Management of osteoradionecrosis with pentoxifylline, tocopherol and clodronate: a systematic review

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Gheed Najah Al-ani

2020, Group 12

Management of osteoradionecrosis with pentoxifylline,

tocopherol and clodronate: a systematic review

Master’s thesis

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FINAL MASTER‘S THESIS IS CONDUCTED

AT THE DEPARTMENT OF

DEPARTMENT OF ORAL SURGERY

STATEMENT OF THESIS ORIGINALITY

I confirm that the submitted Final Master‘s Thesis “management of osteoradionecrosis with pentoxifylline, tocopherol and clodronate”

1. Is done by myself.

2. Has not been used at another university in Lithuania or abroad.

3. I did not used any additional sources that are not listed in the Thesis, and I provide a complete list of references.

I confirm by e-mail, and the work will be signed after the end of the quarantine and emergency situation due to the COVID-19 pandemic in the republic of Lithuania.

(28-4-2020) (Gheed Najah Al-ani) (signature)

CONCLUSION OF FINAL MASTER‘S THESIS ACADEMIC

SUPERVISOR

ON THE DEFENSE OF THE THESIS

(date) (Mindaugas Pranskunas) (signature)

FINAL MASTER‘S THESIS IS APPROVED AT THE DEPARTMENT

(date of approval) (name of the Department and full name of the Head of the Department) (signature)

Final Master‘s Thesis reviewer

(full name) (signature)

Evaluation of Final Master‘s Thesis Defense Board:

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LITHUANIAN UNIVERSITY OF HEALTH SCIENCES FACULTY OF ODONTOLOGY

DEPARTMENT OF ORAL SURGERY

Management of osteoradionecrosis with pentoxifylline, tocopherol and clodronate: a systematic review

Master’s thesis

The thesis was done by

Student ……… Supervisor………

(Signature) (Signature)

………. ………

(name, surname, year, group) (degree, name, surname)

………20…. ………20…. (day/month) (day/month)

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EVALUATION TABLE OF THE MASTER’S THESIS

OF THE TYPE OF SYSTEMIC REVIEW OF SCIENTIFIC

LITERATURE

Evaluation: ... Reviewer: ... Reviewing date: ... No. MT parts MT evaluation aspects Compliance with MT requirements and evaluation Yes Partially No 1 _Summary (0.5 point)

Is summary informative and in compliance with the thesis

content and requirements? 0.3 0.1 0

2 Are keywords in compliance with the thesis essence? 0.2 0.1 0 3 _Introduc-

tion, aim and tasks (1 point)

Are the novelty, relevance and significance of the work

justified in the introduction of the thesis? 0.4 0.2 0 4 Are the problem, hypothesis, aim and tasks formed clearly _{and properly?} 0.4 0.2 0

5 Are the aim and tasks interrelated? 0.2 0.1 0

6 Selection criteria of the studies, search methods and strategy (3.4 points)

Is the protocol of systemic review present? 0.6 0.3 0

7

Were the eligibility criteria of articles for the selected protocol determined (e.g., year, language, publication condition, etc.) 0.4 0.2 0 8

Are all the information sources (databases with dates of coverage, contact with study authors to identify additional studies) described and are the last search day indicated?

0.2 0.1 0 9

Is the electronic search strategy described in such a way that it could be repeated (year of search, the last search day; keywords and their combinations; number of found and selected articles according to the combinations of keywords)? 0.4 0.1 0

10 Is the selection process of studies (screening, eligibility, included in systemic review or, if

applicable, included in the meta-analysis) described? 0.4 0.2 0 11

Is the data extraction method from the articles (types of investigations, participants, interventions, analysed factors, indexes) described?

0.4 0.2 0 12

Are all the variables (for which data were sought and any assumptions and simplifications made) listed and

defined? 0.4 0.2 0

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Information is to be used in data synthesis, described?

14 Were the principal summary measures (risk ratio, _{difference in means) stated?} 0.4 0.2 0 15 Systemiza- tion and analysis of data (2.2 points)

Is the number of studies screened: included upon assessment for eligibility and excluded upon giving the reasons in each stage of exclusion presented?

