Relapsed Rhabdomyosarcoma

Abstract

Relapsed rhabdomyosarcoma (RMS) represents a significant therapeutic challenge. Nearly one-third of patients diagnosed with localized RMS and over two-thirds of patients with metastatic RMS will experience disease recurrence following primary treatment, generally within three years. Clinical features at diagnosis, including primary site, tumor invasiveness, size, stage, and histology impact likelihood of relapse and prognosis post-relapse. Aspects of initial treatment, including extent of surgical resection, use of radiotherapy, and chemotherapy regimen, are also associated with post-relapse outcomes, as are features of the relapse itself, including time to relapse and extent of disease involvement. Although there is no standard treatment for patients with relapsed RMS, several general principles, including tissue biopsy confirmation of diagnosis, assessment of post-relapse prognosis, determination of the feasibility of additional local control measures, and discussion of patient goals, should all be part of the approach to care. Patients with features suggestive of a favorable prognosis, which include those with botryoid RMS or stage 1 or group I embryonal RMS (ERMS) who have had no prior treatment with cyclophosphamide, have the highest chance of achieving long-term cure when treated with a multiagent chemotherapy regimen at relapse. Unfortunately, patients who do not meet these criteria represent the majority and have poor outcomes when treated with such regimens. For this group, strong consideration should be given for enrollment on a clinical trial.

An update on rhabdomyosarcoma risk stratification and the rationale for current and future Children's Oncology Group clinical trials

“…Although knowledge of the molecular mechanisms driving RMS has advanced quickly, the availability of agents that target these molecular drivers has lagged. Current investigational therapies for patients with relapsed or refractory RMS include the use of kinase inhibitors, insulin‐like growth factor antibodies, histone deacetylase inhibitors, and poly ADP ribose polymerase (PARP) inhibitors among other agents and are used alone or in combination with various salvage chemotherapy backbones 73,74 . As the data utilizing molecular biomarkers for risk stratification mature, thus identifying smaller cohorts of patients with different prognoses, our ability to offer appropriate risk‐based therapy for all patients should improve, including for those with the most dismal prognoses.…”

Molecular Targets for Novel Therapeutics in Pediatric Fusion-Positive Non-CNS Solid Tumors

“…However, the FGFR4 inhibitor BGJ398 showed synergy with IGF-1R inhibitor AEW54 in an ARMS cell line, suggesting that FGFR4 may be a promising target in treatment resistance prevention ( Wachtel et al, 2014 ). Relapsed ARMS has also been shown to be responsive to pazopanib, a multi-kinase inhibitor currently in use for soft tissue sarcomas ( Heske and Mascarenhas, 2021 ).…”

“…In the Children’s Oncology Group phase II clinical trial ARST0921, treatment of first-relapse RMS patients with a vinorelbine and cyclophosphamide chemotherapy backbone in combination with either the mTOR inhibitor temsirolimus or the VEGFR inhibitor bevacizumab resulted in 6-month event-free survival rates of 69 and 55%, respectively, with a greater proportion of partial responses in patients treated with temsirolimus ( Heske and Mascarenhas, 2021 ). This data was promising enough to lead to further investigation of temsirolimus in the upfront setting for patients with newly diagnosed intermediate-risk RMS.…”

“…This data was promising enough to lead to further investigation of temsirolimus in the upfront setting for patients with newly diagnosed intermediate-risk RMS. This randomized phase III trial compares conventional cytotoxic chemotherapy with VAC/VI (alternating vincristine, dactinomycin, cyclophosphamide, and vincristine, irinotecan), with the addition of temsirolimus to the conventional VAC/VI chemotherapy backbone ( Heske and Mascarenhas, 2021 ).…”

Single-cell mapping of tumor heterogeneity in pediatric rhabdomyosarcoma reveals developmental signatures with therapeutic relevance

“…In newly diagnosed RMS patients, one-third of localized and two-third of metastatic cases exhibit relapse or disease progression despite intense treatments 16 . In such cases, prognosis is dismal and 5-year overall survival rates drop below 10% for the aRMS subtype, highlighting the urgent need for therapeutic approaches 16 .…”