current management of ewing sarcoma in children and adolescents marie-dominique tabone 1, odile...
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Current management of Ewing sarcoma in children and adolescents
Marie-Dominique Tabone1, Odile Oberlin2
1Unité d’hémato-oncologie pédiatrique, Hôpital A Trousseau, Paris, France
2Service d’oncologie pédiatrique, Institut Gustave Roussy, Villejuif, France
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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
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From Campanacci et al, 785 cases-Bologna
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Introduction (2)
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Bernstein, et al. Oncologist 2006
(A) and (B) : Ewing’s sarcoma appears as sheets of monotonous round cells (Hematoxylin and eosin)
(C): Strong, diffuse membrane staining is observed with MIC2 (CD99)
Ewing sarcoma histologic and immunohistochemical features
Introduction (3)
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Bernstein et al. Oncologist 2006
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
Introduction (4)
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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
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Induction CT Maintenance CT
Cyclo x 7dAdria x 1dweek 1, 3, 5, 8, 11
- Complete surgery RT = 0
- No surgery & good response RT = 35 Gy
- No surgery & poor response RT = 50 Gy
Actino x 6VCR x 11
+
Cyclo x 7 x 6Adria x 1
«Saint Jude» Memphis ES 79 protocol
Local therapy
What did we learn in Ewing sarcoma from past protocols ? (1)
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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 (< 8 cm) versus 64% (> 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 > 100 ml– 5-years OS 66%; 5-years DFS 58% – Histological response shown to be a pronostic factor
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Resections performed after chemotherapy allow to evaluate the histological response to induction chemotherapy
Huvos grading system : mean percentage of residual cells
11 %
What did we learn in Ewing sarcoma from past protocols ? (3)
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< 5 % (n = 61) 75 %
5 to 30 % (n = 14) 40 %
> 30 % (n = 15) 20 %
p < 0.0001
EW 88: DFS according to histological response
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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
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EW 8820 %
49 % EW 93 41 patients33 HD chemo
HD chemo may improve the prognosis of these patients but this should be confirmed by a randomized trial
Historical comparison of outcome of poor responders localized patients (> 30 % cells)
15 patients
What did we learn in Ewing sarcoma from past protocols ? (5)
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72 % < 100 ml (119)
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62 % < 100 ml (79)
29 % > 100 ml (28)
Surgery + Radiation therapy
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
> 100 ml (160)
What did we learn in Ewing sarcoma from past protocols ? (6)
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Pooled French and German data
In patients treated by chemotherapy alone, histological response is the single pronostic factor: volume has no added impact
What did we learn in Ewing sarcoma from past protocols ? (7)
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Other prognostic indicators (1)
• Review of St Jude studies: Rodriguez-Galindo et al, 2007– In patients with localized disease
• Age: 83% 5-years OS < 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%)
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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
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«EURO-EWING 99» Protocol (1)
GPOHF D
Europe-adultes
UK
CH POG
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day 1 day 2 day 3
Vincristine 1.5 mg/m² x
Ifosfamide 3 g/m²/d x x x
Doxorubicin 20 mg/m²/d x xx
Etoposide 150 mg/m²/d x x x
«EURO-EWING 99» Protocol (2)
• Intensive induction chemotherapy : 6 VIDE cycles
• Safety assessment: Juergens et al, 2006
– 4746 courses in 851 patients
– Major adverse reactions were myelosuppression and infections; 5 VIDE related death; 0.1 % GFR< 39ml/mn/1.73m2; 1.9 % tubular phosphate reabsorption rate < 0.8; 2.5 % LVSF < 28%
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Risk groups for localized tumors
Tumor resected after Unresectedchemotherapy only Tumor
< 10 % cells > 10 % cells < 200 ml > 200 ml
Standard High risk group risk group
«EURO-EWING 99» Protocol (3)
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Good histo. response (< 10 % cells)Unresected small tumor (< 200 ml)
VAI x 7
vs
VAC x 7
VAI x 7
vs
Bu-Mel
VIDE x 6
+
RADIOTHERAPY
Induction chemo.
Consolidation chemotherapy
+
SURGERY
VAI
Poor histo. response (> 10 % cells)Unresected large tumor (> 200 ml)
«EURO-EWING 99» Protocol (4)
Treatment of localized tumors
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Comparison of efficacy and toxicity of
8 cycles IVA + lung radiation therapyVIDE x 6
1 VAI + Busulfan-Melphalan
Comparison of efficacy and toxicity
Treatment of isolated lung metastases
(50 % of the metastatic patients)
«EURO-EWING 99» Protocol (5)
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No initial agreement for these patients
Patients were treated by
6 cycles of VIDE
+ Busulfan-Melphalan after good response to VIDE
Treatment of metastases other than lung or pleura(R3 protocol)
«EURO-EWING 99» Protocol (6)
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25 %
35 %
30 %
Whole cohort : 192 pts
Patients who received Bu-Mel 102 pts
«EURO-EWING 99» Protocol (7)
R3 arm
Inclusion in this arm stoped in 2005 due to lack of significant improvement in survival
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• 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
«EURO-EWING 99» Protocol (8)
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«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 (> 10 % residual cells)
• Costal tumor with pleural effusion and spine tumor
– No surgery (54 to 64 grays)
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AEWS 0031 : COG protocol (1)
• Womer et al, ASCO 2008– Could chemotherapy intensification through interval
compression improve outcome ?– Randomized trial
• Patients < 50 years
• Extra dural localized
Ewing sarcoma
– 284 patients in each
group
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AEWS 0031 : COG protocol (2)• Toxicities and number of hospital days similar
in both group
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AEWS 0031 : COG protocol (3)
• 3-Years EFS 65 % in regimen A; 76% in regimen B (p=0.028)
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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
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• 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
Overview of new therapeutic agents in Ewing sarcoma (2)
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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…
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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
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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
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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