0.6 0.3 0 16 Are the characteristics of studies presented in the

included articles, according to which the data were extracted (e.g., study size, follow-up period, type of respondents) presented? 0.6 0.3 0

17 Are the evaluations of beneficial or harmful outcomes for each study presented? (a) simple summary data for each intervention group; b) effect estimates and confidence intervals) 0.4 0.2 0 18

Are the extracted and systemized data from studies presented in the tables according to individual tasks?

0.6 0.3 0 19 Discussion (1.4 points)

Are the main findings summarized and is their relevance

indicated? 0.4 0.2 0

20 Are the limitations of the performed systemic review _discussed? 0.4 0.2 0 21 Does author present the interpretation of the results? 0.4 0.2 0 22 _Conclusions

(0.5 points)

Do the conclusions reflect the topic, aim and tasks of the

Master’s thesis? 0.2 0.1 0

23 Are the conclusions based on the analysed material? 0.2 0.1 0

24 Are the conclusions clear and laconic? 0.1 0.1 0

25

References (1 point)

Is the references list formed according to the

requirements? 0.4 0.2 0

26

Are the links of the references to the text correct? Are the literature sources cited correctly and precisely?

0.2 0.1 0

27 Is the scientific level of references suitable for Master’s _thesis? 0.2 0.1 0

28

Do the cited sources not older than 10 years old form at least 70% of sources, and the not older than 5 years – at least 40%? 0.2 0.1 0

Additional sections, which may increase the collected number of points

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32

Was meta-analysis applied? Are the selected statistical methods indicated? Are the results of each meta-analysispresented? +2 +1 0

General requirements, non-compliance with which reduce the number of points

33 General require- ments

Is the thesis volume sufficient (excluding annexes)?

15-20 pages (-2 points)

<15pages (-5points) 34 Is the thesis volume increased artificially? -2 points -1 point

35 Does the thesis structure satisfy the _{requirements of Master’s thesis?} -1 point -2 points 36 Is the thesis written in correct language, _{scientifically, logically and laconically?} -0.5 point -1 points 37 Are there any grammatical, style or computer _{literacy-related mistakes?} -2 points -1 points

38 Is text consistent, integral, and are the _{volumes of its structural parts balanced?} -0.2 point -0.5 points 39 Amount of plagiarism in the thesis. >20% (not _evaluated)

40 Is the content (names of sections and sub- sections and enumeration of pages) in compliance with the thesis structure and aims?

-0.2 point

-0.5 points

41 Are the names of the thesis parts in compliance with the text? Are the titles of sections and sub-sections distinguished logically and correctly?

-0.2 point

-0.5 points

42 Are there explanations of the key terms and _{abbreviations (if needed)?} -0.2 point -0.5 points

43

Is the quality of the thesis typography (quality of printing, visual aids, binding) good?

-0.2 point

-0.5 points

*In total (maximum 10 points):

*Remark: the amount of collected points may exceed 10 points.

Reviewer’s

comments:___________________________________________________________

___________________________________________________________________________ ___________________________________________________________________________ ___________________________________________________________________________ Reviewer’s name and surname Reviewer’s signature _______________________________ _________________________

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and Mesh termer, and English studies from 2009 until 2019 were chosen. The database search was done using the following keywords; pentoxifylline, tocopherol, and clodronate, and resulted in 113 studies. Screening of titles, abstracts, and full-texts was done. Five reviews that met the inclusion criteria were evaluated and submitted for data extraction.

Results: A total of 5 articles, with a total of 227 participants were included in this systematic

review. The majority of the materials had an agreement on their results. The combination of pentoxifylline plus tocopherol with or without clodronate was found to be useful for the treatment of osteoradionecrosis.

Conclusion: Treatment with pentoxifylline and tocopherol and clodronate has a useful role in

the management of early and moderate stages of ORN. The combination of these drugs appears to be safe and well-tolerated as it showed minimal side effects. However, the results need to be confirmed with further randomized clinical trials.

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1.

