Medulloblastoma

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  • (20% of cases; #1 is low-grade glioma at 35%–50%)
  • 2 diff areas b/c 2 diff germinal matrix zones
  • Molecular pathology: medulloblastoma Numerous investigations have implicated components of the sonic hedgehog ( SHH ) signalling cascade in medulloblastoma pathogenesis 93 . Binding of SHH to its receptor patched ( PTCH1 ) relieves tonic inhibition on the downstream effector smoothened ( SMO ) & allows the release of the Gli family of transcription factors from inhibitory protein complexes that typically include suppressor of fused ( SUFU ) ( Fig. 4 ). - Genomic alterations in components of the SHH signalling pathway, specifically inactivating mutations of  PTCH1 and  SUFU  and/or activating mutations of  SMO , have been found in ~ 15% of sporadic medulloblastomas 94 ,  95,  96,  97 . - Additionally, germline mutations in  PTCH1  cause  Gorlin's syndrome , a rare congenital condition that is characterized by an increased incidence of several tumour types, including medulloblastoma 98 . SHH signalling is known to drive proliferation in the granule neuron precursors of the cerebellum, and pathway dysregulation resulting from genomic alterations of its components presumably drives medulloblastoma formation through analogous downstream effects 99 . -Dysregulation of the Wnt pathway has also been linked to the development of medulloblastoma. Wnt ligand binds to its receptor frizzled (FZD) leading to the release of its downstream effector  β-catenin  from an inhibitory complex that includes the tumour suppressor adenomatous polyposis coli ( APC ) and the axin proteins ( Fig. 4 ). Subsequent nuclear accumulation of β-catenin is thought to mediate its tumorigenic functions, presumably through the activation of target genes such as  MYC , cyclin D1 ( CCND1 ) and RE1-silencing transcription factor ( REST ), which have established roles in cellular proliferation, differentiation and inhibition of apoptosis 114,  115 . - Approximately 20% of sporadic medulloblastomas harbour mutations in  APC ,  AXIN1 ,  AXIN2  or  CTNNB1  (which encodes β-catenin) 116,  117,  118,  119,  120 , and a similarly sized fraction (18%) has separately been shown to exhibit nuclear β-catenin immunostaining 114 . - Furthermore, Turcot's syndrome , which is caused by mutations in  APC , is characterized by an increased incidence of medulloblastoma and other neuroepithelial tumours. Finally, medulloblastomas that are driven by increased Wnt signalling, as shown by nuclear β-catenin staining, may follow a relatively favourable clinical course 121 . Although  in vivo models of Wnt pathway-driven medulloblastomas have yet to emerge, one group has successfully generated  supratentorial PNETS  using, in part, exogenously augmented β-catenin expression 122 . - Loss of chromosome 17p, typically in association with gain of 17q (forming isochromosome 17q: i(17)(q10)) is the most common genetic lesion in medulloblastoma, occurring in 30–50% of cases 123,  124,  125,  126,  127,  128,  129 . Common deletion region of 17p13.2-13.3 includes several confirmed and putative tumour suppressor genes, including  TP53 , the loss of which could presumably facilitate neoplastic behaviour. Germline defects in  TP53 , resulting in Li–Fraumeni syndrome , have been correlated with increased medulloblastoma incidence 19 , and although  TP53  mutations in sporadic medulloblastomas are not particularly common, they seem to confer poor clinical outcome 125,  130 . Additionally, Trp53  loss dramatically enhances medulloblastoma formation in SHH pathway-driven mouse models 112 ,  131,  132 . - Genomic amplification of  MYCN  and  MYC  characterizes a subset of clinically aggressive medulloblastomas that tend to exhibit large cell/anaplastic histological features 130 ,  133 . It has recently been demonstrated that the oncogenic miRNA cluster,  miR-17–92 , is a downstream target of MYC, the expression of which seems to be associated with a wide range of tumour types 134 . Also, MYC or MYCN overexpression facilitates medulloblastoma formation in mice, a characteristic shared with other oncoproteins such as AKT, insulin-like growth factor 2 ( IGF2 ) and  BCL-2  (Refs  102 ,  107 ,  110 ,  135 ). - The Erbb family of RTKs, insulin-like growth factor 1 receptor ( IGF1R ) and PDGFR have also been directly implicated in medulloblastoma pathogenesis , with IGF1R and PDGFR implicated by their association with poor prognosis 115,  136 . One group has documented ERBB2  overexpression in a large proportion of medulloblastomas (28%) 137 , in which it is thought to promote tumorigenesis by activating the Ras–MAPK and AKT pathways and by promoting the expression of pro-metastatic genes such as S100 calcium binding protein A4 ( S100A4 ),  CCL5  (also known as  RANTES ) and  MAP2K5  (also known as  MEK5 ) 138,  139 . Additionally, deletion mutants of  ERBB4  have been found in childhood medulloblastomas 140 , and overexpression of Erbb proteins has been correlated with unfavourable clinical outcome 141 ,  142,  143 .
  • WHO in 1993 separated: Embryonal tumors (differentiation) from PNETs, with medulloblastoma when it occurs in the posterior fossa/infratentorial Small Round Blue Cell Tumors: 1. Lymphoma 2. Ewing 3. Acute lymphoblastic leukemia 4. Rhabdomyosarcoma 5. Neuroblastoma 6. Neuroepithelioma 7. Medulloblastoma 8. Retinoblastoma (Mnemonic: LEARN NMR)
  • Transcriptional profiling: medulloblastoma subclasses . As analogous studies have accomplished for glioma, global transcriptional analyses of medulloblastoma have both emphasized and better conceptualized the molecular heterogeneity inherent to this cancer type. Initial efforts in this regard demonstrated gene expression patterns in medulloblastoma that were distinct from other CNS tumours with similar histological features, such as supratentorial PNET and  atypical teratoid/rhabdoid tumour  (AT/RT) 144 . Furthermore, transcriptional profiles were found to be predictive of clinical outcome and implied tumour cell lineage 136, 144 . On a separate note, one study found that PDGFR and Ras–MAPK signalling correlated with metastatic medulloblastoma, supplementing their array analysis with confirmatory experiments  in vitro 136 . More recently, two integrated genomic investigations have revealed distinct transcriptional subclasses of medulloblastoma that also harbour genomic alterations in oncogenic signalling pathways 145, 146 . Both have identified subgroups centred around dysregulated SHH and Wnt signalling that are also characterized by genomic alterations in pathway-relevant genes ( Table 2 ). More specifically, the SHH-associated group includes all analysed tumours with mutations in  PTCH1  and  SUFU , and the Wnt-associated group contains all tumours with mutations in  CTNNB1 . Additional subclasses are less precisely defined but seem to be somewhat distinct with regard to their associated chromosomal abnormalities, patient age distribution and gene expression-related developmental signatures. Interestingly, medulloblastomas with desmoplastic histology mainly cluster in the SHH group, confirming an association that has previously been made 94 . As with similar analyses carried out for glioma, these studies indicate that transcriptional variation in medulloblastoma may reflect basic differences in oncogenic signalling, and in this way invite the implementation of subclass-specific targeted therapy.
