Optimal Chemotherapy in Untreated and Refractory Ewing's ...€¦ · Optimal Chemotherapy in Untreated and Refractory Ewing's Sarcoma 2nd Singapore ... UKCCSG ET-1 (1978-1986) (Craft

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Optimal Chemotherapy in Untreated and Refractory Ewing's Sarcoma

2nd Singapore Sarcoma Consortium Education and Research Meeting 2014

27 APRIL 2014

< single image >

4.3cm x 5.5cm Dr Soh Shui Yen

Consultant

Haematology/Oncology Service,

Department of Paediatric Subspecialties

KK Women’s and Children’s Hospital

Ewing Sarcoma 1. Background

2. Chemotherapy

• Localized disease

• Metastatic disease

• Recurrent / Refractory disease

3. Last words

Ewing Sarcoma: Background

Ewing Sarcoma Family of Tumours (ESFT)

• First described in 1921

• Classic Ewing Sarcoma of bone

• Soft tissue (extraosseous) ~ 25%

• Peripheral primitive neuroectodermal

tumour (peripheral PNET)

• Askin tumour (chest wall)

• Small round blue cell

• CD99+ PAS-

• EWS gene rearrangement – most

common t(11;22) EWS-FLI1

4

James Stephen Ewing

(25 Dec 1866 – 16 May

1943) is an American

pathologist at Cornell

University

Epidemiology – SEER Data

• 3% of all pediatric cancers

• 2nd most common 10 bone cancer in paeds

• Overall incidence 3 cases / million / year

• Median age: 15 years - Teens > 50%

• Slight male predominance (1.5:1)

• More common in white population

5

Clinical Presentation

• Pain and swelling – primary tumours

o Axial / Extremities (diaphyseal)

• 25% metastatic at diagnosis

o Mets to Lung (50%) / Bone / Marrow

6

Clinical Presentation

7 UKCCSG/MRC, CESS Trials. Coterill et al. JCO 2000.

Lab Features

• Anaemia

• Leukocytosis

• Raised ESR

• Raised LDH

Nothing specific

8

Staging

• Plain radiograph and CT/MRI of primary site

• CT chest

• Bone scan

• Bilateral BMA / trephine

• Whole body MRI / FDG-PET

• Biopsy of equivocal lung nodules or lymph

nodes

9

Prognostic Factors

10

Prognostic Factors

Patient • Younger age better. Older teens have worse outcome. • Females have better outcome.

Disease • Site: Distal > Proximal extremities > Axial > Pelvis (worst) • Size: tumours worse (> 8cm; >100ml-200ml) • Spread/Metastatic disease; Extrapulmonary mets worse • Serum LDH high • Second cancer worse

Biology • Complex karyotype worse • Marrow RT-PCR +ve • p53, 16q loss, Ki67, microsomal gluthatione S-transferase. (EWS-FLI1 not shown to be better)

Response • Response to neoadjuvant chemotherapy

Prognostic Factors


Prognostic Factors


Prognostic Factors


Management

• Systemic chemotherapy

• Local control

• Surgery

• Radiotherapy

• Both surgery and RT

Multi-discipinary team

14

Management

• Ewing Sarcoma is very chemosensitive

• Systemic chemotherapy has a clear and

definite role in the treatment of ESFT

• Without chemotherapy, only 10% survival.

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Chemotherapy

Localized / Metastatic / Recurrent

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North America Europe

Ewing Sarcoma:

Chemotherapy (Localized Disease)

Chemotherapy for Localized Disease

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1st Intergroup Ewing Sarcoma Study (IESS-I)

1973-1978 (Nesbit et al. JCO 1990)

• 342 patients: VAC / VACD / VACD+WLI

• 5 yr RFS 24% / 60% / 44% respectively

Conclusion of IESS-I:

1. Doxorubicin is important

2. Potential role of WLI

North America

IESS-I (Nesbit et al. JCO 1990)

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North America


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2nd Intergroup Ewing Sarcoma Study (IESS-II)

