Isolated limb perfusion with biochemotherapy and oncolytic virotherapy combines with radiotherapy and surgery to overcome treatment resistance in an animal model of extremity soft tissue sarcoma.
The management of locally advanced or recurrent extremity sarcoma often necessitates multimodal therapy to preserve a limb, of which isolated limb perfusion (ILP) is a key component. However, with standard chemotherapeutic agents used in ILP, the duration of response is limited. Novel agents or treatment combinations are urgently needed to improve outcomes. Previous work in an animal model has demonstrated the efficacy of oncolytic virotherapy when delivered by ILP and, in this study, we report further improvements from combining ILP-delivered oncolytic virotherapy with radiation and surgical resection. In vitro, the combination of radiation with an oncolytic vaccinia virus (GLV-1h68) and melphalan demonstrated increased cytotoxicity in a panel of sarcoma cell lines. The effects were mediated through activation of the intrinsic apoptotic pathway. In vivo, combinations of radiation, oncolytic virotherapy and standard ILP resulted in delayed tumour growth and prolonged survival when compared with standard ILP alone. However, local disease control could only be secured when such treatment was combined with surgical resection, the timing of which was crucial in determining outcome. Combinations of oncolytic virotherapy with surgical resection and radiation have direct clinical relevance in extremity sarcoma and represent an exciting prospect for improving outcomes in this pathology.
Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom.|Sarcoma/Melanoma Unit, Department Of Academic Surgery, The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom.
Michelle J
MJ
Wilkinson
Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom.|Sarcoma/Melanoma Unit, Department Of Academic Surgery, The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom.
Henry G
HG
Smith
Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom.|Sarcoma/Melanoma Unit, Department Of Academic Surgery, The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom.
Timothy D
TD
Pencavel
Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom.
David C
DC
Mansfield
Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom.
Joan
J
Kyula-Currie
Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom.
Aadil A
AA
Khan
Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom.
Gráinne
G
McEntee
Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom.
Victoria
V
Roulstone
Sarcoma/Melanoma Unit, Department Of Academic Surgery, The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom.
Andrew J
AJ
Hayes
Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom.
Kevin J
KJ
Harrington
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D010478:Chemotherapy, Cancer, Regional Perfusion; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005121:Extremities; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000235:genetics; D061766:Proton Therapy; D011878:Radiotherapy / Q000379:methods; D051381:Rats; D012008:Recurrence; D012509:Sarcoma / Q000235:genetics / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D014161:Transduction, Genetic; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects
D000970:Antineoplastic Agents; D053148:Caspase 3; D008558:Melphalan
isolated limb perfusion; oncolytic virotherapy; soft tissue sarcoma