title: Combining targeted agents with modern radiotherapy in soft tissue sarcomas.
abstract: Improved understanding of soft-tissue sarcoma (STS) biology has led to better distinction and subtyping of these diseases with the hope of exploiting the molecular characteristics of each subtype to develop appropriately targeted treatment regimens. In the care of patients with extremity STS, adjunctive radiation therapy (RT) is used to facilitate limb and function, preserving surgeries while maintaining five-year local control above 85%. In contrast, for STS originating from nonextremity anatomical sites, the rate of local recurrence is much higher (five-year local control is approximately 50%) and a major cause of death and morbidity in these patients. Incorporating novel technological advancements to administer accurate RT in combination with novel radiosensitizing agents could potentially improve local control and overall survival. RT efficacy in STS can be increased by modulating biological pathways such as angiogenesis, cell cycle regulation, cell survival signaling, and cancer-host immune interactions. Previous experiences, advancements, ongoing research, and current clinical trials combining RT with agents modulating one or more of the above pathways are reviewed. The standard clinical management of patients with STS with pretreatment biopsy, neoadjuvant treatment, and primary surgery provides an opportune disease model for interrogating translational hypotheses. The purpose of this review is to outline a strategic vision for clinical translation of preclinical findings and to identify appropriate targeted agents to combine with radiotherapy in the treatment of STS from different sites and/or different histology subtypes.
authors.affiliation: Department of Radiation Oncology, Centre Hospitalier de L'Université de Montréal, Montréal, Québec, Canada (PW); Research Institute at Nationwide Children's Hospital, Columbus, OH (PH); Departments of Radiation Oncology and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC (DGK); 21st Century Oncology Translational Research Consortium (TRC) Headquarters, Scottsdale, AZ (SEF); Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA (AMM); Department of Radiation Oncology, the Ohio State University, Columbus, OH (MXW); Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA (APD); Radiotherapy Development Branch & Molecular Radiation Therapeutics Branch, Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD (MA, CNC); Clinical Radiation Oncology Branch, National Cancer Institute, Bethesda, MD (BV); Molecular Pharmacology Branch, National Cancer Institute, Bethesda, MD (BAT); Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH (MM); Winship Cancer Institute, Woodruff Health Science Center, Emory University, Atlanta, GA (WJC); Department of Radiation Oncology, Rush University Medical Center, Chicago, IL (DW).
authors.forename: Philip
authors.initials: P
authors.lastname: Wong
authors.affiliation: Department of Radiation Oncology, Centre Hospitalier de L'Université de Montréal, Montréal, Québec, Canada (PW); Research Institute at Nationwide Children's Hospital, Columbus, OH (PH); Departments of Radiation Oncology and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC (DGK); 21st Century Oncology Translational Research Consortium (TRC) Headquarters, Scottsdale, AZ (SEF); Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA (AMM); Department of Radiation Oncology, the Ohio State University, Columbus, OH (MXW); Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA (APD); Radiotherapy Development Branch & Molecular Radiation Therapeutics Branch, Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD (MA, CNC); Clinical Radiation Oncology Branch, National Cancer Institute, Bethesda, MD (BV); Molecular Pharmacology Branch, National Cancer Institute, Bethesda, MD (BAT); Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH (MM); Winship Cancer Institute, Woodruff Health Science Center, Emory University, Atlanta, GA (WJC); Department of Radiation Oncology, Rush University Medical Center, Chicago, IL (DW).
authors.forename: Peter
authors.initials: P
authors.lastname: Houghton
authors.affiliation: Department of Radiation Oncology, Centre Hospitalier de L'Université de Montréal, Montréal, Québec, Canada (PW); Research Institute at Nationwide Children's Hospital, Columbus, OH (PH); Departments of Radiation Oncology and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC (DGK); 21st Century Oncology Translational Research Consortium (TRC) Headquarters, Scottsdale, AZ (SEF); Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA (AMM); Department of Radiation Oncology, the Ohio State University, Columbus, OH (MXW); Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA (APD); Radiotherapy Development Branch & Molecular Radiation Therapeutics Branch, Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD (MA, CNC); Clinical Radiation Oncology Branch, National Cancer Institute, Bethesda, MD (BV); Molecular Pharmacology Branch, National Cancer Institute, Bethesda, MD (BAT); Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH (MM); Winship Cancer Institute, Woodruff Health Science Center, Emory University, Atlanta, GA (WJC); Department of Radiation Oncology, Rush University Medical Center, Chicago, IL (DW).
