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Protocolo de manejo de la osteorradionecrosis resistente al oxígeno hiperbárico PENTOCLO

Protocolo de manejo de la osteorradionecrosis resistente al oxígeno hiperbárico PENTOCLO

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  • 1. Int. J. Radiation Oncology Biol. Phys., Vol. 80, No. 3, pp. 832–839, 2011 Copyright Ó 2011 Elsevier Inc. CME Printed in the USA. All rights reserved 0360-3016/$–see front matter doi:10.1016/j.ijrobp.2010.03.029CLINICAL INVESTIGATION Normal Tissue COMPLETE RESTORATION OF REFRACTORY MANDIBULAR OSTEORADIONECROSIS BY PROLONGED TREATMENT WITH A PENTOXIFYLLINE-TOCOPHEROL-CLODRONATE COMBINATION (PENTOCLO): A PHASE II TRIAL SYLVIE DELANIAN, M.D., PHD.,* CECILE CHATEL, D.D.,y RAPHAEL PORCHER, PH.D.,z JOEL DEPONDT, M.D., ´ PH.D.,x AND JEAN-LOUIS LEFAIX, PH.D.{ *Service d’Oncologie-Radiotherapie, and zDepartement de Biostatistique et Informatique Medicale, Hopital Saint-Louis, APHP, Paris; ´ ´ ´ ˆ y Odontologie, Institut Gustave Roussy, Villejuif; xService de Chirurgie Cervico-Faciale, Hopital Bichat, APHP, Paris; and {CEA/DSV/ ˆ IRCM-LARIA, CIRIL-GANIL, Caen, France Purpose: Osteoradionecrosis (ORN) is a nonhealing wound of the bone that is difficult to manage. Combined treat- ment 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 exponen- tial progressive—(f[t] = a.exp(-b.t)—and significant (p < 0.0001) reduction of exposed bone (D), respectively (months): D2 À42%, D4 À62%, D6 À77%, D12 À92%, and D18 À96%, combined with iterative spontaneous seques- trectomies in 36 patients. All patients experienced complete recovery in a median of 9 months. Clinical improve- ment was measured in terms of discontinuation of analgesics, new fracture, closed skin fistulae, and delayed radiologic improvement: SOMA6 À64%, SOMA12 À89%, and SOMA30 À96%. Conclusion: Long-term PENTOCLO treatment is effective, safe, and curative for refractory ORN and induces mu- cosal and bone healing with significant symptom improvement. These findings will need to be confirmed in a ran- domized trial. Ó 2011 Elsevier Inc. Pentoxifylline, Alpha tocopherol, Clodronate, Osteoradionecrosis, Radiotherapy. INTRODUCTION tal extraction, mostly 6 months to 5 years after irradiation (1). Mandibular ORN symptoms, excluding tumor recurrence, areMandibular osteoradionecrosis (ORN) is a delayed injury diverse, ranging from occult disease to major bone destructioncaused by failure of bone healing several years after head- with soft tissue necrosis and spontaneous complicationsand-neck cancer irradiation. Severe ORN can be life- like osteomyelitis, fistulation, and fracture (2). Multiple riskthreatening and compromise functional prognosis. Although factors predispose to its development: treatment-dependentconformal radiotherapy (RT), by improving the therapeutic ra- factors, including radiotherapy (dose, volume, brachyther-tio, has reduced the incidence of severe complications, ORN is apy), surgery (number, volume, hematoma, infection), andstill unavoidable in a mean 10% of cases, especially after den- Note—An online CME test for this article can be taken at http:// Supported by the Delegation a la Recherche Clinique of the As- ´´ `astro.org/MOC. sistance Publique des Hopitaux de Paris. ˆ Reprint requests to: Dr. Sylvie Delanian, M.D., Ph.D., Service Conflict of interest: none.d’Oncologie-Radiotherapie, Hopital Saint Louis, 1 Ave Claude Vel- ´ ˆ Acknowledgment—The authors thank Charles Guedon and physi-lefaux, 75010 Paris, France. Tel: (33) 1-42-49-97-89; Fax: (33) 1- cians from several Parisian institutions for entrusting their patients42-49-91-97; E-mail: sylvie.delanian@sls.ap-hop-paris.fr to us for treatment. Presented at the 18th Congress of Societe Francaise de Radiother- ´´ ¸ ´ Received Oct 2, 2009, and in revised form Feb 8, 2010. Acceptedapie Oncologique, Paris, November 2007, and the Special Work- for publication March 10, 2010.shop of The Royal College of Surgeons of England, London,November 2007. 832