INTRODUCTION

Radiation therapy is a popular therapeutic modality and plays a crucial role in the management of head and neck malignancy, both alone and in combination with chemotherapy and surgery [4,]. The popularity of radiotherapy treatment is most probably due to its ability to destroy the neoplastic cells and the minimal destruction of healthy cells. Any neoplastic cell can be destroyed by radiation if the dosage that is delivered is sufficient, though a limitation to the treatment is that the surrounding tissues can only tolerate a certain amount of dosage. Radiation will often lead to a compromised vasculature, which will affect both the oral mucosa as well as the bone in the irradiated area. This occurs when the tissue exposed to ionizing radiation that is greater than 5000 rads (50 Gy) [2,3]. Even though the bone tissue is relatively radioresistant, the intense vascular comptonization will lead to the devitalization of the tissue in the long run [4, 20].

Osteoradionecrosis is one of the complications that follow radiation therapy. ORN defined as an area of exposed bone through an opening in the overlying mucosa or skin, which persists as a non-healing region for a period of 3 or more months and not caused by tumor reoccurrence [2].

ORN considered to be a late complication since the vast majority of the cases occur three years post radiation therapy; these cases occur when the irradiated bone becomes devitalized. The reported cases of ORN range from 2-22%. These cases can occur spontaneously or after trauma, such as tooth extraction or infections. In most ORN cases, a triggering factor is often present, an injury to the underlying bone. Bone injuries can occur due to post-irradiation tooth extractions, dentures, and implant placement [2].

The identified clinical features for ORN include ulceration or necrosis of the area of the affected oral mucosa, which will lead to the exposure of the underlying bone. This will be accompanied by severe pain, swelling, malocclusion, or cutaneous fistula, trismus, and dysesthesia. In the case of advanced stages of ORN, ulceration of the overlying skin will be present along with possible pathological fractures of the jaw [2,5].

The management osteoradionecrosis is challenging, and it may not always be successful; until this date, there no standard treatment used [4]; the treatment differs depending on the clinical features and stages of the disease. It can include both conservative and surgical

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confined to advanced stages of ORN only. While conservative treatment options, including antibiotic therapy, recurrent saline irrigation, and HBOT therapy. Historically HBOT treatment was considered to the treatment of choice [4]. Though a prospective randomized study by Annane et al. reported that HBOT did not result in additional benefit compared with placebo, HBOT may also lead to several side effects including oxygen poisoning, damage to the ears, sinuses, and lungs du to pressure, HBOT also reported to cause claustrophobia in patients. Therefore, the treatment of ORN with HBOT is still considered controversial [6]. In 1983, Marx et al. introduced the hypothesis that radiation therapy causes an endarteritis that results in hypocellularity, hypoxia, and hypovascularity [7,23]. Because of this theory on the pathophysiology of the condition, a new treatment proposal has been introduced, which included the combination of pentoxifylline, tocopherol, and clodronate [8,23]

Pentoxifylline used to manage cardiovascular disorders, such as ischemic heart disease and intermittent claudication. In vivo, PTX reported to increase erythrocyte flexibility and vasodilation and inhibit inflammatory reactions, which, in return, helps to improve the peripheral blood flow. It also has an anti-tumor necrosis effect [8,9,23].

Tocopherol, particularly α- tocopherol (vitamin E) [21] leads to an increase in antioxidant concentration in the affected area. Moreover, it helps to decrease the reactive oxygen species, which promotes healthy healing of the injured endothelial tissue [8,10,23].

In addition, clodronate is a non-nitrogenous bisphosphonate. Clodronate functions in decreasing bone resorption through the reduction of osteoclast number and activity. It is also reported to reduce inflammatory cytokines, particularly IL-1b, IL-6, and TNF-a. A unique feature of clodronate among its group of agents is that it has osteoblast stimulation properties, as well as fibroblast proliferation reduction [8,9,23]. Interestingly, in animal studies, these drugs were unable to reverse the progression of human fibrosis individually. Studies on radiation-induced tissue injury at other body sites than head and neck (sternum) report that these drugs are effective synergistically [11]. Moreover, placebo-controlled randomized trials showed that combination treatment was more effective than placebo and single-agent

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1.1 Aim: The purpose of this study was to perform a systematic literature review to evaluate the reported outcomes with the use of pentoxifylline, tocopherol, and clodronate in management of ORN.

