Current management of Ewing sarcoma in children and adolescents

1
Current management of Ewing sarcoma in children
and adolescents

• Marie-Dominique Tabone1, Odile Oberlin2
• 1Unité dhémato-oncologie pédiatrique, Hôpital A
  Trousseau, Paris, France
• 2Service doncologie pédiatrique, Institut
  Gustave Roussy, Villejuif, France

2
Introduction (1)

• Second most common malignant bone tumor in
  children and young adults
• Extraosseous Ewing sarcoma are not exceptional
• Rare in black and asian populations
• Lung, bone and/or bone marrow metastases at
  diagnosis in 20 to 30 of patients

3
Introduction (2)
From Campanacci et al, 785 cases-Bologna
4
Introduction (3)
Ewing sarcoma histologic and immunohistochemical
features

• and (B) Ewings sarcoma appears as sheets of
  monotonous round cells (Hematoxylin and eosin)
• (C) Strong, diffuse membrane staining is
  observed with MIC2 (CD99)

Bernstein, et al. Oncologist 2006
5
Introduction (4)
The reciprocal translocation between chromosomes
11 and 22 results in the formation of an ews-fli1
fusion gene on the abnormal chromosome 22 that
codes for a chimeric transcription factor
Bernstein et al. Oncologist 2006
6
Current goals in management of Ewing sarcoma

• Multimodal therapy improved survival from 10 in
  late 1960s to 65 today
• Prognosis of patients with metastases and/or
  recurrent disease remains poor
• Major goals nowadays include
• Improvement of local and metastatic control
• Better stratification of risk groups
• New therapeutic strategies for high risk patients
• Prevention of late effects

7
What did we learn in Ewing sarcoma from past
protocols ? (1)
Saint Jude Memphis ES 79 protocol
Induction CT
Maintenance CT
Local therapy
- Complete surgery RT 0 - No surgery
good response RT 35 Gy - No surgery
poor response RT 50 Gy
Actino x 6 VCR x 11 Cyclo x 7 x
6 Adria x 1
Cyclo x 7d Adria x 1d week 1, 3, 5, 8, 11
8
What did we learn in Ewing sarcoma from past
protocols ? (2)

• ES 79 results Hayes et al, 1989
• 50 evaluable patients, 17 relapsed (3 metastatic,
  4 local metastatic, 10 local)
• Size of primary tumor was shown to be a
  prognostic factor 82 3-years DFS (lt 8 cm)
  versus 64 (gt 8 cm) 5-years DFS 66
• EW 88 french protocol Oberlin et al, 2001
• Chemotherapy regimen ES 79
• Intensified local treatment
• 114 patients, 57 primary gt 100 ml
• 5-years OS 66 5-years DFS 58
• Histological response shown to be a pronostic
  factor

9
What did we learn in Ewing sarcoma from past
protocols ? (3)
Resections performed after chemotherapy allow to
evaluate the histological response to induction
chemotherapy
Huvos grading system mean percentage of
residual cells
11
10
EW 88 DFS according to histological response
lt 5 (n 61) 75
5 to 30 (n 14) 40
gt 30 (n 15) 20
p lt 0.0001
Mois
11
What did we learn in Ewing sarcoma from past
protocols ? (4)

• ES 87 protocol Meyer et al, 1992
• Ifosfamide/etoposide as upfront window therapy
• 26 patients, 4 CR, 21 PR overall response rate
  96
• EW 93/97 protocol
• Is the prognosis of the intermediate group
  improved by addition of Ifosfamide/etoposide?
• Is it possible to improve the survival of poor
  responders by HD chemotherapy as consolidation
  after surgery ?

