PENTOCLO

Protocolo de manejo de la osteorradionecrosis resistente al oxígeno hiperbárico PENTOCLO

1. CLINICAL INVESTIGATION Normal Tissue
COMPLETE RESTORATION OF REFRACTORY MANDIBULAR
OSTEORADIONECROSIS BY PROLONGED TREATMENT WITH
A PENTOXIFYLLINE-TOCOPHEROL-CLODRONATE COMBINATION (PENTOCLO):
A PHASE II TRIAL
S
YLVIEDELANIAN, M.D., PHD.,*C E´CILECHATEL, D.D.,
y
RAPHAELPORCHER,PH.D.,
z
JOELDEPONDT, M.D.,
P
H.D.,
x
ANDJEAN-LOUISLEFAIX,PH.D.
{
*Service d’Oncologie-Radiothe´rapie, and
z
De´partement de Biostatistique et Informatique Me´dicale, Hoˆpital Saint-Louis, APHP, Paris;
y
Odontologie, Institut Gustave Roussy, Villejuif;
x
Service de Chirurgie Cervico-Faciale, Hoˆpital Bichat, APHP, Paris; and
{
CEA/DSV/
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): D
242%, D462%, D677%, D1292%, and D1896%, 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: SOMA
664%, SOMA 1289%, and SOMA 3096%.
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-
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
Note—An online CME test for this article can be taken athttp://
astro.org/MOC.
Reprint requests to: Dr. Sylvie Delanian, M.D., Ph.D., Service
d’Oncologie-Radiothe´rapie, Hoˆpital Saint Louis, 1 Ave Claude Vel-
lefaux, 75010 Paris, France. Tel: [phone]; Fax: (33) 1-
42-49-91-97; E-mail:[email protected]
Presented at the 18th Congress of Socie´te´ Franc¸aise de Radiothe´r-
apie Oncologique, Paris, November 2007, and the Special Work-
shop of The Royal College of Surgeons of England, London,
November 2007.
Supported by the De´le´gation a` la Recherche Clinique of the As-
sistance Publique des Hoˆpitaux de Paris.
Conflict of interest: none.
Acknowledgment—The authors thank Charles Guedon and physi-
cians from several Parisian institutions for entrusting their patients
to us for treatment.
Received Oct 2, 2009, and in revised form Feb 8, 2010. Accepted
for publication March 10, 2010.
832
CME
Int. J. Radiation Oncology Biol. Phys., Vol. 80, No. 3, pp. 832–839, 2011
Copyright2011 Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/$–see front matter
doi:10.1016/j.ijrobp.2010.03.029

2. 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 osteogenesisviathe 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
Population
Between 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 damage
The 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 4.85.1
years (range, 0.2–29).
PENTOCLO treatment modalities
One 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 1. Baseline screening of participants with complete
data analyzed
Characteristic n
No. of patients N=54
Age (y): meanSD (range) 5910 (30–81)
Head-and-neck tumor
Oral cavity 15
Oropharynx 31
Other 8 (15%)
RT dose level
Exclusive 70–80 Gy 37 (70%)
Postoperative 45–65 Gy 17
Combined head-and-neck cancer treatment:
RT alone 13 (22%)
Surgery + RT 27
Chemotherapy + RT 14
ORN trigger factors:
None (spontaneous) 26
After dental extraction 28
Delays
RT-ORN symptoms (y) 4.85.1 (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 13
Surgery (sequestrectomy/flap) 25
Baseline ORN characteristics
Mean exposed bone (l+w) mm 177.9
lmm 2412 (7–60)
wmm 106 (2–30)
Mean SOMA score 15.73.6 (8–24)
Abbreviations:SD = standard deviation; RT = radiation therapy;
ORN = osteoradionecrosis; PENTOCLO = pentoxifylline, vitamin
E, and clodronate; HBO = hyperbaric oxygen; SOMA = subjective,
objective, management, analytic evaluation of injury.
PENTOCLO trial in osteoradionecrosisdS. D ELANIANet al. 833

