Chemotherapy | Triangle

Combinations of chemotherapy, such as cyclophosphamide and topotecan or irinotecan and temozolomide with or without vincristine, are active in recurrent Ewing sarcoma and can be considered for these patients.[9-14]

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Table 7. Results from Studies that Used Cyclophosphamide and Topotecan Regimens to Treat Patients With Relapsed and/or Refractory Ewing Sarcoma
Study Reference	Trial Phase (Total No. of Patients)	Median Age (Range) (y)	CR/PR	RR	Cyclophosphamide (mg/m2)/Topotecan (mg/m2) × d	Other Agents
II = phase II trial; CR = complete response; PR = partial response; R = retrospective; RR = objective response rate; VCR = vincristine.
Saylors et al.[9]	II (17)	13.8 (1–21)	1/3	29%	250 × 5/0.75 × 5	None
Hunold et al.[11]	R (54)	17.4 (3–49)	0/16	30%	250 × 5/0.75 × 5	None
Farhat et al.[15]	R (14)	11 (2–19)	0/3	21%	250 × 5/0.75 × 5	None
Kebudi et al.[16]	R (14)	13 (3–16)	2/5	50%	250 × 5/0.75 × 5	VCR

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These studies were retrospective. Prospective trials with clearly defined eligibility cohorts and intent-to-treat analyses are lacking. When combined, these studies accrued 99 patients and observed 3 complete remissions and 27 partial remissions. The objective response rate was 30%.

Table 8. Results from Studies that Used Temozolomide and Irinotecan Regimens to Treat Patients With Relapsed and/or Refractory Ewing Sarcoma
Study Reference	Trial Phase (Total No. of Patients)	Median Age (Range) (y)	CR/PR	RR	Temozolomide (mg/m2)/Irinotecan (mg/m2) × d × wk	Other Agents
I = phase I trial; II = phase II trial; Acta Onc = Acta Oncologica; An Ped = Annals of Pediatrics; Clin Cancer Res = Clinical Cancer Research; Exp Opin = Expert Opinion Investigational Drugs; Clin Transl Oncol = Clinical and Translational Oncology; BEV = bevacizumab; CR = complete response; IV = intravenous; N/A = not applicable; PBC = Pediatric Blood and Cancer; Ped Hem Onc = Pediatric Hematology and Oncology; PO = oral; PR = partial response; R = retrospective trial; RR = objective response rate; TMS = temsirolimus; UK = unknown; VCR = vincristine.
Wagner et al. (PBC, 2007) [12]	R (16)	18 (7–33)	1/3	29%	100 × 5/IV 10–20 × 5 × 2	None
Casey et al. (PBC, 2009) [13]	R (19)	19.5 (2–40)	5/7	63%	100 × 5/IV 20 × 5 × 2	None
Hernandez-Marques et al. (An Ped, 2013) [17]	R (8)	13 (6–18)	0/3	37%	80–100 × 5/IV 10–20 × 5 × 2	None
Raciborska et al. (PBC, 2013) [14]	R (22)	14.3	5/7	54%	125 × 5/IV 50 × 5	VCR
McKnall-Knapp et al. (PBC, 2010) [18]	I (1)	N/A	0/1	100%	100 × 5/IV 20 × 5 × 2	VCR
Wagner et al. (PBC, 2010) [19]	I (5)	(<21)	1/1	40%	100–150 × 5/PO 35–90 × 5	VCR
Wagner et al. (PBC, 2013) [20]	I (2)	20, 22	1/1	100%	150 × 5/PO 90 × 5	VCR, BEV
Bagatell et al. (PBC, 2014) [21]	I (7)	(<21)	0/1	14%	100–150 × 5/PO 50–90 × 5	TMS
Kurucu et al. (Ped Hem Onc, 2015) [22]	R (20)	14 (1–18)	UK	55%	100 × 5/IV 20 × 5 × 2	None
Anderson et al. (Exp Opin, 2008) [23]	R (25)	15	7/9	64%	100 × 5/IV 10 × 5 × 2	None
Palmerini et al. (Acta Onc, 2018) [24]	R (51)	21 (3–65)	5/12	34%	100 × 5/IV 40 × 5	None
Salah et al. (Clin Transl Oncol, 2021) [25]	R (53)	20 (5–45)	1/11	28%	100 × 5/IV 40 × 5 in 21 patients; IV 50 × 5 in 24 patients; IV 20 × 5 × 2 in 6 patients	None
Xu et al. (Clin Cancer Res, 2023) [26] 5-day schedule:	II (24)	16.5 ± 7.9	1/4	20.8%	100 × 5/50 × 5	VCR 1.4 mg/m2 day 1
Xu et al. (Clin Cancer Res, 2023) [26] 10-day schedule:	II (22)	15.2 ± 6.3	1/11	54.5%	100 × 5/20 × 5 × 2	VCR 1.4 mg/m2 days 1 and 8

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Most of these studies were retrospective, not prospective. There are only four prospective trials with well-defined eligibility cohorts and report by intent to treat. In addition, there is significant variability among the reports in doses and dose schedules of irinotecan and temozolomide and the use of additional agents. When combined, these studies accrued 275 patients and observed 21 complete remissions and 82 partial remissions. The objective response rate was 37.5%.

