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