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The Evolution of Radiation for HN Rhabdomyosarcoma

Objectives. BackgroundRole of Radiation in Orbital and Parameningeal RMSIRS IV

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The Evolution of Radiation for HN Rhabdomyosarcoma

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    1. The Evolution of Radiation for H&N Rhabdomyosarcoma Parag Sanghvi Department of Radiation Medicine September 20 2006

    2. Objectives Background Role of Radiation in Orbital and Parameningeal RMS IRS IV – Radiation IRS V – Impact of radiation dose reduction

    3. Rhabdomyosarcoma Highly malignant neoplasm arising from embryonal mesenchyme With capacity for skeletal muscle differentiation

    4. Intergroup Rhabdomyosarcoma Study Group COG, CCG, POG IRS I (1972 – 1978) OS 55% IRS II (1978 – 1984) OS 63% IRS III (1984 – 1991) OS 71% IRS IV (1991 – 1997) OS 71% IRS V (1998 – present)

    5. Epidemiology Most common pediatric STS (approximately 50%) 3.5% of all malignancies under age of 15; 2% of all malignancies in 15-19 age group 90 % of all RMS in individuals < 25 years; 60-70% in <10 years Peak age 2- 5 years Incidence in US – 250 cases / year Male preponderance (1.4:1) Racial predisposition (White children 4 times as likely as black children)

    6. Epidemiology 1/3 of RMS patients have other congenital abnormalities GI, GU, CV, CNS Majority of cases are sporadic; but some are associated with genetic conditions Li Fraumeni (p53 mutation) NF 1 Beckwith - Wiedemann

    7. Prognostic Factors Histology Stage Primary site (most important prognostic factor) Tumor Size LN involvement (especially in extremities) Metastatic disease Group Extent of resection Age < 1 and alveolar histology >10 Skull base erosion, CN palsy, Intracranial extension

    8. Histology Gross disease Soft, fleshy tumors with variation in the extent of invasion and necrosis IHC stains to ascertain muscle of origin Antidesmin, antivimentin, anti-muscle specific actin Anti-Myo D Ab

    9. Histology Embryonal Most common 60-70% of all childhood RMS H&N, GU sites Intermediate prognosis Boytroid Subtype of embryonal 10% of all childhood RMS Bladder, vagina, nasopharynx, nares, middle ear, biliary tree Superior prognosis Spindle cell Subtype of embryonal Most common site is paratesticular Superior Prognosis Alveolar 20% of RMS More common in adolescents Tumors involving extremities, trunk, perianal and perineal Undifferentiated Diagnosis of exclusion Previously called pleiomorphic Rare in children, more common in adults

    10. Histology and Survival

    11. Histology and Survival

    12. Staging (based on IRS – V) Stage I Sites Orbit H&N (excluding parameningeal) GU (non-bladder, non-prostate) Biliary tract Tumor invasiveness: T1 or T2 Tumor Size: a or b Lymph node status: any N Metastasis: M0 (T1: confined to anatomic site of origin; T2: extension; a: <5 cm in diameter; b: >5 cm in diameter; N0: no clinically involved LN; N1: clinically involved LN; M1: metastasis present)

    13. Stage II Stage II Sites Parameningeal Nasopharynx/Nasal Cavity Middle Ear and Mastoid region Paranasal Sinuses Infratemporal fossa Pterygopalatine fossa Parapharyngeal space Bladder or Prostate Extremity Stage II Tumor Invasiveness: T1 or T2 Tumor size: a Lymph node status: N0 or Nx Metastasis: M0

    14. Stages III & IV Stage III Sites: Same as Stage II Tumor Invasiveness: T1 or T2 Tumor size and Lymph Node status a N1 b any N Metastasis: M0 Stage IV Sites: All Metastasis: M1

    15. Site of primary tumor

    16. Lymph Node Metastasis IRS I & II

    17. Group Group I: Localized dz; completely resected A. Confined to muscle or organ of origin B. Outside infiltration Group II: Gross Total Resection A: With microscopic residual disease B: Regional lymphatic spread, resected C: Both

