RHABDOMYOSARCOMA

Malignant Round Cell Tumors

Histological D/Ds

RHABDOMYOSARCOMA NHL OSTEOSARCOMA NEUROBLASTOMA EWINGS TUMOR PERIPHERAL NEUROEPITHELIOMA ASKIN TUMOR MERKEL CELL TUMOR SMALL CELL CA LUNG OSTEOMYELITIS ROUND CELL LIPOSARCOMA MALIGNANT HAEMANGIOPERICYTOMA. MESENCHYMAL CONDROSARCOMA.

Malignant Round Cell Tumors

IMMUNOCYTOCHEMISTRY
RMS
S-100 SYNAPTOPHYSIN MIC-2 GENE DESMIN VIMENTIN CHROMOGRANIN MUSCLE SPECIFIC ACTIN (HHF-35) NEUROFILAMENT NEUROSECRETARY GRANULES LUCOCYTE COMMON ANTIGEN CYTOKERATIN CPK (MM & BB) MYOGLOBIN

NB ++ +

PNET ++ ++ ++ +/++

ES +/++ ++ +/++ +/+/+ +/-

MCT

OS

NHL

SCLC

+/+ ++

+ +++ ++ ++ ++ ++ ++

++ +/++ + +/-

++ ++ +++ ++

RHABDOMYOSARCOMA

Highly malignant STS that arises from unsegmented, undifferentiated mesoderm or myotome derived skeletal muscle. Different pathobiologic entities linked by common propensity to develop neoplastic skeletal muscles Heterogeneous group, clinicopathologic entities based on morphologic appearance and genetic make up. Mid 1900, Horn and enterline divided into Embryonal, Alveolar, Botryoid, Pleomorphic subtimes More recently- spindle cell, anaplastic, and refinements such as Undifferentiated and Solid Alveolar.

RHABDOMYOSARCOMA

Histology of these neoplasms is analogous with myogenesis in the developing embryo more correct to define RMS as a tumor derived from primitive mesenchyme and exhibiting a profound tendency towards myogenesis

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, 5% are infants. Peak age 2- 5 years & adolescence Male preponderance (1.5:1) Racial predisposition (White children 4 times as likely as black children)

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

Though it may occur at any site, most frequently involved are.

Site of Primary Tumor

Site H& N (non-PM) Parameningeal GU Orbit Extremities Other Incidence 10% 16% 22% 9% 18% 25%

Site, Age & Histology

Primarily in Infants Embryonal / Botryoid Alveolar / Undifferentiated

UB & Vagina

Trunk & Extremities

Adolescents

Head & Neck

Throughout childhood

Embryonal

Natural History

RMS is a locally invasive Tx often with a pseudocapsule. Potential for local spread along fascia, muscle planes, Lymphatic extn and blood dissemination. Overall risk of reg lymphatic spread=15%-20% LN mets. Rare in orbit but other H&N=15%, MC in Tx from NPx. Paratesticular= 25%, Trunk & extremities= 20%

LN invol risk correlates with Tx invasiveness and size of Tx. Hematogenous spread @ diagnosis ~ 15%

Particularly truncal and extremity MC sites for spread are Lungs, BM & Bone.

Histopathology

Standard classification

Horn & Enterline ( 1958 ) Beckwith & Palmer ( 1978 ) Caillaud et al ( 1989 ) Tsokos et al ( 1990 ) Newton & Colleagues

Cytohistological ( Palmer) Classification

SIOP classification

NCI classification

International Classification

Classification

EMBRYONAL

So named by Berard ( 1894 )

tumeur embryonnaire du muscle striae.

CHILDREN(60-70%) Most common subtype Most common in children, in head & neck, GU sites

EMBRYONAL
Zones of loose & dense cellularity remarkably recapitulate normal embryonal myogenesis, in which loose primitive mesenchyme condenses to form nascent muscle exhibit all cellular phases of myogenesis

dense condensations of rhabdomyoblasts amid foci with a loose myxoid stroma.

They share features with other embryonal neoplasms of childhood, such as Wilms tumors, hepatoblastomas, pancreatoblastomas, and neuroblastomas.

ALVEOLAR

Riopelle and Theriault (1956) 20% of RMS < 1 Yr --- >10 Yr ( Adolescents) Extremities, trunk, perianal, perineal MORE AGGRESSIVE METASTATIC DISEASE

ALVEOLAR RHABDOMYOSARCOMA
Fibrous septa with loose clusters of rounded cells in center - alveolar pattern

Riopelle and Theriault described solid areas lacking fibrosis and resembling lymphoma, a phenomenon further noted by Enzinger and Shiraki: solid pattern in so-called alveolar tumors.

