Use of pentoxifylline and tocopherol in radiation-induced fibrosis and fibroatrophy

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Review

Use of pentoxifylline and tocopherol in radiation-induced fibrosis and fibroatrophy V. Patel a,∗ , M. McGurk b a b

Oral Surgery Dept, Floor 23, Guys Dental Hospital, London Bridge, London, SE1 9RT Department of Oral and Maxillofacial Surgery, Atrium 3, 3rd Floor, Bermondsey Wing, Guy’s Hospital, London, SE1 9RT

Accepted 27 November 2016

Abstract Radiation-induced fibrosis in the head and neck is a well-established pathophysiological process after radiotherapy. Recently pentoxifylline and tocopherol have been proposed as treatments to combat the late complications of radiation-induced fibrosis and a way of dealing with osteoradionecrosis. They both have a long history in the management of radiation-induced fibrosis at other anatomical sites. In this paper we review their use in sites other than the head and neck to illustrate the potential benefit that they offer to our patients. © 2016 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. Keywords: Radiation-induced fibrosis; pentoxifylline; tocopherol

Introduction

Radiation-induced fibrosis

Radiotherapy is used extensively in the treatment of cancers of the head and neck in conjunction with resection, or chemotherapy, or both. The advent of improved delivery of radiation allows it to be targeted to the site of the tumour while reducing exposure to the surrounding healthy tissue. This is never totally successful, as local healthy tissues inevitably develop the side effects of radiotherapy. The impact of postoperative fibrosis is augmented by either resection or chemotherapy. The effects are not immediate but manifest themselves throughout the patient’s life. In this review we report how pentoxifylline and tocopherol have been used to mitigate symptoms of radiation-induced fibrosis at different sites in the body.

Radiation-induced fibrosis leads to fibroatrophy, a condition traditionally considered irreversible that can lead to pain, poor cosmesis, and a lack of function.1 The first effective agents used to reduce it was liposomal copper/zinc (Cu/Zn) superoxide dismutase.2 Based on the beneficial results achieved in these two cases, a study of antioxidant medication with pentoxifylline and tocopherol (vitamin E) was initiated.

∗

Corresponding author. E-mail addresses: [email protected] [email protected] (M. McGurk).

(V.

Patel),

Clinical radiation-induced fibrosis Chronologically there are four recognisable clinical stages: pre-fibrosis, established fibrosis, late fibrosis, and atrophy/necrosis. All patients will experience some degree of fibrosis dependent on the main contributing factors such as the anatomical site and the dose of radiation delivered. The anatomical areas where signs of post-radiation fibrosis are well recognised are breast, skin, small bowel, lung, kidney, and liver.1

http://dx.doi.org/10.1016/j.bjoms.2016.11.323 0266-4356/© 2016 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Patel V, McGurk M. Use of pentoxifylline and tocopherol in radiation-induced fibrosis and fibroatrophy. Br J Oral Maxillofac Surg (2016), http://dx.doi.org/10.1016/j.bjoms.2016.11.323

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Table 1 Risk factors associated with radiation-induced fibrosis. Risk factors Radiotherapy3–8 Total dose Dose/fraction Size of fraction Amount of radiotherapy Timetable for delivery of fraction Salvage radiotherapy Operation9–13 Site previously irradiated Chemotherapy14 Patient-related factors12,15–18 Physiological condition Age (years) Coexisting conditions19–26 Cardiovascular disease Collagen disease Vascular disease

sity of activated fibroblasts (myofibroblasts) in a disorganised extracellular matrix in juxtaposition to paucicellular fibrotic areas that contain poorly proliferative senescent fibroblasts (fibrocytes) in a dense, sclerotic, extracellular matrix.30 In the final phase (late fibroatrophy) there is an attempt at tissue remodelling but the tissue is fragile and late reactivated inflammation is caused by local injury. This ongoing process leads to activation and dysregulation of fibroblastic activity and eventual atrophy. Within the head and neck it is at this stage that osteoradionecrosis develops. This final phase of the model has normally developed by five years after radiotherapy31,32 and continues throughout life. The excess of myofibroblasts is described as hypercellularised fibrosis and manifests as radiation-induced fibrous swellings.30 This deregulation of fibroblasts is similar to the fibrotic reaction seen in the lungs and liver after the impact of viruses, alcohol, or silica.33