  • 2. PENTOCLO trial in osteoradionecrosis d S. DELANIAN et al. 833concomitant chemotherapy; and patient-dependent factors, in- that was not measurable because of trismus, nonexposed bone, orcluding age, hypersensitivity, high blood pressure, diabetes, maxillary lesion, and 9 withdrew because of a change of mind beforeand collagen vascular diseases (3). However, the increased in- the study (2 patients), concomitant progressive cancer (4 patients),cidence and severity of ORN are mainly due to poor dental sta- fatal sepsis (1 patient), human immunodeficiency virus disease (1 pa- tient), and intolerance combined with lupus (1 patient). Conse-tus, local biopsy sites, bone proximity to the initial anatomic quently, 54 eligible treated patients had complete, available, andtumor site, or excessive tobacco and alcohol consumption (1). long-term homogeneous data (Table 1). Informed consent was ob- The management of ORN is usually based on conventional tained from all patients, and the study was approved by the Hospitalmedical care focusing on comorbidity factors such as optimi- Ethics Committee. The patients (43 men, 79%), all of whom hadzation of oral hygiene (alcohol and tobacco consumption, a history of tobacco and alcohol consumption, showed no evidencemouth baths), infection control (antibiotics), and devitalized of recurrent disease on entering the trial.tissue removal (sequestrectomy) for ORN with a good progno-sis (1, 3). Furthermore, its incidence is reduced by preventing RT damage The ORN was caused by standard RT of head-and-neck cancertrauma such as limited dental extraction. If ORN management (9–10 Gy/week), with a total prescribed dose ranging from 45–65always involves conservative measures, recovery at 1 year is Gy (15 postoperative) to 70–75 Gy (39 exclusive RT): RT alonereported in only 8–33% of patients with a good prognosis (4, (n =13), combined with primary or salvage surgery (n =27), and5). Hyperbaric oxygen (HBO) is reported to be effective as combined with chemotherapy (n =14). The mean latency period be-an adjunctive treatment for ORN, but the retrospective trials tween the end of RT and the first ORN symptoms was 4.8 Æ 5.1involved are restricted (18 patients/study), and recovery years (range, 0.2–29).ranges from 15% to 43% after HBO alone, vs. 18% to 90%after HBO combined with limited surgery (4–6). In addition, PENTOCLO treatment modalitiesa recent randomized trial in 68 ORN patients failed to One month before inclusion, all patients were given 4-week dailydemonstrate that HBO had any beneficial effect, inasmuch oral disinfiltrating treatment with 20 mg prednisone plus 2 g amoxicillin-clavulanate plus 1 g ciprofloxacin plus 50 mg flucona-as only 19% in the HBO group recovered vs. 33% in the zole to allow further PENTOCLO penetration, which improvedplacebo group (7). By contrast, refractory ORN (Epstein Stage pain and purulence symptoms by a mean of 20% in all patients.III) required, when technically possible, extensive surgical re-section or reconstruction, such as hemimandibulectomy orclosure of fistulae using myocutaneous flaps (1, 7). The Table 1. Baseline screening of participants with complete data analyzedmore recent technique of the facial artery musculomucosalflap seems to be useful in some patients (8). Characteristic n Today, no universally accepted treatment exists for thissevere condition. Since 1998, we have proposed, in a new No. of patients N = 54 Age (y): mean Æ SD (range) 59 Æ 10 (30–81)theory for ORN pathogenesis, that bone damage is mainly Head-and-neck tumorthe result of radiation-induced fibrosis (RIF) (2, 3, 9) and Oral cavity 15have