BOTRYOID TYPE

Termed by Guersants

sarcoma botryoides

Subtype of Embryonal 10% of all Childhood RMS Mucosal Surface

Vagina Billiary Bladder Nasopharynx

Most common in hollow visceral organs - GU tract Superior Prognosis

BOTRYOID RHABDOMYOSARCOMA
Polypoid, grape-like tumor masses Scattered malignant cells in myxoid stroma

These lesions should abut an epithelial surface, such as that of the bladder, bile duct, vagina, or conjunctiva, and project into the lumen as multinodular excrescences of variable size.

Cambium layer -subepithelial condensation of tumor cells.

SPINDLE CELL

Cavazzana and colleagues ( 1992 )

Subtype of Embryonal MC site is Paratesticular Superior Prognosis whorled spindly appearance akin to that of smooth muscle tumors
relatively differentiated spindle cells having cytologic features reminiscent of smooth muscle tumors.

UNDIFFERENTIATED

Diagnosis of exclusion Previously called Pleomorphic Rare in children More common in Adults ( 30-50 Yrs) In skeletal muscles of older people, thigh

Marked pleomorphism Irregularly arranged cells Multinucliated giant cells

UNDIFFERENTIATED

Enlarged, pleomorphic, hyperchromatic nuclei

Cytogenetics

Alveolar Rhabdomyosarcoma

T(2,13)(p35;q14)

70% of all alveolar RMS Fuses PAX3:FKHR 20% all alveolar RMS Fuses PAX7:FKHR Occurs in younger children, better prognosis MDM2, CDK4

T(1,13)(p36:q14)

Genomic amplification

Near-tetraploidy

Cytogenetics

Embryonal Rhabdomyosarcoma

Loss of heterozygosity at 11p Loss of amplification Hyperploidy 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

Cell cycle control

Cytogenetics

The prognostic value of DNA ploidy and proliferative index (PI) DNA hyperdiploid and tetraploid rhabdomyosarcomas had a favorable prognosis while DNA diploid and polyploid tumors had a poor prognosis.

Am J Clin Pathol 2004;121:358-365

Clinical Presentation

Occurs in multiple primary sites Usually presents as a asymptomatic mass symptoms relate to mass effect on asso. Organ Orbital

Proptosis, ophthalmoplegia Nasal, Aural or sinus obstruction, CN Palsies & headache etc. Hematuria, Urinary obstruction or constipation.

Parameningial

Genitourinary

Location Deep lesions tend to be malignant-Superficial lesions - benign

Size

Larger tumors tend to be malignant Rapidly growing - malignantInfiltrating - malignant

Growth pattern

Metastasis

Sites

Head & Neck

Orbit Non-Parameningial Parameningial Retroperitonial Paratesticular Genitourinary

Trunk

Extremities

Head & Neck (Para-meningeal)

Sites: Nasopharynx, Nasal cavity, PNS, Middle ear, Pterygopalatine fossa. Have propensity for base skull invasion & intracranial extension. Common histological subtype: ERMS. Incidence of lymph node involvement (IRS III): <20%. Possibility of complete surgical excision (IRS III): <25%.

Head & Neck (Non-parammeningeal)

Sites: Parotid, Oral cavity, Oropharynx and Larynx. Common histological subtype: Embryonal RMS. Buccal mucosa: Alveolar RMS Scalp Incidence of lymph node involvement (IRS III): <20%. Prophylactic / Elective nodal irradiation not recommended.

Pelvic RMS:

Urinary Bladder Common histologic subtype: Embryonal RMS Lymph node involvement: 20% (Hypogastric & Ext. iliac) IRS III - Chemo + Radiotherapy Surgery for residual disease IRS III - Bladder preservation: 55% with 90% survival

Paratesticular

Along spermatic cord; from interscrotal area through the inguinal canal. Lymph node involvement: 30% (paraaortic / renal hilar) If LN +ve (radiological): Ipsilateral. Nerve sparing LN dissn./ Regional nodal irradn.

i) dissect entire s.cord after orchidectomy ii) sample abdominopelvic nodes, except for Gr. I iii) scrotal violation / involvement: need scrotal RT.

Orbit

Common histological subtype: Embryonal RMS General treatment policy: Incisional Biopsy for diagnosis Chemo+ RT Radiotherapy volume: Entire orbit need not be included. Shield lachrymal gland & duct. Significant role of 3D CRT / IMRT. Survival: 90-95% at 5years (with CT + RT).