Evidence (chemotherapy):

One phase II study of topotecan and cyclophosphamide showed a response in 6 of 17 patients with Ewing sarcoma.[9] In a similar trial in Germany, 16 of 49 patients had a clinical response.[11]

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Several retrospective studies have demonstrated the activity of temozolomide and irinotecan in patients with recurrent Ewing sarcoma.[13,22,24]

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Several retrospective studies have demonstrated the activity of temozolomide and irinotecan in patients with recurrent Ewing sarcoma.[13,22,24]

In the largest retrospective multicenter study of the combination of temozolomide and irinotecan in patients with recurrent and primary refractory Ewing sarcoma, 51 patients (66% of patients were aged ≥18 years; median age, 21 years) were treated with temozolomide (100 mg/m2/day orally) and irinotecan (40 mg/m2/day intravenously), on days 1 to 5, every 21 days. Twenty-five percent of the patients were in first relapse/progression, while the remainder of the patients were in second or greater relapse/progression.[24]

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Several retrospective studies have demonstrated the activity of temozolomide and irinotecan in patients with recurrent Ewing sarcoma.[13,22,24] › In the largest retrospective multicenter study of the combination of temozolomide and irinotecan in patients with recurrent and primary refractory Ewing sarcoma, 51 patients (66% of patients were aged ≥18 years; median age, 21 years) were treated with temozolomide (100 mg/m2/day orally) and irinotecan (40 mg/m2/day intravenously), on days 1 to 5, every 21 days. Twenty-five percent of the patients were in first relapse/progression, while the remainder of the patients were in second or greater relapse/progression.[24]

Five patients (10%) achieved complete remissions, 12 patients (24%) achieved partial remissions, and 19 patients (37%) had stable disease, with a disease control rate of 71%.

Several retrospective studies have demonstrated the activity of temozolomide and irinotecan in patients with recurrent Ewing sarcoma.[13,22,24] › In the largest retrospective multicenter study of the combination of temozolomide and irinotecan in patients with recurrent and primary refractory Ewing sarcoma, 51 patients (66% of patients were aged ≥18 years; median age, 21 years) were treated with temozolomide (100 mg/m2/day orally) and irinotecan (40 mg/m2/day intravenously), on days 1 to 5, every 21 days. Twenty-five percent of the patients were in first relapse/progression, while the remainder of the patients were in second or greater relapse/progression.[24]

On univariate analysis, the only two factors predicting response to temozolomide and irinotecan in PFS were performance score and lactate dehydrogenase levels.

Several retrospective studies have demonstrated the activity of temozolomide and irinotecan in patients with recurrent Ewing sarcoma.[13,22,24] › In the largest retrospective multicenter study of the combination of temozolomide and irinotecan in patients with recurrent and primary refractory Ewing sarcoma, 51 patients (66% of patients were aged ≥18 years; median age, 21 years) were treated with temozolomide (100 mg/m2/day orally) and irinotecan (40 mg/m2/day intravenously), on days 1 to 5, every 21 days. Twenty-five percent of the patients were in first relapse/progression, while the remainder of the patients were in second or greater relapse/progression.[24]

Two patients were rechallenged with temozolomide and irinotecan after disease remission was induced. Both patients achieved partial remissions on rechallenge. One patient's remission lasted at least 15 cycles and the other remission lasted 22 cycles.[24]

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Several retrospective studies have demonstrated the activity of temozolomide and irinotecan in patients with recurrent Ewing sarcoma.[13,22,24]

A prospective randomized trial compared two schedules of irinotecan given in combination with vincristine and temozolomide for the treatment of recurrent Ewing sarcoma. One schedule administered irinotecan 50 mg/m2 daily for 5 days (d × 5) and the other administered irinotecan 20 mg/m2 daily for 5 days for two consecutive weeks (10 doses; d × 5 × 2).[26]

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Several retrospective studies have demonstrated the activity of temozolomide and irinotecan in patients with recurrent Ewing sarcoma.[13,22,24] › A prospective randomized trial compared two schedules of irinotecan given in combination with vincristine and temozolomide for the treatment of recurrent Ewing sarcoma. One schedule administered irinotecan 50 mg/m2 daily for 5 days (d × 5) and the other administered irinotecan 20 mg/m2 daily for 5 days for two consecutive weeks (10 doses; d × 5 × 2).[26]

The objective response rate at 12 weeks was lower for the patients treated on the d × 5 schedule (5 of 24; 20.8%) than for patients treated on the d × 5 × 2 schedule (12 of 22; 54.5%; P = .019).

