title: Efficacy endpoints of radiation therapy group protocol 0247: a randomized, phase 2 study of neoadjuvant radiation therapy plus concurrent capecitabine and irinotecan or capecitabine and oxaliplatin for patients with locally advanced rectal cancer.
abstract: OBJECTIVE
  To report secondary efficacy endpoints of Radiation Therapy Oncology Group protocol 0247, primary endpoint analysis of which demonstrated that preoperative radiation therapy (RT) with capecitabine plus oxaliplatin achieved a pathologic complete remission prespecified threshold (21%) to merit further study, whereas RT with capecitabine plus irinotecan did not (10%).
  
  
  METHODS
  A randomized, phase 2 trial evaluated preoperative RT (50.4 Gy in 1.8-Gy fractions) with 2 concurrent chemotherapy regimens: (1) capecitabine (1200 mg/m(2)/d Monday-Friday) plus irinotecan (50 mg/m(2)/wk × 4); and (2) capecitabine (1650 mg/m(2)/d Monday-Friday) plus oxaliplatin (50 mg/m(2)/wk × 5) for clinical T3 or T4 rectal cancer. Surgery was performed 4 to 8 weeks after chemoradiation, then 4 to 6 weeks later, adjuvant chemotherapy (oxaliplatin 85 mg/m(2); leucovorin 400 mg/m(2); 5-fluorouracil 400 mg/m(2); 5-fluorouracil 2400 mg/m(2)) every 2 weeks × 9. Disease-free survival (DFS) and overall survival (OS) were estimated univariately by the Kaplan-Meier method. Local-regional failure (LRF), distant failure (DF), and second primary failure (SP) were estimated by the cumulative incidence method. No statistical comparisons were made between arms because each was evaluated individually.
  
  
  RESULTS
  A total of 104 patients (median age, 57 years) were treated; characteristics were similar for both arms. Median follow-up for RT with capecitabine/irinotecan arm was 3.77 years and for RT with capecitabine/oxaliplatin arm was 3.97 years. Four-year DFS, OS, LRF, DF, and SP estimates for capecitabine/irinotecan arm were 68%, 85%, 16%, 24%, and 2%, respectively. The 4-year DFS, OS, LRF, DF, and SP failure estimates for capecitabine/oxaliplatin arm were 62%, 75%, 18%, 30%, and 6%, respectively.
  
  
  CONCLUSIONS
  Efficacy results for both arms are similar to other reported studies but suggest that pathologic complete remission is an unsuitable surrogate for traditional survival metrics of clinical outcome. Although it remains uncertain whether the addition of a second cytotoxic agent enhances the effectiveness of fluorouracil plus RT, these results suggest that further study of irinotecan may be warranted.
authors.affiliation: Medical College of Wisconsin, Madison, Wisconsin.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Wong
authors.affiliation: Radiation Therapy Oncology Group Statistical Center, Philadelphia, Pennsylvania.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Moughan
authors.affiliation: University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio. Electronic address: Neal.Meropol@case.edu.
authors.forename: Neal J
authors.initials: NJ
authors.lastname: Meropol
authors.affiliation: Department of Radiation Oncology and Medical Oncology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.
authors.forename: Pramila Rani
authors.initials: PR
authors.lastname: Anne
authors.affiliation: Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Kachnic
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.affiliation: Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: James C
authors.initials: JC
authors.lastname: Watson
authors.affiliation: Department of Radiation Oncology and Medical Oncology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.
authors.forename: Edith P
authors.initials: EP
authors.lastname: Mitchell
authors.affiliation: The Schiffler Cancer Center, Wheeling, West Virginia.
authors.forename: Jondavid
authors.initials: J
authors.lastname: Pollock
authors.affiliation: Intermountain Medical Center, Murray, Utah.
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Lee
authors.affiliation: Division of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Michael
authors.initials: M
authors.lastname: Haddock
authors.affiliation: Medical College of Wisconsin, Madison, Wisconsin.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Erickson
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Willett
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000069287:Capecitabine; D059248:Chemoradiotherapy / Q000379:methods*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use; D011879:Radiotherapy Dosage; D012004:Rectal Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D016879:Salvage Therapy / Q000379:methods; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D011838:Radiation-Sensitizing Agents; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000069287:Capecitabine; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin