PENTOCLO

CMEInt. J. Radiation Oncology Biol. Phys., Vol. 80, No. 3, pp. 832–839, 2011

Copyright � 2011 Elsevier Inc.Printed in the USA. All rights reserved

0360-3016/$–see front matter

jrobp.2010.03.029
doi:10.1016/j.i
CLINICAL INVESTIGATION Normal Tissue

COMPLETE RESTORATION OF REFRACTORY MANDIBULAROSTEORADIONECROSIS BY PROLONGED TREATMENT WITH

A PENTOXIFYLLINE-TOCOPHEROL-CLODRONATE COMBINATION (PENTOCLO):A PHASE II TRIAL

SYLVIE DELANIAN, M.D., PHD.,* CECILE CHATEL, D.D.,yRAPHAEL 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;yOdontologie, Institut Gustave Roussy, Villejuif; xService de Chirurgie Cervico-Faciale, Hopital Bichat, APHP, Paris; and {CEA/DSV/

IRCM-LARIA, CIRIL-GANIL, Caen, France

Note—astro.org/

Reprind’Oncololefaux, 7542-49-91-

Presentapie Oncoshop ofNovembe

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. Wepreviously showed that the combination of pentoxifylline and vitamin E with clodronate (PENTOCLO) is usefulin 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 yearspreviously received exteriorized refractory mandibular ORN for 1.4 ± 1.8 years, mainly after local surgery andhyperbaric 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 mgciprofloxacin 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�42%, D4�62%, D6�77%, D12�92%, and D18�96%, 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 delayedradiologic improvement: SOMA6 �64%, SOMA12 �89%, and SOMA30 �96%.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. � 2011 Elsevier Inc.

Pentoxifylline, Alpha tocopherol, Clodronate, Osteoradionecrosis, Radiotherapy.

INTRODUCTION

Mandibular osteoradionecrosis (ORN) is a delayed injury

caused by failure of bone healing several years after head-

and-neck cancer irradiation. Severe ORN can be life-

threatening and compromise functional prognosis. Although

conformal radiotherapy (RT), by improving the therapeutic ra-

tio, has reduced the incidence of severe complications, ORN is

still unavoidable in a mean 10% of cases, especially after den-

An online CME test for this article can be taken at http://MOC.t requests to: Dr. Sylvie Delanian, M.D., Ph.D., Servicegie-Radiotherapie, Hopital Saint Louis, 1 Ave Claude Vel-010 Paris, France. Tel: (33) 1-42-49-97-89; Fax: (33) 1-97; E-mail: [email protected] at the 18th Congress of Societe Francaise de Radiother-logique, Paris, November 2007, and the Special Work-

The Royal College of Surgeons of England, London,r 2007.

832

tal extraction, mostly 6 months to 5 years after irradiation (1).

Mandibular ORN symptoms, excluding tumor recurrence, are

diverse, ranging from occult disease to major bone destruction

with soft tissue necrosis and spontaneous complications

like osteomyelitis, fistulation, and fracture (2). Multiple risk

factors predispose to its development: treatment-dependent

factors, including radiotherapy (dose, volume, brachyther-

apy), surgery (number, volume, hematoma, infection), and

Supported by the Delegation a la Recherche Clinique of the As-sistance Publique des Hopitaux de Paris.

Conflict of interest: none.Acknowledgment—The authors thank Charles Guedon and physi-cians from several Parisian institutions for entrusting their patientsto us for treatment.

Received Oct 2, 2009, and in revised form Feb 8, 2010. Acceptedfor publication March 10, 2010.

http://astro.org/MOC

http://astro.org/MOC

mailto:[email protected]

Table 1. Baseline screening of participants with completedata analyzed

Characteristic n

No. of patients N = 54Age (y): mean � SD (range) 59 � 10 (30–81)Head-and-neck tumor

Oral cavity 15Oropharynx 31Other 8 (15%)

RT dose levelExclusive 70–80 Gy 37 (70%)Postoperative 45–65 Gy 17

Combined head-and-neck cancer treatment:RT alone 13 (22%)Surgery + RT 27Chemotherapy + RT 14

ORN trigger factors:None (spontaneous) 26After dental extraction 28

DelaysRT-ORN symptoms (y) 4.8 � 5.1 (0.2–29)ORN symptoms/ PENTOCLO (y) 1.1 � 1.8 (0.1–12)

Failure of previous treatments:Medical alone 23 (42%)HBO and/or 13Surgery (sequestrectomy/flap) 25

Baseline ORN characteristicsMean exposed bone (l+w) mm 17 � 7.9l mm 24 �12 (7–60)w mm 10 � 6 (2–30)Mean SOMA score 15.7 � 3.6 (8–24)

Abbreviations: SD = standard deviation; RT = radiation therapy;ORN = osteoradionecrosis; PENTOCLO = pentoxifylline, vitaminE, and clodronate; HBO = hyperbaric oxygen; SOMA = subjective,objective, management, analytic evaluation of injury.

PENTOCLO trial in osteoradionecrosis d S. DELANIAN et al. 833

concomitant chemotherapy; and patient-dependent factors, in-

cluding age, hypersensitivity, high blood pressure, diabetes,

and collagen vascular diseases (3). However, the increased in-

cidence and severity of ORN are mainly due to poor dental sta-

tus, local biopsy sites, bone proximity to the initial anatomic

tumor site, or excessive tobacco and alcohol consumption (1).

The management of ORN is usually based on conventional

medical care focusing on comorbidity factors such as optimi-

zation of oral hygiene (alcohol and tobacco consumption,

mouth baths), infection control (antibiotics), and devitalized

tissue removal (sequestrectomy) for ORN with a good progno-

sis (1, 3). Furthermore, its incidence is reduced by preventing

trauma such as limited dental extraction. If ORN management

always involves conservative measures, recovery at 1 year is

reported in only 8–33% of patients with a good prognosis (4,

5). Hyperbaric oxygen (HBO) is reported to be effective as

an adjunctive treatment for ORN, but the retrospective trials

involved are restricted (18 patients/study), and recovery

ranges from 15% to 43% after HBO alone, vs. 18% to 90%

after HBO combined with limited surgery (4–6). In addition,

a recent randomized trial in 68 ORN patients failed to

demonstrate that HBO had any beneficial effect, inasmuch

as only 19% in the HBO group recovered vs. 33% in the

placebo group (7). By contrast, refractory ORN (Epstein Stage

III) required, when technically possible, extensive surgical re-

section or reconstruction, such as hemimandibulectomy or

closure of fistulae using myocutaneous flaps (1, 7). The

more recent technique of the facial artery musculomucosal

flap seems to be useful in some patients (8).

Today, no universally accepted treatment exists for this

severe condition. Since 1998, we have proposed, in a new

theory for ORN pathogenesis, that bone damage is mainly

the result of radiation-induced fibrosis (RIF) (2, 3, 9) and

have developed a triple-drug therapy to reduce RIF and

bone destruction and to stimulate osteogenesis via the antiox-

idant pathway (10, 11). We have published impressive

preliminary results using pentoxifylline (PTX) combined

with vitamin E (PE) in 10 ORN patients with a good

prognosis and PE boosted by clodronate (PENTOCLO) in

the first 8 patients with refractory ORN, with complete

mucosal recovery in most of them at 6 months (12).

To assess the maximum efficacy and the time to achieve it,

and the follow-up during PENTOCLO treatment and long af-

terward in patients with refractory ORN, we performed a trial

to define the optimal treatment duration until complete heal-

ing is established.

PATIENTS AND METHODS

PopulationBetween August 2000 and August 2008, 107 ORN patients

recruited from various centers at Saint-Louis Hospital (Paris) were

treated with PENTOCLO: 80 consecutive patients with head-and-

neck cancer and 27 patients with miscellaneous ORN (5 after cervical

RT, 15 sternocostal after breast RT, 7 after pelvic RT) not included

for this evaluation (9). Twenty-six of the 80 patients were excluded

because they did not meet protocol requirements: 8 had measurable

good prognosis ORN already healed with PE alone (12), 9 had ORN

that was not measurable because of trismus, nonexposed bone, or

maxillary lesion, and 9 withdrew because of a change of mind before

the study (2 patients), concomitant progressive cancer (4 patients),

fatal sepsis (1 patient), human immunodeficiency virus disease (1 pa-

tient), and intolerance combined with lupus (1 patient). Conse-

quently, 54 eligible treated patients had complete, available, and

long-term homogeneous data (Table 1). Informed consent was ob-

tained from all patients, and the study was approved by the Hospital

Ethics Committee. The patients (43 men, 79%), all of whom had

a history of tobacco and alcohol consumption, showed no evidence

of recurrent disease on entering the trial.

