PATIENTS AND METHODS
In accordance with EpSSG recommendations, patients with disseminated disease but no evidence of a primary tumor were classified as metastatic and included in the MTS 2008 study. This prospective international trial was conducted from October 2008 to December 2016 (EudraCT, number 2005-000217-35), and enrolled a total of 270 patients from 74 centers in 11 countries. Inclusion criteria were patients under 21 years old with histologically-proven metastatic RMS and no previous treatment. The standard workup included MRI and/or CT of the primary tumor, chest CT scan, and radionuclide bone scan. 18F-FDG-PET/CT was optional; if performed, the results were used to ascertain tumor extent and establish tumor stage. Staging investigations also included bone marrow aspirates and biopsy. Treatment included 9 cycles of induction chemotherapy: 4 cycles of IVADo (ifosfamide 3 g/m2 on days 1 and 2, vincristine 1.5 mg/m2 weekly during the first 7 weeks, then only on day 1 of each cycle, actinomycin-D 1.5 mg/m2 on day 1, given as a single intravenous injection, and doxorubicin 30 mg/m2 iv. on days 1 and 2) followed by 5 cycles of IVA (same as IVADo, but without any doxorubicin). This was followed by 48 weeks of maintenance chemotherapy with iv. vinorelbine 25 mg/m2on days 1, 8 and 15, and daily oral cyclophosphamide 25 mg/m2. Tumor response and all sites of metastases was assessed after the 3rd, 6th, and 9th cycles of chemotherapy, and every 3 months afterwards, focused on primary tumor and involved sites.
The response, evaluated after 3 cycles of IVADo chemotherapy, was classified as complete response (CR) = complete disappearance of all visible disease; partial response (PR) = a tumor volume reduction of more than two-thirds; minor response (MR) = a tumor volume reduction of more than one-third but less than two-thirds. A reduction in volume of less than one-third was recorded as stable disease (SD), while an increase in tumor size or the detection of new lesions was classified as progression of disease (PD) (3). Patients with SD were eligible to switch to 2nd line treatment.
Treatment of all sites of metastases (with surgery, radiotherapy or both) was planned after the first tumor response assessment, and implemented after six cycles of chemotherapy (week 19). If feasible, radiotherapy to all sites of metastases was recommended.
All participating centers had to obtain written approval from their local authorities and ethics committees, and written informed consent from patients and/or their parents or legal guardians.
A literature search was also conducted in the PubMed biomedical database. The search was performed as of June 2021 using the keywords “rhabdomyosarcoma” AND “unknown origin”/ “metastatic”/ “leukemia”. Additional papers derived from the references of the articles retrieved were also analyzed. No restrictions were applied regarding date of publication, but only articles written in English were considered. Our inclusion criteria for the review of patients with metastatic rhabdomyosarcoma were: age between 0 and 18 years and a histologically confirmed diagnosis of RMS.