Risk factors Radiation-induced fibrosis follows irradiation, but the degree of fibrosis is influenced by a number of other factors (Table 1). Clinically it can be either superficial or deep. The former is characterised by hyperpigmentation, epilation, dryness of the skin, and telangiectasia. Adjacent bone may be involved with osteoradionecrosis of the jaws, ribs, and sternum. In contrast the “deep” type is difficult to recognise and classify. It is dependent on the organs involved and an attempt to grade the late effects has been incorporate in the SOMA scale (Subjective, Objective, Medical management, and Analytical evaluation of injury)27 as well as the National Cancer Institute CTCAE (Common Terminology Criteria for Adverse Events).28

Pentoxifylline Pentoxifylline is a methylxanthine derivative licensed for use in peripheral vascular disease. It is available only in tablet formulation (modified release) in the UK. It has four main properties: it increases the deformability of erythrocytse,34 it reduces blood viscosity,34 it inhibits both proliferation of human dermal fibroblasts and production of extracellular matrices,35 and finally it increases the activity of collagenase.35 It also increases sensitivity to radiation when given during radiotherapy, and has a modulating effect34,36,37 in nonradiation-related fibrosis such as submucous fibrosis38 and liver fibrosis.39

Pathophysiology It has three histological patterns: the prefibrotic inflammatory phase, the constitutive fibrotic cellular phase, and the late fibroatrophic phase. These may progress over several years. The prefibrotic phase starts immediately after radiotherapy. Injured endothelial cells produce chemotactic cytokines that trigger an acute inflammatory response. This in turn generates a release of reactive oxygen species from polymorphs and other phagocytes,29 which drives the release of tumour necrosis factor ␣, platelet-derived growth factor, fibroblast growth factor ␤, interleukins 1, 4, and 6, transforming growth factor ␤1 (TGF-␤1), and connective tissue growth factor. These factors activate both fibroblasts and myofibroblasts.29 The endothelial cells succumb to this continual insult, which leads to necrosis of microvessels, ischaemia, and atrophy of tissue. This process highlights the important part played by the endothelial cells. The second phase is known as the constitutive phase and spans the first years after radiotherapy. As a reaction to the early phase of inflammation the affected tissues begin to thicken. Constitutive disease is characterised by a patchwork of active radiation-induced fibrosis that contains a high den-

Tocopherol (vitamin E) Vitamin E, often known as ␣-tocopherol, is an antioxidant and is commonly available in both suspension and liquid capsules. It protects membrane phospholipids from oxidative damage by scavenging the reactive oxygen species that are generated during oxidative stress.40 Additional properties include inhibition of protein kinase C with consequent inhibition of platelet aggregation, production of nitric oxide in endothelial cells, and production of superoxide in neutrophils and macrophages.41 In recent years the safety of high doses of vitamin E has been questioned because of a possible association with lung cancer and cardiovascular disease. In two studies the daily ingestion of >400 IU vitamin E was associated with a generalised increase in all mortality42,43 from any cause, but subsequent meta-analysis has shown that vitamin E is unlikely to affect mortality, regardless of dose,44 and a further recent meta-analysis of various randomised trials in the treatment and prevention of cardiovascular disease found that vitamin E had no effect on survival, beneficial or adverse.45 A large randomised controlled trial of 29 133 male smokers in Finland concluded that ␣-tocopherol may actually have

