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

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
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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
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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
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
 Stage II
 Sites
 Parameningeal
 Nasopharynx/Nasal Cavity
 Middle Ear and Mastoid
region
 Paranasal Sinuses
 Infratemporal fossa
 Pterygopalatine fossa
 Parapharyngeal space
 Bladder or Prostate
 Extremity
 Tumor Invasiveness: T1
or T2
 Tumor size: a
 Lymph node status: N0 or
Nx
 Metastasis: M0
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
Site of primary tumor
Site
Incidence
H& N (non-PM)
10%
Parameningeal
16%
GU
22%
Orbit
9%
Extremities
18%
Other
25%
Lymph Node Metastasis
IRS I & II
Site
% LN Metastasis
Extremity
Upper
Lower
12%
16%
9%
GU
Paratesticular
Bladder
Prostate
26%
6%
5%
GYN
1%
H&N
Orbit
Other
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
Incidence
I
16%
II
20%
III
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
 Cell cycle control
 Myogenesis = Mesenchymal
fibroblast  Skeletal muscle
 Controlled by MyoD protein
family (Myogenin, MYF5,
MYF6)
 Can stain RMS cells with antiMyoD Ab
 Tumor Suppressor
Genes
 P53 mutation
 Protooncogenes
 N-myc amplification
 Especially seen in
alveolar histology
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
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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
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Orbital RMS
 IRS III
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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
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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)
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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+
 Meningeal Involvement
46%
73%
54%
 Primary Site
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NP/NC
Ear/Mas
PPS
PNS
PPF/ITF
74%
73%
72%
57%
53%
 None
 CNP/CBBE
 Any ICE
77%
65%
60%
 Histology
 Emb/Boy
 Alv/Und
 Other
70%
59%
65%
 Tumor Size
 <5 cm
 >5 cm
71%
67%
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
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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
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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
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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
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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