Management of Ewing sarcoma family of tumors: Current scenario and unmet need

Table 1 Randomized studies of chemotherapy in upfront treatment of Ewing sarcoma family tumors

Study	Patients (n)	Intervention1	Outcome	P	Comments
IESS I[78]	Localized (342)	(1) VAC	5-yr RFS 24%		Beneficial of doxorubicin and benefit of lung RT
		(2) VACD	60%	--
		(3) VAC + Lung RT	44%
IESS II[29]	Non-pelvic, localized (214)	VACD	5-yr RFS	0.04	Intermittent, high dose better
		(1) Intermittent, high dose (3 weekly)	73%
		(2) Continuous, moderate dose (weekly)	56%
POG-CCSG INT-0091[6]	Localized (398)	(1) VDC	5-yr RFS 54%	0.005	IE is beneficial in addition to VDC in localized but not in metastatic disease
		(2) VDC + IE	69%
	Metastatic (120)	(1) VDC	22%	NS
		(2) VDC + IE	22%
POG-CCSG	Localized (478)		5-yr EFS	NS	Dose intensification not effective
INT-154[32]		(1) VDC + IE (standard)	70%
		(2) VDC + IE (intensified)	72%
COG AEWS0031[33]	Localized (568)	(1) VDC + IE (3 weekly)	5-yr EFS 65%	0.05	3-weekly better than 2-weekly with no increase in toxicity
		(2) VDC + IE (2 weekly)	73%
EICESS92[7]	n = 155	SR (localized and < 100 mL) 4#VAIA → 8# VAIA vs 8#VACD	3-yr EFS 73% vs 74%	NS	Cyclophosphamide and ifosfamide is similar in efficacy in SR patients
	n = 492	HR (metastatic, > 100 mL)	47% vs 52%	0.12	No benefit of etoposide in HR patients
		14# VAIA vs 14#EVAIA
Euro-Ewing 99[49]	Detailed in Table 2

¹All chemotherapy regimens mentioned in the table is used in neoadjuvant setting followed-by local therapy (in terms of surgery and/or radiotherapy) followed by further adjuvant chemotherapy. EFS: Event free survival; EVAIA: Etoposide, vincristine, dactinomycin, ifosfamide, doxorubicin; HR: High risk; IE: Ifosfamide, etoposide; NS: Not significant; RFS: Relapse free survival; RT: Radiotherapy; SR: Standard risk; VAC: Vincristine, dactinomycin, cyclophosphamide; VACD: Vincristine, dactinomycin, cyclophosphamide, doxorubicin; VAIA: Vincristine, dactinomycin, ifosfamide, doxorubicin; VDC: Vincristine, doxorubicin, cyclophosphamide.

Table 2 Euro-Ewing 99 trial design and details

Randomized arm	Patients	n	Randomization	3-yr EFS
Arm 1	SR, Localized (good histologic response, < 200 mL + RT)	856	6#VIDE + 1#VAI f/b 7#VAI vs 7#VAC	78% vs 75%
Arm 2	HR, Localized (poor histologic response, ≥ 200 mL and RT alone)	---	6#VIDE + 1#VAI f/b 7# VAI vs BuMel (n = 281)	45% (BuMel)
	Lung metastasis only	---	6#VIDE + 1#VAI f/b 7# VAI + WLI vs BuMel	---
Arm 3	Extrapulmonary metastasis	---	6#VIDE + 1#VAI f/b BuMel/TreoMel vs clinical trial	---

BuMel: Busulphan and melphalan; EFS: Event free survival; f/b: Followed-by; HR: High risk; n: Number; RT: Radiotherapy; SR: Standard risk; TreoMel: Tresulphan and melphalan; VAC: Vincristine, dactinomycin, cyclophosphamide; VAI: Vincristine, dactinomycin, ifosfamide; VIDE: Vincristine, ifosfamide, doxorubicin, etoposide; WLI: Whole lung irradiation.

Table 3 Selected studies of high dose chemotherapy with stem cell rescue in Ewing sarcoma family tumors

Study (type)	Disease setting	n	Conditioning	Conclusion
CESS (restrospective)[78]	Recurrent or progressive disease (HDC after CR or PR)	73	BuMel (15) TreoMel (38) Other (20)	Early relapse - poor prognostic
Société Française des Cancers de l’Enfant (prospective)[8]	Metastatic at diagnosis	75	BuMel	Beneficial for lung only or bone metastases
Italian Sarcoma Group/Scandinavian Sarcoma Group IV Protocol (phase II)[9]	Metastatic at diagnosis (lung or single bone metastasis)	79	BuMel ± TBI	HDC with WLI is effective
Italian Sarcoma Group/Scandinavian Sarcoma Group III Protocol (prospective)[34]	High risk, localized	126	BuMel	Effective and feasible in patients with PR after chemotherapy
Euro-Ewing 99 (prospective)[10]	Metastatic at diagnosis	169	BuMel (123) Mel (15) Others (20)	Effective in Bone and Bone marrow metastases
EBMT registry (retrospective)[79]	Metastatic and HR, localized (n = 2411) Recurrent (n = 719)	3695	Heterogeneous regimens	Prognostic factors: Age, response to treatment, BuMel regimen

BuMel: Busulphan and melphalan; CR: Complete response; ESFT: Ewing sarcoma family of tumors; HDC: High dose chemotherapy; HR: High risk; n: Number; PR: Partial response; TBI: Total body irradiation; TreoMel: Treosulphan and melphalan; WLI: Whole lung irradiation.

Table 4 Data on Irinotecan-temozolamide salvage regimen in recurrent/refractory Ewing sarcoma family tumors

Ref.	n	Irinotecan schedule	ORR (n)	Toxicity (grade 3 and 4)
Kurucu et al[65]	20	20 mg/m2 (D1-5 and D8-D12)	55% (11)	Diarrhea - 9.2%
				Neutropenia - 11.3%
McNall-Knapp et al[64]	25	15 mg/m2vs 20 mg/m2 (D1-5 and D8-D12)1	20% (5)	Diarrhea - 5%
Raciborska et al[63]	22	50 mg/m2 (D1-D5)1	50% (12)	Diarrhea - 15%
				Hematological - 10%
Wagner et al[62]	16	10-20 mg/m2 (D1-5 and D8-D12) - 3 weekly vs 4 weekly	25% (4)	Diarrhea - 11%
Casey et al[61]	20	20 mg/m2 (D1-5 and D8-D12)	63%	Diarrhea - 4.5%
				Hematological - 22%

¹With vincristine. ESFT: Ewing sarcoma family of tumors; n: Number; ORR: Overall response rate.