title: Complete restoration of refractory mandibular osteoradionecrosis by prolonged treatment with a pentoxifylline-tocopherol-clodronate combination (PENTOCLO): a phase II trial.
abstract: OBJECTIVE
  Osteoradionecrosis (ORN) is a nonhealing wound of the bone that is difficult to manage. Combined treatment with pentoxifylline and vitamin E reduces radiation-induced fibrosis and ORN with a good prognosis. We previously showed that the combination of pentoxifylline and vitamin E with clodronate (PENTOCLO) is useful in healing sternocostal and some mandibular ORN. Is PENTOCLO effective in ORN of poor prognosis?
  
  
  METHODS
  54 eligible patients previously irradiated for head and neck cancer (among 72 treated) a mean 5 years previously received exteriorized refractory mandibular ORN for 1.4 ± 1.8 years, mainly after local surgery and hyperbaric oxygen had been ineffective. The mean length of exposed bone (D) was 17 ± 8 mm as primary endpoint, and the mean Subjective, Objective, Management, and Analytic evaluation of injury (SOMA) score was 16 ± 4. Between August 2000 and August 2008, all patients were given daily oral PENTOCLO: 800 mg pentoxifylline, 1,000 IU vitamin E, and 1,600 mg clodronate 5 days per week alternating with 20 mg prednisone and 1,000 mg ciprofloxacin 2 days per week. The duration of treatment was related to consolidated healing.
  
  
  RESULTS
  Prolonged treatment (16 ± 9 months) was safe and well tolerated. All patients improved, with an exponential progressive--(f[t] = a.exp(-b.t)--and significant (p < 0.0001) reduction of exposed bone (D), respectively (months): D(2) -42%, D(4) -62%, D(6) -77%, D(12) -92%, and D(18) -96%, combined with iterative spontaneous sequestrectomies in 36 patients. All patients experienced complete recovery in a median of 9 months. Clinical improvement was measured in terms of discontinuation of analgesics, new fracture, closed skin fistulae, and delayed radiologic improvement: SOMA(6) -64%, SOMA(12) -89%, and SOMA(30) -96%.
  
  
  CONCLUSIONS
  Long-term PENTOCLO treatment is effective, safe, and curative for refractory ORN and induces mucosal and bone healing with significant symptom improvement. These findings will need to be confirmed in a randomized trial.
authors.affiliation: Service d'Oncologie-Radiothérapie, Hôpital Saint-Louis, APHP, Paris, France. sylvie.delanian@sls.ap-hop-paris.fr
authors.forename: Sylvie
authors.initials: S
authors.lastname: Delanian
authors.forename: Cécile
authors.initials: C
authors.lastname: Chatel
authors.forename: Raphael
authors.initials: R
authors.lastname: Porcher
authors.forename: Joel
authors.initials: J
authors.lastname: Depondt
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Lefaix
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D002939:Ciprofloxacin / Q000627:therapeutic use; D004002:Clodronic Acid / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D006258:Head and Neck Neoplasms / Q000532:radiotherapy; D006801:Humans; D008297:Male; D008336:Mandibular Diseases / Q000188:drug therapy*; D008875:Middle Aged; D010025:Osteoradionecrosis / Q000188:drug therapy*; D010431:Pentoxifylline / Q000627:therapeutic use*; D011241:Prednisone / Q000627:therapeutic use; D011379:Prognosis; D024505:Tocopherols / Q000627:therapeutic use*
chemical_list: D050071:Bone Density Conservation Agents; D004338:Drug Combinations; C559761:pentoxifylline-tocopherol-clodronate; D004002:Clodronic Acid; D002939:Ciprofloxacin; D024505:Tocopherols; D010431:Pentoxifylline; D011241:Prednisone