Several retrospective studies have demonstrated the activity of temozolomide and irinotecan in patients with recurrent Ewing sarcoma.[13,22,24]

A retrospective review of published series compared the results of treatment with irinotecan and temozolomide with a 10-day schedule to treatment with a 5-day schedule.[27]

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Several retrospective studies have demonstrated the activity of temozolomide and irinotecan in patients with recurrent Ewing sarcoma.[13,22,24] › A retrospective review of published series compared the results of treatment with irinotecan and temozolomide with a 10-day schedule to treatment with a 5-day schedule.[27]

Among 89 patients treated with a 10-day irinotecan schedule, there were 47 objective responses (53%).

Several retrospective studies have demonstrated the activity of temozolomide and irinotecan in patients with recurrent Ewing sarcoma.[13,22,24] › A retrospective review of published series compared the results of treatment with irinotecan and temozolomide with a 10-day schedule to treatment with a 5-day schedule.[27]

Among 180 patients treated with a 5-day irinotecan schedule, there were 52 responses (29%).

Several retrospective studies have demonstrated the activity of temozolomide and irinotecan in patients with recurrent Ewing sarcoma.[13,22,24] › A retrospective review of published series compared the results of treatment with irinotecan and temozolomide with a 10-day schedule to treatment with a 5-day schedule.[27]

The two studies that used the 5-day irinotecan schedule reported median times to progression of 3.0 and 3.9 months, respectively.

Several retrospective studies have demonstrated the activity of temozolomide and irinotecan in patients with recurrent Ewing sarcoma.[13,22,24] › A retrospective review of published series compared the results of treatment with irinotecan and temozolomide with a 10-day schedule to treatment with a 5-day schedule.[27]

The four studies that used the 10-day irinotecan schedule reported median times to progression of 4.6, 5.5, 8.3, and 9.5 months, respectively.

The combination of docetaxel either with gemcitabine or irinotecan has achieved objective responses in patients with relapsed Ewing sarcoma.[28][Level of evidence C1]; [29,30][Level of evidence C3]

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High-dose ifosfamide (3 g/m2 per day for 5 days = 15 g/m2) has shown activity in patients whose Ewing sarcoma recurred after therapy that included standard ifosfamide (1.8 g/m2 per day for 5 days = 9 g/m2).[31][Level of evidence C3]

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European investigators are performing a prospective study to compare four regimens for the treatment of patients with recurrent Ewing sarcoma.[32] The rEECur phase II/III adaptive multiarm trial is the first to compare regimens in a randomized design. Patients aged 4 to 50 years with refractory or recurrent Ewing sarcoma and healthy enough to receive chemotherapy were randomly assigned to receive one of four regimens: topotecan and cyclophosphamide (TC), irinotecan and temozolomide (IT), gemcitabine and docetaxel (GD), or high-dose ifosfamide.[33]

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European investigators are performing a prospective study to compare four regimens for the treatment of patients with recurrent Ewing sarcoma.[32] The rEECur phase II/III adaptive multiarm trial is the first to compare regimens in a randomized design. Patients aged 4 to 50 years with refractory or recurrent Ewing sarcoma and healthy enough to receive chemotherapy were randomly assigned to receive one of four regimens: topotecan and cyclophosphamide (TC), irinotecan and temozolomide (IT), gemcitabine and docetaxel (GD), or high-dose ifosfamide.[33]

Pairwise comparison showed that GD was the least effective.

European investigators are performing a prospective study to compare four regimens for the treatment of patients with recurrent Ewing sarcoma.[32] The rEECur phase II/III adaptive multiarm trial is the first to compare regimens in a randomized design. Patients aged 4 to 50 years with refractory or recurrent Ewing sarcoma and healthy enough to receive chemotherapy were randomly assigned to receive one of four regimens: topotecan and cyclophosphamide (TC), irinotecan and temozolomide (IT), gemcitabine and docetaxel (GD), or high-dose ifosfamide.[33]

Imaging response and survival outcomes after TC were marginally better than after IT. However, in a phase II comparison, ifosfamide had significantly better PFS and OS than TC. As a result, ifosfamide was the most effective regimen in this setting, although with significant renal and neurological toxicity.

European investigators are performing a prospective study to compare four regimens for the treatment of patients with recurrent Ewing sarcoma.[32] The rEECur phase II/III adaptive multiarm trial is the first to compare regimens in a randomized design. Patients aged 4 to 50 years with refractory or recurrent Ewing sarcoma and healthy enough to receive chemotherapy were randomly assigned to receive one of four regimens: topotecan and cyclophosphamide (TC), irinotecan and temozolomide (IT), gemcitabine and docetaxel (GD), or high-dose ifosfamide.[33]

The study is ongoing and has recruited over 570 patients. The study is now comparing ifosfamide and lenvatinib with ifosfamide, carboplatin, and etoposide.[34]

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