  • Anaplastic variant: - pleomorphic nuclei prominent nuclei, abundant cytoplasm, larges areas of necrosis, high itotoc activity, high apoptosis, cellular atypica, - EFS 60% compared to >75% (nonanaplastic)
  • - Torticollis 2/2 foramen magnum involvement Head tilt- think CN4 palsy 2/2 tumor comp by ext into cerebral aqueduct (Nl:usually intorts the eye, causes downgaze and looks laterally) Abnl: Eye extors, deviate’s upward (hypetropia) and drifts inward- resulting in head tilt - CN6 stretched and compressed at petroclival/Gruber’s ligmament in hydrocephalus - Vision changes usually 2/2 papilledema - If sided dysmetria 2/2 cerebellar hemispheric desmoplastic variant - lesions in vermis more likely to cause gait ataxia than unilateral symptoms - If severe weakness think tumor compression of spinal cord/nerve roots i.e. radiculopathy Infants – only sign may be bulging ant fontanelles w/wide split cranial sutures (coronal and metopic)
  • Infants – only sign may be bulging ant fontanelles w/wide split cranial sutures (coronal and metopic)
  • T1 + / - Gad – Endhance on T1 No T2 shown- if T2 then hyperintensity on T2-weighted images and hydrocephalus Medulloblastoma - Midline, vemrian or rood, - hyperdense on CT w/out contrast , enhance homogenously - exophytic, extend into CPA - Hypointense on T1 w/out gad, homogenous enhancement on T1 w/gad No T2 shown- if T2 then hyperintensity on T2-weighted images and hydrocephalus Ependymoma - IntrA ventricular- cast of lumen- 50% are calcified Astrocytoma - usually not vascular on angio Choroid Plexus papilloma- trigone of lat ventricle- calcified Brainstem Glioma – shows attachment to floor of 4 th ventricle - present with cranial nerve palsies - hydrocephalus less common Juvenille Pilocytic Astrocytoma - 2/3 are cystic w/mural nodule, cyst fluid more dense than CSF Hemangioblastoma - cystic or solid - angio shows hypervascularity & stain Mets - most common intraaxial neoplastic post fossa mass in adult, not kids
  • - Fundoscopic exam for papilledema r/o herniation risk 1 st CSF sampling usually days 12-16 following resection Baseline audiometry: likely to see cisplatin and RT to CN7 so often used as a decision point for technique and further therapy - Usually no Bx, just get excised
  • Can Reduce ICP D1 w/Diamox/Acetazolamide No risk for CSF dissemination following shunt placement w/medulloblastoma Wait to LP following CT/MR imaging of brain to r/o herniation risk, and 10-14 d post op to avoid surgical debris contamination of CSF (FP).
  • Randomized Phase 3 427 children <21 years, with medulloblastoma, pineoblastoma, ependymoblastoma, central neuroblastoma, PNET, or malignant ependymoma, with unfavorable features. For ST-PNET required M+ staging. Children age >1.5 years (n=328) received post-op CSI with Arm A) vincristine, lomustine, prednisone vs. Arm B)  8-in-1  (cisplatin, procarbazine, lomustine, vincristine, cyclophosphamide, methylprednisolone, hydroxyurea, cytarabine). RT: - age >3 received CSI 36 Gy, boost to 50.4-54 Gy spine mets and 54 Gy primary brain site; age <3 received CSI 23.4 Gy with boost to 45 Gy. Children age <1.5 years (n=99) were not randomized and received only Arm B
  • PF mutism: 2/2 dentorubrothalamic pathway disruption- - axons from the contralateral dentate nucleus of the cerebellum->red nucleus ->vent lat & vent ant nuclei of the thalamus. ->1o M cortex. Acts to coordinate the initiation, planning and timing of movement. Cerebellar dysfunction is truncal and appendicular Supranuclear palsies- eyes, swallowing etc.
  • - Chang Staging- Mainly historical significance -
  • Can Reduce ICP D1 w/Diamox/Acetazolamide No risk for CSF dissemination following shunt placement w/medulloblastoma Wait to LP following CT/MR imaging of brain to r/o herniation risk, and 10-14 d post op to avoid surgical debris contamination of CSF (FP).
  • Cushing was an accomplished writer and a gifted artist. While at Johns Hopkins medical School, Cushing became close friends with Sir William Osler, who was the first professor of medicine there. Cushing later wrote a biography of Osler, for which the was awarded the Pulitzer Prize in 1926. His artistic talents were encouraged Max Brodel, a medical illustrator at Johns Hopkins. As a result, Cushing would make drawings immediately after an operation (above and below), which contained information about how the procedure had been performed, and soon became a central part of his surgical reports. Cushing was also interested in the history of medicine, and frequented antique bookshops to acquire volumes for his collection. In particular, he was interested in the work of  Andreas Vesalius , the 16th century Belgian anatomist and physician who revolutionized medical illustration. Cushing died on October 7th, 1939, as the result of a myocardial infarction. At the time, he was researching a book about Vesalius. His heart attack was triggered while he was lifting one of Vesalius's tomes.
  • Moya Moya Syndrome Median latent period for development was 40mo s/p RT (range, 4–240). Early age groups & those w/NF1 are most susceptible to RT induced Moya Moya Syndrome - International Journal of Radiation Oncology*Biology*Physics. Volume 65, Issue 4, 15 July 2006, Pages 1222-1227. Radiation-induced moyamoya syndrome Snehal S. Desai B.S., Arnold C. Paulino M.D.  ,  , Wei Y. Mai M.D., Bin S. Teh M.D. Incidence: 27.7% @ 2 yrs, 53.2% @ 4yrs, 74.5% @ 6 yrs, & 95.7% @ 12 yrs after RT. Kids w/ALL tx w/PCI -Cumulative incidence of MoS in our series was 0.46 ± 0.02% at 8 years Moyamoya syndrome following childhood acute lymphoblastic leukemia. Akira Kikuchi MD, PhD, Miho Maeda MD,Ryoji Hanada MD, Yuri Okimoto MD, PhD, Koichi Ishimoto MD, PhD, Takashi Kaneko MD, PhD, Koichiro Ikuta MD, Masahiro Tsuchida MD, PhD. Pediatric Blood & Cancer Volume 48 ,  Issue 3 ,  pages 268–272 ,  March 2007. Secondary Malignancies - Incidence of SMNs is around 10–20% 30 years after treatment 1 . 5 yr OS w/ MB is 73% 1 , but the 30 yr cumulative incidence of SMNs is 31% Smith, M. A.  et al . Outcomes for children and adolescents with cancer: challenges for the twenty-first century.  J. Clin. Oncol.   28 , 2625–2634 (2010). Friedman, D. L.  et al . Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study .  J. Natl. Cancer Inst.   102 , 1083–1095 (2010).  Cumulative incidence @ 30 yrs: 20.5% (95% confidence interval [CI] = 19.1% to 21.8%) for all subsequent neoplasms, 7.9% (95% CI = 7.2% to 8.5%) for second malignant neoplasms (excluding non-melanoma skin cancer), 9.1% (95% CI = 8.1% to 10.1%) for non-melanoma skin cancer, 3.1% (95% CI = 2.5% to 3.8%) for meningioma. Cognitive impairment (Limit temporal lobe dose!) - Predictors: <7 yoa most imp, dose, high IQ, F>M - Rate: Falls for >5 yrs depending on age at dx - If < 7 yoa @ tx then 5points/yr - If > 7yoa @ tx then 1 point/yr Endocrine: (-) GH->(-) growth (threshold ~10 Gy ) - Thyroid Carotid Artery Stenosis Ototoxicity