Busulfan (600 mg /m2) Melphalan (140 mg
/m2) Stem cell transplant
12
What did we learn in Ewing sarcoma from past
protocols ? (5)
Historical comparison of outcome of poor
responders localized patients (gt 30 cells)
41 patients 33 HD chemo
49
EW 93
15 patients
EW 88
20
HD chemo may improve the prognosis of these
patients but this should be confirmed by a
randomized trial
13
What did we learn in Ewing sarcoma from past
protocols ? (6)
lt 100 ml (119)
72
Surgery Radiation therapy
60
gt 100 ml (160)
62
lt 100 ml (79)
gt 100 ml (28)
29
Radiation therapy alone
Local therapy as an impact on survival (EFS of EW
88 / 93 studies) surgery has a significant
impact on prognosis of large primaries
14
What did we learn in Ewing sarcoma from past
protocols ? (7)
Pooled French and German data
In patients treated by chemotherapy alone,
histological response is the single pronostic
factor volume has no added impact
15
Other prognostic indicators (1)

• Review of St Jude studies Rodriguez-Galindo et
  al, 2007
• In patients with localized disease
• Age 83 5-years OS lt 14 years versus 65 in
  patients older than 14 years
• Type of local control 5-years OS 65, 77, 92
  respectively for RT alone, surgery alone and
  surgery RT
• In patients with metastatic disease, those with
  isolated lung metastases fared somewath better
  than those with extrapulmonary lesions (5-years
  OS 54 versus 27)

16
Other prognostic indicators (2)

• Schleiermacher et al, 2003
• 125 patients with localized disease
• Detection of EWS-FLI-1 or EWS-ERG transcripts by
  TR-PCR in blood and/or BM is associated with an
  increased risk of systemic relapse
• Type of fusion genes (Zoubeck et al, 1996 de
  Alava et al, 1998) and secondary structural
  chromosomal changes (Maurici et al, 1998
  Zielenska et al, 2001 Hattingert et al, 2002)?
• Pronostic impact of type of fusion genes not
  confirmed in EuroEwing patients

17
EURO-EWING 99 Protocol (1)
GPOH
D
F
UK
Europe-adultes
CH
POG
18

• EURO-EWING 99 Protocol (2)
• Intensive induction chemotherapy 6 VIDE cycles

day 1 day 2 day 3 Vincristine 1.5
mg/m² x Ifosfamide 3 g/m²/d x x x Doxorubic
in 20 mg/m²/d x x x Etoposide
150 mg/m²/d x x x

• Safety assessment Juergens et al, 2006
• 4746 courses in 851 patients
• Major adverse reactions were myelosuppression
  and infections 5 VIDE related death 0.1 GFRlt
  39ml/mn/1.73m2 1.9 tubular phosphate
  reabsorption rate lt 0.8 2.5 LVSF lt 28

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EURO-EWING 99 Protocol (3)
Risk groups for localized tumors
Tumor resected after
Unresected chemotherapy only Tumor lt
10 cells gt 10 cells lt 200 ml
gt 200 ml Standard High
risk group risk group
20
EURO-EWING 99 Protocol (4)
Treatment of localized tumors
Induction chemo.
Consolidation chemotherapy
R A D I O T H E R A P Y
VAI x 7vs VAC x 7
S U R G E R Y
Good histo. response (lt 10 cells) Unresected
small tumor (lt 200 ml)
VIDE x 6
VAI
VAI x 7vs Bu-Mel
Poor histo. response (gt 10 cells) Unresected
large tumor (gt 200 ml)
21
EURO-EWING 99 Protocol (5)
Treatment of isolated lung metastases
(50 of the metastatic patients)
Comparison of efficacy and toxicity
Comparison of efficacy and toxicity of
8 cycles IVA lung radiation
therapy VIDE x 6 1 VAI Busulfan-Melphalan

22
EURO-EWING 99 Protocol (6)
Treatment of metastases other than lung or
pleura (R3 protocol)
No initial agreement for these patients Patients
were treated by 6 cycles of VIDE
Busulfan-Melphalan after good response to VIDE
23
EURO-EWING 99 Protocol (7)
Whole cohort 192 pts
R3 arm
29
25
Patients who received Bu-Mel 102 pts
Inclusion in this arm stoped in 2005 due to lack
of significant improvement in survival
35
30
24
EURO-EWING 99 Protocol (8)

• Severe toxicities observed in patients that
  received spine or bowel radiotherapy and busulfan
• Spine irradiation should be limited to 30 gray,
  and bowel irradiation should also be limited in
  dose and field
• Conventional chemotherapy should be prefered to
  Bu-Mel if local treatment includes a large volume
  of the bowel irradiation