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beneficial effects, as fewer prostate cancers were identified in the test group than among the controls.46 Evidence to support the activity of pentoxifylline and vitamin E Pentoxifylline and vitamin E are effective in reducing radiation-induced fibrosis, either individually or when combined (which is the most common approach). Much of the work has been undertaken by two groups, one based in Iowa, USA47,48 and the other in Paris, France.1,22,31,32,49–62 The combination of the two drugs inhibits intracellular signalling in response to TGF-␤63,64 and connective tissue growth factor,65 both of which have an important role in the pathogenesis.66,67 Animal studies In a randomised controlled trial of 104 mice treated with either prophylactic saline or pentoxifylline after various doses of radiation, pentoxifylline reduced the incidence and severity of late radiation injury.47 Lefaix et al52 found that alone it had no influence on fibrosis whereas, when it was given together with vitamin E to pigs with radiation-induced fibrosis, they showed regression of about 30% of length and 50% of width and depth. Histological evaluation of the areas of regression showed that the residual scar tissue was surrounded by normal muscle and subcutaneous tissue. In a study of the use of the combination for radiation induced myocardial fibrosis in rats, both treatment protocols induced a significant improvement in left ventricular diastolic dysfunction.68 Radiation-induced fibrosis of the lung was also prevented in a randomised controlled trial in rats when the two drugs were given immediately after radiotherapy.69 These results were confirmed by Bese et al.70 Clinical studies Prevention: Pentoxifylline was tested against placebo to see if it would prevent radiation- induced (early or late) damage to lung tissue, and it had a significant beneficial effect. This was confirmed in a randomised control trial of pentoxifylline and placebo during radiotherapy of the head and neck (six weeks during, and two weeks afterwards).71 Patel et al72 used prophylaxis with the combination a month before, and continued for three months after, dental extractions in patients who were having radiotherapy to the head and neck to protect against osteoradionecrosis. This series showed that only one of 82 patients undergoing 390 extractions developed osteoradionecrosis (rate/tooth 0.3%). Breast, chest wall, and lung: The use of the two drugs to counter radiation-induced fibrosis has been most common in breast oncology, where the combination was shown to reverse late radiotherapy skin damage among patients treated for cancers of the breast and head and neck,49 and the maximum response (68% regression of fibrosis) was evident by 24 months.53 A risk of rebound was likely if the duration of treatment was too short. In 2003, Delanian et al51 published a

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randomised, placebo-controlled trial with four balanced treatment groups (pentoxifylline plus vitamin E compared with pentoxifylline plus placebo compared with placebo plus vitamin E compared with placebo plus placebo). Results showed that the mean surface regression of fibrosis was significant with combined pentoxifylline and vitamin E compared with double placebo. These results were echoed in a more recent randomised controlled trial73 that showed a significant reduction in fibrosis when patients were treated with the combined drugs, as shown measurements of by tissue compliance. Most studies of combined pentoxifylline and vitamin E have shown the beneficial effects in limiting radiationinduced fibrosis of the breast, although there have been some conflicting results. Gothard et al74 found no benefits when the combination was compared with placebo in a randomised controlled trial that investigated oedema of the arm and fibrosis as outcomes. Magnusson et al,75 in contrast, found the opposite. The combination was successful in treating severe exteriorised osteoradionecrosis of the sternum with surrounding radiation-induced fibrosis of the breast in a case report by Delanian and Lefaix.59 They also added clodronate, and found impressive regression of fibrosis and healing of the osteoradionecrosis after three years. Pelvic, genitouterine, and other sites: The use of the combination increased endometrial thickness and uterine artery blood flow as shown on ultrasonography in patients who had had radiotherapy in childhood and presented later with fibroatrophic uterine lesions.76 It also seemed to improve the pregnancy rate in patients with a thin endometrium by increasing endometrial thickness and improving ovarian function; this was most evident in patients who had previously been given total body irradiation.77 In a retrospective analysis by Hille et al78 of patients treated with the combination for radiation-induced proctitis/enteritis they found that over a period of six months it led to relief of their symptoms in 15/21 patients. Gothard et al79 also found that after a six months’ course the fibrosis improved in those who had had pelvic radiation. There was no further improvement at 12 months. Other irradiated tissues such as lumbosacral polyradiculopathy have responded to pentoxifylline and vitamin E in combination with clodronate,50 as have patients with cerebral radionecrosis after sterotactic radiotherapy.80 Head and neck: In recent years pentoxifylline and vitamin E has attracted interest as a possible way of managing osteoradionecrosis.54,81,60 In 2000, Delanian et al61 reported a mini-case series of 6/7 cases that completely healed after three months of exteriorised osteoradionecrosis of the mandible treated with the combination. In 2005 this work was followed with a larger series of 18 patients, again with exteriorised osteoradionecrosis treated with the combination, but in eight cases supplemented with clodronate. All patients had improved at six months, and showed a mean reduction of 84% of exposed length of bone; overall 16/18 had healed completely.