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
authors.affiliation: Department of Radiation Oncology, Centre Hospitalier de L'Université de Montréal, Montréal, Québec, Canada (PW); Research Institute at Nationwide Children's Hospital, Columbus, OH (PH); Departments of Radiation Oncology and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC (DGK); 21st Century Oncology Translational Research Consortium (TRC) Headquarters, Scottsdale, AZ (SEF); Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA (AMM); Department of Radiation Oncology, the Ohio State University, Columbus, OH (MXW); Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA (APD); Radiotherapy Development Branch & Molecular Radiation Therapeutics Branch, Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD (MA, CNC); Clinical Radiation Oncology Branch, National Cancer Institute, Bethesda, MD (BV); Molecular Pharmacology Branch, National Cancer Institute, Bethesda, MD (BAT); Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH (MM); Winship Cancer Institute, Woodruff Health Science Center, Emory University, Atlanta, GA (WJC); Department of Radiation Oncology, Rush University Medical Center, Chicago, IL (DW).
authors.forename: Steven E
authors.initials: SE
authors.lastname: Finkelstein
authors.affiliation: Department of Radiation Oncology, Centre Hospitalier de L'Université de Montréal, Montréal, Québec, Canada (PW); Research Institute at Nationwide Children's Hospital, Columbus, OH (PH); Departments of Radiation Oncology and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC (DGK); 21st Century Oncology Translational Research Consortium (TRC) Headquarters, Scottsdale, AZ (SEF); Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA (AMM); Department of Radiation Oncology, the Ohio State University, Columbus, OH (MXW); Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA (APD); Radiotherapy Development Branch & Molecular Radiation Therapeutics Branch, Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD (MA, CNC); Clinical Radiation Oncology Branch, National Cancer Institute, Bethesda, MD (BV); Molecular Pharmacology Branch, National Cancer Institute, Bethesda, MD (BAT); Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH (MM); Winship Cancer Institute, Woodruff Health Science Center, Emory University, Atlanta, GA (WJC); Department of Radiation Oncology, Rush University Medical Center, Chicago, IL (DW).
authors.forename: Arta M
authors.initials: AM
authors.lastname: Monjazeb
authors.affiliation: Department of Radiation Oncology, Centre Hospitalier de L'Université de Montréal, Montréal, Québec, Canada (PW); Research Institute at Nationwide Children's Hospital, Columbus, OH (PH); Departments of Radiation Oncology and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC (DGK); 21st Century Oncology Translational Research Consortium (TRC) Headquarters, Scottsdale, AZ (SEF); Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA (AMM); Department of Radiation Oncology, the Ohio State University, Columbus, OH (MXW); Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA (APD); Radiotherapy Development Branch & Molecular Radiation Therapeutics Branch, Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD (MA, CNC); Clinical Radiation Oncology Branch, National Cancer Institute, Bethesda, MD (BV); Molecular Pharmacology Branch, National Cancer Institute, Bethesda, MD (BAT); Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH (MM); Winship Cancer Institute, Woodruff Health Science Center, Emory University, Atlanta, GA (WJC); Department of Radiation Oncology, Rush University Medical Center, Chicago, IL (DW).
authors.forename: Meng
authors.initials: M
authors.lastname: Xu-Welliver
authors.affiliation: Department of Radiation Oncology, Centre Hospitalier de L'Université de Montréal, Montréal, Québec, Canada (PW); Research Institute at Nationwide Children's Hospital, Columbus, OH (PH); Departments of Radiation Oncology and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC (DGK); 21st Century Oncology Translational Research Consortium (TRC) Headquarters, Scottsdale, AZ (SEF); Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA (AMM); Department of Radiation Oncology, the Ohio State University, Columbus, OH (MXW); Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA (APD); Radiotherapy Development Branch & Molecular Radiation Therapeutics Branch, Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD (MA, CNC); Clinical Radiation Oncology Branch, National Cancer Institute, Bethesda, MD (BV); Molecular Pharmacology Branch, National Cancer Institute, Bethesda, MD (BAT); Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH (MM); Winship Cancer Institute, Woodruff Health Science Center, Emory University, Atlanta, GA (WJC); Department of Radiation Oncology, Rush University Medical Center, Chicago, IL (DW).