25
EURO-EWING 99 Protocol (9)

• Radiotherapy
• Before surgery to be discussed in case of poor
  clinical response after 2 VIDE
• After surgery (30 to 54 grays)
• In case of uncomplete resection
• In case of poor histological response (gt 10
  residual cells)
• Costal tumor with pleural effusion and spine
  tumor
• No surgery (54 to 64 grays)

26
AEWS 0031 COG protocol (1)

• Womer et al, ASCO 2008
• Could chemotherapy intensification through
  interval compression improve outcome ?
• Randomized trial
• Patients lt 50 years
• Extra dural localized
• Ewing sarcoma
• 284 patients in each
• group

27
AEWS 0031 COG protocol (2)

• Toxicities and number of hospital days similar in
  both group

28
AEWS 0031 COG protocol (3)

• 3-Years EFS 65 in regimen A 76 in regimen B
  (p0.028)

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Overview of new therapeutic agents in Ewing
sarcoma (1)

• Conventional chemotherapy
• Cyclophosphamide/topotecan 2 CR 4 PR / 17
  patients in phase II study (Saylors et al, 2001)
• Temozolomide/irinotecan 1 CR 3 PR / 14
  patients (Wagner et al, 2007)
• Treosulfan (busulfan analogue)/melphalan first
  results presented at Berlin SIOP 2008 relevance
  to be confirmed with longer follow-up and larger
  cohort of patients results do not seem better
  than busulfan for patients with extra pulmonary
  metastatic disease

30
Overview of new therapeutic agents in Ewing
sarcoma (2)

• Alternate approaches
• Mammalian target of rapamycin (m-TOR) inhibitors
• m-TOR is a protein kinase that plays a pivotal
  role in the control of cell growth and
  development, and Ewing sarcoma pathobiology
  (Mateo-Lozano et al, 2003)
• Rapamycin (sirolimus) and rapamycin analogues are
  currently being evaluated (MacKenzie et al, 2007
  Mita et al, 2008)
• IGFR-1 inhibitors
• IGF1 is a direct target of Ewing sarcoma fusion
  proteins (Cironi et al, 2008)
• In response to the stimulatory ligands IGF-1 and
  IGF-2, IGFR-1 signaling results in proliferative
  and antiapopototic effects (Ryan et al, 2008)
• Several on-going phase I/II clinical trials
  evaluate various compounds (monoclonal antibodies
  or small molecules) that target IFGR-1

31
Overview of new therapeutic agents in Ewing
sarcoma (3)

• Anti VEGF receptors therapy
• Angiogenesis is essential for the growth,
  progression and metastasis of solid tumors
• VEGF have been detected at elevated levels in
  serum and/or urine of adults and children with
  cancer (Tabone et al)
• In mouse model, blocking VEGFR- 2 reduce Ewing
  sarcoma growth and increase tumor cell apoptosis
  (Zhou et al, 2007)
• Antisense oligonucleotides targeted against
  junction EWS-FLI-1 oncogen
• Inhibition of tumor growth in nude mice by
  antisense oligonucleotides delivered intra
  tumorally by nanocapsules or nanospheres
  (Maksimenko et al, 2005)
• Bisphosphonates, immunotherapy

32
Management and prevention of late effects (1)

• Orthopedic sequelae linked to surgery and/or
  radiation induced growth disturbances
• Second malignancies
• Radio induced bone sarcoma
• Secondary leukemia
• Anthracycline dose-related cardiomyopathy
• Alkylating agents and/or radiation associated
  infertility
• Renal tubular dysfonction caused by ifosfamide

33
Management and prevention of late effects (2)

• Euro-Ewing 99 include for standard risk patients
  a randomized comparison of late toxicity of
  maintenance chemotherapy 7 cycles VAC (more
  toxic for fertility) versus 7 cycles IVA (more
  toxic for kidney)
• Sperm cryopreservation should be offered to
  postpubertal boys, ovarian transposition or
  cryopreservation in girl when appropriate
• Abdominopelvic mesh compartmentalization (Haider
  et al, 2006)
• Close monitoring of secondary malignancies
  incidence

34
Conclusions

• Increased knowledge of underlying molecular basis
  of Ewing sarcoma
• On-going clinical trials test novel therapies
  designed to thwart critical pathways responsible
  for this malignancy
• We can hopefully expect that in the future,
  combined treatment including these targeted
  therapies will improve survival of high risk
  patients