RT damageThe ORN was caused by standard RT of head-and-neck cancer

(9–10 Gy/week), with a total prescribed dose ranging from 45–65

Gy (15 postoperative) to 70–75 Gy (39 exclusive RT): RT alone

(n =13), combined with primary or salvage surgery (n =27), and

combined with chemotherapy (n =14). The mean latency period be-

tween the end of RT and the first ORN symptoms was 4.8 � 5.1

years (range, 0.2–29).

PENTOCLO treatment modalitiesOne month before inclusion, all patients were given 4-week daily

oral disinfiltrating treatment with 20 mg prednisone plus 2 g

amoxicillin-clavulanate plus 1 g ciprofloxacin plus 50 mg flucona-

zole to allow further PENTOCLO penetration, which improved

pain and purulence symptoms by a mean of 20% in all patients.

Table 2. Osteoradionecrosis modified SOMA score

Subjective (G1–G4)Pain (occasional/minimal, intermittent/tolerable, persistent/

intense, refractory)Mastication (difficulty with solid, with soft foods, gastrostomy)

Objective (G1–G4)Bone exposed (minimum ulceration, <2 cm, 2–4 cm, >4 cm/

fracture)Trismus (minimum, 1- to 2-cm opening, 0.5–1 cm, <0.5-cm

opening)Management (G1–G4)

Pain (occasional, regular nonnarcotic, regular narcotic, surgery)Bone exposed (mouth bath, antibiotics, debridement/HBO, large

surgery)Analytic (G1–G4)

Mandibular X-ray (questionable changes, osteoporosis/mosaic,sequestra, fracture)

Abbreviations: SOMA = subjective, objective, management, an-alytic evaluation of injury; HBO = hyperbaric oxygen.

834 I. J. Radiation Oncology d Biology d Physics Volume 80, Number 3, 2011

The PENTOCLO dose was based on pharmacokinetic data, on

clinical use and long-term safety in other diseases, and on several

dose variations determined by trial and error during our 10 years

of clinical experience with 900 RIF, ORN, and plexitis patients

(13). Each patient was given a daily combination of twice-daily

400 mg PTX (800 mg/day) plus 500 IU vitamin E (1,000 IU/day)

and once-daily 1,600 mg/day clodronate from Monday to Friday

(5 days/week), alternating with 20 mg prednisone plus 1,000mg ci-

profloxacin on the weekend (2 days/week). The PTX dose was

reduced from 1,200 to 800 mg/day to avoid adverse effects in pa-

tients without vascular disease. The vitamin E dose provided suffi-

cient antioxidant activity and allowed PTX synergy (increased from

500 to 1,000mg/day). Clodronate dose reduction from 7 to 5 days/

week was sufficient to provide antimacrophagic activity without

causing a calcium problem. Prednisone/ciprofloxacin 2 days/week

was sufficient to provide intermittent acute anti-inflammatory and

antiseptic action.

The duration of treatment was based on observed progressive

ORN regression and on the published long-term effects of PE, to

avoid a rebound effect (14).

Outcome measuresParticipants were reviewed by two investigators before, during,

and after the end of treatment with 3-year follow-up. Quantitative

assessment included measurements of the mean dimensions (D) of

superficial soft tissue necrosis describing exposed bone osteoradio-

necrosis (EB-orn): (length + width)/2. The primary endpoint was

the relative D regression defined as (D at x months – D at inclusion)/

D at inclusion, correlated with the extent of recovery of EB-orn

(Table 1).