authors.forename: Adam P
authors.initials: AP
authors.lastname: Dicker
authors.affiliation: Department of Radiation Oncology, Centre Hospitalier de L'Université de Montréal, Montréal, Québec, Canada (PW); Research Institute at Nationwide Children's Hospital, Columbus, OH (PH); Departments of Radiation Oncology and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC (DGK); 21st Century Oncology Translational Research Consortium (TRC) Headquarters, Scottsdale, AZ (SEF); Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA (AMM); Department of Radiation Oncology, the Ohio State University, Columbus, OH (MXW); Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA (APD); Radiotherapy Development Branch & Molecular Radiation Therapeutics Branch, Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD (MA, CNC); Clinical Radiation Oncology Branch, National Cancer Institute, Bethesda, MD (BV); Molecular Pharmacology Branch, National Cancer Institute, Bethesda, MD (BAT); Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH (MM); Winship Cancer Institute, Woodruff Health Science Center, Emory University, Atlanta, GA (WJC); Department of Radiation Oncology, Rush University Medical Center, Chicago, IL (DW).
authors.forename: Mansoor
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Department of Radiation Oncology, Centre Hospitalier de L'Université de Montréal, Montréal, Québec, Canada (PW); Research Institute at Nationwide Children's Hospital, Columbus, OH (PH); Departments of Radiation Oncology and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC (DGK); 21st Century Oncology Translational Research Consortium (TRC) Headquarters, Scottsdale, AZ (SEF); Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA (AMM); Department of Radiation Oncology, the Ohio State University, Columbus, OH (MXW); Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA (APD); Radiotherapy Development Branch & Molecular Radiation Therapeutics Branch, Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD (MA, CNC); Clinical Radiation Oncology Branch, National Cancer Institute, Bethesda, MD (BV); Molecular Pharmacology Branch, National Cancer Institute, Bethesda, MD (BAT); Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH (MM); Winship Cancer Institute, Woodruff Health Science Center, Emory University, Atlanta, GA (WJC); Department of Radiation Oncology, Rush University Medical Center, Chicago, IL (DW).
authors.forename: Bhadrasain
authors.initials: B
authors.lastname: Vikram
authors.affiliation: Department of Radiation Oncology, Centre Hospitalier de L'Université de Montréal, Montréal, Québec, Canada (PW); Research Institute at Nationwide Children's Hospital, Columbus, OH (PH); Departments of Radiation Oncology and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC (DGK); 21st Century Oncology Translational Research Consortium (TRC) Headquarters, Scottsdale, AZ (SEF); Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA (AMM); Department of Radiation Oncology, the Ohio State University, Columbus, OH (MXW); Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA (APD); Radiotherapy Development Branch & Molecular Radiation Therapeutics Branch, Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD (MA, CNC); Clinical Radiation Oncology Branch, National Cancer Institute, Bethesda, MD (BV); Molecular Pharmacology Branch, National Cancer Institute, Bethesda, MD (BAT); Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH (MM); Winship Cancer Institute, Woodruff Health Science Center, Emory University, Atlanta, GA (WJC); Department of Radiation Oncology, Rush University Medical Center, Chicago, IL (DW).
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Teicher
authors.affiliation: Department of Radiation Oncology, Centre Hospitalier de L'Université de Montréal, Montréal, Québec, Canada (PW); Research Institute at Nationwide Children's Hospital, Columbus, OH (PH); Departments of Radiation Oncology and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC (DGK); 21st Century Oncology Translational Research Consortium (TRC) Headquarters, Scottsdale, AZ (SEF); Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA (AMM); Department of Radiation Oncology, the Ohio State University, Columbus, OH (MXW); Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA (APD); Radiotherapy Development Branch & Molecular Radiation Therapeutics Branch, Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD (MA, CNC); Clinical Radiation Oncology Branch, National Cancer Institute, Bethesda, MD (BV); Molecular Pharmacology Branch, National Cancer Institute, Bethesda, MD (BAT); Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH (MM); Winship Cancer Institute, Woodruff Health Science Center, Emory University, Atlanta, GA (WJC); Department of Radiation Oncology, Rush University Medical Center, Chicago, IL (DW).
