Non-Rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS) in Pediatric and Young Adult Patients

Incidence of cancer (A) and soft tissue sarcomas (B) in the AYA population.

Soft tissue sarcomas, the fifth most common solid tumors in children, are relatively rare and account for about 6-7% of all childhood malignancies. About half of these tumors are rhabdomyosarcomas, and nonrhabdomyosarcoma soft tissue sarcomas (NRSTSs) account for the remainder (ie, about 4% of childhood malignancies).

NRSTSs are heterogeneous tumors that have varied biology and histology. The most common types in the pediatric population include fibrosarcoma, synovial cell sarcoma, fibrosarcoma, and malignant peripheral nerve sheath tumor. Other histologic types include hemangiopericytoma, alveolar soft part sarcoma, leiomyosarcoma, liposarcoma, epithelioid sarcoma, and desmoplastic small round cell tumor.

Childhood NRSTs are not well studied. Because soft tissue sarcomas are most common in adults, many treatment modalities are extrapolated from experiences in adult patients. However, many pediatric tumors differ from their adult counterparts in terms of clinical behaviors and outcomes. The prognoses of infants and young children with NRSTSs tend to be better than those of adolescents and adults with similar diagnoses. 

Summary of results of targeted therapies in STS

Class of drugs	Drug studied	Phases	Main results	References
TKI	Imatinib	II	Response in GIST, not in other histologies	69,70
	Dasatinib	II	Response in undifferentiated pleomorphic sarcoma, currently being studied in more indolent types of STS	71
	Semaxinib	II	No significant anti-STS activity	75
	Pazopanib	II and III	Approved by the US FDA for the treatment of STS as second- line treatment. Pediatric and adult trials ongoing	76,77
	Regorafenib	II	Improved OS and PFS in LMS and improved PFS in other sarcomas	86
	Sunitinib	I and II	Activity in ASPS	92–94
	Cediranib	I/II	Activity in ASPS	97
	Vandetanib, gafetinib, and erlotinib	Preclinical and early clinical	Appeared promising in STS, but no conclusive studies yet	100–102
	Sorafenib	II	No objective responses	105
	Tivozanib	II	Response in metastatic and nonresectable STS (median follow-up 5.5 months)	106
mTOR inhibitors	Temsirolimus	I	Tolerable in combination with chemotherapy or other targeted agents. Phase II study results pending	108,109
	Sirolimus	II	In combination with cyclophosphamide or pazopanib some patients with PR or SD	110,118
	Everolimus	I and II	Investigated as monotherapy and in combination with figitumumab, or imatinib without RECIST response	115–117
Other pathways	Histone deacetylase inhibitors; multiple agents	I and II	SB939, abexinostat with or without doxorubicin, vorinostat with bortezomib: tolerable and indication of potential clinical benefit; panobinostat: 36% SDs and no CRs or PRs. Preclinical data encouraging	122–124,126,128,129
	Heat-shock protein 90 inhibitors; multiple agents	I	Retaspimycin hydrochloride: SD (60% at 6 weeks and 18% at 12 weeks). AAG tolerable in children. Ganetespib with sirolimus under investigation	135,137
	SINE	I preclinical	Tolerable, preliminary evidence of activity	139,141
Immunotherapy	IGF-1R; multiple agents	I and II	Promising preclinically, but no consistent benefit in Phase II trials. Currently no further clinical studies	113,143–148
	Bevacizumab	I	Alone and in combination with several traditional chemotherapeutics tolerable but clinical benefit unclear	35,150,151
	Olaratumab	I/II	In combination with doxorubicin, improved PFS and OS, but mostly older adults	154
	Ipilimumab	Pilot	Stopped early due to low accrual	156
	Checkpoint inhibition		Anti-PD-1 therapy promising in several solid tumors. First clinical trial in STS currently ongoing. Additional molecules targeting LAG2, Tim3, and BTLA4 emerging
	Tumor vaccines; multiple targets	I	Vaccine against SS18, GD2, GD3, and NY-ESO showed antibody induction. Phase II clinical data pending	170,171,173,174
	Autologous T cell transfer (NY-ESO T cell receptor)	I	In synovial sarcoma promising (four out of six with response). Follow-up study currently ongoing	176
	CAR T cells		Mostly tested in hematologic malignancies and some bone sarcomas, but potentially promising modality especially in combination with immune-modulatory therapeutics

Abbreviations: AAG, 17-N-allylamino-17-demethoxygeldanamycin; ASPS, alveolar soft part sarcoma; CAR, chimeric antigen receptor; CRs, complete remissions; FDA, Food and Drug Administration; GIST, gastrointestinal stromal tumor; IGF-1R, insulin-like growth factor-1 receptor; LMS, leiomyosarcomas; mTOR, mechanistic target of rapamycin; OS, overall survival; PFS, progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; SINE, selective inhibitors of nuclear export; STS, soft tissue sarcoma; TKI, tyrosine kinase inhibitor.