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Current management of Ewing sarcoma in children and adolescents Marie-Dominique Tabone 1, Odile...
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Transcript of Current management of Ewing sarcoma in children and adolescents Marie-Dominique Tabone 1, Odile...
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
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
From Campanacci et al, 785 cases-Bologna
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Introduction (2)
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)
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)
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
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)
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
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
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)
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)
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%)
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
«EURO-EWING 99» Protocol (1)
GPOHF D
Europe-adultes
UK
CH POG
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%
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)
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
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)
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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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
• 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)
«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)
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
AEWS 0031 : COG protocol (2)• Toxicities and number of hospital days similar
in both group
AEWS 0031 : COG protocol (3)
• 3-Years EFS 65 % in regimen A; 76% in regimen B (p=0.028)
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
• 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)
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…
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
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
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