Extremity

Common histological subtype: Alveolar RMS Lymph node involvement: 27-30% General treatment policy: W/E + LN sampling Chemo + RT . Radiotherapy: No RT if R0 & N0 & 5cm tumor (primary surgery). Entire LN region irradiated if sampling +ve. Strip of tissue spared for lymph drainage.

Retroperitoneal:

Common histological subtype: Alveolar RMS General treatment policy: W/E + Chemo + RT Poor prognosis: 5year survival - 40%.

Diagnostic Evaluation

Thorough physical examination Routine Blood examination Histopathologic evaluation

Biopsy Immunohistochemistry Cytokeratin, Vimentin, Smooth muscle Actin, Desmin, S100, CD31,34

FISH RT PCR

CT/MRI of primary

Diagnostic Evaluation

Site specific

H&N, Parameningial- CSF examination

GU - Examination under anesthesia Intravenous pyelography for retroperitoneal tumors Cystoscopy Chest X ray Bone marrow biopsy Bone scan

Metastatic workup

HISTOLOGY AND SURVIVAL

Grouping
A I B A II B C A III IV B
LOCALISED DISEASE, COMPLETELY RESECTED CONFINED TO MUSCLE / ORGAN OF ORIGIN
LOCALISED DISEASE, COMPLETELY RESECTED INFILTRATES OUTSIDE ORGAN OF ORIGIN COMPROMISED OR REGIONAL RESECTION GROSSLY RESECTED + MICROSCOPIC RESIDUAL DISEASE COMPROMISED OR REGIONAL RESECTION REGIONAL SPREAD; RESECTED COMPLETELY COMPROMISED OR REGIONAL RESECTION REGIONAL SPREAD; RESIDUAL DISEASE INCOMPLETE RESECTION WITH GROSS RESIDUAL DISEASE BIOPSY ONLY INCOMPLETE RESECTION WITH GROSS RESIDUAL DISEASE MAJOR RESECTION (> 50%)

DISTANT METASTASIS @ DIAGNOSIS

Group
Group I II III IV Incidence 16% 20% 48% 16%

Histology, Stage and Group vs. Survival

Staging

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)

Stage II

Stage II

Stage II
Tumor Invasiveness: T1 or T2 Tumor size: a Lymph node status: N0 or Nx Metastasis: M0

Sites Parameningeal

Nasopharynx/Nasal Cavity Middle Ear and Mastoid region Paranasal Sinuses Infratemporal fossa Pterygopalatine fossa Parapharyngeal space

Bladder or Prostate Extremity

Stage III & IV

Stage III

Stage IV
Sites: All Metastasis: M1

Sites: Same as Stage II Tumor Invasiveness: T1 or T2 Tumor size and Lymph Node status a N1 b any N Metastasis: M0

RHABDOMYOSARCOMA Part-II

Dr. Pramod Tike ,JR-II Dr. Kanhu Patro, SR-II Dept. Of Radiation Oncology, TMH

TREATMENT

RHABDOMAYOSARCO MA

TREATMENT SEQUENCE

CHEMOTHERAPY REGIMEN

IRS-IV protocol

LOCAL THERAPY

SURGERY GUIDELINES

If wide resection is possible surgery with resection and suitable reconstruction. If chemotherapy has not been very effective (as judged from clinical response, post chemo MRI) and wide resection is not feasibleablative surgery in the form of an amputation is recommended. Maintenance chemotherapy is subsequently used. Surgery should be reasonable i.e.: removal of tumor bulk with maximum preservation of organ & function.

RADIOTHERAPY

INDICATION ALL STAGE EXCEPT GR-1 EMBRYONAL HISTOLOGY DOSE MARGIN TIMING

RT-TIMING

Base skull erosion DAY- 0 Cranial nerve palsy meningeal invasion None of the above features - "week 9".

RADIOTHERAPY-MARGIN

Gross pre-chemotherapy volume + 2cm. Modified in special sites adjacent to critical structures In sites where tumor grows into body cavities: postchemo volume + 2cm. Microscopic disease (IRS group I & II)

Gross pre-chemotherapy volume + margin Phase I - Gross pre-chemotherapy volume + margin Phase II - Post-chemotherapy / volume + margin*

Gross disease (IRS group III)

Dose
Microscopic disease (IRS group I & II) 41.4Gy / 23# / 4.5wks (@1.8Gy / fr.) Gross disease (IRS group III): a) Age 5yrs, Residual tumor 5cm 45Gy / 25# / 5wks (@1.8Gy / fr.) b) Age 6yrs, Residual tumor < 5cm Phase I - 41.4Gy / 23# / 4.5wks (@1.8Gy / fr.) Phase II - 10Gy / 5# / 1wk (@1.8Gy / fr.) c) Age 10yrs, Residual tumor 5cm, Extremity lesion Phase I - 41.4Gy / 23# / 4.5wks (@1.8Gy / fr.) Phase II - 15Gy / 7# / 1wk (@1.8Gy / fr.)

