EWS/PNET: Systemic Therapy

There is no standard second-line regimen following relapse after the first‐line treatment. Several regimens have been tried, mostly retrospective evidence is available with only a few Phase 1/2 trials. No single regimen had been proven to be superior to others. Various regimens (Table 3) with promising results includes temozolomide + irinotecan ± vincristine, cyclophosphamide + topotecan, gemcitabine + docetaxel, high dose ifosfamide, ifosfamide + etoposide ± carboplatin (ICE).62,83,102,119-123 Responses with targeted therapy and immunotherapy have been poor.

Among the various regimens, temozolomide combined with irinotecan has the most encouraging results. Additional vincristine has also been used with this regimen. Among overall 176 combined patients from various studies, responses had been observed in around 40% of patients.119,124 This regimen is well tolerated with lower myelotoxicity and fewer grade 3/4 toxicities (diarrhoea 5–10%, neuropathy 4–12%) compared with other salvage regimens. Irinotecan has been tried by the oral route, and initial studies have shown similar efficacy as the parenteral route. As oral temozolomide is available, this regimen may be considered for oral therapy.119

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Topotecan and cyclophosphamide combination has shown some efficacy with 32% response rate in 99 patients from various studies. Grade 3/4 hematological toxicity was observed in more than 50% of patients.120,121 Gemcitabine with docetaxel has 29% response rate in 29 treated patients. Grade 3/4 neutropenia was seen in around 70% of patients.102,122 Ifosfamide, etoposide, and carboplatin (ICE) combination and high dose Ifosfamide had shown good efficacy but the cost of toxicity (100% Grade 3/4 haematological toxicity).62,123 A retrospective study from India has shown encouraging results with oral metronomic therapy using tamoxifen, etoposide, and cyclophosphamide. In 49 relapsed sarcoma patients, the majority of which was EWS, responses were observed in 59% of patients.125 Ongoing clinical trials using novel therapeutics for the management of refractory Ewing’s sarcoma are given in Table no. 5.

The Euro Ewing Consortium is currently conducting a multi-armed phase II/III randomized study (rEECur study) in patients aged 2–50 years with recurrent EWS. (ISRCTN 36453794). In Phase II patients will receive one of four regimens, cyclophosphamide/topotecan, gemcitabine/docetaxel, high dose ifosfamide, or temozolomide/irinotecan. In Phase III two regimens with a higher objective response rate will be tested with progression-free survival as the primary endpoint.

EWS/PNET: Targeted Therapy

Various pathways have been identified in EWS, as targets which may help in disease control. These include insulin growth factor receptor 1 (IGF-1R), vascular endothelial growth factor receptors (VEGFR), MET, EWS-FLI1 fusion, DNA repair protein PARP1, lysine-specific demethylase 1 (LSD-1), and placenta growth factor (PGF).126–133

IGF-1R is expressed on EWS tumour cells and drives the growth of tumour cells. Initial trials with monoclonal antibodies against IGF −1R showed some encouraging results but larger studies failed to provide significant results. Studies have been done in combination with an mTOR inhibitor, but also failed to provide meaningful benefit. Current trials of IGF-1R in combination with conventional chemotherapy are ongoing [NCT02306161].134–137

Targeting angiogenesis has been attempted with modest success using regorafenib, and cabozantinib. In heavily pre-treated adult patients treated with regorafenib, response was observed in 10% and 73% of patients were progression-free at 8 weeks.137 With MET inhibitor cabozantinib responses have been observed in around 28% and 24% of patients were progression-free at 6 months.129

EWS-FLI1 is the principal driver of tumour growth in EWS. EWS-FLI1 fusion protein is a possible target for therapy in relapsed cases; however, it is very difficult to target.131 BRD4 protein is a member of the bromodomain and extra terminal domain (BET) family of proteins, is a transcriptional regulator required for the EWS-FLI1 fusion protein function. Bromodomain inhibitors inhibit gene expression of EWS-FLI1.132 Clinical trials using bromodomain inhibitors are currently ongoing [NCT02419417, NCT03220347].

Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in various cellular processes including DNA repair and genomic stability. The expression of PARP1 is elevated in EWS. Olaparib did not have an objective clinical response in a phase 2 trial, though patients were not selected based on biomarkers.138 Currently, trials are undergoing which are selecting patients based on actionable mutation olaparib (NCT03233204), talazoparib (NCT02116777) and niraparib (NCT02044120).

Lysine-specific demethylase 1 (LSD-1) regulates histone methylation and influences the epigenetic state of cells, is upregulated in EWS. It is a transcriptional repressor of downstream targets of EWS/FLI1 and inhibits tumour growth.139 Clinical trials are currently ongoing with LSD −1 inhibitors [NCT03514407, NCT03600649]. Other targets that have been identified are NKX2.2, HSP90, FOX01 and ATR.140

EWS/PNET: Immunotherapy

Immunotherapy targeting PD-1/PD-L1 axis has shown disappointing results in relapsed EWS. PDL1 expression has observed in around 20% of cases; however, these have low mutational tumour burden (TMB), and low level of tumour infiltrating lymphocytes (TIL).43,141 No objective responses have been observed in patients treated with the anti-PD-1 antibody pembrolizumab or nivolumab.111,142

A novel strategy in the field of immunotherapy for EWS known as Vigil or FANG has shown promising results. In this tumor cells are obtained by biopsy or resection and transfected with a plasmid containing the rhGMCSF (recombinant human GM-CSF) transgene and the shRNAfurin(short hairpin RNA inactivating furin). This leads to the upregulation of the immune system by inhibition of TGF-beta1 and 2 mediated pathways.139,143 Ghisoli et al144 have reported a 1-year survival of 73% for relapsed EWS patients treated with Vigil compared to 23% for those treated with conventional chemotherapy. A phase III trial is currently undergoing in which relapsed EWS patients are treated with temozolomide/irinotecan combination with and without Vigil [NCT03495921].


The role of HDT followed by ASCT is doubtful in relapsed EWS due to the lack of any prospective trial in this population. Various retrospective analyses have shown the benefit of HDT followed by ASCT. However, ASCT was done in the patients responding to initial chemotherapy. This limits the role of ASCT in relapsed EWS and it is not routinely recommended.145–147 Temozolomide/Irinotecan-based chemotherapy may be favored due to higher responses and lower toxicity.

Infantile Fibrosarcoma

Infantile fibrosarcoma (IF) also known as congenital fibrosarcoma is a rare soft tissue tumor that presents at birth or develops in the 1st year of life. They represent approximately 5% to 10% of all sarcomas in infants.148–150 It has a reciprocal translocation, t(12;15)(p13;q25), resulting in ETV6/NTRK3 gene fusion in which the ETV6 (TEL) gene from 12p13 fuses with the NTRK3 gene (Trk C) on 15q25.151

The European Paediatric Soft Tissue Sarcoma Study Group evaluated a conservative therapeutic strategy in 50 infants with localized IFS. The initial surgery was performed if it could be done without mutilation. No further therapy was given if negative margins (group I/R0; n=11) or microscopic positive margins (group II/R1; n=8). Non-alkylator-based chemotherapy vincristine-actinomycin (VA) was administered to those with initial inoperable tumours (group III/R2; n=31). Response to chemotherapy was observed in 68% of patients. The 3-year event-free survival was 84% and the overall survival 94.0% at a median follow-up of 4.7 years.152

As discussed, ETV6/NTRK3 gene fusion is found in patients with IF. Larotrectinib is an oral ATP-competitive inhibitor of TRK A, B, and C. In a phase I/II basket trial involving 55 adults and paediatric patients with advanced or metastatic tumours with TRK fusion proteins, seven patients with IF were included. All patients responded to larotrectinib with two patients achieved complete remission and five achieved partial responses.153 Larotrectinib was approved by the FDA for use in adults and children with solid tumours with an NTRK gene fusion without a known acquired resistance mutation, which are either metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or who have progressed following treatment.

In a patient with IF, upfront surgical resection should be considered. If the tumour is very large and a mutilating surgery is expected, neoadjuvant therapy similar to RMS may be administered. In cases of relapsed and metastatic IF, where the tumour is not surgically amenable, the patient should be started on larotrectinib or enrolled in a clinical trial. Summary of current modalities is mentioned in Table 4, recent novel therapeutic approaches are given in Table 5.

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