title: Twice-daily radiotherapy as concurrent boost technique during two chemotherapy cycles in neoadjuvant chemoradiotherapy for resectable esophageal carcinoma: mature results of phase II study.
abstract: OBJECTIVE
  To determine the toxicities of neoadjuvant chemoradiotherapy using a three-drug regimen (cisplatin, 5-fluorouracil, and paclitaxel) and a conventional radiotherapy (RT) schedule combined with a concurrent boost technique during chemotherapy cycles, and to determine the rate of tumor response, overall survival, and impact of pathologic tumor response on survival.
  
  
  METHODS
  The eligibility criteria included resectable adenocarcinoma or squamous cell carcinoma (T2-T3N0-N1M0), performance score < or =2, and no significant comorbidities for trimodality therapy. Chemotherapy consisted of two cycles of cisplatin, 5-fluorouracil, and paclitaxel. A concurrent boost technique was used in RT for 2 levels of radiation doses: 58.5 Gy in 34 fractions within 5 weeks to the gross tumor volume and 45 Gy in 25 fractions within 5 weeks to the clinical target volume by administering a boost dose of 13.5 Gy in 9 fractions, 1.5 Gy/fraction, as a second daily fraction for 9 days on Days 1-5 and 29-32 of the chemotherapy cycles.
  
  
  RESULTS
  We enrolled 46 patients in the study. The paclitaxel dose was started at 75 mg/m(2) (n = 7) and escalated to 125 mg/m(2) (n = 5), at which point, dose-limiting toxicities occurred. Thereafter, paclitaxel at 100 mg/m(2) was used for an additional 34 patients. Toxicities included Grade 4 neutropenia (22%), febrile neutropenia requiring hospital admission (20%), Grade 3 (48%) and Grade 4 (7%) acute esophagitis, and paclitaxel-associated anaphylaxis (4%). Of the 46 patients, 3 (6.5%) died of treatment-related complications, 1 of pneumonia during induction therapy and 2 of postoperative complications (5% of the 40 patients who underwent resection). The histopathologic tumor response was a pathologic complete response (pT0N0) in 18 (45%) of 40 patients who underwent resection and 18 (39%) of all 46 registered patients. Minimal residual disease (pT1N0) at the primary site was present in 5 (11%) and residual disease in 23 (50%) of all 46 patients. The minimal follow-up for all long-term survivors (n = 16) was 5.5 years. The median survival time was 34 months, and the overall survival rate was 57%, 50%, and 37% at 2, 3, and 5 years, respectively. The 5-year overall survival (56% vs. 24%, p = 0.0214) and disease-free survival (48% vs. 6%) were significantly better statistically for patients with a pathologic complete response and minimal residual disease than for those with residual disease. All long-term survivors beyond 5.5 years without recurrence accrued from patient cohorts with a pathologic complete response or minimal residual disease.
  
  
  CONCLUSIONS
  An incorporation of twice-daily RT as a concurrent boost to the conventional daily RT schedule during chemotherapy cycles is feasible and warrants additional study for radiation dose intensification. Such research would be prudent for both improved long-term survival and organ preservation in esophageal carcinoma.
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, 100 Blossom Street, Boston, MA 02114, USA. nchoi@partners.org
authors.forename: Noah
authors.initials: N
authors.lastname: Choi
authors.forename: Sung D
authors.initials: SD
authors.lastname: Park
authors.forename: Thomas
authors.initials: T
authors.lastname: Lynch
authors.forename: Cameron
authors.initials: C
authors.lastname: Wright
authors.forename: Marek
authors.initials: M
authors.lastname: Ancukiewicz
authors.forename: John
authors.initials: J
authors.lastname: Wain
authors.forename: Dean
authors.initials: D
authors.lastname: Donahue
authors.forename: Douglas
authors.initials: D
authors.lastname: Mathisen
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000532:radiotherapy / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000532:radiotherapy / Q000601:surgery; D002945:Cisplatin / Q000008:administration & dosage; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy* / Q000601:surgery; D005240:Feasibility Studies; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D017239:Paclitaxel / Q000008:administration & dosage; D011878:Radiotherapy / Q000009:adverse effects; D011879:Radiotherapy Dosage; D015996:Survival Rate
chemical_list: D017239:Paclitaxel; D002945:Cisplatin; D005472:Fluorouracil