1.2 Task: To evaluate the treatment outcomes of the drug combination pentoxifylline and tocopherol and clodronate (PENTOCLO).

1.3 Hypothesis: This systematic review hypothesizes that the use of the drug combination will give positive outcomes.

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2. SELECTION CRITERIA OF THE STUDIES. SEARCH METHODS AND STRATEGY

Bioethics Approval code- BEC-OF-143

2.1 Focus Question

The presented focus question was developed according to the population, intervention, comparison and outcome (PICO) study design.

Table 1.

Population (P) Patients who underwent radiation therapy,

and who were diagnosed with ORN Intervention (I) Clinical evaluation after medical treatment

Comparator or control group (C) Comparison of treatment results with condition before medical treatment

Outcomes (O) Clinical recovery and stability of the

condition

Focus questions Does the drug combination PENTOCLO

results in effective treatment outcomes?

2.2 Types of publications

The systematic review included studies on humans published in the English language. 2.3 Types of studies

The systematic review included all human studies published between 2009-2019, that reported the treatment outcomes of PENTOCLO.

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2.6 Systematic review organization

This systematic review was conducted under the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) recommendations in order to analyze and determine the possible outcomes of the use of pentoxifylline, tocopherol and clodronate as a treatment option for ORN.

2.7 Search methods

An electronic literature search was performed on electronic databases accessed through the online library of Lithuanian University Of Health Sciences (EZproxy). Databases that were chosen by the author included PubMed and ScienceDirect.

The search was conducted using the following keywords: osteoradionecrosis, pentoxifylline, tocopherol, and clodronate.

2.8 Literature search strategy

A detailed electronic literature research was carried out by the assessment of different articles from different scientific and included the keywords that were selected. Medical subjects' headings (MesH) terms were used to increase the precision of the search and find articles regardless of the terminology used by the author. Thus, the keywords that were used in the search were in the following combination: "Osteoradionecrosis" [Text Word] OR "Osteoradionecrosis" [Mesh] AND "Pentoxifylline" [Text Word] OR "Pentoxifylline" [Mesh] AND "tocopherol" [Text Word] OR "tocopherol" [Mesh] AND "clodronate" [Text Word] OR "clodronate" [Mesh]. Then the search was narrowed down to only English studies performed on humans, which were published between January 1st, 2009, till December 31st, 2019.

2.9 Inclusion and exclusion criteria

Inclusion and exclusion criteria were adjusted in order to help the author to find and identify only the relevant articles for the review. In order to assess the references for eligibility, titles, and abstracts of the initially selected articles, when electronic research was done, were reviewed to evaluate if the articles meet the inclusion criteria. Articles that did not meet the inclusion criteria were ruled out.

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Inclusion criteria • English articles

• Osteoradionecrosis in maxilla and mandible • Human studies

• Retrospective studies • Prospective studies • Clinical trials

• Studies conducted between 2009 and 2019 • Follow up period >6 months

Exclusion criteria • Non- English articles • Duplicate articles

• Case reports, literature review, systematic review • Prophylactic use of medication

• Studies conducted earlier than 2009

2.10 Selection of studies

The author reviewed all articles that were selected. First, the titles and abstracts were screened and reviewed to assess the inclusion and exclusion criteria. The articles that did not meet the inclusion criteria were ruled out. Then full-text reading of the included articles was achieved. The initial search of the two databases showed 158 articles. After applying the three additional filters, "English," "humans," "2009-2019," 45 articles were ruled out, and 113 articles remained. Then the duplicated articles were sorted out. Finally, the remaining articles were reviewed to assess the inclusion and exclusion criteria.

