The Evolution of Radiation for H&N Rhabdomyosarcoma

Parag Sanghvi Department of Radiation Medicine September 20 2006

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

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

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%

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)

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

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

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

Histology
Embryonal
Most common 60-70% of all childhood RMS H&N, GU sites Intermediate 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

Boytroid
Subtype of embryonal 10% of all childhood RMS Bladder, vagina, nasopharynx, nares, middle ear, biliary tree Superior prognosis

Undifferentiated
Diagnosis of exclusion Previously called pleiomorphic Rare in children, more common in adults

Histology and Survival

Histology and Survival

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)

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

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

Bladder or Prostate Extremity

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

Stage IV
Sites: All Metastasis: M1

Metastasis: M0

Site of primary tumor

Site H& N (non-PM)
Parameningeal GU Orbit Extremities Other

Incidence 10%
16% 22% 9% 18% 25%

Lymph Node Metastasis IRS I & II

Site Extremity Upper Lower
GU Paratesticular Bladder Prostate GYN H&N Orbit Other

% LN Metastasis 12% 16% 9% 26% 6% 5%

1% 6% 0% 8%

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

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

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

IV

16%

Histology, Stage and Group vs. Survival

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

Cytogenetics
Embryonal Rhabdomyosarcoma
Loss of heterozygosity at 11p15.5 Loss of amplification Hyperploidy

Tumor Suppressor Genes

P53 mutation

Protooncogenes
N-myc amplification Especially seen in alveolar histology

Cell cycle control

Myogenesis = Mesenchymal fibroblast Skeletal muscle Controlled by MyoD protein family (Myogenin, MYF5, MYF6) Can stain RMS cells with antiMyoD Ab

The Role of Radiation Therapy in Orbital and Parameningeal Rhabdomyosarcoma

Orbital RMS

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%

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

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

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

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

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

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

Meningeal Involvement
46% 73% 54%
74% 73% 72% 57% 53% None CNP/CBBE Any ICE 77% 65% 60% 70% 59% 65% 71% 67%

Primary Site

Histology
Emb/Boy Alv/Und Other

Tumor Size
<5 cm >5 cm

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

Multiple Fields
Dose modulation within each field

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
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%

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

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