developed a triple-drug therapy to reduce RIF and Oropharynx 31bone destruction and to stimulate osteogenesis via the antiox- Other 8 (15%)idant pathway (10, 11). We have published impressive RT dose level Exclusive 70–80 Gy 37 (70%)preliminary results using pentoxifylline (PTX) combined Postoperative 45–65 Gy 17with vitamin E (PE) in 10 ORN patients with a good Combined head-and-neck cancer treatment:prognosis and PE boosted by clodronate (PENTOCLO) in RT alone 13 (22%)the first 8 patients with refractory ORN, with complete Surgery + RT 27 Chemotherapy + RT 14mucosal recovery in most of them at 6 months (12). ORN trigger factors: To assess the maximum efficacy and the time to achieve it, None (spontaneous) 26and the follow-up during PENTOCLO treatment and long af- After dental extraction 28terward in patients with refractory ORN, we performed a trial Delaysto define the optimal treatment duration until complete heal- RT-ORN symptoms (y) 4.8 Æ 5.1 (0.2–29) ORN symptoms/ PENTOCLO (y) 1.1 Æ 1.8 (0.1–12)ing is established. Failure of previous treatments: Medical alone 23 (42%) PATIENTS AND METHODS HBO and/or 13 Surgery (sequestrectomy/flap) 25Population Baseline ORN characteristics Between August 2000 and August 2008, 107 ORN patients Mean exposed bone (l+w) mm 17 Æ 7.9recruited from various centers at Saint-Louis Hospital (Paris) were l mm 24 Æ12 (7–60)treated with PENTOCLO: 80 consecutive patients with head-and- w mm 10 Æ 6 (2–30)neck cancer and 27 patients with miscellaneous ORN (5 after cervical Mean SOMA score 15.7 Æ 3.6 (8–24)RT, 15 sternocostal after breast RT, 7 after pelvic RT) not included Abbreviations: SD = standard deviation; RT = radiation therapy;for this evaluation (9). Twenty-six of the 80 patients were excluded ORN = osteoradionecrosis; PENTOCLO = pentoxifylline, vitaminbecause they did not meet protocol requirements: 8 had measurable E, and clodronate; HBO = hyperbaric oxygen; SOMA = subjective,good prognosis ORN already healed with PE alone (12), 9 had ORN objective, management, analytic evaluation of injury.
  • 3. 834 I. J. Radiation Oncology d Biology d Physics Volume 80, Number 3, 2011 The PENTOCLO dose was based on pharmacokinetic data, on Table 2. Osteoradionecrosis modified SOMA scoreclinical use and long-term safety in other diseases, and on severaldose variations determined by trial and error during our 10 years Subjective (G1–G4) Pain (occasional/minimal, intermittent/tolerable, persistent/of clinical experience with 900 RIF, ORN, and plexitis patients intense, refractory)(13). Each patient was given a daily combination of twice-daily Mastication (difficulty with solid, with soft foods, gastrostomy)400 mg PTX (800 mg/day) plus 500 IU vitamin E (1,000 IU/day) Objective (G1–G4)and once-daily 1,600 mg/day clodronate from Monday to Friday Bone exposed (minimum ulceration, <2 cm, 2–4 cm, >4 cm/(5 days/week), alternating with 20 mg prednisone plus 1,000mg ci- fracture)profloxacin on the weekend (2 days/week). The PTX dose was Trismus (minimum, 1- to 2-cm opening, 0.5–1 cm, <0.5-cmreduced from 1,200 to 800 mg/day to avoid adverse effects in pa- opening)tients without vascular disease. The vitamin E dose provided suffi- Management (G1–G4)cient antioxidant activity and allowed PTX synergy (increased from Pain (occasional, regular nonnarcotic, regular narcotic, surgery)500 to 1,000mg/day). Clodronate dose reduction from 7 to 5 days/ Bone exposed (mouth bath, antibiotics, debridement/HBO, large surgery)week was sufficient to provide antimacrophagic activity without Analytic (G1–G4)causing a calcium problem. Prednisone/ciprofloxacin 2 days/week Mandibular X-ray (questionable changes, osteoporosis/mosaic,was sufficient to provide intermittent acute anti-inflammatory and sequestra, fracture)antiseptic action. The duration of treatment was