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Figure 2. PRISMA flowchart

Records identified through database searching (n =120) S c r e e n in g In c lu d e d El ig ib il ity Id e n ti fi c a ti o n

Additional records identified through other sources

(n = 1)

Records after duplicates removed (n = 100)

Titles and abstracts were screened and

selected (n= 49)  (n = )

Records excluded, due to: Irrelevant context Lack of information (n=32) Full-text articles assessed for eligibility (n = 17) Full-text articles excluded according to exclusion criteria: 1. Follow up period <6 months 2. Due to unavailability in English language 3. Published before 2009 4. Unpublished studies   Articles included  (n = 5)

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2.11 Risk of bias assessment

Included aarticles were reviewed and assessed by The Cochrane recommendations for

systematic reviews of interventions by Higgins and Green [24]. The seven key domains were included when evaluating studies (Table 3).

Table 3. Risk of bias

Domain Patel et al. [2016] Hayashi et al. [2015] D’ Souza et al. [2014] Delanian et al. [2016] Robard et al. [2014] Random sequence generation

Unclear High risk Low risk Unclear High risk

Allocation concealment

Unclear Unclear Low risk Unclear High risk Blinding of

participants and personnel

High risk High risk High risk High risk High risk

Blinding of outcome assessment

Unclear Unclear Unclear Unclear Unclear

Incomplete outcome data

Low risk Low risk Low risk Low risk Low risk Selective

reporting

Low risk Low risk Low risk Low risk Low risk Other bias Low risk Low risk Low risk Low risk Low risk

Risk of bias level Unclear risk of bias Unclear risk of bias Low risk of bias Unclear risk of bias High risk of bias

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3.

SYSTEMIZATION AND ANALYSIS OF DATA

3.1 Results

A total of 113 publications were retrieved, and 15 articles thoroughly reviewed. Exclusion was done by duplication and irrelevant titles and abstracts. Five articles were selected for this systematic review. The articles that met the inclusion criteria and proven eligibility were submitted for data extraction. Information about the study design, sample size/, radiation therapy, risk factors, medical treatment protocol, side effects, as well as the summary of the treatment results, were extracted and recorded.

The selected studies methods and results were summarized in (figure 3).

3.2 Descriptive results

A total of 227 participants that were treated with pentoxifylline, tocopherol with or without clodronate were evaluated in the five reviewed studies of this systematic review. Two retrospective clinical studies were included, two prospective and one clinical phase II trial. The study of Patel et al. reported the treatment outcomes of PENTO combination alone and the outcomes when other treatment options were used with PENTO simultaneously [12]. While D'Souza et al. compared the treatment of PENTO along with doxycycline and HBO therapy and reported the outcomes of both treatments [13],

Hayashi et al. Studied the efficiency of PENTO treatment through a prospective clinical analysis and reported the outcomes and the duration of treatment [14].

The treatment outcomes of PENTOCLO were reported in the studies of Delanian et al. and Robard et al. [15,16] both of these studies followed the same protocol, both studies included the administration of both antibiotics and corticosteroids prior to starting the ORN medical treatment.

Exact side effects of the treatment were reported by Delanian et al. [15] and Hayashi et al. study [14].

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Figure 4. Characteristics of included studies

Reference Study design Sample size

Radiation therapy

Causes/ risk factors

Size of lesion/ staging Treatment protocol Mean healing time Safety/ adverse effects Outcomes Patel et al. [2016] Retrospective study 62 EBRT + IMRT Dose of irradiation: not mentioned Spontaneously, Dental extraction

Notani grading system: Grade I (31)

Grade II (14) Grade III (17)

PTX: 800 mg/ day, TOC: 1000 IU/day Group 1: PENTO alone Group 2: PENTO + A/B Group 3: PENTO + debridement Group 4: PENTO + resection Group 5: PENTO + HBOT Mean follow up period: 2-36 mo Mean healing time: 8 mo

Not mentioned Group 1: 56% resolution Group 2: 27% resolution Group 3: 6% resolution Group 4: 66% resolution Group 5: 0% resolution Hayashi et al. [2015] Uncontrolled prospective study 13 IMRT Irradiation dose: 60 Gy Spontaneously, Dental extraction, Periodontal pathology N/A PTX: 800 mg/ day, TOC: 1000 IU/day Mean follow-up period: 1-33 mo Mena healing time: 13 mo Gastrointestina l and allergy issues (1 patient) no other side effects 11/13 patients showed improvement (85%) D’ Souza et