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Delanian et al54 developed a regimen (PENTOCLO − PENtoxifylline − TOcopherol − CLOdronate) and when they used this with prednisolone and ciprofloxacin (two days/week) they obtained impressive results in a recalcitrant group of 54 patients with exteriorised refractory mandibular osteoradionecrosis (that had been present for 1.4 (+/−1.8) years). The amount of exposed bone reduced by 42% (two months), 62% (four months), 77% (six months), 92% (12 months), and 96% at (18 months).54 This group’s most recent publication81 echoed the beneficial effect of PENTOCLO with a healing rate of 59%. Since it was recognised that bisphosphonates could cause medication-related osteonecrosis of the jaw there has been a reluctance to use clodronate for such patients. The results obtained with pentoxifylline and vitamin E alone match those achieved by the PENTOCLO regimen, with a healing rate of 9/25 (36%) and stabilisation of the osteoradionecrosis in 8/25 cases (32%).82 Hayashi et al,83 reported 85% of 13 patients had resolution of their disease, and Patel et al84 (in a retrospective analysis of 62 patients with osteoradionecrosis) reported resolution in 14/25 patients (56%). When the necrotic sites were obviously infected the disease resolved in only 6/22 (27%), which emphasises the importance of treating any infection first. Pentoxifylline and vitamin E may have other uses in head and neck surgery. In a small cohort study of trismus by Chua et al,85 an eight-week course of pentoxifylline resulted in improved mouth opening and reduced fibrosis. Ferreria et al,86 in a randomised controlled trial of prophylactic vitamin E, found a reduction in both pain and radiation mucositis by 36% of 28 patients in whom vitamin E mouthwash was compared with placebo.

Table 2 Other pharmacological approaches to the management of radiation-induced fibrosis. Drug/treatment and type of fibrosis D-penicillamine Scleroderma87 Colchicine Cirrhosis of the liver88–90 Idiopathic interstitial pulmonary fibrosis91 Cutaneous radiation fibrosis92 Interferon Cirrhosis of the liver90 Idiopathic interstitial pulmonary fibrosis91 Captopril Radiation pneumonitis93 Radiation nephropathy94,95 Hyperbaric oxygen Osteoradionecrosis96,97 Bovine liposomal Cu/Zn superoxide dismutase Radiation-induced fibrosis62,98,99–101 Corticosteroids Radiation nephropathy102 Non-steroidal anti-inflammatory drugs Radiation pneumonitis103

Conflict of Interest We have no conflicts of interest.

Ethics statement/confirmation of patients’ permission No ethical approval or patients’ consent required.

References Alternatives to pentoxifylline in radiation-induced fibrosis A pharmacological solution to fibrosis has long been an objective, but the promise shown in early animal studies has not always transferred successfully to humans.32 Table 2 shows other ways to manage fibrosis.

Conclusion Although the use of pentoxifylline and vitamin E in the head and neck is new, this combination of drugs has a long-established track record in the management of radiationinduced fibrosis at other sites. Pharyngeal fibrosis and some severe types of osteoradionecrosis are currently incurable, have a considerable impact on the quality of life, and detract from what would otherwise have been a successful course of radiotherapy. The combination offers the prospect of limiting the effects of radiation-induced fibrosis and may provide part of the solution to treating its consequences.

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Please cite this article in press as: Patel V, McGurk M. Use of pentoxifylline and tocopherol in radiation-induced fibrosis and fibroatrophy. Br J Oral Maxillofac Surg (2016), http://dx.doi.org/10.1016/j.bjoms.2016.11.323