Secondary endpoints included modified Subjective, Objective,

Management, and Analytic evaluation of injury (SOMA) score, with

qualitative and quantitative personal item variations to allow regular

treatment follow-up (Table 2) (15). Assessment by measuring percent-

age changes in D and SOMA score was done every month (1 month

[M1]), every 2 months (M2) until complete mucosal healing, then every

3 months. Patients acted as their own controls (paired data). Regular

X-ray and dental computed tomography scans were performed.

OsteoradionecrosisORN developed a mean 5 years after RT, either spontaneously (26/

54) or after trauma such as dental extraction or biopsy (28/54). ORN

gradually worsened despite medical care including amoxicillin (n =

17), HBO (n = 13) and/or local surgical procedures as sequestrectomy

or flap (n = 24). None of these treatments had a lasting beneficial effect

on ORN, but they sometimes reduced acute inflammation. At base-

line, ORN was exteriorized without healing for 1.4� 1.8 years (range,

0.1–12) with mean EB-orn D0 at 17 � 8 mm (Table 1).

All patients had combined symptoms (Table 2) as local pain or

minimal infection, but 36/54 patients (66.6%) had one or more com-

bined severe symptoms such as skin fistula in 16, chronic osteitis in

23 (purulence), facial edema in 6, fracture without shifting in 8, and

inferior dental neuropathy in 12. All 54 patients had very severe

ORN: one third with Epstein Stage II as 18 chronic persistent

ORN without healing over several months or years, and two-

thirds with Epstein Stage III as 36 active progressive ORN including

fistula, fracture, or osteitis. The mean baseline SOMA0 score was

15.7 � 3.6 (Table 1).

Statistical analysisData are presented as counts for qualitative variables, and mean

(�SD) for quantitative variables. Change in ORN dimensions

with treatment was analyzed using nonlinear mixed models. Several

competing models were consecutively considered and compared us-

ing the Bayesian Information Criterion model (16) including deter-

mination of the random effects and the correlation and variance

structure of residuals that gave the best model fitting. These methods

predict the ORN dimensions of a patient measured at a given time-

point as a function of time: the predicted change for a given patient

varies around the average prediction for all patients according to

these random components. The effects of age, time since RT, trigger

factors, previous treatment, and combined head-and-neck cancer

treatment on the change in ORN dimensions were tested.

The probability of complete EB-orn healing over time was esti-

mated using a nonparametric method for interval censored data

(17). Model-based predictions were additionally obtained consider-

ing that ORN dimensions lower than 0.5 mm indicated complete

healing, both for the patients in the study and for the population,

the latter by using numeric simulations.

All tests were two-sided, and a p value under 0.05 was considered

as significant. All analyses were performed using R.1.7.1 software

(The R Development Core Team, Vienna, Austria; http://r-project.

org).

RESULTS

Adverse eventsAcute safety was satisfactory: no patient stopped the treat-

ment because of an adverse event. One patient stopped treat-

ment at 1 year: misunderstanding of the disease and

treatment-related epigastralgia, instead of ORN improve-

ment.

Twelve of 54 patients (22%) experienced minimal adverse

effects, but were included, like the others, in the analysis.

Grade 1–2 discomfort during the first weeks of treatment

was due to nausea-epigastralgia (4 patients), asthenia (2 pa-

tients), headache (1 patient), vertigo (1 patient), insomnia

(1 patient); these patients remained in the study after resolu-

tion by transient (2–4 weeks) reduction in PTX dose (400 mg/

day) or symptomatic treatment with omeprazole or heptami-

nol; 2 patients with gastrostomy experienced problems with

crushed PTX tablets. In a previous randomized trial, we

found no significant differences between PE, PTX, vitamin

http://r-project.org

http://r-project.org

Table 3. Mean exposed bone–ORN regression, complete mucosal healing with recovery rate (observed, estimated), and SOMA scoreregression during PENTOCLO treatment

TimeNo. of treated

patientsMean ORN exposed

bone mm (mean � SD)Complete observedrecovery rate (%)

Healing estimatedrecovery rate (%)

SOMA score(mean � SD)