authors.forename: C Norman
authors.initials: CN
authors.lastname: Coleman
authors.affiliation: Department of Radiation Oncology, Centre Hospitalier de L'Université de Montréal, Montréal, Québec, Canada (PW); Research Institute at Nationwide Children's Hospital, Columbus, OH (PH); Departments of Radiation Oncology and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC (DGK); 21st Century Oncology Translational Research Consortium (TRC) Headquarters, Scottsdale, AZ (SEF); Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA (AMM); Department of Radiation Oncology, the Ohio State University, Columbus, OH (MXW); Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA (APD); Radiotherapy Development Branch & Molecular Radiation Therapeutics Branch, Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD (MA, CNC); Clinical Radiation Oncology Branch, National Cancer Institute, Bethesda, MD (BV); Molecular Pharmacology Branch, National Cancer Institute, Bethesda, MD (BAT); Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH (MM); Winship Cancer Institute, Woodruff Health Science Center, Emory University, Atlanta, GA (WJC); Department of Radiation Oncology, Rush University Medical Center, Chicago, IL (DW).
authors.forename: Mitchell
authors.initials: M
authors.lastname: Machtay
authors.affiliation: Department of Radiation Oncology, Centre Hospitalier de L'Université de Montréal, Montréal, Québec, Canada (PW); Research Institute at Nationwide Children's Hospital, Columbus, OH (PH); Departments of Radiation Oncology and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC (DGK); 21st Century Oncology Translational Research Consortium (TRC) Headquarters, Scottsdale, AZ (SEF); Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA (AMM); Department of Radiation Oncology, the Ohio State University, Columbus, OH (MXW); Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA (APD); Radiotherapy Development Branch & Molecular Radiation Therapeutics Branch, Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD (MA, CNC); Clinical Radiation Oncology Branch, National Cancer Institute, Bethesda, MD (BV); Molecular Pharmacology Branch, National Cancer Institute, Bethesda, MD (BAT); Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH (MM); Winship Cancer Institute, Woodruff Health Science Center, Emory University, Atlanta, GA (WJC); Department of Radiation Oncology, Rush University Medical Center, Chicago, IL (DW).
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Curran
authors.affiliation: Department of Radiation Oncology, Centre Hospitalier de L'Université de Montréal, Montréal, Québec, Canada (PW); Research Institute at Nationwide Children's Hospital, Columbus, OH (PH); Departments of Radiation Oncology and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC (DGK); 21st Century Oncology Translational Research Consortium (TRC) Headquarters, Scottsdale, AZ (SEF); Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA (AMM); Department of Radiation Oncology, the Ohio State University, Columbus, OH (MXW); Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA (APD); Radiotherapy Development Branch & Molecular Radiation Therapeutics Branch, Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD (MA, CNC); Clinical Radiation Oncology Branch, National Cancer Institute, Bethesda, MD (BV); Molecular Pharmacology Branch, National Cancer Institute, Bethesda, MD (BAT); Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH (MM); Winship Cancer Institute, Woodruff Health Science Center, Emory University, Atlanta, GA (WJC); Department of Radiation Oncology, Rush University Medical Center, Chicago, IL (DW). dian_wang@rush.edu.
authors.forename: Dian
authors.initials: D
authors.lastname: Wang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068258:Bevacizumab; D002453:Cell Cycle / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D006801:Humans; D007191:Indazoles; D007211:Indoles / Q000627:therapeutic use; D000074324:Ipilimumab; D058990:Molecular Targeted Therapy; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077594:Nivolumab; D010671:Phenylurea Compounds / Q000627:therapeutic use; D051736:Proto-Oncogene Proteins c-mdm2 / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D018714:Radiotherapy, Adjuvant; D012509:Sarcoma / Q000188:drug therapy* / Q000276:immunology / Q000532:radiotherapy* / Q000601:surgery; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D013449:Sulfonamides / Q000627:therapeutic use; D000077210:Sunitinib; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007191:Indazoles; D007211:Indoles; D000074324:Ipilimumab; D010671:Phenylurea Compounds; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D009536:Niacinamide; D000068258:Bevacizumab; D000077594:Nivolumab; C516667:pazopanib; D000077157:Sorafenib; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D051358:Cyclin-Dependent Kinase 4; D000077210:Sunitinib