  • POG 8631/CCG 923  (1986-1990) --  CSI 36 Gy vs. CSI 23.4 Gy "Low-stage medulloblastoma: final analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation." (Thomas PR, J Clin Oncol. 2000 Aug;18(16):3004-11.) Randomized. 126 patients, low risk (>3 years, complete resection T1-T2, later also T3a, M0) standard CSI 36(20*1.8) vs. reduced CSI 23.4(13*1.8); both followed by posterior fossa boost to 54(30*1.8) Gy.  Study closed prematurely due to high relapse in reduced arm 5-year EFS: standard CSI 67% vs. reduced CSI 52% (p=0.080) 8-year EFS: standard CSI 67% vs. reduced CSI 52% (p=0.141) These data confirm the original one-sided conclusions but suggest that differences are less marked with time Conclusion: Reduced CSI 23.4 alone is insufficient; may need concurrent chemo
  • SIOP I   "Adjuvant chemotherapy for medulloblastoma: the first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I)." (Tait DM, Eur J Cancer. 1990 Apr;26(4):464-9.) Randomized. 286 patients, 15 countries. Treated with CSI, Randomized to +/- chemo (concurrent vincristine, then CCNU/vincristine maintenance) Survival: 5-year 53%, 10-year 45%. No difference between arms Subgroup benefit: subtotal surgery, brainstem involvement, T3-T4 disease
  • SIOP II  (1984-1989) -  "Prospective randomised trial of chemotherapy given before radiotherapy in childhood medulloblastoma. International Society of Paediatric Oncology (SIOP) and the (German) Society of Paediatric Oncology (GPO)" Bailey et al. Med Pediatr Onc 25(3):166-78, 1995 Randomized. 364 patients. SIOP I low risk (total/subtotal resection, no brain stem invasion, M0) randomized to +/- adjuvant chemo (vincristine, methotrexate, procarbazine), and then randomized to standard CSI 35 Gy vs. reduced CSI 25 Gy. Boost posterior fossa to 55 Gy. High risk randomized to +/- adjuvant chemo, then standard CSI and additional post-RT chemo Outcome: No advantage to pre-RT chemo. Worse outcomes both EFS and QOL/KPS for standard risk patients HIT 91, 2000  - "Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomized trial HIT '91." (Kortmann RD, Int J Radiat Oncol Biol Phys. 2000 Jan 15;46(2):269-79.) Subset report of 158 medulloblastoma patients (137 randomized). Median F/U 2.5 years Outcomes: 3 yr RFS: RT->chemo 78% vs. chemo->RT 65% (SS), NS if age 3-6 years Negative prognosis: M2/3 disease, age <8 years. M1 not a bad prognostic factor CCG 9892  -  "Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy" Packer et al. JCO 17(7):2127-36, 1999 Pilot study – Single Arm - Reduced dose (23.4 Gy) CSI w/ concurrent vincristine (comp to 35 Gy for standard risk patients historical dose). Post fossa boost to 55.8 Outcomes: - PFS 86% at 3 yrs, 79% at 5 yrs  CCG A9961 reduced CSI dose
  • CCG A9961  (1996-2000)  "Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma" Packer et al. JCO 24(25):4204-8, 2006. Randomized. 421 patients, standard risk. Reduced dose RT (23.4 Gy CSI + 55.8 Gy to posterior fossa) and concurrent vincristine, Randomized to adjuvant: CCNU, cisplatin and vincristine or Cyclophosphamide, cisplatin, vincristine 5-year outcome: EFS 81%, OS 86%. No difference by chemo arm Prognostic factors: anaplasia OS 75% vs. 89% (SS) Relapse: PF alone 32%, disseminated 40%, PF+disseminated 25% Toxicity: 25% with delayed onset mutism, hypotonia, cerebellar deficits, supranuclear CN deficits, extreme irritability, and/or emotional lability. ~50% residual deficits at 1 year Conclusion: Reduced dose CSI works in large groups of standard risk patients , Chemo CCNU vs. Cytoxan euivalent but cytoxan + toxicities
  • Goal: Assess efficacy of HD RT to the PF & LD RT to the spinal axis, Retrospective : 60 patients w/biopsy-proven medulloblastoma treated at the Joint Center for Radiation Therapy (JCRT) between 1968 and 1984. 5 & 10 yr actuarial survival - 68% vs. 44%, respectively. - Median time to recurrence was 19 months. - Extent of surgery (GTR vs. STR favorable) , age (Infants <2 yoa had (-) 5 yr aOS 48%), and radiation dose to the posterior fossa all were of prognostic value. - The posterior fossa was the predominant site of recurrence and accounted for 78% of all failures. - Local control in the posterior fossa was dose dependent. - 79% of patients receiving >50 Gy were controlled vs. 33% that received <50 Gy (P less than 0.02). There were no supratentorial failures, and there was only one isolated spinal cord failure. There were no solitary spinal failures in 24 patients who received a median dose of only 2400 cGy to the spinal axis. We concluded that low-dose irradiation to the spine and whole brain may be indicated with maintenance of a posterior fossa dose of greater than 5000 cGy.
  • Not a single figure illustrating toxicity "Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors." (Duffner et al., N Engl J Med. 1993; 328(24):1725-31) Prospective, 198 Patients <3yoa from 1986- postoperatively chemo w/2 x 28d C of cytoxan+vincristine,  1 x 28d C Cis/Etop. Repeated until the dz progressed or for 2 yrs in 132 children 24 months of age at diagnosis and for one year in 66 children 24 to 36 months of age at diagnosis.  Received radiation therapy.
  • Not a single figure illustrating toxicity Outcomes: After 2C Cytox/Vincr, a CR/PR was obtained in 30% RR best in MB, malignant gliomas, or ependymomas . No response w/brain-stem gliomas or embryonal tumors PFS: 41% @1yr for 1-2yoa & 39% for <2yoa MV analysis: embryonal tumors as a significant adverse prognostic feature (relative risk, 2.2; 95 percent confidence interval, 1.4 to 3.4) CR favorable (relative risk, 0.33; 95 percent confidence interval, 0.20 to 0.54). CR to chemo asso w/PFS approaching that achieved with GTR
  • Not a single figure illustrating toxicity A comparison of cognitive evaluations obtained at base line and after one year of chemotherapy revealed no evidence of deterioration in cognitive function.
  • German Pediatric Brain Tumor Study Group, 2005  (1992-1997) - "Treatment of Early Childhood Medulloblastoma by Postoperative Chemotherapy Alone." (Rutkowski S et al. New Engl J Med 352:978-986, 2005. ) Prospective, Multinstitutional 43 children <3, 28% had M2-M3 disease. - Max SR, -> MRI/CT Intraventricular reservoir (Ommaya) for MTX. Chemotherapy started in 2-4 weeks, 3x 2-mo C of cyclophosphamide, MTX (intraventricular and intravenous) with leucovorin, vincristine, carboplatin, and etoposide, divided into four administrations per cycle, with one week between each cycle. Methotrexate was intraventricular and intravenous. Treatment stopped after 3rd cycle. If no CR, then went on to XRT or other treatment.
