Metastatic Rhabdomyosarcoma: Results of the European Paediatric Soft Tissue Sarcoma Study Group MTS 2008 Study and Pooled Analysis With the Concurrent BERNIE Study

Abstract

PURPOSE Outcome for patients with metastatic rhabdomyosarcoma (RMS) is poor. This study presents the results of the MTS 2008 study with a pooled analysis including patients from the concurrent BERNIE study. PATIENTS AND METHODS In MTS 2008, patients with metastatic RMS received four cycles of ifosfamide, vincristine, and actinomycin D (IVA) plus doxorubicin, five cycles of IVA, and 12 cycles of maintenance chemotherapy (low-dose cyclophosphamide and vinorelbine). The BERNIE study randomly assigned patients to the addition or not of bevacizumab to the same chemotherapy. Local therapy (surgery/radiotherapy) was given to the primary tumor and all metastatic sites when feasible. RESULTS MTS 2008 included 270 patients (median age, 9.6 years; range, 0.07-20.8 years). With a median follow-up of 50.3 months, 3-year event-free survival (EFS) and overall survival (OS) were 34.9% (95% CI, 29.1 to 40.8) and 47.9% (95% CI, 41.6 to 53.9), respectively. In pooled analyses on 372 patients with a median follow-up of 55.2 months, 3-year EFS and OS were 35.5% (95% CI, 30.4 to 40.6) and 49.3% (95% CI, 43.9 to 54.5), respectively. Patients with ≤ 2 Oberlin risk factors (ORFs) had better outcome than those with ≥ 3 ORFs: 3-year EFS was 46.1% versus 12.5% ( P < .0001) and 3-year OS 60.0% versus 26.0% ( P < .0001). Induction chemotherapy and maintenance appeared tolerable; however, about two third of patients needed dose adjustments during maintenance. CONCLUSION Outcome remains poor for patients with metastatic RMS and multiple ORFs. Because of the design of the studies, it was not possible to determine whether the intensive induction regimen and/or the addition of maintenance treatment resulted in apparent improvement of outcome compared with historical cohorts. Further studies, with novel treatment approaches are urgently needed, to improve outcome for the group of patients with adverse prognostic factors.

Pediatric Non-Rhabdomyosarcoma Soft Tissue Sarcomas: Standard of Care and Treatment Recommendations from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG)

“…96,97 Attempts to improve the outcome over the past 10-20 years have included aggressive surgery, hyperthermic peritoneal perfusion with cisplatin chemotherapy (HIPEC), high-dose chemotherapy with autologous peripheral stem cell rescue, whole abdomen radiotherapy, and targeted therapy with monoclonal antibodies and multikinase inhibitors. [98][99][100][101][102][103][104][105][106] Whilst awaiting new effective therapies and dedicated trials, the EpSSG recommends an intensive therapeutic approach to DSRCT patients, such as Kushner's P6 regimen (which includes VDCy and IE chemotherapy), 98 the IVADo regimen used for metastatic rhabdomyosarcoma, 107 or chemotherapy with irinotecan, ifosfamide, vincristine, actinomycin-D (IrIVA). 108 Intensive chemotherapy should be integrated with local control measures, including aggressive surgery (with debulking of large peritoneal tumors and resection of all detectable nodules), and whole abdominopelvic radiotherapy.…”

Metastatic rhabdomyosarcoma with exclusive distant lymph node involvement: A European Pediatric Soft tissue sarcoma Study Group (EpSSG) report

“…In 2008, the protocol was amended to also include patients with metastases at diagnosis; this study was named EpSSG MTS 2008. 2 The trials included previously untreated patients aged 0-21 years with a histologically proven diagnosis of RMS. We identified patients with metastatic disease confined to distant lymph nodes only.…”

“…A prospective phase III international clinical trial for patients with localized RMS (EpSSG RMS 2005) was conducted from October 2005 to December 2016. In 2008, the protocol was amended to also include patients with metastases at diagnosis; this study was named EpSSG MTS 2008 2 . The trials included previously untreated patients aged 0–21 years with a histologically proven diagnosis of RMS.…”

“…The prognosis of patients with metastatic rhabdomyosarcoma (RMS) has not substantially changed in the past decades, and only modest improvements have been achieved in the most recent trials performed by the Children's Oncology Group (COG) and by the European Pediatric Soft tissue sarcoma Study Group (EpSSG). [1][2][3][4] The outcome is not uniformly poor and we can distinguish groups of patients with different prognoses. Patients with metastatic disease but with no adverse prognostic features (i.e., Oberlin score of 0) have a better outcome, with a 3-year event-free survival (EFS) reaching 50%.…”

Shedding a Light on the Challenges of Adolescents and Young Adults with Rhabdomyosarcoma

“…A major contribution to the discussion of access to care comes from the recent cohort study from the EpSSG, which analysed clinical findings, treatment data, toxicity and outcome of RMS patients registered onto the two clinical protocols, i.e., the EpSSG RMS 2005—phase 3 randomised trial for localised RMS (open from 2006 to 2016) [ 8 , 9 ]—and the EpSSG MTS 2008 protocol—prospective, observational, single-arm study for metastatic RMS (open from 2010 to 2016) [ 47 ]. The study aimed to compare AYA patients (defined here as those aged 15–21 years at diagnosis) with those aged 0–14 years old.…”