    18. Group Group III: Incomplete resection with gross residual disease A: After biopsy only B: After major resection (more than 50%) Group IV: Distant metastases @ diagnosis

    19. Group

    20. Histology, Stage and Group vs. Survival

    21. Cytogenetics Alveolar Rhabdomyosarcoma T(2,13)(p35;q14) 70% of all alveolar RMS Fuses PAX3:FKHR T(1,13)(p36:q14) 20% all alveolar RMS Fuses PAX7:FKHR Occurs in younger children, better prognosis Genomic amplification MDM2, CDK4 Near-tetraploidy

    22. Cytogenetics Embryonal Rhabdomyosarcoma Loss of heterozygosity at 11p15.5 Loss of amplification Hyperploidy Cell cycle control Myogenesis = Mesenchymal fibroblast ? Skeletal muscle Controlled by MyoD protein family (Myogenin, MYF5, MYF6) Can stain RMS cells with anti-MyoD Ab Tumor Suppressor Genes P53 mutation Protooncogenes N-myc amplification Especially seen in alveolar histology

    23. The Role of Radiation Therapy in Orbital and Parameningeal Rhabdomyosarcoma

    24. Orbital RMS

    25. Orbital RMS 9% of all RMS Most common single H&N site Usually diagnosed early; presents with eye swelling, globe displacement 2/3 of cases are Group III Can invade meninges via SOF 84% Embryonal; 10% Alveolar 5 y OS for Embryonal 94%; for Alveolar 74%

    26. Histology and Survival

    27. Historical management Orbital Exenteration was standard treatment until mid 1960s High rate of local failure Poor survival Late 1960s, Cassady et al. showed that RT after biopsy offered local control in 4/5 patients

    28. Orbital RMS IRS I Group I patients randomized to VAC +/- RT Group II VA + RT +/- C Group III/IV VAC + RT +/- Adriamycin Pts with Group II or III disease 85-94% OS @ 6 years 5 y OS 89%; 3/6 deaths 2/2 other causes Complete or Partial surgical excision no longer recommended standard of care

    29. Orbital RMS IRS II Group I VA or VAC (no RT) Group II VA + RT +/- C Group III VAC +RT +/- Adriamycin No improvement in any of the more intensive chemotherapy arms OS/FFS better in all arms compared to IRS I

    30. Orbital RMS IRS III Group I VA only Groups II and III, VA +RT No difference in OS or FFS compared to IRS II 3 y/o FFS 92% and OS 100% IRS IV Group I VA only Group II VA + CD RT Group III VAC vs. VAI vs. VIE AND CD RT vs. HF XRT RT doses 50.4 Gy vs. 59.4 Gy Groups I & II pts. 3 y FFS 91%, OS 100% (no change compared to IRS III

    31. Orbital RMS IRS IV Group III, 3 y FFS 94%, OS 98% No difference in the 3 chemotherapy arms or the 2 RT arms However, when compared to IRS III, pts. with 3 drug chemotherapy regimens did better than VA regimen IRS V Due to concern for treatment related toxicities Chemotherapy C/I/E dropped; back to VA RT dose decreased to 45 Gy

    32. SIOP MMT 84 trial Evaluated eliminating radiation in Group II/III patients 34 patients treated initially with VA alone RT reserved for those who did not achieve a complete response 22 patients initially did not get radiation ? 11 failed locally 10/11 salvaged with RT + chemotherapy 3/11 developed distant mets ? 2 died 4 y/o EFS 62%; 4y/o OS 84%

    33. Orbital RMS

    34. Conclusions Total surgical extenteration no longer standard of care Chemotherapy alone in Group I patients is effective Chemo + RT for Group II and III patients Future trend for RT Dose reduction Electrons, Protons IMRT treatment planning

    35. Parameningeal RMS

    36. Parameningeal RMS

    37. Parameningeal RMS 16 % of all RMS 41 % of all H&N RMS Most cases in children < 8 -10 years of age Can extend intra-cranially and produce neoplastic meningitis (35% of all PM RMS) <20% have LN involvement (IRS III) Most have favorable histology (Embryonal: Alveolar 4:1)

