The Evolution of Radiation for H

1
The Evolution of Radiation for HN
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 lt 25 years 60-70
  in lt10 years
• Peak age 2- 5 years
• Incidence in US 250 cases / year
• Male preponderance (1.41)
• 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
• lt 1 and alveolar histology
• gt10
• 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

• 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

• Embryonal
• Most common
• 60-70 of all childhood RMS
• HN, GU sites
• Intermediate prognosis
• Boytroid
• Subtype of embryonal
• 10 of all childhood RMS
• Bladder, vagina, nasopharynx, nares, middle ear,
  biliary tree
• Superior prognosis

10
Histology and Survival
11
Histology and Survival
12
Staging (based on IRS V)

• Stage I
• Sites
• Orbit
• HN (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 lt5 cm in diameter b gt5 cm in
  diameter N0 no clinically involved LN N1
  clinically involved LN M1 metastasis present)

13
Stage II

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

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

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 MetastasisIRS 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 _at_ diagnosis

19
Group
20
Histology, Stage and Group vs. Survival
21
Cytogenetics

• Alveolar Rhabdomyosarcoma
• T(2,13)(p35q14)
• 70 of all alveolar RMS
• Fuses PAX3FKHR
• T(1,13)(p36q14)
• 20 all alveolar RMS
• Fuses PAX7FKHR
• 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 HN 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 _at_ 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
R infratemporal mass invading through the petrous
bone
36
Parameningeal RMS
L Ear
37
Parameningeal RMS

• 16 of all RMS
• 41 of all HN RMS
• Most cases in children lt 8 -10 years of age
• Can extend intra-cranially and produce neoplastic
  meningitis (35 of all PM RMS)
• lt20 have LN involvement (IRS III)
• Most have favorable histology (Embryonal
  Alveolar 41)

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 HN 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 lt
  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 _at_ 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
CSI ? WBRT ? IF/WBRT ? IF
44
PM RMS IRS II - IV
45
Primary Site
46
Primary Site and Meningeal Involvement
47
Prognostic Factors 5 y FFS

• Age
• lt1 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
• lt5 cm 71
• gt5 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
35
18
5 y LFR overall 20 RT lt 2 weeks 18 gt2
weeks 35
51
Timing of RT in patients with ICE
16
37
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
23
17
56
CNS Failure and Radiation Fields
9
9
57
Multivariate analysis

• Statistically significant worse prognostic
  factors controlling for tumor size
• Age gt 10 (p 0.002)
• RT dose lt47.5 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 gt 5 cm benefited from dose gt
  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

59
(No Transcript)
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 HN 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 HN
• 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 HN 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 HN 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 gt 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)
VA chemotherapy RT starts _at_ week 3
83
Low Risk PM (Embryonal/Boytroid)
Chemotherapy Group I VA, if Stage 3 or Group II
VAC RT starts _at_ week 3
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 AStage 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 _at_ 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
HN (non-PM, non Orbit)
95
HN 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