Optimal Chemotherapy in Untreated and Refractory Ewing's ...€¦ · Optimal Chemotherapy in...
Transcript of Optimal Chemotherapy in Untreated and Refractory Ewing's ...€¦ · Optimal Chemotherapy in...
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
11 UKCCSG/MRC, CESS Trials. Coterill et al. JCO 2000.
Prognostic Factors
12 UKCCSG/MRC, CESS Trials. Coterill et al. JCO 2000.
Prognostic Factors
13 UKCCSG/MRC, CESS Trials. Coterill et al. JCO 2000.
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.
15
Chemotherapy
Localized / Metastatic / Recurrent
16
North America Europe
Ewing Sarcoma:
Chemotherapy (Localized Disease)
Chemotherapy for Localized Disease
18
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)
19
North America
Chemotherapy for Localized Disease
20
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)
21
North America
Higher initial doxorubicin dose intensity
Chemotherapy for Localized Disease
22
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
Chemotherapy for Localized Disease
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
Chemotherapy for Localized Disease
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
Chemotherapy for Localized Disease
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)
COG AEWS0031 (Womer et al. JCO 2012)
27
North America
(~42 weeks)
(~29 weeks) Interval compressed
Chemotherapy for Localized Disease
28
COG AEWS0031 (Womer et al. JCO 2012)
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
COG AEWS0031 (Womer et al. JCO 2012)
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
Chemotherapy for Localized Disease
30
COG AEWS1031 (Ongoing Phase III)
• Addition of VTC
(vincristine/topotecan/cyclophosphamide) to
standard VDC/IE interval compressed backbone
North America
Chemotherapy for Localized Disease
31
Chemotherapy for Localized Disease
32
VACA (VACD) VAIA (VAID) EVAIA (EVAID) VIDE
Chemotherapy for Localized Disease
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
Chemotherapy for Localized Disease
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
Chemotherapy for Localized Disease
35
EURO-EWING 99
Europe Juergens et al/ Pediatr Blood Cancer 2006.
Chemotherapy for Localized Disease
36
Chemotherapy for Localized Disease
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
Chemotherapy for Localized Disease
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
40 UKCCSG/MRC, CESS Trials. Coterill et al. JCO 2000.
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
54 UKCCSG/MRC, CESS Trials. Coterill et al. JCO 2000.
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
This presentation contains information which is confidential and/or legally privileged. No part of this presentation may be disseminated, distributed, copied, reproduced or relied upon without the expressed authorisation of SingHealth.