based on observed progressive Abbreviations: SOMA = subjective, objective, management, an-ORN regression and on the published long-term effects of PE, to alytic evaluation of injury; HBO = hyperbaric oxygen.avoid a rebound effect (14). with treatment was analyzed using nonlinear mixed models. Several competing models were consecutively considered and compared us-Outcome measures ing the Bayesian Information Criterion model (16) including deter- Participants were reviewed by two investigators before, during, mination of the random effects and the correlation and varianceand after the end of treatment with 3-year follow-up. Quantitative structure of residuals that gave the best model fitting. These methodsassessment included measurements of the mean dimensions (D) of predict the ORN dimensions of a patient measured at a given time-superficial soft tissue necrosis describing exposed bone osteoradio- point as a function of time: the predicted change for a given patientnecrosis (EB-orn): (length + width)/2. The primary endpoint was varies around the average prediction for all patients according tothe relative D regression defined as (D at x months – D at inclusion)/ these random components. The effects of age, time since RT, triggerD at inclusion, correlated with the extent of recovery of EB-orn factors, previous treatment, and combined head-and-neck cancer(Table 1). treatment on the change in ORN dimensions were tested. Secondary endpoints included modified Subjective, Objective, The probability of complete EB-orn healing over time was esti-Management, and Analytic evaluation of injury (SOMA) score, with mated using a nonparametric method for interval censored dataqualitative and quantitative personal item variations to allow regular (17). Model-based predictions were additionally obtained consider-treatment follow-up (Table 2) (15). Assessment by measuring percent- ing that ORN dimensions lower than 0.5 mm indicated completeage changes in D and SOMA score was done every month (1 month healing, both for the patients in the study and for the population,[M1]), every 2 months (M2) until complete mucosal healing, then every the latter by using numeric simulations.3 months. Patients acted as their own controls (paired data). Regular All tests were two-sided, and a p value under 0.05 was consideredX-ray and dental computed tomography scans were performed. as significant. All analyses were performed using R.1.7.1 software (The R Development Core Team, Vienna, Austria; http://r-project.Osteoradionecrosis org). ORN developed a mean 5 years after RT, either spontaneously (26/54) or after trauma such as dental extraction or biopsy (28/54). ORNgradually worsened despite medical care including amoxicillin (n = RESULTS17), HBO (n = 13) and/or local surgical procedures as sequestrectomyor flap (n = 24). None of these treatments had a lasting beneficial effect Adverse eventson ORN, but they sometimes reduced acute inflammation. At base- Acute safety was satisfactory: no patient stopped the treat-line, ORN was exteriorized without healing for 1.4 Æ 1.8 years (range, ment because of an adverse event. One patient stopped treat-0.1–12) with mean EB-orn D0 at 17 Æ 8 mm (Table 1). ment at 1 year: misunderstanding of the disease and All patients had combined symptoms (Table 2) as local pain or treatment-related epigastralgia, instead of ORN improve-minimal infection, but 36/54 patients (66.6%) had one or more com- ment.bined severe symptoms such as skin fistula in 16, chronic osteitis in Twelve of 54 patients (22%) experienced minimal adverse23 (purulence), facial edema in 6, fracture without shifting in 8, and effects, but were included, like the others, in the analysis.inferior dental neuropathy in 12. All 54 patients had very severe Grade 1–2 discomfort during the first weeks of