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Figure 4. continued Reference Study design Sample size Radiation therapy Cause/risk factors Size of lesion/ staging Treatment protocol Mean healing time Safety/adverse effects Outcomes Delanian et al. [2016] Phase II clinical trial 54 55-65 Gy: 13 patients 65-75 Gy: 5 patients Spontaneously, Dental extraction Lesion size: 17 mm Epstien staging system: Stage II:18 Stage III:36 PTX: 400 mg 2x/day TOC: 1000 IU 1x/day and patient and CLO: 1600 mg 5x/week Pd: 20 mg 1x/day Cp: 1g 1x/day Mean follow- up time: 6 +/- 36 mo Mean healing time: 9 +/- 3 mo 12 patients had minimal adverse effects: nausea, vertigo, headache, insomnia, diarrhea, asthenia 100 % regression Robard et al. [2014] Uncontrolled Prospective study 27 54-136 Gy Tobacco, alcohol consumption Authors own classification Stage I: 6 Stage II:14 Stage III: 5 Stage IV: 0 1st_{phase of} treatment: a/b and corticosteroids for 4-6 weeks 2nd_{phase of} treatment: PENTOCLO protocol along with Pd Follow-up time: 40 mo healing time: 110 +/- 76 days (3,7 +/- 2,5 mo) Well tolerated, with few side effects 59% recovery 30% stability 4%progression

IMRT, intensity modulated radiotherapy; EBRT, external beam radiation therapy; PTX, pentoxifylline; TOC, tocopherol; PENTO, PTX+TOC; CLO, clodronate; Pd, prednisolone; Cp, ciprofloxacin; D, doxycycline; HBOT, hyperbaric oxygen therapy

Notani grading system: grade I, ORN restricted to alveolar bone; grade II, confined to the alveolar bone and/or mandible above the level of inferior alveolar canal; grade III, including the mandible below the level of the inferior alveolar canal and/or the presence of skin fistula and/or pathologic fracture

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4.

DISCUSSION 4.1 Discussion of the results

This systematic review focused on assessing the effectiveness of PENTOCLO in the management of osteoradionecrosis. Studies that investigated the treatment outcomes reviewed. Out of the 113 articles assessed for eligibility, five studies selected for extraction and analysis of the results. Despite the limited number of the included articles, a conclusion was obtainable. Most of the articles had an agreement on their results, as they were relatively alike. The results of the review showed that treatment measurements were successful. All five studies included showed a significant improvement or stability of ORN when using PENTOCLO.

In the first prospective clinical trial conducted by Delanian et al. [11]., All patients included had failed other conservative treatment measurements as antibiotic therapy, HBO, and/or minimal sequestrectomy. These patients then received a daily oral administration of 800 mg of PTX b.i.d and 1,000 IU of TOC q.d., while the most severe cases received and addition of 1600 mg CLO 5x/week, for at least six months. The treatment resulted in 89% progression in a mean duration of 6 months [11]. Based on these results achieved, another subsequent study was conducted by the same investigators, to study the effectiveness and safety of a prolonged PENTOCLO treatment. All patients treated with PENTOCLO combination along with antibiotics and corticosteroids for 6-36 months [15]. All patients showed a 100% regression of exposed bone, mucosal coverage, and symptomatic relief. Only minimal side effects were reported, which were eliminated by alteration and reduction of drug dosage. Furthermore, spontaneous sequestrectomy reported in 67% of the patients, and the author stated that PENTOCLO helped to separate necrotic bone from vital bone and therefore accelerate the healing process. Another study by Robard et al. revealed that the combination mentioned above resulted in 60% healing in all cases in less than four months duration, with a few