  • Outcomes: 5 yr OS & PFS: 66% and 58% GTR 93% and 82% vs. STR 56% and 50% M2/M3 38% and 33% Remission (no RT): GTR: 14/17 (82%) with GTR 21/31 (68%) with M0-M1; 3/12 (25%) with M2-M3 . RR to chemo: 62% in pts with measurable disease . Higher general intelligence in pts who did not receive XRT (compared to pts from prior trials). Conclusion: Post-op chemo alone is promising in young children without mets
  • Let's say you're working on nerve cells, measuring their firing frequency. When you drop a chemical on them, they seem to fire more slowly. You've got some normal mice and some mutant mice. You want to see if their cells are differently affected by the chemical. So you measure the firing rate before and after applying the chemical, first in the mutant mice, then in the normal mice. When you drop the chemical on the mutant mice nerve cells, their firing rate drops, by 30%, say. With the number of mice you have this difference is statistically significant, and so unlikely to be due to chance. That's a useful finding, which you can maybe publish. When you drop the chemical on the normal mice nerve cells, there is a bit of a drop, but not as much – let's say 15%, which doesn't reach statistical significance. But here's the catch. You can say there is a statistically significant effect for your chemical reducing the firing rate in the mutant cells. And you can say there is no such statistically significant effect in the normal cells. But you can't say mutant and normal cells respond to the chemical differently: to say that, you would have to do a third statistical test, specifically comparing the "difference in differences", the difference between the chemical-induced change in firing rate for the normal cells against the chemical-induced change in the mutant cells.
  • Prone vs. Supine - Largely patient preference and practicality (Green Journal) Head in a head rest with neck extended Immobilized with a head mask or aquaplast immobilization device that m aximally immobilizes patient’s head Neck extension avoids the thoracic spine field from exiting through the patient’s jaw and oral mucosa Ensure the jaw and base of skull are in the same plane - Prone: Allows for maximal straightening of the lumbar curvature. Immobilizes patient’s torso and hips
  • Prone vs. Supine - Largely patient preference and practicality (Green Journal) Head in a head rest with neck extended Immobilized with a head mask or aquaplast immobilization device that m aximally immobilizes patient’s head Neck extension avoids the thoracic spine field from exiting through the patient’s jaw and oral mucosa Ensure the jaw and base of skull are in the same plane - Prone: Allows for maximal straightening of the lumbar curvature. Immobilizes patient’s torso and hips
  • - head in a head rest with neck extended and is immobilized with a head mask or aquaplast immobilization device Maximally immobilizes patient’s head Neck extension avoids the thoracic spine field from exiting through the patient’s jaw and oral mucosa Ensure the jaw and base of skull are in the same plane -Prone: Allows for maximal straightening of the lumbar curvature. Immobilizes patient’s torso and hips
  • - Spine Iso can stay in same spot, here we plan all 4 shifts in same plan to make setup markings easy - In this case we chaning the interface between the cranial and spinal field to avoid hot/cold spots.
  • - head in a head rest with neck extended and is immobilized with a head mask or aquaplast immobilization device Maximally immobilizes patient’s head Neck extension avoids the thoracic spine field from exiting through the patient’s jaw and oral mucosa Ensure the jaw and base of skull are in the same plane -Prone: Allows for maximal straightening of the lumbar curvature. Immobilizes patient’s torso and hips
  • Preresection volume
  • Wedged pair- % dose still w/cochlea dose but outside the 50% IDL
  • Dose Constraints: Cochlea V30 <50% Optic nerves & chiasm MTD: 60 Gy (RTOG protocols currently recommend 55 Gy; pediatric CCG protocols recommend 50.4 Gy)
  • 3 field= wedged pair w/cone to post fossa to limit cochlea dose IDL not available in old Pinnacle
  • **Similar study through Children’s Hospital of Philadelphia – CSI 18Gy followed by IFRT Phase II Study of Adjuvant Reduced-Dose Craniospinal Radiotherapy With Vincristine Followed By Maintenance Chemotherapy in Children With Newly Diagnosed Standard-Risk Posterior Fossa Primitive Neuroectodermal Tumor or Medulloblastoma Phase:  Phase II Age:  3 to 30 at initial diagnosis Protocol IDs: CHP-693 , CHP-IRB-2001-12-2301, NCI-V01-1680, NCT00031590
  • This is a randomized, open-label, factorial-designed, multicenter study. Patients are stratified according to location of disease and dissemination status (M0 medulloblastoma with > 1.5 cm² residual tumor vs M+ medulloblastoma vs M0 supratentorial primitive neuroectodermal tumor [SPNET] with < 1.5 cm² residual tumor vs M0 SPNET with > 1.5 cm² residual tumor vs M+ SPNET vs M0 diffusely anaplastic medulloblastoma ). Patients are randomized to 1 of 4 treatment arms. Arm I (standard chemoradiotherapy and standard maintenance therapy): Chemoradiotherapy:  Patients undergo radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40 and receive vincristine IV over 1 minute on days 1, 8, 15, 22, 29, and 36. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. Maintenance therapy:  Patients receive cisplatin IV over 6 hours on day 1, vincristine IV over 1 minute on days 1 and 8, and cyclophosphamide IV over 1 hour on days 2 and 3. Patients also receive filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 4 and continuing until blood counts recover (at least 10 days). Treatment repeats every 28 days for a total of 6 courses in the absence of disease progression or unacceptable toxicity. Arm II (standard chemoradiotherapy plus carboplatin and standard maintenance therapy): Chemoradiotherapy:  Patients receive carboplatin IV over 15 minutes once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40 and undergo radiotherapy and receive vincristine as in arm I. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. Maintenance therapy:  Patients receive maintenance therapy as in arm I. Arm III (standard chemoradiotherapy, standard maintenance therapy plus isotretinoin, and continuation therapy with isotretinoin): Chemoradiotherapy:  Patients undergo chemoradiotherapy as in arm I. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. Maintenance therapy:  Patients receive oral isotretinoin twice daily on day 1 and days 16-28 and cisplatin, vincristine, cyclophosphamide, and G-CSF as in arm I maintenance therapy. Treatment repeats every 28 days for a total of 6 courses in the absence of disease progression or unacceptable toxicity. Patients then proceed to continuation therapy. Continuation therapy:  Patients receive oral isotretinoin twice daily on days 15-28. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Arm IV (standard chemoradiotherapy plus carboplatin, standard maintenance therapy plus isotretinoin, and continuation therapy with isotretinoin): Chemoradiotherapy:  Patients undergo chemoradiotherapy as in arm II. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. Maintenance therapy:  Patients receive maintenance therapy as in arm III. Patients then proceed to continuation therapy. Continuation therapy:  Patients receive continuation therapy as in arm III.
  • SINGLE ARM PILOT STUDY CCG 9892   PMID 10561268   "Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy" Packer et al. JCO 17(7):2127-36, 1999 Pilot study evaluating reduced dose (23.4 Gy) CSI w/ concurrent vincristine as alternative to 35 Gy for standard risk patients. Post fossa boosted to 55.8 PFS 86% at 3 yrs, 79% at 5 yrs This study served as the basis for CCG A9961 reduced CSI dose
  • Medulloblastoma

    1. 1. John T. Lucas Jr. Resident - Radiation Oncology Wake Forest University North Carolina Baptist Medical Center
    2. 2. <ul><li>Overview </li></ul><ul><li>Epidemiology </li></ul><ul><li>Pathogenesis </li></ul><ul><li>Classification </li></ul><ul><li>Pathology </li></ul><ul><li>Presentation </li></ul><ul><li>Workup </li></ul><ul><li>Surgical Management </li></ul><ul><li>Treatment </li></ul><ul><ul><li>Role of Radiotherapy </li></ul></ul><ul><ul><li>Role of Chemotherapy </li></ul></ul><ul><ul><li>Radiotherapy Techniques </li></ul></ul>
    3. 3. Blue rubber bleb nevus - 15 mo M Photo courtesy of Johns Hopkins University School of Medicine dermatlas 2001.