treatmentORN: one third with Epstein Stage II as 18 chronic persistent was due to nausea-epigastralgia (4 patients), asthenia (2 pa-ORN without healing over several months or years, and two-thirds with Epstein Stage III as 36 active progressive ORN including tients), headache (1 patient), vertigo (1 patient), insomniafistula, fracture, or osteitis. The mean baseline SOMA0 score was (1 patient); these patients remained in the study after resolu-15.7 Æ 3.6 (Table 1). tion by transient (2–4 weeks) reduction in PTX dose (400 mg/ day) or symptomatic treatment with omeprazole or heptami-Statistical analysis nol; 2 patients with gastrostomy experienced problems with Data are presented as counts for qualitative variables, and mean crushed PTX tablets. In a previous randomized trial, we(ÆSD) for quantitative variables. Change in ORN dimensions found no significant differences between PE, PTX, vitamin
  • 4. PENTOCLO trial in osteoradionecrosis d S. DELANIAN et al. 835 Table 3. Mean exposed bone–ORN regression, complete mucosal healing with recovery rate (observed, estimated), and SOMA score regression during PENTOCLO treatment No. of treated Mean ORN exposed Complete observed Healing estimated SOMA score Time patients bone mm (mean Æ SD) recovery rate (%) recovery rate (%) (mean Æ SD)Baseline 54 17.2 Æ 7.9 15.7 Æ 3.62 mo 54 10.3 Æ 7.5 3 (5.5%) 5.6% 11.5 Æ 4.14 mo 48 7.3 Æ 7.4 10 (21%) 20.2% 8.5 Æ 4.46 mo 46 4.4 Æ 6.1 20 (43.5%) 42.4% 5.8 Æ 4.59 mo 43 2.9 Æ 5 26 (60.5%) 59.2% 4.5 Æ 4.212 mo 39 1.6 Æ 3.3 26 (67%) 64.6% 3.2 Æ 3.018 mo 25 0.8 Æ 2.2 21 (84%) 78.8% 2.0 Æ 2.524 mo 20 0.8 Æ 2.4 18 (90%) 85.9% 1.4 Æ 2.230 mo 16 0 16 (100%) 100% 0.8 Æ 1.236 mo 14 0 14 (100%) 100% 0.4 Æ 0.9 Abbreviations: ORN = osteoradionecrosis; SOMA = subjective, objective, management, analytic evaluation of injury; PENTOCLO = pen-toxifylline, vitamin E, and clodronate; SD = standard deviation.E, and double placebo groups in terms of tolerability (dis- (p < 0.0001 as compared with a model with residual EB-comfort) during treatment (18). When diarrhea was present orn). Model-based predictions fitted the observed values(1 patient), clodronate was reduced to 800 mg/day, but this quite well for each individual patient’s EB-orn regression,patient remained in the study for analysis. as illustrated in Fig. 2. This model showed significant EB- Long-term safety was excellent, with no patient stopping orn regression (p < 0.0001). None of the variables testedtreatment because of severe adverse side effects, but PENTO- was found to modify this treatment effect significantly. Me-CLO was stopped at 6 months because of transient regressive dian time to complete response was an estimated 9 monthsoral exostosis (mandible) in 2 patients, in parallel with a good (Fig. 3).response (2 patients). After discontinuation of drug. After stoppage of PENTO- CLO, no rebound EB-orn effect was observed over severalPrimary analyses months of follow-up. Exposed bone regression during PENTOCLO treatment.PENTOCLO was effective over several months resulting inexponential EB-orn regression until complete healing with Secondary analysesmucosal recovery. PENTOCLO was stopped before mucosal All patients responded to treatment and symptom severityrecovery in 15 of 54 patients, who were nonetheless assessed diminished exponentially as assessed by the SOMA scoreuntil their last follow-up. Three patients were immediatelylost to follow-up (before M4). Other causes of loss tofollow-up were: 1 vascular stroke after high blood pressure(M2), 6 fatal sepsis (M2-M18) due to local severe infectionwith facial cellulitis, bone fracture, fistula, or pulmonary in-fection, because of persistence of co-morbidity factors ashigh tobacco-alcohol consumption, HIV, severe undernour-ishment.), and 5 recurrent or second head-neck or lung can-cer (M2-M18) as