Treatment at the time of relapse depends on many factors, viz. site of recurrence, previous treatment received, and individual patient preference. There are no clear guidelines for the treatment of relapsed RMS. Treatment of recurrent childhood RMS should include multimodality options including chemotherapy, surgery and radiotherapy whenever feasible as summarized in Table 4. In the case of localized disease where surgery is possible, initial surgical resection should be attempted followed by chemotherapy and radiotherapy. If the initial disease is unresectable, initial chemotherapy followed by local therapy, ie, surgery or radiotherapy should be done. Surgery may also be attempted in patients with fewer lung metastases. Radiotherapy is an important modality in recurrent RMS, especially in cases where a patient has not received prior radiotherapy and if surgical excision is not feasible.58–60 In the case of gross metastatic disease, palliative chemotherapy may be administered based on chemotherapeutic agents received at the time of initial diagnosis.

Chemotherapy has an important role in the treatment of relapsed RMS. However, there is no clear data for the choice of chemotherapy due to lack of comparative trials and heterogeneity of the trial population. Patients should be encouraged to enrol in clinical trials if available. If the patient has previously received two drug VA (vincristine and actinomycin D) therapy, full course of VAC (vincristine, actinomycin D and cyclophosphamide) may be administered at relapse. Patients who have received VAC, options include Ifosfamide, carboplatin, and etoposide (ICE); cyclophosphamide/topotecan; irinotecan, temozolomide, vincristine; gemcitabine, docetaxel; vinorelbine; temsirolimus; and combination of above agents. Various regimens are summarized in Table 1.

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Table 1

Table 2

Table 3

Table 4

Ifosfamide, carboplatin, and etoposide (ICE) has been commonly used regimen in the past, but has significant hematologic toxicity. In a prospective trial of 92 patients with relapsed solid tumours including 14 relapsed RMS, responses were seen in 43% of patients.61 In Children’s Cancer group pooled analysis of three phase I/II trials using ICE in 27 relapsed/refractory RMS patients, the response was observed in two-third of patients.62

Cyclophosphamide/topotecan has been tested in some phase II trials. In one study 10 out of 15 RMS patients responded, however, all patients had partial response.63 In an Italian study, topotecan/cyclophosphamide was combined with carboplatin/etoposide in 38 patients with recurrent or refractory RMS. Response was seen in around one-third of patients but the 5-year OS (17%) and PFS (14%) rates were poor. Rates of haematological toxicity were high.64

Vincristine and irinotecan with/without other drugs are the most commonly used regimens in the current era due to good response rates and manageable toxicity. However, gastrointestinal toxicity and neuropathy remain of concern. A Children’s Oncology Group (COG) prospective, randomized trial (COG-ARST0121) showed no significant difference between responses in two schedules of vincristine/irinotecan.65 In a European Soft Tissue Sarcoma Study Group (EpSSG) study, 120 patients with recurrent or refractory RMS were randomized to vincristine and irinotecan (VI) or vincristine, irinotecan, and temozolomide (VIT). The VIT arm was associated with higher response rates and better survival.66

High dose chemotherapy (HDT) followed by autologous hematopoietic stem cell transplantation (AHSCT) has also been tried for patients with RMS in relapse as well as upfront setting. However, available data did not show a significant benefit with this approach.67,68

PAX-FOXO1 fusion protein is expressed in tumor cells in RMS has been historically difficult to target. Novel approaches are currently being developed designed to target either PAX-FOXO1 or its co-regulators. Experimental approach using nanoparticles as a vehicle to transport siRNA to downregulate PAX-FOXO1 has been demonstrated in vitro studies.69 Cell line studies have shown that targeting BET bromodomain protein BRD4 which is a coregulator of PAX-FOXO1 by JQ1 inhibits PAX-FOXO1 function.70 Similarly, targeting chromatin helix DNA binding protein 4 (CHD4) which acts as a coregulator of PAX-FOXO1is feasible in preclinical models.71 Potential targets in receptor tyrosine kinase are IGF-1R, FGFR4, PDGFR, ALK, MET, VEGFR and ERBB2. NOTCH and Smo are being evaluated as the target in developmental pathways.72

Various trials involving nivolumab (NCT02304458), pembrolizumab (NCT02332668), IGF-1 inhibitors (NCT03041701), Wee1 inhibitor (NCT02095132) and CDK4 inhibitors (NCT03709680) are currently undergoing. The summary of the current ongoing clinical trials involving novel therapeutic approaches to RMS is summarized in Table 5.

Table 5

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