Rhabdomyosarcoma (1)

The Evolution of Radiation for H&N RhabdomyosarcomaParag SanghviDepartment of Radiation MedicineSeptember 20 2006

ObjectivesBackgroundRole of Radiation in Orbital and Parameningeal RMSIRS IV Radiation IRS V Impact of radiation dose reduction

RhabdomyosarcomaHighly malignant neoplasm arising from embryonal mesenchymeWith capacity for skeletal muscle differentiation

Intergroup Rhabdomyosarcoma Study GroupCOG, CCG, POGIRS 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)

EpidemiologyMost common pediatric STS (approximately 50%)3.5% of all malignancies under age of 15; 2% of all malignancies in 15-19 age group90 % of all RMS in individuals < 25 years; 60-70% in

Epidemiology1/3 of RMS patients have other congenital abnormalitiesGI, GU, CV, CNSMajority of cases are sporadic; but some are associated with genetic conditionsLi Fraumeni (p53 mutation)NF 1Beckwith - Wiedemann

Prognostic FactorsHistologyStagePrimary site (most important prognostic factor)Tumor SizeLN involvement (especially in extremities)Metastatic diseaseGroupExtent of resectionAge < 1 and alveolar histology>10Skull base erosion, CN palsy, Intracranial extension

HistologyGross diseaseSoft, fleshy tumors with variation in the extent of invasion and necrosisIHC stains to ascertain muscle of originAntidesmin, antivimentin, anti-muscle specific actinAnti-Myo D Ab

HistologyEmbryonalMost common 60-70% of all childhood RMSH&N, GU sitesIntermediate prognosisBoytroidSubtype of embryonal10% of all childhood RMSBladder, vagina, nasopharynx, nares, middle ear, biliary treeSuperior prognosis

Spindle cellSubtype of embryonalMost common site is paratesticularSuperior PrognosisAlveolar20% of RMSMore common in adolescentsTumors involving extremities, trunk, perianal and perinealUndifferentiatedDiagnosis of exclusionPreviously called pleiomorphicRare in children, more common in adults

Histology and Survival

Staging (based on IRS V)Stage ISitesOrbitH&N (excluding parameningeal) GU (non-bladder, non-prostate)Biliary tractTumor invasiveness: T1 or T2Tumor Size: a or bLymph node status: any NMetastasis: M0

(T1: confined to anatomic site of origin; T2: extension; a: 5 cm in diameter; N0: no clinically involved LN; N1: clinically involved LN; M1: metastasis present)

Stage IIStage IISitesParameningealNasopharynx/Nasal CavityMiddle Ear and Mastoid regionParanasal SinusesInfratemporal fossaPterygopalatine fossaParapharyngeal spaceBladder or ProstateExtremity

Stage IITumor Invasiveness: T1 or T2Tumor size: aLymph node status: N0 or NxMetastasis: M0

Stages III & IVStage IIISites: Same as Stage IITumor Invasiveness: T1 or T2Tumor size and Lymph Node statusa N1b any NMetastasis: M0Stage IVSites: AllMetastasis: M1

Site of primary tumor

SiteIncidenceH& N (non-PM)10%Parameningeal16%GU22%Orbit9%Extremities18%Other25%

Lymph Node MetastasisIRS I & II

Site% LN MetastasisExtremityUpperLower12%16%9%GUParatesticularBladderProstate26%6%5%GYN1%H&NOrbitOther6%0%8%

GroupGroup I: Localized dz; completely resectedA. Confined to muscle or organ of originB. Outside infiltrationGroup II: Gross Total ResectionA: With microscopic residual diseaseB: Regional lymphatic spread, resectedC: Both

GroupGroup III: Incomplete resection with gross residual diseaseA: After biopsy onlyB: After major resection (more than 50%)Group IV: Distant metastases @ diagnosis

Group

GroupIncidenceI16%II20%III48%IV16%

Histology, Stage and Group vs. Survival

CytogeneticsAlveolar RhabdomyosarcomaT(2,13)(p35;q14)70% of all alveolar RMSFuses PAX3:FKHRT(1,13)(p36:q14)20% all alveolar RMSFuses PAX7:FKHROccurs in younger children, better prognosisGenomic amplificationMDM2, CDK4Near-tetraploidy

CytogeneticsEmbryonal RhabdomyosarcomaLoss of heterozygosity at 11p15.5Loss of amplificationHyperploidyCell cycle controlMyogenesis = Mesenchymal fibroblast Skeletal muscleControlled by MyoD protein family (Myogenin, MYF5, MYF6)Can stain RMS cells with anti-MyoD Ab

Tumor Suppressor GenesP53 mutationProtooncogenesN-myc amplification Especially seen in alveolar histology