    4. 4. Jason T. Huse & Eric C. Holland. Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma . Nature Reviews Cancer   10 , 319-331 (May 2010)
    5. 5. <ul><li>~15% have activating mutations in PTCH1, SUFU and/or SMO </li></ul><ul><li>PTCH1 germline mutations cause Gorlin's syndrome </li></ul><ul><li>~20% of sporadic harbour mutations in APC, AXIN1, AXIN2 or CTNNB1  </li></ul><ul><li>Turcot's syndrome, (mut in APC), has + incidence of MB </li></ul><ul><li>30–50% of cases have del: 17p + gain of 17q (forming isochr 17q: i(17)(q10)) = most common genetic lesion in MB </li></ul><ul><li>del 17p – has TP53, add 17q has MYCN ( Grotzer CCR 2001) (upstream of Akt, IGF2, BCL2) </li></ul>Jason T. Huse & Eric C. Holland. Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma . Nature Reviews Cancer   10 , 319-331 (May 2010)
    6. 7. Jason T. Huse & Eric C. Holland. Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma . Nature Reviews Cancer   10 , 319-331 (May 2010) <ul><li>Other poor prognostic markers: + ErbB2 – Gilbertson CCR 1997 </li></ul>
    7. 8. Jason T. Huse & Eric C. Holland. Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma . Nature Reviews Cancer   10 , 319-331 (May 2010) <ul><li>- 1 st descr 1925 Bailey & Cushing </li></ul><ul><li>* Homer-Wright rosettes </li></ul><ul><li>Staining: </li></ul><ul><li>+ for neuron-specific enolase, </li></ul><ul><li>+ synaptophysin </li></ul><ul><li>+ nestin </li></ul>
    8. 11. Differential?
    9. 12. Timeline H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16
    10. 13. Surgical Management - Ventriculostomy–Endoscopic 3 rd vntrcl vs. Ext ventr drain - Shunt may + risk of ipsilateral hearing decrease - Suboccipital Craniotomy - NTR: <1.5cm 2 residual on postop MRI - STR: 51-90% resection Timeline H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16 J Clin Oncol. 1999 Mar;17(3):832-45. Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study. Zeltzer PM, Boyett JM, Li H, Wisoff JH, Geyer JR, McGuire-Cullen P, Stehbens JA, Shurin SB, Packer RJ.
    11. 14. Surgical Management Does Extent of Resection Matter? Timeline H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16 J Clin Oncol. 1999 Mar;17(3):832-45. Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study. Zeltzer PM, Boyett JM, Li H, Wisoff JH, Geyer JR, McGuire-Cullen P, Stehbens JA, Shurin SB, Packer RJ. - 5yr EFS (-) in STR vs. GTR (54 vs 78%)
    12. 15. Surgical Management Timeline H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16 J Clin Oncol. 1999 Mar;17(3):832-45. Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study. Zeltzer PM, Boyett JM, Li H, Wisoff JH, Geyer JR, McGuire-Cullen P, Stehbens JA, Shurin SB, Packer RJ.
    13. 16. <ul><li>Sequelae </li></ul><ul><li>- Asceptic Meninigitis </li></ul><ul><li>- CSF Leak </li></ul><ul><li>- 15-25% Posterior Fossa Syndrome </li></ul><ul><ul><li>Mutism, ataxia, dysphagia, hypotonia, mood lability </li></ul></ul><ul><ul><li>Monitor 24-48 hrs post resection </li></ul></ul><ul><ul><li>Permanent in 50% </li></ul></ul>Timeline H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16
    14. 17. <ul><li>Staging </li></ul><ul><li>- M stage most prognostic </li></ul><ul><li>- CSF should be assessed 10-14 d post-op </li></ul><ul><li>Risk Stratification </li></ul><ul><li>- Standard Risk – 5 yr EFS 80% </li></ul><ul><li>>3yoa, GTR/NTR <1.5cm 2 Resid & M0 </li></ul><ul><li>- High Risk – 5 yr EFS 60% </li></ul><ul><ul><li><3yoa, unresectable/STR </li></ul></ul><ul><ul><li>or >1.5cm2 residual, &/or M+ </li></ul></ul><ul><li>Prognosis </li></ul><ul><li>- f(x) of risk, histology, and M stage </li></ul>
    15. 18. Timeline – Standard Risk H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16 d18-31 CSI 23.4 Gy cc/w qwk Vincristine Cone Down to Posterior Fossa to 36 Gy d18-22 Cone Down to R-Cavity/Resid Dz or PF to 55.8Gy d18-31 d18-31 8C q6wk Adj Cis/CCNU/Vinc d31-367 H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16 Timeline – High Risk d18-31 CSI 36 Gy cc/w qwk Vincristine Cone Down to Posterior Fossa to 36 Gy d18-22 Cone Down to R-Cavity/Resid Dz or PF to 55.8Gy d18-31 d18-31 8C q6wk Adj Cis/CCNU/Vinc d31-367 Timeline – <3 yoa H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection, & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16 Cytox/Vinc/MTX/ Carbo/VP-16/IT MTX d18-3 yoa Salvage RT or Re-Resection d12-16
    16. 19. 1969 Bloom et al at Royal Marsden J Clin Oncol. 2000 Aug;18(16):3004-11. Low-stage medulloblastoma: final analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation. Thomas PR, Deutsch M, Mulhern R, Stehbens JA, Langston J, Stanley P, Duffner P, Rorke L, Cherlow J, Friedman HS, Finlay JL, Vietti TJ, Kun LE.hue BR, Marymont MH, Muraszko K, Langston J, Sposto R. <ul><li>Role of Radiotherapy: Historical Perspective </li></ul><ul><li>Original series from Cushing & Baylor </li></ul><ul><li>showed only 1/61 survivors w/surgery alone </li></ul><ul><li>Addition of Adj RT from 1969 Royal </li></ul><ul><li>Marsden showed 25% OS @ 10 yrs w/CSI </li></ul><ul><li>Historical dose was CSI to 36 Gy w/cone </li></ul><ul><li> down to PF to 50-54 Gy </li></ul><ul><li>Single most effective tx for MB, however </li></ul><ul><ul><li>sequelae have changed dosing & fields </li></ul></ul>
    17. 20. Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children's Cancer Group study. Ris MD, Packer R, Goldwein J, Jones-Wallace D, Boyett JM. J Clin Oncol. 2001 Aug 1;19(15):3470-6. Medulloblastoma in childhood: progressive intellectual deterioration. Hoppe-Hirsch E, Renier D, Lellouch-Tubiana A, Sainte-Rose C, Pierre-Kahn A, Hirsch JF. Childs Nerv Syst. 1990 Mar;6(2):60-5. <ul><li>Role of Radiotherapy: Sequelae </li></ul><ul><li>Moya moya syndrome </li></ul><ul><ul><li>Incidence ranges widely </li></ul></ul><ul><li>- Secondary Malignancies </li></ul><ul><li>- Cognitive impairment (Limit temporal lobe dose!) </li></ul><ul><li>- Predictors: <7 yoa most imp, dose, high IQ, F>M </li></ul><ul><li>- Rate: Falls for >5 yrs depending on age at dx </li></ul><ul><li>- If < 7 yoa @ tx then 5points/yr </li></ul><ul><li>- If > 7yoa @ tx then 1 point/yr </li></ul><ul><li>- Endocrine: (-) GH->(-) growth (threshold ~10 Gy) </li></ul><ul><li>- Thyroid </li></ul><ul><li>- Carotid Artery Stenosis </li></ul><ul><li>- Ototoxicity </li></ul>
    18. 21. Timeline – Standard Risk H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16 d18-31 CSI 23.4 Gy cc/w qwk Vincristine Cone Down to Posterior Fossa to 36 Gy d18-22 Cone Down to R-Cavity/Resid Dz or PF to 55.8Gy d18-31 d18-31 8C q6wk Adj Cis/CCNU/Vinc d31-367 J Clin Oncol. 2000 Aug;18(16):3004-11. Low-stage medulloblastoma: final analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation. Thomas PR, Deutsch M, Mulhern R, Stehbens JA, Langston J, Stanley P, Duffner P, Rorke L, Cherlow J, Friedman HS, Finlay JL, Vietti TJ, Kun LE.hue BR, Marymont MH, Muraszko K, Langston J, Sposto R. Goal: Reduce CSI dose related neuro/endo/cognitive sequelae of RT 126 Patients age 3-21 w/ M0 MB - RT: CSI to 23.4Gy w/PF boost to 55.8Gy vs. CSI 36Gy w/ PF boost to 54Gy - No Concurrent w/1.5mg/m2 Vinc qwk x 8C - No Adj Chemo Outcome: SS Diff in 5 yr EFS 67% (36Gy) vs. 52% (23.4Gy) - Trial stopped early Role of Radiotherapy: Dose POG 8631 CCG 923
    19. 22. Timeline – Standard Risk H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16 d18-31 CSI 23.4 Gy cc/w qwk Vincristine Cone Down to Posterior Fossa to 36 Gy d18-22 Cone Down to R-Cavity/Resid Dz or PF to 55.8Gy d18-31 d18-31 8C q6wk Adj Cis/CCNU/Vinc d31-367 Eur J Cancer. 1990 Apr;26(4):464-9. Adjuvant chemotherapy for medulloblastoma: the first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I). Tait DM, Thornton-Jones H, Bloom HJ, Lemerle J, Morris-Jones P. Goal: Improve EFS w/Chemo? 286 Patients age 3-21 w/ M0 MB - RT: CSI to 36 Gy w/PF boost to 55.8Gy - (+/-) Concurrent : w/1.5mg/m2 Vinc qwk x 8C - (+/-) Adj Chemo: Vinc/CCNU Outcomes: - Similar to CCG 942 - 5 yr EFS ~ Equivalent ** No benefit to Adj Chemo - Subgroup benefit in STR, brainstem dz, >T3 dz Role of Radiotherapy: RT + Adj Chemo SIOP 1
    20. 23. Timeline – Standard Risk H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16 d18-31 CSI 23.4 Gy cc/w qwk Vincristine Cone Down to Posterior Fossa to 36 Gy d18-22 Cone Down to R-Cavity/Resid Dz or PF to 55.8Gy d18-31 d18-31 8C q6wk Adj Cis/CCNU/Vinc d31-367 Eur J Cancer. 1990 Apr;26(4):464-9. Adjuvant chemotherapy for medulloblastoma: the first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I). Tait DM, Thornton-Jones H, Bloom HJ, Lemerle J, Morris-Jones P. <ul><li>Multiple Interval Studies: </li></ul><ul><li>SIOP II : tried to decrease CSI dose from 35 to 25 Gy adding adj chemo </li></ul><ul><ul><li>Worse EFS and KPS/QOL following CSI+Adj Chemo compared to CSI </li></ul></ul><ul><li>HIT 91 : compared order of RT vs. Chemo </li></ul><ul><ul><li>EFS SS in RT immediate post-Op group </li></ul></ul><ul><li>-CCG 9892 : Pilot trying 23.4Gy CSI w/CC (Vinc) +Adj.Chemo (CCNU/Cis/Vinc) </li></ul><ul><li>- Equivalent EFS, OS relative to historical controls w/ 36 Gy CSI </li></ul>Role of Radiotherapy: RT + Adj Chemo
    21. 24. Timeline – Standard Risk H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16 d18-31 CSI 23.4 Gy cc/w qwk Vincristine Cone Down to Posterior Fossa to 36 Gy d18-22 Cone Down to R-Cavity/Resid Dz or PF to 55.8Gy d18-31 d18-31 8C q6wk Adj Cis/CCNU/Vinc d31-367 Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol. 2006 Sep 1;24(25):4202-8. Packer RJ, Gajjar A, Vezina G, Rorke-Adams L, Burger PC, Robertson PL, Bayer L, LaFond D, Donahue BR, Marymont MH, Muraszko K, Langston J, Sposto R. Goal: Replace CCNU w/Cytox 2/2 limited activity in MB 421 Patients age 3-21 w/ M0 MB - RT: CSI to 23.4Gy w/PF boost to 55.8Gy - Concurrent w/1.5mg/m2 Vinc qwk x 8C - Adj : CCNU/ Cis /Vinc vs. Cytoxan/ Cis /Vinc Outcomes: Equivalent EFS, OS - SS diff in G3/4 Tox + in Cytoxan group Role of Radiotherapy: CC ChemoRT+Adj Chemo CCG A9961
    22. 25. Role of Radiotherapy: Cone Down to >50 Gy Goal: Assess efficacy of HD RT to the PF & LD RT to the spinal axis, - Retrospective - 60 patients w/bx-proven MB treated at JCRT from 1968-1984. Outcome: - >50Gy ~ 79% LC vs. <50Gy ~ 33% LC ( P < 0.02) Timeline – Standard Risk H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16 d18-31 CSI 23.4 Gy cc/w qwk Vincristine Cone Down to Posterior Fossa to 36 Gy d18-22 Cone Down to R-Cavity/Resid Dz or PF to 55.8Gy d18-31 d18-31 8C q6wk Adj Cis/CCNU/Vinc d31-367 Hughes EN ,  Shillito J ,  Sallan SE ,  Loeffler JS ,  Cassady JR ,  Tarbell NJ . Cancer.  1988 May 15;61(10):1992-8. Medulloblastoma at the joint center for radiation therapy between 1968 and 1984. The influence of radiation dose on the patterns of failure and survival.
    23. 26. H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16 Timeline – High Risk d18-31 CSI 36 Gy cc/w qwk Vincristine Cone Down to Posterior Fossa to 36 Gy d18-22 Cone Down to R-Cavity/Resid Dz or PF to 55.8Gy d18-31 d18-31 8C q6wk Adj Cis/CCNU/Vinc d31-367 Role of Radiotherapy: High Risk Dz - Unresectable/STR or >1.5cm2 residual, &/or M+ - Immediate Post RT 2/2 HIT 91 - If M2 or M3 then, - 50.4Gy to intracranial mets - 50.4 Gy boost to focal spinal mets below cauda equina - 45 Gy above cauda equina - 39.6 Gy to diffuse spinal disease
    24. 27. Timeline – <3 yoa H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection, & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16 Cytox/Vinc/MTX/ Carbo/VP-16/IT MTX d18-3 yoa Role of Radiotherapy: <3 yoa Delay RT w/Chemo Goal: Delay RT till 3 yoa in order to (-) RT sequelae in malignant brain tumors 198 patients all <3yo at dx, Any M stage 31% MB  38% GTR, 62% STR Baby POG1 Salvage RT or Re-Resection d12-16 N Engl J Med. 1993 Jun 17;328(24):1725-31. Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. Duffner PK, Horowitz ME, Krischer JP, Friedman HS, Burger PC, Cohen ME, Sanford RA, Mulhern RK, James HE, Freeman CR, et al.