usually observed in such a population (4patients with progressive cancer were excluded just before in-clusion). The remaining patients had long-term PENTOCLOfor 16 Æ9 months (6-36 months). Observed values. (Table 3, Fig. 1)- Mean exposed boneORN regression was D2 42 Æ27% at 2 months, D4 62Æ29%, D6 77 Æ28%, D9 86 Æ23%, D12 92 Æ14%, D18 96Æ13%, D24 96 Æ14%, D30 and D36 100%. Modeling. From the observed changes in EB-orn dimen-sions during treatment, several models were postulated andthe best representative model of the time-course of regressionwas found to have the following exponential form: f(t) =a .exp (-b.t), where t represents the time from treatment onset Fig. 1. Regression of exposed bone osteoradionecrosis during treat- ment with pentoxifylline, vitamin E, and clodronate individual pa-in months, and a and b correspond respectively to ORN di- tient data (gray solid lines), estimated average variation (blackmension at baseline and the kinetics of response. The model solid line) with pointwise 95% confidence interval (dotted lines)showed that the average ORN dimension decreased to zero and 90% prediction interval (dashed lines).
  • 5. 836 I. J. Radiation Oncology d Biology d Physics Volume 80, Number 3, 2011 Fig. 2. Individual relative exposed bone osteoradionecrosis dimension variations in 54 patients given long-term pentox- ifylline, vitamin E, and clodronate: observed values (o) and model-based prediction (solid lines).(Table 3): local pain, fistula, osteitis, and trismus reductions The patient’s age, time since RT, trigger factors, previousuntil disappearance. Mean SOMA scores improved signifi- treatment or type of head-neck cancer treatment had no effectcantly (p < 0.0001): SOMA2 28 Æ14%, SOMA4 48 Æ19%, on the progression of ORN healing (NS).SOMA6 64 Æ22%, SOMA9 73 Æ21%, SOMA12 81 Æ15%, Regular X-rays and dental computed tomography assess-SOMA18 88 Æ13%, SOMA24 91 Æ11%, SOMA30 96 Æ5% ment showed slow but gradual and delayed improvement,and SOMA36 98 Æ4%. with more homogeneous bone (Fig. 4). Two-thirds (36/54) of treated patients underwent seques-trectomy with 5-10 mm mean diameter (3-20 mm) during DISCUSSIONthe medical consultation, whereas the other 18/54 patientsdid not undergo SEQ: 19/36 patients with 1 SEQ (53%) dur- The therapeutic value of PENTOCLO in ORN was first il-ing PENTOCLO, 8 patients with 2 SEQ, 5 patients with 3 lustrated in a woman with severe 7-cm exteriorized radionec-SEQ, and 4 patients with 4 SEQ. These 36 patients had a total rosis of the sternum, 29 years after breast cancer irradiation,of 65 sequestrectomies in 18 months, 80% (52/65) in the first who ehibited complete healing and restoration on magnetic6 months of treatment: 31 SEQ in (M1-M2), 13 SEQ in (M3- resonance imaging after 3 years of treatment (9).M4), 9 SEQ in (M5-M6), 8 SEQ in (M7-M9), 3 SEQ in (M12), The present study emphasizes that refractory exposed2 SEQ in (M18). Each SEQ preceded a level of local improve- mandible ORN is still frequent and always severe. Patientsment then better healing, after a kind of foreign body extrac- with ORN have to be treated aggressively and quickly beforetion with purulence and foul smell. any specific treatment effect; 5 died because of fatal sepsis,
  • 6. PENTOCLO trial in osteoradionecrosis d S. DELANIAN et al. 837 infection, simple dissolution, and osteoporosis (premature aging), with osteocytes reaching the end of their lifespan without replacement (20). Bone gradually becomes hypocel- lular (fewer osteoblasts) and reduced bone matrix formation, compensated by fibrosis. Our ORN management was based on this pathophysio- logic understanding, with new light shed on RIF (3). This strategy to improve bone healing consisted of (a) reduction of infection and purulence in irradiated bone by vigorous ini- tial 4-week antiseptic