Miralbell et al female--M0 Clinical features favorably influencing survival in pediatric medulloblastoma: univariate analysis

AuthorPeriod#ptsGenderAgeT-stage M-stage Hershatter et al >T2NE Evans et al >4 years-M0 Jenkin et al Wara et al female--M0 Miralbell et al female--M0 Clinical features favorably influencing survival in pediatric medulloblastoma: multivariate analysis

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

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

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

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

Junction (brain-spine) in a sagittal slice

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

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

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

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

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

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

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

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

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

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%)

Results: EFS & OS by site and deviation status

Results: outcome & cumulative effect of treatment deviations 5-year DeviationsEFSOS %76.3% % (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 with severe side effects: Growth & musculoskeletal Endocrine & fertility Neuropsychologic Secondary cancers

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: Gy Ovaries: 2-12 Gy

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

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 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

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

3-D conformal radiotherapy Brainstem glioma 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%)

IMRT3-D conformal RT

IMRT3-D conformal RT Tumor

3-D conformal RTIMRT Pituitary gland

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

Brainstem glioma 3-D conformal radiotherapy (CRT)

Brainstem glioma 3-D conformal with dynamic mMLC & IMRT

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

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

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

Axial view: cochlear level 3-D CRT IMRT

Comparative planning 3-D mMLC (CRT) 3 -D mMLC (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 O. chiasm Rt & Lt Cochleae O. nerves

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

Secondary cancers Observed/expected ratios (95% CI): - Hodgkin disease:9.7 ( ) - Soft-tissue sarcoma:7.0 ( ) - Neuroblastoma:6.6 ( ) - CNS tumors:4.4 ( ) 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 X- ray beams on the incidence of treatment- induced 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 XRTIMXT ProtonsIMPT

Standard XRTIMRT (X-rays) Protons

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

ICRP #60: organ-specific probability of fatal 2 nd cancer (%) per Sv -1 & lethality OrganM t L t Oesophagus Stomach Colon Breast Lung Bone Thyroid

RMS: Estimated absolute yearly rate (%) of 2 nd cancer X-raysIMXTProtonsIMPT Yearly rate RR compared to X-rays

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

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