title: Risk factors and model for predicting toxicity-related treatment discontinuation in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF)-targeted therapies are standard treatment for metastatic renal cell carcinoma (mRCC); however, toxicities can lead to drug discontinuation, which can affect patient outcomes. This study was aimed at identifying risk factors for toxicity and constructing the first model to predict toxicity-related treatment discontinuation (TrTD) in mRCC patients treated with VEGF-targeted therapies.
  
  
  METHODS
  The baseline characteristics, treatment outcomes, and toxicity data were collected for 936 mRCC patients receiving first-line VEGF-targeted therapy from the International Metastatic Renal Cell Carcinoma Database Consortium. A competing risk regression model was used to identify risk factors for TrTD, and it accounted for other causes as competing risks.
  
  
  RESULTS
  Overall, 198 (23.8%) experienced TrTD. Sunitinib was the most common VEGF-targeted therapy (77%), and it was followed by sorafenib (18.4%). The median time on therapy was 7.1 months for all patients and 4.4 months for patients with TrTD. The most common toxicities leading to TrTD included fatigue, diarrhea, and mucositis. In a multivariate analysis, significant predictors for TrTD were a baseline age ≥60 years, a glomerular filtration rate (GFR) <30 mL/min/1.73 m(2) , a single metastatic site, and a sodium level <135 mmol/L. A risk group model was developed that used the number of patient risk factors to predict the risk of TrTD.
  
  
  CONCLUSIONS
  In the largest series to date, age, GFR, number of metastatic sites, and baseline sodium level were found to be independent risk factors for TrTD in mRCC patients receiving VEGF-targeted therapy. Based on the number of risk factors present, a model for predicting TrTD was built to be used as a tool for toxicity monitoring in clinical practice.
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Marina D
authors.initials: MD
authors.lastname: Kaymakcalan
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Wanling
authors.initials: W
authors.lastname: Xie
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Laurence
authors.initials: L
authors.lastname: Albiges
authors.affiliation: Department of Medicine, Cross Cancer Institute, Edmonton, Canada.
authors.forename: Scott A
authors.initials: SA
authors.lastname: North
authors.affiliation: British Columbia Cancer Agency, Vancouver, Canada.
authors.forename: Christian K
authors.initials: CK
authors.lastname: Kollmannsberger
authors.affiliation: British Columbia Cancer Agency, Vancouver, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Smoragiewicz
authors.affiliation: Tom Baker Cancer Center, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Nils
authors.initials: N
authors.lastname: Kroeger
authors.affiliation: Tom Baker Cancer Center, University of Calgary, Calgary, Alberta, Canada.
authors.forename: J Connor
authors.initials: JC
authors.lastname: Wells
authors.affiliation: Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Rha
authors.affiliation: Asan Medical Center, Seoul, Korea.
authors.forename: Jae Lyun
authors.initials: JL
authors.lastname: Lee
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Rana R
authors.initials: RR
authors.lastname: McKay
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: André P
authors.initials: AP
authors.lastname: Fay
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Guillermo
authors.initials: G
authors.lastname: De Velasco
authors.affiliation: Department of Medicine, Cross Cancer Institute, Edmonton, Canada.
authors.forename: Daniel Y C
authors.initials: DY
authors.lastname: Heng
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D000077784:Axitinib; D000068258:Bevacizumab / Q000008:administration & dosage / Q000009:adverse effects; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D016208:Databases, Factual; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D060831:Hand-Foot Syndrome / Q000209:etiology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects; D007191:Indazoles / Q000008:administration & dosage / Q000009:adverse effects; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D058990:Molecular Targeted Therapy / Q000009:adverse effects* / Q000379:methods; D052016:Mucositis / Q000139:chemically induced; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects; D011237:Predictive Value of Tests; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D000077157:Sorafenib; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D010671:Phenylurea Compounds; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000068258:Bevacizumab; C516667:pazopanib; D000077157:Sorafenib; D000077784:Axitinib; D000077210:Sunitinib
keywords: International Metastatic Renal Cell Carcinoma Database Consortium (IMDC); VEGF-targeted therapies; model; renal cell carcinoma; risk factors; toxicity; treatment discontinuation