Baseline 54 17.2 � 7.9 15.7 � 3.62 mo 54 10.3 � 7.5 3 (5.5%) 5.6% 11.5 � 4.14 mo 48 7.3 � 7.4 10 (21%) 20.2% 8.5 � 4.46 mo 46 4.4 � 6.1 20 (43.5%) 42.4% 5.8 � 4.59 mo 43 2.9 � 5 26 (60.5%) 59.2% 4.5 � 4.212 mo 39 1.6 � 3.3 26 (67%) 64.6% 3.2 � 3.018 mo 25 0.8 � 2.2 21 (84%) 78.8% 2.0 � 2.524 mo 20 0.8 � 2.4 18 (90%) 85.9% 1.4 � 2.230 mo 16 0 16 (100%) 100% 0.8 � 1.236 mo 14 0 14 (100%) 100% 0.4 � 0.9

Abbreviations: ORN = osteoradionecrosis; SOMA = subjective, objective, management, analytic evaluation of injury; PENTOCLO = pen-toxifylline, vitamin E, and clodronate; SD = standard deviation.

Fig. 1. Regression of exposed bone osteoradionecrosis during treat-ment with pentoxifylline, vitamin E, and clodronate individual pa-tient data (gray solid lines), estimated average variation (blacksolid line) with pointwise 95% confidence interval (dotted lines)and 90% prediction interval (dashed lines).


E, and double placebo groups in terms of tolerability (dis-

comfort) during treatment (18). When diarrhea was present

(1 patient), clodronate was reduced to 800 mg/day, but this

patient remained in the study for analysis.

Long-term safety was excellent, with no patient stopping

treatment because of severe adverse side effects, but PENTO-

CLO was stopped at 6 months because of transient regressive

oral exostosis (mandible) in 2 patients, in parallel with a good

response (2 patients).

Primary analysesExposed bone regression during PENTOCLO treatment.

PENTOCLO was effective over several months resulting in

exponential EB-orn regression until complete healing with

mucosal recovery. PENTOCLO was stopped before mucosal

recovery in 15 of 54 patients, who were nonetheless assessed

until their last follow-up. Three patients were immediately

lost to follow-up (before M4). Other causes of loss to

follow-up were: 1 vascular stroke after high blood pressure

(M2), 6 fatal sepsis (M2-M18) due to local severe infection

with facial cellulitis, bone fracture, fistula, or pulmonary in-

fection, because of persistence of co-morbidity factors as

high 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 (4

patients with progressive cancer were excluded just before in-

clusion). The remaining patients had long-term PENTOCLO

for 16 �9 months (6-36 months).

Observed values. (Table 3, Fig. 1)- Mean exposed bone

ORN regression was D2 42 �27% at 2 months, D4 62

�29%, D6 77 �28%, D9 86 �23%, D12 92 �14%, D18 96

�13%, D24 96 �14%, D30 and D36 100%.

Modeling. From the observed changes in EB-orn dimen-

sions during treatment, several models were postulated and

the best representative model of the time-course of regression

was found to have the following exponential form: f(t) =

a .exp (-b.t), where t represents the time from treatment onset

in months, and a and b correspond respectively to ORN di-

mension at baseline and the kinetics of response. The model

showed that the average ORN dimension decreased to zero

(p < 0.0001 as compared with a model with residual EB-

orn). Model-based predictions fitted the observed values

quite well for each individual patient’s EB-orn regression,

as illustrated in Fig. 2. This model showed significant EB-

orn regression (p < 0.0001). None of the variables tested

was found to modify this treatment effect significantly. Me-

dian time to complete response was an estimated 9 months

(Fig. 3).

After discontinuation of drug. After stoppage of PENTO-

CLO, no rebound EB-orn effect was observed over several

months of follow-up.

Secondary analysesAll patients responded to treatment and symptom severity

diminished exponentially as assessed by the SOMA score

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

until disappearance. Mean SOMA scores improved signifi-

cantly (p < 0.0001): SOMA2 28 �14%, SOMA4 48 �19%,

SOMA6 64 �22%, SOMA9 73 �21%, SOMA12 81 �15%,

SOMA18 88 �13%, SOMA24 91 �11%, SOMA30 96 �5%

and SOMA36 98 �4%.

