Dr Soh Shui Yen
Paediatric Haematology / Oncology
KK Women’s and Children’s Hospital
12 September 2015
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Rhabdomyosarcoma:
Risk Stratification and
Overview of Systemic
Treatment
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Rhabdomyosarcoma
• STS ~7-8% of all childhood cancers; Most common STS in children is RMS
• Younger children (age < 5 yrs): – ~ 60% of STS are RMS
– Incidence of RMS ~ 8 per million
• Older children / adolescents: – ~ 20-40% of STS are RMS
– Incidence of RMS ~ 4 per million
– Incidence of RMS decreases with age; Incidence of NRSTS increases with age
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Rhabdomyosarcoma
• Arises in any site (except bone and CNS)
• Histology subtypes with different molecular
characteristics and clinical behaviour
• Various prognostic factors contribute to risk and
treatment stratification
• Treatment philosophies / approaches – differ
between large international collaborative groups
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RMS - Major Clinical Studies:
North America Europe
Intergroup RMS Study (IRS) -IRS-I (1972-1978) -IRS-II (1978-1984) -IRS-III (1984-1991) -IRS-IV (1991-1997) -IRS-V (1997-2005) - D9602/D9803/D9802
COG ARST
SWOG / CCSG POG / CCG 2000: COG – STS committee
SIOP MMT (Malignant Mesenchymal Tumour) -SIOP 75 -MMT 84 -MMT 95
German CWS (Cooperative Weichteilsarkom Studie) – CWS 81. 86, 91, 96 Italian RMS Group – RMS 79, 88 European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) – RMS-2005
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Multimodality Management of RMS
Surgery
Chemotherapy
Radiotherapy
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Multimodality Management of RMS
Surgery
Chemotherapy
Radiotherapy More aggressive local therapies. Better EFS.
Less aggressive local therapies. Lower EFS.
Overall Survival
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Prognostic Factors in RMS
1. Patient age
2. Tumour site
3. Tumour size / invasiveness
4. Histology subtype
5. Stage
6. Clinical Group
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Age of Patient at Diagnosis
Better prognosis
• Young children
(Age ~ between 1 to 10 years)
Worse prognosis
• Infants
• Older children / adolescents
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Site of Primary Tumour
Favorable Sites
• Orbit
• Superficial head and neck (non-parameningeal)
• Biliary tree
• Genitourinary - Paratestis, vagina
(Non-bladder; non-prostate)
Unfavorable Sites
• All others
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Size / Invasiveness of Primary Tumour
Tumour size
(a) Diameter 5cm or less
(b) Diameter more than 5cm
Tumour invasiveness
TNM “T1”: tumour confined to anatomic site of origin
TNM “T2”: tumour extending &/or fixed to surrounding
structures
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Histology
Embryonal RMS Alveolar RMS
Younger age Older age
Central sites Peripheral sites
Less invasive More invasive
Infrequent distant mets Frequent distant mets
Better survival outcome PFS ~ 40% - 90%
Worse survival outcome PFS ~ 0% - 60%
~20% PAX7-FOXO1 (t1;13) ~60% PAX3-FOXO1 (t2;13)
ERMS is ‘easier’ ARMS is ‘aggressive’
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Stage and Group in RMS
Staging in RMS
• Extent of disease at diagnosis
• Includes disease site (favorable versus unfavorable)
Grouping in RMS
• Extent of disease after initial surgery, and before chemotherapy / radiotherapy
• Powerful prognostic factor (IRS studies)
• Influenced by other factors
e.g. site and invasiveness; surgeon; patient/family; other therapeutic considerations (systemic chemo; local radiation)
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Staging and Grouping
Pre-Treatment TNM Staging Post-Surgical Grouping
Stage 1: Favorable site T1/T2; Any size; Any N; M0
Group I: Complete excision of localised disease (Ia / Ib)
Stage 2: Unfavorable site T1/T2; Size ≤ 5cm; N0/Nx; M0
Group II: Microscopic residual disease (IIa / IIb / IIc)
Stage 3: Unfavorable site T1/T2; Size ≤ 5cm AND N1; OR > 5cm AND Any N; M0
Group III: Gross residual disease (IIIa / IIIb)
Stage 4: Distant mets (M1) Group IV: Distant mets
Favorable sites = orbit, superficial head & neck, biliary tree, paratestis, vagina
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Staging and Grouping
Post-Surgical Grouping
Group I: Complete excision of localised disease Ia - Confined to muscle or organ of origin Ib - Contiguous involvement - infiltration outside the muscle or organ of origin
Group II: Microscopic residual disease / GTR with evidence of regional spread IIa - Grossly resected tumor with microscopic residual disease IIb - Regional disease with involved nodes, completely resected, no microscopic residual. IIIc - Regional disease with involved nodes, grossly resected, but with evidence of microscopic residual and/or histologic involvement of the most distal regional node
Group III: Gross residual disease IIIa – After biopsy only (<50% resected) IIIb – After >50% resection of primary tumour
Group IV: Distant mets
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Prognostic Factors and Risk Stratification
Risk Group
Age
Site
Size Histology
Stage
Group
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COG
Low Intermediate High
Histology ERMS only Any Any
Stage & Group
• Stage 1, Group I-III • Stage 2/3, Group I/II
• ARMS Stage 1-3 Group I-III • ERMS Stage 2/3, Group III • ERMS Group IV, Age < 10
Stage 4 / Group IV
Further subdivided
EpSSG
Low Standard High V. High Mets
Subgroup A B C D E F G H
Histology ERMS ERMS ERMS ERMS ERMS ERMS ARMS ARMS
Site Any Any Fav Unfav Unfav Any Any Any
Size / Age Fav Unfav Any Fav Unfav Any Any Any
Nodal (N) N0 N0 N0 N0 N0 N1 N0 NX
Group I I II,III II,III II,III II,III I,II,III I,II,III
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Prognostic Factors in Metastatic RMS
Oberlin et al. JCO2008.