The Role of Radiation Therapy in Orbital and Parameningeal Rhabdomyosarcoma

Orbital RMS

Orbital RMS9% of all RMSMost common single H&N siteUsually diagnosed early; presents with eye swelling, globe displacement2/3 of cases are Group IIICan invade meninges via SOF84% Embryonal; 10% Alveolar5 y OS for Embryonal 94%; for Alveolar 74%

Historical managementOrbital Exenteration was standard treatment until mid 1960sHigh rate of local failurePoor survivalLate 1960s, Cassady et al. showed that RT after biopsy offered local control in 4/5 patients

Orbital RMSIRS IGroup I patients randomized to VAC +/- RTGroup II VA + RT +/- CGroup III/IV VAC + RT +/- AdriamycinPts with Group II or III disease 85-94% OS @ 6 years5 y OS 89%; 3/6 deaths 2/2 other causesComplete or Partial surgical excision no longer recommended standard of care

Orbital RMSIRS IIGroup I VA or VAC (no RT)Group II VA + RT +/- CGroup III VAC +RT +/- AdriamycinNo improvement in any of the more intensive chemotherapy armsOS/FFS better in all arms compared to IRS I

Orbital RMSIRS IIIGroup I VA onlyGroups II and III, VA +RT No difference in OS or FFS compared to IRS II 3 y/o FFS 92% and OS 100%IRS IVGroup I VA onlyGroup II VA + CD RTGroup III VAC vs. VAI vs. VIE AND CD RT vs. HF XRTRT doses 50.4 Gy vs. 59.4 GyGroups I & II pts. 3 y FFS 91%, OS 100% (no change compared to IRS III

Orbital RMSIRS IVGroup III, 3 y FFS 94%, OS 98%No difference in the 3 chemotherapy arms or the 2 RT armsHowever, when compared to IRS III, pts. with 3 drug chemotherapy regimens did better than VA regimenIRS VDue to concern for treatment related toxicitiesChemotherapy C/I/E dropped; back to VART dose decreased to 45 Gy

SIOP MMT 84 trialEvaluated eliminating radiation in Group II/III patients34 patients treated initially with VA aloneRT reserved for those who did not achieve a complete response22 patients initially did not get radiation 11 failed locally10/11 salvaged with RT + chemotherapy3/11 developed distant mets 2 died4 y/o EFS 62%; 4y/o OS 84%

Orbital RMS

ConclusionsTotal surgical extenteration no longer standard of careChemotherapy alone in Group I patients is effectiveChemo + RT for Group II and III patientsFuture trend for RTDose reductionElectrons, ProtonsIMRT treatment planning

Parameningeal RMSR infratemporal mass invading through the petrous bone

Parameningeal RMSL Ear

Parameningeal RMS16 % of all RMS41 % of all H&N RMSMost cases in children < 8 -10 years of ageCan extend intra-cranially and produce neoplastic meningitis (35% of all PM RMS)

Parameningeal RMSMeningeal penetration and leptomeningeal tumor cell seeding must be assessed Complete surgical extirpation almost never possible76% are Group III (IRS III)Hence, surgery is generally either a biopsy or subtotal resection

Parameningeal RMS - SitesNasal Cavity/Nasopharynx/Paranasal Sinuses can invade through basal foramina, sinus roofsMiddle Ear can extend through tegmen tympani into the middle cranial fossa or through posterior mastoid into the posterior cranial fossaParapharyngeal spacePterygopalatine / Infratemporal fossa

PM RMS IRS I3 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 diagnosisMeningeal extension was likely fatal 90%Associated with inadequate margins and doses < 50 Gy

PM RMS IRS II -IIIIRS IIIncrease field size to sequential CSI for patients with any meningeal extensionLocal + WBRT Wk 0Spinal RT Wk 6Dose age and tumor size dependent40 55 GyIRS II (1980 1984) and IRS III (1984 1987)Omit spinal irradiation; WBRT for any meningeal extensionStart @ Wk 0Dose age and tumor size dependent41.4 50.4 Gy

PM RMS IRS IVIRS IV Pilot (1987 1991)Local XRT for CNP or CBBE Wk 0WBRT for ICE Wk 0IRS IV (1991 1997)Local XRT for any meningeal extensionDoseFor Group III disease, RT question was about hyperfractionation59.4 Gy (1.1 Gy bid) vs. 50.4 Gy

PM RMS IRS II - IV

CSIWBRT IF/WBRT IF

PM RMS IRS II - IV

Primary Site

Primary Site and Meningeal Involvement

Prognostic Factors 5 y FFSAge

5 y/o FFS & OS by Meningeal involvement

5 y FFS and OS by Histology and Meningenal Involvement

Timing of RT in patients with meningeal involvement5 y LFR overall 20%; RT < 2 weeks 18%; >2 weeks 35%35%18%

Timing of RT in patients with ICE16%37%

LF vs. FFS and Meningeal Involvement

Local Failure by Radiation Dose

Did people really get WBRT?