Two-thirds (36/54) of treated patients underwent seques-

trectomy with 5-10 mm mean diameter (3-20 mm) during

the medical consultation, whereas the other 18/54 patients

did not undergo SEQ: 19/36 patients with 1 SEQ (53%) dur-

ing PENTOCLO, 8 patients with 2 SEQ, 5 patients with 3

SEQ, and 4 patients with 4 SEQ. These 36 patients had a total

of 65 sequestrectomies in 18 months, 80% (52/65) in the first

6 months of treatment: 31 SEQ in (M1-M2), 13 SEQ in (M3-

M4), 9 SEQ in (M5-M6), 8 SEQ in (M7-M9), 3 SEQ in (M12),

2 SEQ in (M18). Each SEQ preceded a level of local improve-

ment then better healing, after a kind of foreign body extrac-

tion with purulence and foul smell.

The patient’s age, time since RT, trigger factors, previous

treatment or type of head-neck cancer treatment had no effect

on the progression of ORN healing (NS).

Regular X-rays and dental computed tomography assess-

ment showed slow but gradual and delayed improvement,

with more homogeneous bone (Fig. 4).

DISCUSSION

The therapeutic value of PENTOCLO in ORN was first il-

lustrated in a woman with severe 7-cm exteriorized radionec-

rosis of the sternum, 29 years after breast cancer irradiation,

who ehibited complete healing and restoration on magnetic

resonance imaging after 3 years of treatment (9).

The present study emphasizes that refractory exposed

mandible ORN is still frequent and always severe. Patients

with ORN have to be treated aggressively and quickly before

any specific treatment effect; 5 died because of fatal sepsis,

Fig. 3. Estimated probability for exposed bone osteoradionecrosiscomplete healing by treatment with pentoxifylline, vitamin E, andclodronate: observed values (solid line), model-based predictionfor study patients (dashed line), and model-based prediction for pop-ulation (dotted line); median at 9 months.


whereas 5 had head-neck recurrence or a second cancer.

Moreover, in our 54 treated patients with refractory ORN,

progressive instead of previous local surgery and/or HBO

treatment over a mean 17 months in 69% of patients (37/

54) led to rapid improvement and total tissue restoration after

PENTOCLO: half the patients recovered in 6 months, two-

thirds in 1 year, and nearly all after 2 years (median, 9

months). Spontaneous sequestrectomy in 2/3 patients (with-

out surgical procedure) during the first 6 months of PENTO-

CLO seems critical because it speeds the healing process:

PENTOCLO helped separate sequestra (eliminated dead

bone) from living bone (boosted tissue), thus allowing heal-

ing. There was no case of programmed surgery. There was no

difference in improvement or recovery obtained in the treated

patients presenting long after irradiation, with long-term

ORN, with or without dental extraction. In our experience,

major surgery was necessary only in some salvage cases (cel-

lulitis, fracture with displacement).

Although the clinical features of ORN have been known

for decades, its pathophysiology is poorly understood.

Descriptions of ORN tissue lesions suggest either

hypovascular-hypoxic or bone fibroatrophy involvement

(2). The role of hypoxia was suggested by the histologic areas

of necrosis in severely damaged irradiated tissues (4). More-

over, the mandible is predisposed to ischemic radionecrosis

because of obliteration of the inferior alveolar artery and im-

pairment of revascularization by branches of the facial artery

(19). The hypothesis of RIF focuses on the defective irradi-

ated bone and the imbalance between tissue synthesis and

degradation (3). Histopathologic features of ORN are a mo-

saic of osteogenesis areas within extended areas of osteolysis

(pagetoıd appearance). Defective bone tissue is a result of

several types of degradation: osteoclastic (macrophagic) re-

sorption, osteocytic osteolysis overwhelmed by bacterial

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.

