title: A Phase Ib/II Study of Gemcitabine and Docetaxel in Combination With Pazopanib for the Neoadjuvant Treatment of Soft Tissue Sarcomas.
abstract: CONCLUSIONS
  Our results highlight some of the challenges in the management of soft tissue sarcomas, which requires close cooperation between surgeons and medical oncologists and a careful selection of patients. The incidence of hepatotoxicity was a concerning finding and had been previously reported in patients treated with pazopanib.Although pharmacokinetic analysis was not part of this study, concomitant treatment with pazopanib has been recently reported to increase docetaxel exposure, which may explain the increased toxicity of combination regimens. It remains possible that lower doses of combined gemcitabine, docetaxel, and pazopanib may be tolerable. However, caution should be exercised in future trials investigating similar combinations.
  
  
  BACKGROUND
  For extremity soft tissue sarcomas (STS), surgical resection remains the standard of care, and the addition of chemotherapy is controversial. This was a phase Ib/II trial of neoadjuvant therapy for patients with STS.
  
  
  METHODS
  Patients with high grade, extremity STS of >8 cm and amenable to definitive resection were treated with up to four 21-day cycles of 900 mg/m(2) gemcitabine on days 1 and 8, 75 mg/m(2) docetaxel on day 8, and 400 mg of pazopanib daily (GDP), followed by surgery and, if indicated, radiation therapy. Primary and secondary endpoints (phase Ib portion) were the safety and rate of pathologic response.
  
  
  RESULTS
  The trial was discontinued because of slow accrual after inclusion of five patients (leiomyosarcoma: two; undifferentiated pleomorphic sarcoma: three). Two patients completed four treatment cycles: one underwent surgery and one had insufficient response and received additional therapies. Three patients discontinued treatment because of toxicity. Grade 3 adverse events included hypertension, fatigue, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation, hoarseness, and myelotoxicity. There were no complete or partial responses. One patient had ≥ 90% pathologic response. Among four patients who underwent resection, three remain free of disease, and one patient eventually relapsed.
  
  
  CONCLUSIONS
  GDP combination used in the neoadjuvant setting resulted in significant toxicity; despite pathologic responses, no objective responses occurred.
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Rodrigo R
authors.initials: RR
authors.lastname: Munhoz
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA Weill Cornell Medical College, New York, New York, USA.
authors.forename: Sandra P
authors.initials: SP
authors.lastname: D'Angelo
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA Weill Cornell Medical College, New York, New York, USA.
authors.forename: Mrinal M
authors.initials: MM
authors.lastname: Gounder
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA Weill Cornell Medical College, New York, New York, USA.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Keohan
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA Weill Cornell Medical College, New York, New York, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Chi
authors.affiliation: Columbia University Medical Center, New York, New York, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Carvajal
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA Weill Cornell Medical College, New York, New York, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Singer
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA Weill Cornell Medical College, New York, New York, USA.
authors.forename: Aimee M
authors.initials: AM
authors.lastname: Crago
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA Weill Cornell Medical College, New York, New York, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Landa
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA Weill Cornell Medical College, New York, New York, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Healey
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA Weill Cornell Medical College, New York, New York, USA.
authors.forename: Li-Xuan
authors.initials: LX
authors.lastname: Qin
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA Weill Cornell Medical College, New York, New York, USA.
authors.forename: Meera
authors.initials: M
authors.lastname: Hameed
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Marietta O
authors.initials: MO
authors.lastname: Ezeoke
authors.affiliation: University of California at Los Angeles, Los Angeles, California, USA.
authors.forename: Arun S
authors.initials: AS
authors.lastname: Singh
authors.affiliation: Northwestern University, Chicago, Illinois, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Agulnik
authors.affiliation: University of California at Los Angeles, Los Angeles, California, USA.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Chmielowski
authors.affiliation: University of Chicago, Chicago, Illinois USA.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Luke
authors.affiliation: Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Van Tine
authors.affiliation: Columbia University Medical Center, New York, New York, USA.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA Weill Cornell Medical College, New York, New York, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Tap
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA Weill Cornell Medical College, New York, New York, USA dicksonm@mskcc.org.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dickson
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D006801:Humans; D007191:Indazoles; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011743:Pyrimidines / Q000008:administration & dosage*; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage*; D043823:Taxoids / Q000008:administration & dosage*; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; C516667:pazopanib; D000093542:Gemcitabine