1978-1982 (Burgert et al. JCO 1990)

• 214 patients; Localized non-pelvic

• VACD - Higher dose q3w VS Low dose wkly

• 5 yr EFS 73% VS 56%

Conclusion of IESS-II:

1. Dose intensity is important

North America

IESS-II (Burgert et al. JCO 1990)

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North America

Higher initial doxorubicin dose intensity


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POG/CCG INT-0091 (Grier et al. NEJM 2003)1988-92

• VDC only VS VDC-IE

• Localized (n=398): 5 yr EFS 54% VS 69%

Conclusion of INT-0091:

1. VDC-IE : New North American standard of

care for patients with localized Ewing.

VCR 2mg/m2 (max2mg), Dox 75mg/m2 bolus, CPM 1.2g/m2

Ifos 1.8g/m2 x 5 days (9g/m2/course), VP16 100mg/m2 x 5 days

Dactinomycin 1.25mg/m2 when Dox > 375mg/m2

Q3wks x 17 courses

North America


23

POG/CCG INT-0154 (Granowetter et al. JCO 2009)

North America

VDC/IE –

standard (over

48wks) VS

Intensified

Cyclo/Ifos (over

30wks); similar

total doses


24

POG/CCG INT-0154 (Granowetter et al. JCO 2009)

• 5-yr EFS 72.1% (n=231) VS 70.1% (n=247)

Conclusion of INT-0154 (1995-98):

1. Intensified dosing of alkylating agents

• did not improve outcome.

• increased toxicities.

North

America


25

COG AEWS0031 (Womer et al. JCO 2012) 2001-5

• studied the value of increasing dose intensity

by interval compression

• VDC/IE q2wks VS q3wks

• n=568; same cumulative; Similar toxicities

• 5-yr EFS 73% VS 65% (p=0.045)

North

America

COG AEWS0031 (Womer et al. JCO 2012)

26

North America

(~42 weeks)

(~29 weeks) Interval compressed

Mean cycle duration: Regimen A 22.45 +/- 4.87 days; Regimen B 17.29 +/- 5.40 days (p<0.001)


27

North America

(~42 weeks)

(~29 weeks) Interval compressed


28


VDC/IE with interval compression (+GCSF) is

now the current standard for localized Ewing

Sarcoma in North America

Unfavorable prognostic factors:

older patients (>18), pelvic location

North America


29

North America

Drug Per Cycle Total Cumulative

Vincristine 2mg/m2 (max 2mg) 14mg/m2

Doxorubicin 75mg/m2 over 48hrs 375mg/m2

Cyclophosphamide 1.2g/m2 8.4g/m2

Ifosfamide 1.8g/m2/day x 5 days (9g/m2/cycle)

63g/m2

Etoposide 100mg/m2/day x 5 days (500mg/m2/cycle)

3.5g/m2


30

COG AEWS1031 (Ongoing Phase III)

• Addition of VTC

(vincristine/topotecan/cyclophosphamide) to

standard VDC/IE interval compressed backbone

North America


31


32

VACA (VACD) VAIA (VAID) EVAIA (EVAID) VIDE


33

Non-Randomized Studies Chemo Results

UKCCSG ET-1 (1978-1986) (Craft et al. EJC 1997)

VACD 45/120 alive

CESS-81 (1981-1985) (Jurgens et al. Cancer 1988)

VACD 93 patients. 5-yr DFS 55%. Worse if >100ml or > 10% viable.

CESS-86 (1986-1991) (Paulussen et al. JCO 2001)

VACD (<100ml) VAID (≥100ml or axial)

301 patients; 10-yr DFS 52%. Multivariate – VAID superior.

SFOP EW88 (1988-1991) (Oberlin et al. BJC 2001)

CD + VA/CD 141 patients. 5yr DFS 58%.Worse if > 5% viable tumour.