PENTOCLO efficacyUsed alone, none of the drugs included in PENTOCLO

proved able to reverse RIF or ORN. They were, however, ex-

cellent antifibrotic and antinecrotic agents (11). PTX has

been reported in RIF to reduce pain or trismus and improve

some leg functional deficits (22) and to accelerate healing

in radiation soft tissue necrosis (23, 24). Vitamin E seemed

to reduce breast RIF. By contrast, combined PE is efficient

and safe in experimental (25, 26) and superficial RIF, with

half RIF regression at 6 months and a two-thirds maximum

response after a mean of 2 years (14), and in good-

prognosis ORN (12). Clodronate is a nonaminobisphospho-

nate, which reduces chronic inflammation by inhibiting the

delayed hypersensitivity granuloma response, osteoclastic re-

sorption due to the inhibition of osteoclast recruitment and

activity, and in vitro fibroblastic proliferation, and which

shortens osteoclast lifespan (27, 28). Clodronate used in

large-scale trials had unexpected effects on the viscera by

preventing metastatic diffusion, thereby underlining its pos-

sible effects on tissues other than bone (29). Clodronate re-

duced a case of bone marrow fibrosis with normalization of

blood counts by stopping transfusions over an 8-month pe-

riod, after failure of androgen-interferon treatment (30).

PENTOCLO allowed rapid and definitive mucosa and skin

healing in mandibular ORN patients and slow progressive

new bone formation as shown by X-rays, and computed to-

mography. Moreover, PENTOCLO successfully treated non-

exposed thoracic or pelvic ORN and radiation-induced

plexitis in 90 patients (Delanian, unpublished information).

PENTOCLO safety profile. Short-term safety was good

and did not differ from that in the placebo group in our pre-

vious randomized study. PENTOCLO long-term safety in

this study was good. However, we chose not to include pa-

tients with active cancer because of the high healing power

of PE and its unknown interference with cancer. Vitamin E,

usually safe (31), has been reported to be protective against

prostate cancer, but data are not conclusive in lung cancer

prevention. A meta-analysis of randomized trials in

Fig. 4. Images of a 51-year-old woman with 25� 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 ofdiarrhea (SOMA8 at 3), symptomatic normalization at M12 (SOMA12 at 1) without radiologic change, then (b) delayedradiologic restoration at M18 despite stoppage of treatment at M12.


cardiovascular diseases found no beneficial or adverse effect

of vitamin E on survival (32). However, another meta-

analysis showed that doses of vitamin E higher than 400

IU/day for longer than 1 year in chronic cardiovascular dis-

ease may increase all-cause mortality (33). Bayesian model

averaging in meta-analysis showed that ‘‘vitamin E intake

is unlikely to affect mortality regardless of dose’’ (34). In vitrostudies showed pro-oxidant effects of high doses of vitamin E

that were inhibited by vitamin C: a randomized trial in 8,171

women receiving daily 600 IU vitamin E, 500 mg vitamin C,

and 50 mg beta-carotene, individually or in combination,

failed to show any difference after 9.4 years of treatment

(35). Clodronate, which has been extensively used clinically

over the past 20 years, is safe. Unlike aminobisphosphonates

(pamidronate, zoledronate), clodronate has a significant direct

action on osteoblastic cells and increases bone formation,

without antiangiogenic effects; the in vitro effect of clodro-

nate on endothelial cells and fibroblasts is particularly mar-

ginal (36), and no serious case of osteonecrosis of the jaw

has yet been reported (37, 38). Three years of adjuvant

clodronate in primary breast cancer (randomized trial) in

primary breast cancer showed significant prevention of

osteoporosis in 268 cases and improved overall survival in

290 patients with bone marrow micrometastasis (39). Long

term PENTOCLO seems to be safe.

CONCLUSION

PENTOCLO effectively reduces progressive septic man-

dible ORN. The impressive and rapid clinical recovery

achieved suggests that theory and practice could be the basis

of ORN management in the future. PENTOCLO, an

etiology-based treatment, when combined with repeated se-

questrectomy, improves prognosis from poor to good; there-

fore, ORN management reserves extensive surgery for

salvage cases (cellulitis, fracture with displacement, exten-

sive exposed bone >1 cm) All drugs are available, inexpen-

sive, well tolerated, and safe. Further randomized clinical

trials are necessary to confirm these results.


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Health & Medicine

PENTOCLO