3. 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 measures
Participants 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 atxmonths – 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
[M
1]), 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.
Osteoradionecrosis
ORN 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 1.41.8 years (range,
0.1–12) with mean EB-orn D
0at 178mm(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 SOMA
0score was
15.73.6 (Table 1).
Statistical analysis
Data 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 apvalue 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 events
Acute 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
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 OncologydBiologydPhysics Volume 80, Number 3, 2011

4. 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 analyses
Exposed 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 M
4). Other causes of loss to
follow-up were: 1 vascular stroke after high blood pressure
(M
2), 6 fatal sepsis (M
2-M
18) 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 (M
2-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 169 months (6-36 months).
Observed values.(Table 3,Fig. 1)- Mean exposed bone
ORN regression was D
24227% at 2 months, D
462
29%, D
67728%, D 98623%, D 129214%, D 1896
13%, D
249614%, D 30and D36100%.
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 inFig. 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 analyses
All patients responded to treatment and symptom severity
diminished exponentially as assessed by the SOMA score
Table 3. Mean exposed bone–ORN regression, complete mucosal healing with recovery rate (observed, estimated), and SOMA score
regression during PENTOCLO treatment
Time
No. of treated
patients
Mean ORN exposed
bone mm (meanSD)
Complete observed
recovery rate (%)
Healing estimated
recovery rate (%)
SOMA score
(meanSD)
Baseline 54 17.2 7.9 15.73.6
2 mo 54 10.37.5 3 (5.5%) 5.6% 11.54.1
4 mo 48 7.37.4 10 (21%) 20.2% 8.54.4
6 mo 46 4.46.1 20 (43.5%) 42.4% 5.84.5
9 mo 43 2.95 26 (60.5%) 59.2% 4.54.2
12 mo 39 1.63.3 26 (67%) 64.6% 3.23.0
18 mo 25 0.82.2 21 (84%) 78.8% 2.02.5
24 mo 20 0.82.4 18 (90%) 85.9% 1.42.2
30 mo 16 0 16 (100%) 100% 0.81.2
36 mo 14 0 14 (100%) 100% 0.40.9
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 (black
solid line) with pointwise 95% confidence interval (dotted lines)
and 90% prediction interval (dashed lines).
PENTOCLO trial in osteoradionecrosisdS. D ELANIANet al. 835

5. (Table 3): local pain, fistula, osteitis, and trismus reductions
until disappearance. Mean SOMA scores improved signifi-
cantly (p< 0.0001): SOMA
22814%, SOMA 44819%,
SOMA
66422%, SOMA 97321%, SOMA 128115%,
SOMA
188813%, SOMA 249111%, SOMA 30965%
and SOMA
36984%.
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 (M
1-M2), 13 SEQ in (M3-
M
4), 9 SEQ in (M5-M6), 8 SEQ in (M7-M9), 3 SEQ in (M12),
2 SEQ in (M
18). 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. 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).
836 I. J. Radiation OncologydBiologydPhysics Volume 80, Number 3, 2011

6. 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
(pagetoı¨d 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 efficacy
Used 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, andin vitrofibroblastic 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. 3. Estimated probability for exposed bone osteoradionecrosis
complete healing by treatment with pentoxifylline, vitamin E, and
clodronate: observed values (solid line), model-based prediction
for study patients (dashed line), and model-based prediction for pop-
ulation (dotted line); median at 9 months.
PENTOCLO trial in osteoradionecrosisdS. D ELANIANet al. 837

7. 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 vitro
studies 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; thein vitroeffect 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.
Fig. 4. Images of a 51-year-old woman with 2512 mm exposed bone osteoradionecrosis for 6 months: Subjective, Ob-
jective, Management, Analytic evaluation of injury (SOMA
0at 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 (SOMA
8at 3), symptomatic normalization at M12(SOMA12at 1) without radiologic change, then (b) delayed
radiologic restoration at M
18despite stoppage of treatment at M12.
838 I. J. Radiation OncologydBiologydPhysics Volume 80, Number 3, 2011

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