Europe


34

EICESS-92 (Paulussen et al. JCO 2008) 1992 - 1999

• 492 Std Risk (<100ml): VAID + VAID vs VACD

• 3 yr EFS 74% vs 73% (similar outcomes)

• 155 High Risk(>100ml or mets): VAID vs EVAID

• 3 yr EFS 47% vs 52% (not significant)

Europe


35

EURO-EWING 99

Europe Juergens et al/ Pediatr Blood Cancer 2006.


36


37

North America Europe

VDC / IE Interval compressed

VIDE Then VAI or VAC (or BuMel)

Cumulative doses: Vincristine 14 mg/m2

Doxorubicin 375mg/m2 Ifosfamide 63 g/m2 Etoposide 3.5 g/m2 Cyclophosphamide 8.4g/m2

Cumulative doses: Vincristine 21mg/m2 Doxorubicin 360mg/m2 Ifosfamide 102 or 60 g/m2 Etoposide 2.7g/m2 Cyclophosphamide 0 or 10.5

~ 29 weeks ~ 42 weeks


38

SUMMARY

• Doxorubicin is important; Alkylating agents too

• Dose intensity important – give chemo on time

• North America: VDC/IE q2wks

• Europe: VIDE (EuroEwing)

• Expected survival outcome ~ 70-75%

• Better: Smaller tumour; Non-Pelvic; Younger

• Worse: Larger tumour; Pelvic; Older

Ewing Sarcoma:

Chemotherapy (Metastatic Disease)

Metastatic Disease


5 yr EFS 29%

5 yr EFS 19%

5 yr EFS 8%

Chemotherapy for Metastatic Disease

41

POG/CCG INT-0091 (Grier et al. NEJM 2003) 1988-92

• VDC only VS VDC-IE

• 120 patients with mets: 5 yr EFS 22% (no diff)

Conclusion of INT-0091:

1. Addition of IE to VDC does not improve

outcome for patients with metastatic

Ewing

North America

POG/CCG INT-0091 (Grier et al. NEJM 2003)

42

North America

VDC-IE

VDC-IE

VDC

VDC

Non-metastatic

Metastatic

Chemotherapy for Metastatic Disease

43

POG/CCG INT-0091 (Miser et al. PBC 2007) 1988-92

• Additional Arm C (metastatic) – dose intensified

cyclophosphamide, ifosfamide and doxorubicin

• 60 patients: 5 yr EFS 28% OS 29%; 3 toxic

deaths; 6 SMN (died).

Conclusion of INT-0091: Intensified chemo -

more toxic but outcome not better.

North America

Metastatic Disease – High Dose Therapy?

44

Study PatieLants

Conditioning Results

CCG 7951 Meyers et al. JCO 2001.

32 patients; bone or marrow mets

Melphalan Etoposide TBI

2 yr EFS 20%

French Oberlin et al. JCO 2006.

45 patients; bone or marrow mets

Busulfan Melphalan

EFS 18%

MetaEICESS “HyperME” * Burdach et al. Ann Oncol 2000.

17 patients; multifocal primary Ewing

Melphalan Etoposide TBI

Only 1/17 event free survivor

MetaEICESS “TandemME” Burdach et al. JCO 2003.

17 patients; multifocal primary Ewing

Melphalan Etoposide

4/17 event-free survivors

* Allogeneic or autologous stem cells

Metastatic Disease

45

Role of high dose therapy (“megatherapy”)

- Difficult to determine benefit

- Selection of patients to go for high dose therapy

o Most studies only include patients who achieve

second remisssion

Busulfan

46

Significant toxicities

- Lung fibrosis

- VOD / SOS

- Irreversible transverse myelitis causing tetraplegia

Contraindicated if previous / anticipated irradiation to

axial sites / lungs / brain / spinal cord (>30Gy)

Treosulfan

-Much better safety profile

-Promising in vitro activity

Lung Mets Only

47

Euro-EWING-Intergroup - EE99 • Ongoing study o isolated lung mets

• Randomisation (R2 pulm) - consolidation phase o VAI chemo + WLI o OR BuMel HDT with SCT (no WLI)

