title: Frequent dose interruptions are required for patients receiving oral kinase inhibitor therapy for advanced renal cell carcinoma.
abstract: OBJECTIVE
  Recent advances for patients with advanced or metastatic renal cell carcinoma (RCC) have been shown to improve progression-free survival with both response rates and disease stabilizing activity. Sorafenib, a multikinase inhibitor, and sunitinib, an inhibitor of vascular endothelial growth factor-r and platelet-derived growth factor-r, have been approved by the Food and Drug Administration since 2005/2006. This retrospective analysis of patients treated with both aforementioned kinase inhibitors for advanced RCC presents data related to their antitumor effects as well as safety profile with particular attention to dose interruption and modification requirements.
  
  
  METHODS
  This was a retrospective review of patients diagnosed with RCC either with advanced disease at initial presentation or after first-line therapy, who received either continuous sorafenib 400 mg bid or sunitinib 50 mg Qday for 4 weeks on and 2 weeks off until disease progression or untoward drug reaction. Tumor response was evaluated by response evaluation criteria in solid tumors criteria, and adverse events were graded by National Cancer Institute-Common Toxicity Criteria.
  
  
  RESULTS
  From December 2005 to May 2008, 34 patients were followed. Twenty-two patients received sorafenib first line, 10 received sunitinib first line, and 2 patients received sorafenib as third-line therapy. Twenty-nine were evaluable for response rates. There were 10 patients (34%) who had stabilization of disease, 8 patients (28%) who had a partial response, and 11 patients (38%) who had progression of disease. The progression-free survival median was 8 months. Of the 34 patients evaluable for toxicities, grade 3 or 4 adverse event occurred in 19 patients (56%). These patients required either dose modifications and/or treatment interruptions within an average of the first 2 weeks of treatment. Eight patients (24%) required drug discontinuation. Eleven patients (32%) required dose reductions, but were able to resume the targeted dose after slow dose escalation. Three patients (9%) remain dose reduced for greater than 12 weeks.
  
  
  CONCLUSIONS
  Sorafenib and sunitinib have extended patients' disease-free survival by several months; however, the initial grade 3 or 4 adverse event presented in the literature appear to have been under-reported. Our experience suggests that the first 4 weeks of treatment is the most likely timeframe within which drug reactions occur. Therefore, careful monitoring and possibly additional clinical visits are warranted during this time period. Although a significant percentage of patients require dose modification, many can be restarted and titrated up to the targeted dose.
authors.affiliation: Department of Medicine, Section of Hematology and Oncology, Medical College of Georgia School of Medicine, 1120 15th Street, Augusta, GA 30912, USA. dblavine@gmail.com
authors.forename: David B T
authors.initials: DB
authors.lastname: La Vine
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Coleman
authors.forename: Carol H
authors.initials: CH
authors.lastname: Davis
authors.forename: Christine E
authors.initials: CE
authors.lastname: Carbonell
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Davis
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D004334:Drug Administration Schedule; D003875:Drug Eruptions / Q000209:etiology*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D007037:Hypothyroidism / Q000139:chemically induced; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D012189:Retrospective Studies; D000077157:Sorafenib; D000077210:Sunitinib
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D009536:Niacinamide; D000077157:Sorafenib; D000077210:Sunitinib