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.