title: High pathological response rate in locally advanced esophageal cancer after neoadjuvant combined modality therapy: dose finding of a weekly chemotherapy schedule with protracted venous infusion of 5-fluorouracil and dose escalation of cisplatin, docetaxel and concurrent radiotherapy.
abstract: BACKGROUND
  This phase I study was aimed at defining the toxicity profile and pathological response rate of a neoadjuvant schedule including weekly docetaxel and cisplatin, protracted venous infusion (PVI) of 5-FU and concomitant radiotherapy (RT) in locally advanced esophageal cancer.
  
  
  METHODS
  The schedule consisted of a first phase of chemotherapy alone and a second phase of concurrent chemoradiation. Initial doses were: docetaxel and cisplatin 20 mg/m2 on days 1, 8, 15, 29, 36 and 43 plus 5-FU 150 mg/m2 PVI on days 1-21 and 29-49; RT (40 Gy) started on day 29. In the following steps the doses were escalated up to docetaxel 35 mg/m2 and cisplatin 25 mg/m2 on days 1, 8, 15, 29, 36, 43, 50 and 57 plus 5-FU 180 mg/m2 PVI on days 1-21 and 150 mg/m2 PVI on days 29-63 concurrently with RT 50 Gy.
  
  
  RESULTS
  Forty-seven patients were enrolled and 46 completed the planned treatment. During the concomitant phase, grade 3-4 hematological toxicities occurred in three patients (6.5%) (or 3/174 cycles) and non-hematological toxicities in six patients (13%) (or 7/179 cycles). A pathological downstaging was obtained in 59.6% of the cases (28/47): complete remission (pCR) in 14 patients, near pCR (residual microfoci on the primary pN0) in eight patients, pT2 pN0 in three patients and partial response on the primary with positive lymph nodes in three patients. Six (13%) and 13 (28%) patients were considered stable and non-responders, respectively. In the last dose level, eight pCR and four near-pCR were obtained out of 15 patients. The maximum tolerable dose was not formally defined because dose escalation was stopped at the last dose level.
  
  
  CONCLUSIONS
  This schedule represents a feasible treatment and the high pathological response rate is extremely encouraging; the doses found in the last dose-level are the basis for an ongoing phase II study at our institution.
authors.affiliation: Divisione di Oncologia Medica, 1 Divisione Clinicizzata di Chirurgia Generale, Divisione di Radioterapia Oncologica, Servizio di Anatomia Patologica, Azienda Ospedaliera-Università di Verona, Verona. felice.pasini@univr.it
authors.forename: F
authors.initials: F
authors.lastname: Pasini
authors.forename: G
authors.initials: G
authors.lastname: de Manzoni
authors.forename: C
authors.initials: C
authors.lastname: Pedrazzani
authors.forename: A
authors.initials: A
authors.lastname: Grandinetti
authors.forename: E
authors.initials: E
authors.lastname: Durante
authors.forename: M
authors.initials: M
authors.lastname: Gabbani
authors.forename: A
authors.initials: A
authors.lastname: Tomezzoli
authors.forename: C
authors.initials: C
authors.lastname: Griso
authors.forename: A
authors.initials: A
authors.lastname: Guglielmi
authors.forename: G
authors.initials: G
authors.lastname: Pelosi
authors.forename: S
authors.initials: S
authors.lastname: Maluta
authors.forename: G L
authors.initials: GL
authors.lastname: Cetto
authors.forename: C
authors.initials: C
authors.lastname: Cordiano
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin; D005472:Fluorouracil