    25. 28. Timeline – <3 yoa H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection, & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16 Cytox/Vinc/MTX/ Carbo/VP-16/IT MTX d18-3 yoa Role of Radiotherapy: <3 yoa Delay RT w/Chemo Baby POG1 Salvage RT or Re-Resection d12-16 N Engl J Med. 1993 Jun 17;328(24):1725-31. Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. Duffner PK, Horowitz ME, Krischer JP, Friedman HS, Burger PC, Cohen ME, Sanford RA, Mulhern RK, James HE, Freeman CR, et al. - 60-70% ended up requiring RT, re-resection 2/2 progression @ 1-2 yrs
    26. 29. Timeline – <3 yoa H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection, & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16 Cytox/Vinc/MTX/ Carbo/VP-16/IT MTX d18-3 yoa Role of Radiotherapy: <3 yoa Delay RT w/Chemo Baby POG1 Salvage RT or Re-Resection d12-16 N Engl J Med. 1993 Jun 17;328(24):1725-31. Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. Duffner PK, Horowitz ME, Krischer JP, Friedman HS, Burger PC, Cohen ME, Sanford RA, Mulhern RK, James HE, Freeman CR, et al. Toxicity: - G5 Tox in 4 kids - 50% w/Hemorrhagic Cystitis - >90% N/V - 26% Ototoxicity (hearing loss) - Growth stunting SS - 2 Tx Related secondary malignancies - No SS impact on NeuroCog f(x) in 34 kids assessed
    27. 30. Timeline – <3 yoa H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection, & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16 Cytox/Vinc/MTX/ Carbo/VP-16/IT MTX d18-3 yoa Role of Radiotherapy: <3 yoa PostOp Chemo only 43 patients all <3yo at dx, Any M stage Goal: Chemo alone for 3 yoa German PBT Study Group Salvage RT or Re-Resection d12-16
    28. 31. Timeline – <3 yoa H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection, & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16 Cytox/Vinc/MTX/ Carbo/VP-16/IT MTX d18-3 yoa Role of Radiotherapy: <3 yoa PostOp Chemo only <ul><li>- Patients w/<GTR had marked (-) in EFS, OS </li></ul><ul><li>44% ended up needing salvage RT (mostly classic) </li></ul><ul><li>- Of 31 w/M0 dz, 10 required RT for salvage </li></ul><ul><li>- Of 12 w/>M1 dz, 9 received RT for salvage </li></ul>
    29. 32. Timeline – <3 yoa H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection, & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16 Cytox/Vinc/MTX/ Carbo/VP-16/IT MTX d18-3 yoa Role of Radiotherapy: <3 yoa PostOp Chemo only Conclusion - At <3 yoa c/s delay RT is poss - At 3 yoa c/s CSI & Adj Chemo - If desmoplastic then may avoid RT altogether - Intra Ventricular chemo not w/o neuro/cognitive sequelae - 44% w/i Ventricular chemo got w/leukencephalopathy
    30. 33. Radiotherapy: Techniques CSI: - Goal: deliver a uniform dose throughout the subarachnoid space encompassing the entire intracranial vault & spinal canal - Setup: Prone vs. Supine Prone - Prone on a torso cushion or alpha cradle - Hyperextend neck w/head immobilized w/an aquaplast immobilization device Supine - Thermoplastic Mask - Supine on flat body cushion w/legs on combifix +++ + Anesthesia Possible (-) + Allows Field Matching +++ ++ Comfort Supine Prone
    31. 34. Radiotherapy: Techniques CSI: - Simulate Spine 1 st - Allows calculation of collimator angle for cranial fields - Spine borders: Sup: C2 Inf: inf S2 (end of thecal sac) Lat: 1cm lat to pedicles - May avoid multiple spinal fields by rotating collimator or + SSD - Field Length: If <35 cm use 100cm SSD, if >35 cm then 120 cm SSD - OARs: optic structures, lenses, mandible, thyroid gland, lung, heart, liver, kidneys and small bowel
    32. 35. Radiotherapy: Techniques CSI: - Multiple Spinal Fields: - If multiple spinal fields, then match at depth of mid spinal cord - Inf spinal field should have iso @ sup border of field to ½ beam block - Match fields at L1-L2 region as depth changes most here - Skin Gap = ([0.5 x Length x d]/ SSD1) + ([0.5 x length 2 x d]/SSD2)
    33. 36. Radiotherapy: Techniques CSI: - Simulate Head 2 nd - Borders: Sup: flash skin Inf: 0.5-1cm cribiform plate Ant: 1cm ant vertbrl bodies Post: 2-2.5cm post to eye - Collimator Angle: i.e. matching divergence of spinal fields = arctan (½ length of Sup Spine field / SSD) - Couch Angle: i.e. match diverging cranial fields = arctan (½ length cranial field / SAD) - OARs- pituitary, optics, lenses, mandible, thyroid gland - Tx fields: opposed lateral cranial fields
    34. 37. Radiotherapy: Techniques CSI: Gap Shifting/Feathering - Every 9 Gy: Extend inf cranial field inf by 1 cm Shift upper spinal field inf by 1 cm Shorten lower spine field by 1 cm - Cranial Iso stays in same spot, Spine Iso and inf jaw moves - Recalculate Couch Angle EACH TIME
    35. 38. Radiotherapy: Techniques CSI:
    36. 39. Radiotherapy: Techniques Posterior Fossa Boost: - Use 3D CRT and MR planning
    37. 40. Radiotherapy: Techniques
    38. 41. Radiotherapy: Techniques
    39. 42. Radiotherapy: Techniques
    40. 43. Current Trials: PF vs. IFRT Boost Phase III Randomized Standard-Dose vs. Reduced-Dose CSI and PF Boost vs IFRT in Comb/ w/Vinc,Cis,Lomustine , & Cytoxan in kids w/Newly Dx’d Standard-Risk MB . COG-ACNS0331 , ACNS0331, NCT00085735 Population:  3 to 7 yrs, Standard Risk MB Intervention: 2 randomizations -Standard-dose vs reduced-dose CSI (18Gy) concurrent w/Vinc -PF boost vs tumor bed boost -Adjuvant Vinc/Cis/Lomustine/Cytoxan 1 o Outcomes: EFS & OS 2 o Outcomes: - Patterns of failure -Cognitive, auditory, & endocrinologic effects -Compare the audiologic and endocrinologic toxicity -Develop prognostic gene expression signature -Assess QOL & KPS pre&post tx