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than the mean healing duration reported by Delanian et al. and Robard er al. [15, 16]. Whether healing occurred without the use of clodronate, or whether clodronate shortened the recovery time is difficult to know due to the study design and the fact that other factors play a role in outcomes and healing time of the treatment, like type of radiation therapy used, etiology and risk factors as well as the stage of ORN extent. Both Patel et al. and Robard et al. reported that healing was faster in patients who were treated by surgery and adjuvant radiotherapy alone compared with those who treated with chemoradiotherapy [12, 16]. Robard et al. also reported that ORN was diagnosed faster in patients who underwent chemoradiotherapy compared with those patients who had adjuvant radiotherapy, and the author observed longer healing time with those patients as well [16]. Healing also influenced by the etiology of ORN, Patel et al. reported a higher healing rate in spontaneous ORN compared with induced ORN cases [12]. When dental infections were the causative factor for ORN, the medical treatment was ineffective, neither PENTO alone or along with antibiotic therapy [12]. Therefore, the data suggest that infection should be resolved before the start of the treatment. Etiological risk factors, as tobacco smoking and alcohol consumption played a significant role, patients who continued smoking during the treatment had poorer and slower healing, reported both Hayashi et al. and Robard et al. [12, 14] Therefore, management of ORN should not only be confined to medical treatment, but also to manage risk factors as well as prevention of traumas such as dental infections, and extractions post radiation therapy. Furthermore, treatment also influenced by the extent of the condition. Both D'Souza et al. and Patel et al. classified ORN according to Notani classification [12, 14, 25], Delanian et al. used the Epstein grading system [15, 25], while Robard et al. provided his classification based on the length of exposed bone [14], while Hayashi et al. did not provide information about ORN grading [12]. The was a significant cure rate in ORN grade I and II, while medical treatment of grade III was based mainly on stabilization of the condition; however, treatment of grade III had less sensible outcomes. D'Souza reported a recovery of 2/3 of patients with grade I and II, and 40% of the ten patients with grade III were stable [14]. Moreover, Patel et al. reported a 56% regression of patients with grade I and II [12].

In addition, the use of antibiotics and anti-inflammatory was recommended by the majority of authors. Robard et al. suggested the use of antibiotics and corticosteroids treatment for 4-6 weeks, as a start to control and minimize tissue infiltration before the start of PENTOCLO [16, 15]. Patel at el used antibiotic therapy simultaneously along with PENTO treatment (if there was clinical evidence of infection) [12], In contrast to results reported by Robert et al.,

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(27%) [12, 16]. While PENTO alone achieved improvement in 14 of 25 patients (56%). Antibiotic therapy was also used by D'Souza et al., specifically doxycycline (100mg/day) simultaneously along with PTX and tocopherol [14]. Becau se local medical microbiologists favored the use of tetracycline for organisms associated with ORN and the pharmacokinetics of doxycycline. Though the author discussed consideration to avoid the use of antibiotics due to the excellent outcome reported by previous studies [14].

Generally, no adverse effects or complications reported in any of the studies. The literature supports the safety of the treatment regimen. Moreover, the most significant rate of healing and clinical improvement reported were in mild and moderate ORN cases (stage II and III).

4.2 limitations to this systematic review

This systematic review presents a number of limitations. Only five studies were included in this review. Therefore, the comparison of the outcomes was based mainly on these few studies. Moreover, the studies included in this systematic review were mainly retrospective analysis and non-blinded trials; further randomized and controlled clinical trials are necessary to validate the findings. Furthermore, clodronate was included in only two studies. Thus, no conclusion about the effectiveness of clodronate can be drawn. An additional limitation is the sample size. Each reviewed study had included a sample size varying from 13 to 62 individuals. Although this sample size is sufficient to observe the outcomes, a larger sample size would assist in evaluating the effectiveness of the treatment.

5.

CONCLUSION

According to the analyzed data, we can conclude that treatment with pentoxifylline and tocopherol and clodronate has an effective role in the management of early and moderate stages of ORN. The combination of these drugs appears to be well tolerated as it did not show adverse side effects. The highly satisfactory and rapid clinical recovery suggests that PENTOCLO could make the baseline of ORN management in the future. Further randomized

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Management of osteoradionecrosis with pentoxifylline, tocopherol and clodronate: a systematic review

Gheed Najah Al-ani