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Systemic Chemotherapy
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RMS is Chemo-sensitive
Heyn et al. (CCSG) Cancer 1974.
Group I – VCR/AMD
Group I – No chemo
Group II – VCR/AMD
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VINCRISTINE, ACTINOMYCIN-D,
CYCLOPHOSPHAMIDE (VAC) OR
IFOSFAMIDE (IVA)
Chemotherapy for RMS:
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Cyclophosphamide or Ifosfamide
• IRS / COG – VAC regime
Cyclophosphamide: More gonadotoxic
• EpSSG – IVA regime
Ifosfamide: More nephrotoxic
• Efficacy – No difference (IRS-IV)
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Doxorubicin
• Effective drug in RMS/STS
• IRS studies – randomised VAC versus
VAC+anthracycline (VAC alternating with VadrC)
No difference
• EpSSG RMS 2005 – evaluating doxorubicin as
part of multi-drug regimen (“IVADo”), with
improved dose-intensity
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Low Risk RMS – IRS / COG
Subset 1 – ERMS; Stage 1/2, Group I/II; Stage 1, Group III (orbit) D9602: VA x 45 weeks. FFS 89%, OS 97%. (Raney et al. JCO2011) Subset of low risk RMS can have OS>90% with 2-drug chemo. ARST0331: VAC x 4, then VA x 4; 22 wks; CPM total 4.8g/m2.FFS 89%, OS 98% Shorter duration (22 wks) of treatment with lower dose CPM(4.8g/m2) did not compromise FFS. (Walterhouse et al. JCO2014)
Subset 2 – ERMS; Stage 1, Group III (non-orbit); Stage 3, Group I/II IRS-IV: VAC – 45 weeks; CPM total 26.4g/m2 – FFS 84%, OS 95% D9602: CPM 28.6g/m2 - 3yr EFS 83%, OS 93% (Raney et al. JCO2011) ARST0331: increased failure rate (3yr EFS only 66%) with reduced dose CPM to 4.8g/m2 (ASCO Abstract 2012)
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Low Risk RMS – IRS / COG D9602
D9602 (Raney et al. JCO2011)
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Low Risk RMS – EpSSG RMS 2005
• VA x 8 over 22 weeks
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Intermediate Risk RMS
IRS-IV (JCO2001)
• VAC vs VAI vs VIE: No difference; FFS 73%
COG D9803 (Arndt et al. JCO2009)
• VAC vs VAC/VTC: 4-yr EFS 73% vs 68%
COG ARST0531
• VAC vs VAC/VI
• Reduced CPM dose
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VAC still the standard chemo for RMS
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Intermediate Risk RMS
SIOP-MMT-95 (Oberlin et al. JCO2012)
Addition of carboplatin, epirubicin, and VP16 to IVA did not
improve outcome (3-year OS: 82% (IVA); 80% (IVA plus
carboplatin, epirubicin, and etoposide)
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Cyclophosphamide
• Dose escalation from 0.9g/m2/dose (IRS-III) to
2.2g/m2/dose (IRS-IV) did not improve FFS of ARMS
• Toxicities – hematologic, infections, hepatopathy,
gonadotoxicity, second malignancy
• ARST: Dose reduction from 2.2g/m2/dose to
1.2g/m2/dose (awaiting results)
• EpSSG RMS 2005: low dose oral
cyclophosphamide with IV Vinorelbine as
maintenance (6-12 months) in higher risk patients
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High Risk RMS
• Generally EFS < 50%
• D9802: VI window had better response rate
• ARST0431: VI/Interval compressed VDC-IE/VAC –
prelim results promising – 18m FFS 66% OS 80%
(ASCO2010)
• Adding novel agents to ARST0431 backbone:
– Cixutumumab
– Temozolomide
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Relapsed / Refractory RMS
Conventional chemo options:
• Topotecan / Cyclophosphamide
• Irinotecan +/- Temozolomide +/- Vincristine
• Carboplatin / Etoposide +/- Ifosfamide
• Vinorelbine +/- Cyclophosphamide
• Gemcitabine / Docetaxel
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Relapsed / Refractory RMS
Novel Agents:
• Cixutumumab (mAb against IGF1-R)
• Temozolomide
• Bevacizumab (Avastin) – mAb against VEGF-A
• mTOR inhibitor
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SUMMARY
• Various prognostic factors contribute to complex
risk and treatment stratification.
• VAC (or VAI in Europe) remains standard.
• Lower risk disease – reducing treatment
toxicities while maintaining good outcome
• Higher risk disease / relapsed refractory disease
– ongoing evaluations of novel agents.
• Interplay between various factors.
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THANK YOU
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