title: Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy--a multicenter randomized trial.
abstract: OBJECTIVE
  To compare conventional fractionation radiation therapy (RT), Arm A, vs. split-course accelerated hyperfractionated RT (S-AHF), Arm B, vs. conventional fractionation RT plus concomitant chemotherapy (CT), Arm C, in terms of survival and toxicity for advanced, unresectable epidermoid tumors of oropharynx.
  
  
  METHODS
  Between January 1993 and June 1998, 192 previously untreated patients affected with Stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were accrued in a multicenter, randomized Phase III trial (ORO 93-01). For Arms A and C, 66-70 Gy in 33-35 fractions, 5 days a week, were administered in 6.5-7 weeks to tumor and positive nodes. In Arm B, the dose delivered to tumor and involved nodes was 64-67.2 Gy, giving 2 fractions of 1.6 Gy every day with an interfraction interval of at least 4 h and preferably 6 h, 5 days a week. At 38.4 Gy, a 2-week split was planned; after the split, RT was resumed with the same modality. In Arm C, CT regimen consisted of carboplatin and 5-fluorouracil (CBDCA 75 mg/m(2), Days 1-4; 5-FU 1,000 mg/m(2) i.v. over 96 h, Days 1-4, recycling every 28 days (at 1st, 5th, and 9th week).
  
  
  RESULTS
  No statistically significant difference was detected in overall survival (p = 0.129): 40% Arm A vs. 37% Arm B vs. 51% Arm C were alive at 24 months. Similarly, there was no statistically significant difference in terms of event-free survival (p = 0.196): 20% for Arm A, 19% for Arm B, and 37% for Arm C were event free at 24 months. On the contrary, the 2-year disease-free survival was significantly different among the three arms (p = 0.022), with a superiority for Arm C. At 24 months, the proportion of patients without relapse was 42% for Arm C vs. 23% for Arm A and 20% for Arm B. Patients in Arm A less frequently developed G3+ acute mucositis than their counterparts in Arm B or C (14.7% vs. 40.3% vs. 44%). Regarding the CT-related acute toxicity, apart from 1 case of fatal nephrotoxicity, only hematologic G3+ (Grade 3 or higher) acute sequelae were observed (World Health Organization scale), most commonly leukopenia (22.7%). Arm C showed slightly more G3+ skin, s.c. tissue, and mucosal late side effects (RTOG scale), although significant sequelae were relatively uncommon, and mucosal sequelae were most commonly transient. The occurrence of persistent G3 xerostomia was comparable in all three treatment arms.
  
  
  CONCLUSIONS
  The combination of simultaneous CT and RT with the regimen of this trial is better than RT alone in advanced oropharyngeal squamous-cell carcinomas, by increasing disease-free survival. This improvement, however, did not translate into an overall survival improvement, and was associated with a higher incidence of acute morbidity.
authors.affiliation: Rep. di Radioterapia, Dipartimento di Fisiopatologia Clinica, Università, Firenze, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Olmi
authors.forename: Sergio
authors.initials: S
authors.lastname: Crispino
authors.forename: Carlo
authors.initials: C
authors.lastname: Fallai
authors.forename: Valter
authors.initials: V
authors.lastname: Torri
authors.forename: Francesca
authors.initials: F
authors.lastname: Rossi
authors.forename: Andrea
authors.initials: A
authors.lastname: Bolner
authors.forename: Maurizio
authors.initials: M
authors.lastname: Amichetti
authors.forename: Marco
authors.initials: M
authors.lastname: Signor
authors.forename: Raffaella
authors.initials: R
authors.lastname: Taino
authors.forename: Massimo
authors.initials: M
authors.lastname: Squadrelli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Colombo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ardizzoia
authors.forename: Pietro
authors.initials: P
authors.lastname: Ponticelli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Franchin
authors.forename: Emilio
authors.initials: E
authors.lastname: Minatel
authors.forename: Carlo
authors.initials: C
authors.lastname: Gobitti
authors.forename: Guido
authors.initials: G
authors.lastname: Atzeni
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gava
authors.forename: Monica
authors.initials: M
authors.lastname: Flann
authors.forename: Silvia
authors.initials: S
authors.lastname: Marsoni
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D003131:Combined Modality Therapy; D019583:Dose Fractionation, Radiation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009959:Oropharyngeal Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000532:radiotherapy*; D010166:Palliative Care; D010349:Patient Compliance; D011878:Radiotherapy / Q000009:adverse effects; D016879:Salvage Therapy; D015996:Survival Rate