North America

Europe

48

North America

Europe

49

Extra-pulmonary Mets

50

Euro-EWING 99 (Ladenstein et al. JCO 2010)

• 281 patients with extrapulmonary mets

• 169 (60%) HDT/SCT – BuMel 136/169 (80%)

o Remission status before HDT affects EFS

• CR before HDT – 3 yr EFS 57%

• PR before HDT – 3 yr EFS 32%

• SD / PD before HDT – 3 yr EFS 24%

• Whole cohort 3yr EFS (281 patients) 27%

Metastatic Ewing Sarcoma

51

• Outcome remains poor. No good options yet…

• Isolated lung mets (Euro Ewing Intergroup)

o Induction with VIDE

o Consolidate with VAI/WLI versus BuMel

• Extrapulmonary mets – even worse

o Further intensifying chemo – not working

o HDT ?? May benefit those who achieve CR

Ewing Sarcoma:

Chemotherapy (Recurrent /

Refractory Disease)

Recurrent / Refractory Disease

53

• A third of patients will develop relapse

• Metastatic disease – higher risk for relapse

• Very dismal outcome – 5yr EFS ~10%

• Time to recurrence most prognostic (INT0091)

o Relapse > 2yrs from initial diagnosis

• Response to salvage treatment also prognostic

• No standard / established treatment regimen

Recurrent Disease


Recurrent Disease - Chemotherapy

55

Factors to consider:

1. Prior treatment

2. Organ function

3. Active drug combinations

Recurrent Disease – Conventional Salvage Options

56

1. Topotecan / Cyclophosphamide

2. Irinotecan / Temozolomide

3. Ifosfamide / Etoposide

4. High dose Ifosfamide 15g/m2

5. Ifosfamide / Carboplatin / Etoposide (ICE)

6. Gemcitabine / Docetaxel

Recurrent Disease – High Dose Therapy

57

Role of high dose therapy (“megatherapy”)

- Difficult to determine benefit

- Selection of patients to go for high dose therapy

o Most studies only include patients who achieve

second remisssion

Novel Strategies

58

• Conventional chemotherapy only cures 70-75% of

localized ESFT and 25% of those with mets

• Limit to increasing dose intensity of cytotoxics

• Tumour biology and druggable targets

• Era of targeted therapies

o More targeted and more effective

o Less toxic

Novel Strategies

59

• Disappointing results so far o TKI (some ESFT cell lines cKIT+ PDGFR+) o HDAC inhibition o Trabectedin

• Potential benefit ? o PARP inhibition (Olaparib – syngergism with TMZ) o IGF-1 and mTOR pathway (co)inhibition – (e.g.

Cixutumumab + Temsirolimus) o Anti-angiogenic approaches (e.g. VBL + Celecoxib) o Immunotherapy – NK cell, dendritic cell vaccine o Zoledronic acid +/- chemo

Ewing Sarcoma: Last Words…

Late Effects

61

1. Orthopedic

2. Pelvic / GI

3. Second malignant neoplasm

• Therapy-related MDS / AML

(1-2%; 2-5yrs)

• Solid tumour e.g. Osteosarcoma

4. Cardiotoxicity

5. Renal / Tubular toxicity

6. Infertility

Adult Patients

62

• Same principles apply

• Older adults may not tolerate intensive

chemotherapy that well

SUMMARY

63

Induction

VDC/IE VIDE

Consolidation

VDC/IE VAC vs VAI vs BuMel (pr)

Localized

Induction

VIDE

Consolidation

VAI vs BuMel

Lung Mets Only

Induction

VIDE

Consolidation

HDT (BuMel)

Other Mets

Conventional Salvage Chemo

Relapse / Refractory

CR

Novel / Experimental

CR

Disease Prior Treatment Organ Function Response to treatment

Thank you

< single image >

4.3cm x 5.5cm

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Optimal Chemotherapy in Untreated and Refractory Ewing's ...€¦ · Optimal Chemotherapy in Untreated and Refractory Ewing's Sarcoma 2nd Singapore ... UKCCSG ET-1 (1978-1986) (Craft