    38. Parameningeal RMS Meningeal penetration and leptomeningeal tumor cell seeding must be assessed Complete surgical extirpation almost never possible 76% are Group III (IRS III) Hence, surgery is generally either a biopsy or subtotal resection

    39. Parameningeal RMS - Sites Nasal Cavity/Nasopharynx/Paranasal Sinuses ? can invade through basal foramina, sinus roofs Middle Ear ? can extend through tegmen tympani into the middle cranial fossa or through posterior mastoid into the posterior cranial fossa Parapharyngeal space Pterygopalatine / Infratemporal fossa

    40. PM RMS IRS I 3 y PFS 46% Orbit 91 % Non-PM H&N 75% Meningeal extension occurred in 35% of cases at a median time of 5 months after diagnosis Meningeal extension was likely fatal 90% Associated with inadequate margins and doses < 50 Gy

    41. PM RMS – IRS II -III IRS II Increase field size to sequential CSI for patients with any meningeal extension Local + WBRT – Wk 0 Spinal RT – Wk 6 Dose age and tumor size dependent 40 –55 Gy IRS II (1980 – 1984) and IRS III (1984 – 1987) Omit spinal irradiation; WBRT for any meningeal extension Start @ Wk 0 Dose age and tumor size dependent 41.4 – 50.4 Gy

    42. PM RMS – IRS IV IRS IV Pilot (1987 –1991) Local XRT for CNP or CBBE – Wk 0 WBRT for ICE – Wk 0 IRS IV (1991 – 1997) Local XRT for any meningeal extension Dose For Group III disease, RT question was about hyperfractionation 59.4 Gy (1.1 Gy bid) vs. 50.4 Gy

    43. PM RMS – IRS II - IV

    44. PM RMS – IRS II - IV

    45. Primary Site

    46. Primary Site and Meningeal Involvement

    47. Prognostic Factors – 5 y FFS Age <1 46% 1-9 73% 10+ 54% Primary Site NP/NC 74% Ear/Mas 73% PPS 72% PNS 57% PPF/ITF 53% Meningeal Involvement None 77% CNP/CBBE 65% Any ICE 60% Histology Emb/Boy 70% Alv/Und 59% Other 65% Tumor Size <5 cm 71% >5 cm 67%

    48. 5 y/o FFS & OS by Meningeal involvement

    49. 5 y FFS and OS by Histology and Meningenal Involvement

    50. Timing of RT in patients with meningeal involvement

    51. Timing of RT in patients with ICE

    52. LF vs. FFS and Meningeal Involvement

    53. Local Failure by Radiation Dose

    54. Did people really get WBRT?

    55. Local Failure and Radiation Fields

    56. CNS Failure and Radiation Fields

    57. Multivariate analysis Statistically significant worse prognostic factors controlling for tumor size Age > 10 (p = 0.002) RT dose <47.5 Gy (p = 0.01) Meningeal Impingement (p =0.001) Timing of RT was NOT a significant factor

    58. Conclusions Availability of cross-sectional imaging improved ability to diagnose ICE and hence led to better treatment planning and earlier delivery of RT Patients with tumors > 5 cm benefited from dose > 47.5 Gy WBRT not necessary to achieve high control rates; but good planning is! Timing of RT – impacted LF rates but not FFS; not significant on multivariate analysis

    60. Background IRS II and IRS III showed local relapse rate of 16% and LR relapse rate of 32 % respectively in Group III patients RCT comparing hyperfractionation vs. conventional fractionation in Group III patients Hyperfractionation = More than 1 fraction a day Goal to improve LCR by 10% without increasing late side effects Rationale based on 10-15% improvement seen in LRC in other H&N cancers in adults with HF

    61. Criteria / Treatment Logistics Stage 1, 2, and 3 and Group III patients CF = 50.4 Gy in 1.8 Gy/fraction given daily HF = 59.4 GY in 1.1 Gy/fraction given bid atleast 6 hours apart Pre-op/Pre-chemo volume + 2 cm margin RT started week 9 or week 0 if cord compression or any meningeal involvement