Local Failure and Radiation Fields23%17%

CNS Failure and Radiation Fields9%9%

Multivariate analysisStatistically significant worse prognostic factors controlling for tumor sizeAge > 10 (p = 0.002)RT dose

ConclusionsAvailability of cross-sectional imaging improved ability to diagnose ICE and hence led to better treatment planning and earlier delivery of RTPatients with tumors > 5 cm benefited from dose > 47.5 GyWBRT 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

BackgroundIRS II and IRS III showed local relapse rate of 16% and LR relapse rate of 32 % respectively in Group III patientsRCT comparing hyperfractionation vs. conventional fractionation in Group III patientsHyperfractionation = More than 1 fraction a dayGoal to improve LCR by 10% without increasing late side effectsRationale based on 10-15% improvement seen in LRC in other H&N cancers in adults with HF

Criteria / Treatment LogisticsStage 1, 2, and 3 and Group III patientsCF = 50.4 Gy in 1.8 Gy/fraction given dailyHF = 59.4 GY in 1.1 Gy/fraction given bid atleast 6 hours apartPre-op/Pre-chemo volume + 2 cm marginRT started week 9 or week 0 if cord compression or any meningeal involvement

Results OS and FFS

FFS CF vs. HF

5 y Failure Rates

ConclusionHyperfractionation did NOT improve local, regional or distant control over conventional fractionation for Group III tumors

IMRTThe next step in radiation treatment planning after 3DInverse planning with computer-assisted optimizationDose paintingSharp dose fall off outside target volume with selective avoidance of critical structures and tissuesMultiple FieldsDose modulation within each fieldBetter immobilization, longer treatment time

Patient Characteristics28 patients21 parameningeal, 3 orbit, 4 other H&N7% Group II, 89% Group III, 4% Group IV21% Stage I, 21% Stage 2, 54% Stage 3, 4% Stage 457% Embryonal, 32% Alveolar, 11% UndifferentiatedMedian RT dose 50.4 Gy (41.4 55.8 Gy)Median F/U 2 years

Results3 y/o LCROrbit 100%Non PM H&N 100%PM 95%1 patient with Stage IV failedAlveolar/paranasal sinus Local/Regional/Distant mets irradiatedFailed Locally3 y/o RCROverall 93%Orbit 100%Non PM H&N 100%PM 93%3 y/o DFSOverall 65%PM 60%Other sites 80%

ICE and Survival

Low RiskSub-group AHistology: Embryonal / BoytroidStage 1, Groups I, II(N0)Stage 1, Group III(N0) Orbit onlyStage 2, Group I(N0)

Low RiskSubgroup BHistology: Embryonal /BoytroidStage 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 primaryStage 3, Grp I or II (N0 or N1) - 5cm with + LN or > 5cm primary regardless of LN status, - margins or microscopic residual dz.

Rationale5 y OS (IRS IV) 90-95%5 y FFS 78-89%Primary site, Tumor size and T stage were not prognostic

Rationale

Low Risk - D9602

Low Risk Orbit (Embryonal /Boytroid)VA chemotherapyRT starts @ week 3

Low Risk PM (Embryonal/Boytroid)Chemotherapy: Group I VA, if Stage 3 or Group II VACRT starts @ week 3

Patient Characteristics

Stage 1, Group IIAXRT dose reduction from IRS IV41.4 Gy 36 Gy60 pts accruedVA ChemotherapyDecrease in FFS/OS currently attributed to less chemotherapy when compared to IRS IV

Outcomes - Subgroup AStage 1 Group IIA

Subgroup A Stage 1 Group III Orbit77 patients assigned to VA therapy and reduced RT doseXRT dose reduced from 50.4 /59.4 from IRS IV to 45 Gy10 relapses (all had a local failure component); 3 deathsFFS and OS @ 3 years 88% and 97%The decrease in FFS/OS in IRS V compared to IRS IV partly attributed to less chemotherapyIt is similar to results from IRS III with VA chemotherapy

Outcomes Subgroup A Orbit

Subgroup B Stage 2/3 Group IIA (N0)16 patients accrued; treated with VAC chemotherapy and reduced dose RTRT dose reduced from 41.4 Gy 36 GyNo impact on FFS with reduced dose RT

Subgroup B Stage 2/3 Group IIA (N0)

Intermediate Risk D9803

ChemotherapyRandomizes patients to VAC vs. VTCT TopotecanTopoisomerase I inhibitorS phase specific

Orbit Alveolar/Undiff

H&N (non-PM, non Orbit)

H&N PM Grp III (all histologies)

High Risk D9802

PM RMS Stage IV/Group IV

ThanksAcknowledgements:Dr. Carol MarquezDr. John HollandDr. Charles Thomas

Rhabdomyosarcoma (1)

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