The document discusses the treatment of medulloblastoma, a type of brain tumor. It provides details on the role of radiotherapy in treatment, including: 1) Radiotherapy has historically been the most effective treatment when combined with surgery, improving survival rates from 1 in 61 to 25% at 10 years with craniospinal irradiation. 2) Several studies evaluated reducing craniospinal irradiation doses and adding chemotherapy, finding equivalent survival but reduced side effects. 3) Current standard treatment involves 23.4Gy craniospinal irradiation with chemotherapy, followed by a posterior fossa boost to 55.8Gy.

1. John T. Lucas Jr. Resident - Radiation Oncology Wake Forest University North Carolina Baptist Medical Center

3. Blue rubber bleb nevus - 15 mo M Photo courtesy of Johns Hopkins University School of Medicine dermatlas 2001.

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)

11. Differential?

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

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.

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%)

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.

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

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

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

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

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.

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

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.

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

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

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

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

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

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

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)

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

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

38. Radiotherapy: Techniques CSI:

39. Radiotherapy: Techniques Posterior Fossa Boost: - Use 3D CRT and MR planning

40. Radiotherapy: Techniques

41. Radiotherapy: Techniques

42. Radiotherapy: Techniques

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

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

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

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

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

49. End

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

52. CCSG 942 (Evans et al., J Neurosurg 1990;72:572-582 )