24. Ewing’s Family of Tumors
24.1 General considerations
The Ewing’s family of tumors includes classical Ewing’s sarcoma of bone and soft tissues, peripheral primitive neuroectodermal tumors (pPNET), Askin tumor, and other less frequent variants, all sharing the presence of chromosomal translocations which result in gene fusions between EWS gene and a member of the ETS family of transcription factors (mainly FLI1 or ERG).
Ewing’s tumors are typically treated with a multimodality approach including conventional dose chemotherapy, radiotherapy and/or surgery. Lung irradiation in patients with isolated lung metastases is associated with a reduced risk of lung recurrence and overall relapse free survival. Patients with combined metastases (e.g.bone,bone marrow, lung) have a worse prognosis.
“Megatherapy” regimens with hematopoietic stem cell rescue so far have failed to improve the results.
Patients preferably should be entered into one of the carefully designed multicentre,international trials, which are likely to recruit sufficient numbers to answer their specific questions. Only a few representative examples of chemotherapy regimens of the complex, multidisciplinary approaches are, therefore,outlined here.
Literature: for review e.g.
De ALAVA and PARDO, Int. J. Surg.Pathol. 9(2001):7-17
KUSHNER and MEYERS,J.Clin. Oncol.19(2001):870-880 (dose-intensive/myeloablative therapy)
PINKERTON et al, Eur.J.Cancer 37 (2001):1338-1344 (metastatic Ewing’s sarcoma)
WEBER and SIM,J.Orthop. Sci.6 (2001):366-371
WEST, Curre.Opin.Oncol.12(2000):323-329
24.2 Ewing’s sarcoma
24.2.1 Study IESS-MD1
Phase 1 (weeks 0-8)
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Vincristine 1.5mg/m² i.v. d 1,8,15,22,29,36 (max 2 mg) |
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Cyclophosphamid 500mg/m² i.v. d 1,8,15,22,29,36 |
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Doxorubicin 60mg/m² i.v. d 36 |
Plus radiotherapy
Phase 2 (weeks9-68)
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Dactinomycin 0.015mg/kg i.v. d 1-5 |
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Vincristine 1.5mg/m² i.v. d 15,22,29,36,43 (max 2 mg) |
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Cyclophosphamide 500mg/m² i.v. d 15,22,29,36,43 |
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Doxorubicin 60mg/m² i.v. d 43 |
To be repeated after a therapy-free interval of 3 weeks 6 times
Phase 3 (weeks 69-98)
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Dactinomycin 0.015mg/kg i.v. d 1-5,7 |
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Vincristine 1.5mg/m² i.v. d 15,22,29,36,43 (max 2 mg) |
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Cyclophosphamide 500mg/m² i.v. d 15,22,29,36,43 |
To be repeated after a therapy-free interval of 3 weeks 3 times
Literature:
CANGIR et al,Cancer 66(1990):887-893
NESBIT et al,J.Clin.Oncol.8(1990):1664-1674
In study IESS –MD2 the doxorubicin dose was increased to 75mg/m² and 5-flourouracil was added without an influence on the overall outcome.
24.2.2 VAIA and modifications
EICESS 92
Stratification in standard-risk (no metastases,tumore volume<100ml) and high-risk(all others).
Overall 14 chemotherapy cycles were planned, with local therapy , consisting of surgery and / or radiotherapy after cycle 4.
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Course 1 2 3 4 5 6 7 8 9 10 11 12 13 14
VACA c d c d c d c d c d Arm A SR VAIA a b a b VAIA a b a b VAIA a b a b a b a b a b Arm B
HR EVAIA e f e f EVAIA e f e f e f e f e f Arm C
Week 1 4 7 10 12 13 16 19 22 25 28 31 34 37 40 |
VAIA
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Vincristine 1.5mg/m² i.v.(push) d 1+ 21 (a+b) |
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Doxorubicin 20mg/m² i.v.(4 h inf) d 1-3 (a) |
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Ifosfamide 2000mg/m² i.v.(1 h inf) d 1-3,21-23 (a+b) with mesna uroprotection |
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Dactinomycin 0.5mg/m² i.v.(push) d 21-23 (b) |
VACA
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Phase 3 (weeks 69-98)
To be repeated after a therapy-free interval of 3 weeks 3 times
Literature: CANGIR et al,Cancer 66(1990):887-893 NESBIT et al,J.Clin.Oncol.8(1990):1664-1674
In study IESS –MD2 the doxorubicin dose was increased to 75mg/m² and 5-flourouracil was added without an influence on the overall outcome.
24.2.2 VAIA and modifications EICESS 92 Stratification in standard-risk (no metastases,tumore volume<100ml) and high-risk(all others).
Overall 14 chemotherapy cycles were planned, with local therapy , consisting of surgery and / or radiotherapy after cycle 4.
VAIA
VACA
Ewing’s Family of Tumor 143
EVAIA
Literature: PAULUSSEN et al, Ann.Oncol.9 (1998):275-281(analysis of 171 patients with primary metastatic disease from EICESS studies) and Klin. Padiatr. 211 (1999): 276-283(first results of the European Intergroup Cooperative Ewing’s Sarcoma study EICESS 92. publication in German).
ET-2(UKCCSG/MRC study)
* With mesna uroprotection
IVAD3 to be repeated every three weeks x 4,followed by surgery and/or radiotherapy and VC during radiotherapy, then IVAD2 to be repeated every three weeks x 3,then IVA to be repeated every three weeks x 10 (stop at 52 weeksfrom diagnosis).
Literature: CRAFT et al,J.Clin.Oncol.16(1998):3628-3633
24.3 Peripheral neuroectodermal tumors(PNET) Due to similarities between PNETs and Ewing’s sarcomas a Ewing’s- directed therapeutic approach is considered appropriate.e.g. Induction
To be repeated every 3 weeksx 3 (weeks 0, 3, 6).Followed by
To be repeated every 3 weeks x 3 (weeks 9, 12, 15). Surgery and/or radiotherapy followed on week 17
144 Ewing’s Family of Tumors
Maintenance Alternating cycles of ifosfamide , etoposide (weeks 25, 39, 53) and cylophosphamide, doxorubicin( weeks 28, 31, 42, 45, 56, 59) as for induction and
*Weeks 18*,19,20*, 21,22*, 23,24*,34*, 35,36*,37,38*, 48*,49,50*, 51,52*
Literature: GURURANGAN et al,J.Pediatr. Hematol. Oncol.20(1998):55-61
24.3 Ewing’s family of tumors in adults The natural history and prognosis are not different from those found in children. Pediatric chemotherapy protocols at full dose- e.g.IVAD regimens (see 23.2.2. ET-2)- or the MAID regimen developed for adult soft tissue sarcomas(see 45.2.2.3) can be used.
Literature: ANTMAN et al, Cancer 82(1998): 1288-1295 BACCI et al, Acta Oncol. 39(2000):111-116 (retrospective analysis of patients > 39 years old). FIZAZI et al,J. Clin. Oncol. 16(1998):3736-3743 VERRILL et al, Ann. Oncol.8 (1997):1099-1105) |