FOLLOW-UP- Frequency

Every 3 monthly for the 1st yr Every 6 monthly for the 2nd & 3rd yr Yearly thereafter

FOLLOW UP- Investigations

Relevant History Physical examination & documentation Haematological evaluation: Hb, TC, Platelet Liver Function Tests (LFT) Renal Function Tests (RFT) Radiological evaluation: CXR X-ray of local part Bone scans CT chest Bone Scan/ CT scan chest is done every 6 months for the first 2 years and every year for the next 3 years. Other investigations (MRI/ CT Scan of local part) to be done as specified after discussion in the Pediatric joint clinic.

Intergroup Rhabdomyosarcoma Study Group

COG, CCG, POG

IRS I (1972 1978) IRS II (1978 1984) IRS III (1984 1991) IRS IV (1991 1997) IRS V (1998 present)

OS 55% OS 63% OS 71% OS 71%

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%

Histology and Survival

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

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

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

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% 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

IRS IV

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 Due to concern for treatment related toxicities Chemotherapy C/I/E dropped; back to VA RT dose decreased to 45 Gy

IRS V

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%

Orbital RMS

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

Parameningeal RMS

R infratemporal mass invading through the petrous bone

Parameningeal RMS

L Ear

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)

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

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

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

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 Omit spinal irradiation; WBRT for any meningeal extension Start @ Wk 0 Dose age and tumor size dependent 41.4 50.4 Gy

IRS II (1980 1984) and IRS III (1984 1987)

PM RMS IRS IV

IRS IV Pilot (1987 1991)

Local XRT for CNP or CBBE Wk 0 WBRT for ICE Wk 0 Local XRT for any meningeal extension Dose

IRS IV (1991 1997)

For Group III disease, RT question was about hyperfractionation

59.4 Gy (1.1 Gy bid) vs. 50.4 Gy

PM RMS IRS II - IV
CSI WBRT IF/WBRT IF

PM RMS IRS II - IV

Primary Site

Primary Site and Meningeal Involvement

Prognostic Factors 5 y FFS

Age

Meningeal Involvement

<1 1-9 10+ NP/NC Ear/Mas PPS PNS PPF/ITF

46% 73% 54% 74% 73% 72% 57% 53%

None CNP/CBBE Any ICE Emb/Boy Alv/Und Other <5 cm >5 cm

77% 65% 60% 70% 59% 65% 71% 67%

Histology

Primary Site

Tumor Size

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 involvement

35%

18%

5 y LFR overall 20%; RT < 2 weeks 18%; >2 weeks 35%

Timing of RT in patients with ICE

16%

37%

LF vs. FFS and Meningeal Involvement

Local Failure by Radiation Dose

Did people really get WBRT?

Local Failure and Radiation Fields

23%

17%

CNS Failure and Radiation Fields

9%

9%

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

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

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

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

Results OS and FFS

FFS CF vs. HF

5 y Failure Rates

Conclusion

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

IMRT

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 Dose modulation within each field

Multiple Fields

Better immobilization, longer treatment time

IMRT

IMRT

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

Results

3 y/o LCR

3 y/o RCR

Orbit 100% Non PM H&N 100% PM 95% 1 patient with Stage IV failed Alveolar/paranasal sinus Local/Regional/Distant mets irradiated

Overall 93% Orbit 100% Non PM H&N 100% PM 93% Overall 65% PM 60% Other sites 80%

3 y/o DFS

Failed Locally

Histology and Survival

ICE and Survival

IRS V

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)

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.

Rationale

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

Rationale

Rationale

IRS V

Low Risk - D9602

Low Risk Orbit (Embryonal /Boytroid)

VA chemotherapy RT starts @ week 3

Low Risk PM (Embryonal/Boytroid)

Chemotherapy: Group I VA, if Stage 3 or Group II VAC RT starts @ week 3

Patient Characteristics

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

Outcomes - Subgroup A Stage 1 Group IIA

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

Outcomes Subgroup A Orbit

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

Subgroup B Stage 2/3 Group IIA (N0)

Intermediate Risk D9803

Chemotherapy

Randomizes patients to VAC vs. VTC T Topotecan

Topoisomerase I inhibitor S 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

PM RMS Stage IV/Group IV