    62. Results – OS and FFS

    63. FFS – CF vs. HF

    64. 5 y Failure Rates

    65. Conclusion Hyperfractionation did NOT improve local, regional or distant control over conventional fractionation for Group III tumors

    66. IMRT

    67. IMRT The next step in radiation treatment planning after 3D Inverse planning with computer-assisted optimization Dose painting Sharp dose fall off outside target volume with selective avoidance of critical structures and tissues Multiple Fields Dose modulation within each field Better immobilization, longer treatment time

    68. IMRT

    69. IMRT

    70. Patient Characteristics 28 patients 21 parameningeal, 3 orbit, 4 other H&N 7% Group II, 89% Group III, 4% Group IV 21% Stage I, 21% Stage 2, 54% Stage 3, 4% Stage 4 57% Embryonal, 32% Alveolar, 11% Undifferentiated Median RT dose 50.4 Gy (41.4 – 55.8 Gy) Median F/U 2 years

    71. Results 3 y/o LCR Orbit 100% Non PM H&N 100% PM 95% 1 patient with Stage IV failed Alveolar/paranasal sinus Local/Regional/Distant mets irradiated Failed Locally 3 y/o RCR Overall 93% Orbit 100% Non PM H&N 100% PM 93% 3 y/o DFS Overall 65% PM 60% Other sites 80%

    72. Histology and Survival

    73. ICE and Survival

    74. IRS V

    75. Low Risk Sub-group A Histology: Embryonal / Boytroid Stage 1, Groups I, II(N0) Stage 1, Group III(N0) Orbit only Stage 2, Group I(N0)

    76. Low Risk Subgroup B Histology: Embryonal /Boytroid Stage 1, Grp II (N1) – microscopic residual dz. Stage 1, Grp III (N1) orbit only – gross residual dz. Stage 1, Grp III (N0 or N1) – gross residual dz. Stage 2, Grp II (N0) – microscopic residual dz, ? 5cm primary Stage 3, Grp I or II (N0 or N1) - ? 5cm with + LN or > 5cm primary regardless of LN status, - margins or microscopic residual dz.

    77. Rationale 5 y OS (IRS – IV) 90-95% 5 y FFS 78-89% Primary site, Tumor size and T stage were not prognostic

    78. Rationale

    79. Rationale

    80. IRS V

    81. Low Risk - D9602

    82. Low Risk – Orbit (Embryonal /Boytroid)

    83. Low Risk – PM (Embryonal/Boytroid)

    84. Patient Characteristics

    85. Stage 1, Group IIA XRT dose reduction from IRS IV 41.4 Gy ? 36 Gy 60 pts accrued VA Chemotherapy Decrease in FFS/OS currently attributed to less chemotherapy when compared to IRS IV

    86. Outcomes - Subgroup A Stage 1 Group IIA

    87. Subgroup A – Stage 1 Group III Orbit 77 patients assigned to VA therapy and reduced RT dose XRT dose reduced from 50.4 /59.4 from IRS IV to 45 Gy 10 relapses (all had a local failure component); 3 deaths FFS and OS @ 3 years – 88% and 97% The decrease in FFS/OS in IRS V compared to IRS IV partly attributed to less chemotherapy It is similar to results from IRS III with VA chemotherapy

    88. Outcomes – Subgroup A Orbit

    89. Subgroup B – Stage 2/3 Group IIA (N0) 16 patients accrued; treated with VAC chemotherapy and reduced dose RT RT dose reduced from 41.4 Gy ? 36 Gy No impact on FFS with reduced dose RT

    90. Subgroup B – Stage 2/3 Group IIA (N0)

    91. Intermediate Risk – D9803

    92. Chemotherapy Randomizes patients to VAC vs. VTC T – Topotecan Topoisomerase I inhibitor S – phase specific

    93. Orbit – Alveolar/Undiff

    94. H&N (non-PM, non Orbit)

    95. H&N PM – Grp III (all histologies)

    96. High Risk – D9802

    97. PM RMS – Stage IV/Group IV

    98. PM RMS – Stage IV/Group IV

    99. Thanks Acknowledgements: Dr. Carol Marquez Dr. John Holland Dr. Charles Thomas

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