    41. 44. Current Trials: Protons vs. Photons Proton Beam Radiotherapy for Medulloblastoma and Pineoblastoma Phase:  Phase II Age:  3 to 25 Protocol IDs: 09-361 , P01CA021239, NCT01063114
    42. 45. Current Trials: Radio-immunotherapy <ul><li>Phase II Pilot Study of Post-Op Intrathecal Radioimmunotherapy , Reduced-Dose CSI w/IMRT Boost, & Chemo in Standard-Risk MB MSKCC-02088 , NCT00058370 </li></ul><ul><li>I ntrathecal I 131 MAb 3F8 (anti-GD2 ganglioside MAb on d1-8. </li></ul><ul><li>Following above-> EBRT/IMRT concurrent w/ Vinc IV qwk for 8 wks </li></ul><ul><li>6 wks s/p RT (4 weeks after vincristine), patients receive </li></ul><ul><li>Cis, Lomustine, Vincristine </li></ul><ul><li>Tx rpts q6 wks for up to 8C if no progression </li></ul>
    43. 46. Treatment: Current Trials- Hyperfractionated Phase 3 Multi -Protocol Study of Conv Reduced-Dose or Hyperfx’d RT & Combo Chemo in kids w/IC MB, Supratentorial PNET, or Ependymoma GPOH-HIT-2000 , EU-205105, NCT00303810 Protocol HIT-2000-AB4 ≥ 4 yoa @ Dx w/M0 MB - Hyperfx’d RT vs. Conv reduced-dose RT  Adj Vinc, lomustine, & Cis Protocol HIT-2000-BIS4 < 4 yoa @ Dx w/M0 MB - 5C of cytoxan, vinc, mtx, carbo, etop, & IT mtx - If Residual dz s/p 3C  undergo conv fx’d reduced-dose RT Protocol MET-HIT-2000-AB4 ≥ 4 yoa @ Dx w/M+ MB - 2C of BIS4 Chemo  Hyperfx’d RT & receive AB4 Chemo - (+) OR to chemo BIS4  HD chemo Protocol MET-HIT-2000-BIS4 < 4 yoa @ dx w/M+ MB - 2-4C of carbo/etop IV contin over 96 hrs - (+) OR  HD carbo/etop/cytoxan & thiotepa - If Residual dz  Conv fx’d reduced-dose radiotherapy
    44. 47. Current Trials: High Risk MB Evaluating HD Chemo w/PBSCT support in high risk patients: High Risk Primitive Neuroectodermal (PNET) Brain Tumors in Childhood . P hase:  Phase II Age:  10 and under Protocol IDs: PNET HR , NCT00180791 Total Marrow Irradiation Added to an Alkylator -Intense Conditioning Regimen for Patients With High Risk or Relapsed Solid Tumors Phase:  Phase I Age:  70 and under Protocol IDs: 2005LS023 , UMN-MT2004-30, 0504M69306, UMN-2005LS023, NCT00623077 Phase III Randomized Study of Standard CRT w/or w/out Carbo Followed by Standard Maint Tx w/or w/out Isotretinoin & Continuation Tx w/ Isotretinoin vs No Continuation Tx in Pediatric Patients With Newly Diagnosed, Previously Untreated, High-Risk MB or Supratentorial PNET . COG-ACNS0332 , ACNS0332, NCT00392327
    45. 48. Treatment: Current Trials Risk-Adapted Therapy for Young Children With Embryonal Brain Tumors, Choroid Plexus Carcinoma or Ependymoma Phase:  No phase specified A ge:  Under 3 at diagnosis Protocol IDs: SJYC07 , SJCRH-SJYC07, NCT00602667
    46. 49. End
    47. 50. Timeline – Standard Risk H&P Labs MRI Brain/Spine Ancillary Tests Presentation Surgical Bx, Resection & or Shunt d0 d1 d2 d3-4 Post op MRI Brain MRI Spine CSF Cytology d12-16 d18-31 CSI 23.4 Gy cc/w qwk Vincristine Cone Down to Posterior Fossa to 36 Gy d18-22 Cone Down to R-Cavity/Resid Dz or PF to 55.8Gy d18-31 d18-31 8C q6wk Adj Cis/CCNU/Vinc d31-367 J Clin Oncol. 1999 Jul;17(7):2127-36. Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group Study. Packer RJ, Goldwein J, Nicholson HS, Vezina LG, Allen JC, Ris MD, Muraszko K, Rorke LB, Wara WM, Cohen BH, Boyett JM. Goal: Reduce CSI dose related neuro/endo/cog sequelae of RT w/Adj Chemo 65 Patients age 3-10 w/M0 MB - RT: CSI to 23.4Gy w/PF boost to 55.8Gy - Concurrent w/1.5mg/m2 Vinc qwk x 8C - Adj : CCNU/ Cis /Vinc Outcomes: Equivalent EFS, OS relative to historical controls w/ 36 Gy CSI Role of Radiotherapy: CC ChemoRT+Adj Chemo CCG 9892
    48. 52. CCSG 942 (Evans et al., J Neurosurg 1990;72:572-582 )
    49. 53. CCSG 942 cont. <ul><li>311 pts from 6/1975-7/1981 </li></ul><ul><ul><li>233 medulloblastoma, 88 ependymoma </li></ul></ul><ul><li>Surgery  (RT + V)  CCNU/V/Prednisone </li></ul><ul><li>RT: 35-40Gy CSI with 50-55Gy to Posterior fossa </li></ul>
    50. 54. CCSG 942 cont. <ul><li>5yr PFS: 59% (RT+Chemo) to 50% (RT) [not sig.] </li></ul><ul><li>5yr OS: 65% for both groups </li></ul>
    51. 55. CCSG 942 cont. <ul><li>5yr PFS </li></ul><ul><li>Low Risk: </li></ul><ul><ul><li>Addition of chemo did not help (65% vs. 60%) </li></ul></ul>
    52. 56. CCSG 942 cont. <ul><li>High Risk: </li></ul><ul><ul><li>Addition of chemo with significant reduction of 5yr PFS (46% vs. 0%) [p=0.006] </li></ul></ul>
    53. 57. SIOP I cont. <ul><li>71% vs. 53% (p=0.007) 53% vs. 48% (p ns) </li></ul>
    54. 58. SIOP II (Bailey et al., Med Pediatr Oncol 1995;25:166-178) <ul><li>Sandwich therapy </li></ul><ul><ul><li>High Risk: Surgery  CCNU/Procarbazine/MTX  RT (35Gy CSI and 55Gy to post fossa)  CCNU/V </li></ul></ul><ul><ul><li>Low Risk: Surgery  CCNU/Procarb/MTx  randomized to 35Gy vs. 25 Gy CSI </li></ul></ul><ul><li>No stastistical differences in any group </li></ul>
    55. 59. SIOP II cont. <ul><li>CSI Chemo 5yr PFS </li></ul><ul><li>35Gy neg 60% </li></ul><ul><li> pos 75% </li></ul><ul><li> 25Gy neg 69% </li></ul><ul><li> pos 41% (p=0.07) </li></ul>
    56. 60. SIOP I cont. <ul><li>Benefit of chemo for high risk group </li></ul><ul><li>58% vs 25% (P<0.005) 52.1% vs. 33.3% (P<0.01) </li></ul>
    57. 61. SIOP I cont. <ul><li>48% vs. 25% (P=0.002) </li></ul>
    58. 62. Packer et al. (Packer et al., J Neurosurg 81:690-698,1994) <ul><li>RT + cisplatin/CCNU/vincristine </li></ul>
    59. 63. Packer et al. cont. <ul><li>63 pts from 1983-1991: 85% 5yr PFS </li></ul>
    60. 64. Packer et al. <ul><li>Reduced dose as good for reduced dose for low risk group: 83% for both groups for 5yr actuarial survival rate </li></ul>

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