treatment with amoxicillin-clavulanate/ ciprofloxacin, fluconazole, and methylprednisolone, allow- ing further treatment penetration and stopping ORN worsen- ing without danger (21); (b) marked reduction of the microscopic RIF, sometimes combined with phenotypic reversion of the irradiated osteoblasts, which enhance osteo- genesis by the synergistic combination of PE; and (c) arrest of bone destruction by inhibition of osteolysis, combined with removal of bone sequestra with clodronate.Fig. 3. Estimated probability for exposed bone osteoradionecrosiscomplete healing by treatment with pentoxifylline, vitamin E, andclodronate: observed values (solid line), model-based prediction PENTOCLO efficacyfor study patients (dashed line), and model-based prediction for pop- Used alone, none of the drugs included in PENTOCLOulation (dotted line); median at 9 months. proved able to reverse RIF or ORN. They were, however, ex- cellent antifibrotic and antinecrotic agents (11). PTX haswhereas 5 had head-neck recurrence or a second cancer. been reported in RIF to reduce pain or trismus and improveMoreover, in our 54 treated patients with refractory ORN, some leg functional deficits (22) and to accelerate healingprogressive instead of previous local surgery and/or HBO in radiation soft tissue necrosis (23, 24). Vitamin E seemedtreatment over a mean 17 months in 69% of patients (37/ to reduce breast RIF. By contrast, combined PE is efficient54) led to rapid improvement and total tissue restoration after and safe in experimental (25, 26) and superficial RIF, withPENTOCLO: half the patients recovered in 6 months, two- half RIF regression at 6 months and a two-thirds maximumthirds in 1 year, and nearly all after 2 years (median, 9 response after a mean of 2 years (14), and in good-months). Spontaneous sequestrectomy in 2/3 patients (with- prognosis ORN (12). Clodronate is a nonaminobisphospho-out surgical procedure) during the first 6 months of PENTO- nate, which reduces chronic inflammation by inhibiting theCLO seems critical because it speeds the healing process: delayed hypersensitivity granuloma response, osteoclastic re-PENTOCLO helped separate sequestra (eliminated dead sorption due to the inhibition of osteoclast recruitment andbone) from living bone (boosted tissue), thus allowing heal- activity, and in vitro fibroblastic proliferation, and whiching. There was no case of programmed surgery. There was no shortens osteoclast lifespan (27, 28). Clodronate used indifference in improvement or recovery obtained in the treated large-scale trials had unexpected effects on the viscera bypatients presenting long after irradiation, with long-term preventing metastatic diffusion, thereby underlining its pos-ORN, with or without dental extraction. In our experience, sible effects on tissues other than bone (29). Clodronate re-major surgery was necessary only in some salvage cases (cel- duced a case of bone marrow fibrosis with normalization oflulitis, fracture with displacement). blood counts by stopping transfusions over an 8-month pe- Although the clinical features of ORN have been known riod, after failure of androgen-interferon treatment (30).for decades, its pathophysiology is poorly understood. PENTOCLO allowed rapid and definitive mucosa and skinDescriptions of ORN tissue lesions suggest either healing in mandibular ORN patients and slow progressivehypovascular-hypoxic or bone fibroatrophy involvement new bone formation as shown by X-rays, and computed to-(2). The role of hypoxia was suggested by the histologic areas mography. Moreover, PENTOCLO successfully treated non-of necrosis in severely damaged irradiated tissues (4). More- exposed thoracic or pelvic ORN and radiation-inducedover, the mandible is predisposed to ischemic radionecrosis plexitis in 90 patients (Delanian, unpublished information).because of obliteration of the inferior alveolar artery and im- PENTOCLO safety profile. Short-term safety was goodpairment of revascularization by branches of the facial artery and did not differ from that in the placebo group in our pre-(19). The hypothesis of RIF focuses on the defective irradi- vious randomized study. PENTOCLO long-term safety inated bone and the imbalance between tissue synthesis and this study was good. However, we chose not to include pa-degradation (3). Histopathologic features of ORN are a mo- tients with active cancer because of the high healing powersaic of osteogenesis areas within extended areas of osteolysis of PE and its unknown interference with cancer. Vitamin E,(pagetoıd appearance). Defective bone tissue is a result of ¨ usually safe (31), has been reported to be protective againstseveral types of degradation: osteoclastic (macrophagic) re- prostate cancer, but data are not conclusive in lung cancersorption, osteocytic osteolysis overwhelmed by bacterial prevention. A meta-analysis of randomized trials in
  • 7. 838 I. J. Radiation Oncology d Biology d Physics Volume 80, Number 3, 2011 Fig. 4. Images of a 51-year-old woman with 25 Â 12 mm exposed bone osteoradionecrosis for 6 months: Subjective, Ob- jective, Management, Analytic evaluation of injury (SOMA0 at 16) with (a) a marked bone loss on a Dentascan at baseline, mucosal recovery after 8 months of pentoxifylline, vitamin E, and clodronate, with halving of clodronate dosage because of diarrhea (SOMA8 at 3), symptomatic normalization at M12 (SOMA12 at 1) without radiologic change, then (b) delayed radiologic restoration at M18 despite stoppage of treatment at M12.cardiovascular diseases found no beneficial or adverse effect clodronate in primary breast cancer (randomized trial) inof vitamin E on survival (32). However, another meta- primary breast cancer showed significant prevention ofanalysis showed that doses of vitamin E higher than 400 osteoporosis in 268 cases and improved overall survival inIU/day for longer than 1 year in chronic cardiovascular dis- 290 patients with bone marrow micrometastasis (39). Longease may increase all-cause mortality (33). Bayesian model term PENTOCLO seems to be safe.averaging in meta-analysis showed that ‘‘vitamin E intakeis unlikely to affect mortality regardless of dose’’ (34). In vitrostudies showed pro-oxidant effects of high doses of vitamin E CONCLUSIONthat were inhibited by vitamin C: a randomized trial in 8,171women receiving daily 600 IU vitamin E, 500 mg vitamin C, PENTOCLO effectively reduces progressive septic man-and 50 mg beta-carotene, individually or in combination, dible ORN. The impressive and rapid clinical recoveryfailed to show any difference after 9.4 years of treatment achieved suggests that theory and practice could be the basis(35). Clodronate, which has been extensively used clinically of ORN management in the future. PENTOCLO, anover the past 20 years, is safe. Unlike aminobisphosphonates etiology-based treatment, when combined with repeated se-(pamidronate, zoledronate), clodronate has a significant direct questrectomy, improves prognosis from poor to good; there-action on osteoblastic cells and increases bone formation, fore, ORN management reserves extensive surgery forwithout antiangiogenic effects; the in vitro effect of clodro- salvage cases (cellulitis, fracture with displacement, exten-nate on endothelial cells and fibroblasts is particularly mar- sive exposed bone >1 cm) All drugs are available, inexpen-ginal (36), and no serious case of osteonecrosis of the jaw sive, well tolerated, and safe. Further randomized clinicalhas yet been reported (37, 38). Three years of adjuvant trials are necessary to confirm these results.
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