British Journal of Radiology 75 (2002),467-469 © 2002 The British Institute of Radiology
Complete healing of severe osteoradionecrosis with treatment combining pentoxifylline, tocopherol and clodronate
S Delanian, MD, PhD
1 and
J-L Lefaix, PhD
2
1 Service d'Oncologie-Radiothérapie, Hôpital Saint-Louis APHP, 1 Ave Claude Vellefaux, 75010 Paris and 2 Laboratoire de Radiotoxicologie, CEA-DSV-DRR, BP12, 91680 Bruyères-Le-Chatel, France
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Abstract
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Osteoradionecrosis (ORN) is a late terminal sequela of irradiation that does not resolve spontaneously. In a preliminary study, a combination of pentoxifylline (PTX), tocopherol (Vit-E) and clodonate has been shown to be of clinical benefit with more than 50% regression of progressive ORN observed at 6 months in 12 patients. A 68-year-old woman presenting with severe exteriorized osteoradionecrosis had received radiotherapy for breast cancer 29 years previously. She had palpable breast fibrosis, including the sternum (15 cm x 11 cm) and a painful fistulous track in the upper part of the bone (orifice diameter 10 mm) surrounded by local inflammatory signs, and chronic osteitis with sequestra extrusion. MRI showed deep radiation-induced fibrosis below this area without cancer recurrence, and complete bone destruction over an area of 7 cm x 4 cm. Oral PTX (800 mg day-1), Vit.E (1000 IU day-1) and clodronate (1600 mg day-1) were administered daily for 3 years and were well tolerated. The patient exhibited regular clinical improvement until complete closure of the fistula and total regression of the clinical fibrosis. MRI confirmed the good response and showed heterogeneous restoration of the sternum, which was filled with new tissue. This is the first time that antifibrotic treatment with combined PTX–Vit.E plus clodronate has been shown to have a significant effect on necrosis, by completely reversing severe progressive ORN and the associated radiation-induced fibrosis.
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Introduction
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Osteoradionecrosis (ORN) is a severe delayed radiation-induced injury, characterized by bone tissue necrosis and failure to heal [1]. ORN either stabilizes or gradually worsens and is notoriously difficult to manage [2]. Usual therapeutic approaches have included the limitation of unfavourable associated events, antibiotic-corticoid medication and the removal of necrotic tissue [2, 3]. The use of hyperbaric oxygen has led to the improvement or stabilization of moderate ORN [4]. Extensive surgical reconstruction, when technically possible, may be necessary in cases of progressive ORN [2]. However, no reference medical treatment exists for this chronic pathological process. Hence, there is a need to develop an alternative treatment based on the understanding of the mechanism of ORN. A case is described here of complete healing induced by treatment with combined pentoxifylline–tocopherol (PTX–Vit.E) and clodronate in a patient with progressive severe ORN.
A 68-year-old woman treated in 1969 with conservative surgery and radiotherapy for left-sided breast cancer, gradually developed worsening radiation-induced plexopathy and lymphoedema of the arm from 1972. In March 1996, she was admitted to hospital for lymphangitis of the arm, severe thoracic cellulitis and purulent pleural effusion. In September 1996 she presented with presternal soft tissue disruption, which steadily progressed. In February 1998, she presented at the Saint-Louis Hospital with extensive fibrosis of the left breast involving the skin and underlying mammary tissue over a palpable area of 15 cm x 11 cm, including the sternum (Figure 1a
). We observed a large painful fistulous track (orifice diameter 10 mm) in the upper part of the bone (Figure 1a), major local inflammatory signs around this track and chronic osteitis of the sternum with spontaneous extrusion of sequestra, combined with severe flaccid paralysis and lymphoedema of the left upper limb. MRI showed deep fibrosis extending to this area but no evidence of recurrence of cancer (Figure 2a). There was severe osteoradionecrotic invasion of the sternum with complete bone destruction over an area of 7 cm x 4 cm (Figure 2a).
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Figure 1. (A) Clinical photograph in February 1998 of the radiation-induced fibrotic volume with a cutaneous thoracic projection of 15 cm x 11 cm fibrosis outlined and large fistulous track in the upper part of the sternum. (B) In June 2001, after 3 years of treatmentwith combined pentoxifylline-tocopherol and clodronate, total fibrosis regression (dotted line for residual skin firmness) has occurred and the fistula has closed.
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Figure 2. MRI, 1,5 Tesla, T2 weighted sagittal images. (A) The upper part of the sternum, with a large area of radionecrosis (arrow) in February 1998. (B) Sternum restoration with new filling tissue(arrow) combined with striking reduction of presternal radiation-induced fibrosis after 3 years of treatment with combined pentoxifylline-tocopherol and clodronate.
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The patient was given antibiotic-corticoid treatment for one month consisting of 2 g day-1 amoxicillin–clavulanic acid, 50 mg day-1 fluconazole and 16 mg day-1 methylprednisolone. In March 1998, daily oral treatment with 800 mg pentoxifylline (PTX) and 1000 IU tocopheral (Vit.E) was started. Since June 1998, 1600 mg day-1 clodronate 5 days per week, and antibiotic–corticoid treatment 2 days per week with 1 g day-1 ciprofloxacin and 16 mg day-1 methylprednisolone, have been added to this combination. From June 1998 until June 2001, the patient underwent physical examination every 3 months.
There was regular clinically assessable improvement, which began during the second month of PTX–Vit.E treatment. After 3 months of this treatment (June 1998), we observed cessation of fibrosis, pruritis oedema of the hand and bad odour, a decrease in cutaneous inflammation and purulent discharge, and a reduction of the fistula orifice diameter to 6 mm. After 6 months of treatment, the discharge was greatly reduced. At 12 months (February 1999), sequestrum extrusion had stopped, cutaneous inflammation had disappeared, the fibrotic area had regressed to 9 cm x 7 cm and the diameter of the fistula orifice had fallen to 5 mm x 3 mm. At 18 months (July 1999), MRI scan showed a 50% improvement, and after 2 years (March 2000) the fistula orifice had diminished to 1 mm x 0.5 mm. By June 2001 the clinical response was complete (Figure 1b
), with total regression of clinical fibrosis, a closed fistula and the disappearance of local and general inflammation, except for brachial plexopathy. The last MRI scan confirmed the regression of deep fibrosis and showed heterogeneous restoration of the bone of the sternum, which was filled with new tissue (Figure 2b). The antibiotic–corticoid treatment (2 days per week) was stopped after June 2001, when cutaneous healing was complete. The overall treatment was very well tolerated, without further symptoms. Owing to the severity of radiation damage, combined PTX–Vit.E and clodronate treatment of this patient is being continued for at least 1 year.
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Discussion
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The literature contains few reports concerning the treatment of progressive ORN, an irreversible late complication of radiotherapy. Although the pathogenesis of ORN may often involve vascular hypoxia [4], ORN was recently suggested to be triggered by a predominantly fibro-atrophic mechanism [3, 5, 6]. Treatment with combined PTX–Vit.E and clodronate may be promising for several reasons. First, PTX alone has been shown to reduce the duration of healing of late soft tissue necrosis in 15 patients [7]. Second, combined PTX–Vit.E treatment has recently been shown to significantly reduce the radiation-induced fibrotic process in a phase II clinical trial of 50 patients with soft tissue fibrosis [8], and results have been confirmed histologically in animal experiments [9]. The reduction of microscopic radiation-induced fibrosis, which is always associated with the necrotic process, may allow tissue restoration. This, in turn, may reverse defective osteoblastic healing. Lastly, clodronate is a well known biphosphonate that inhibits osteoclastic bone destruction [10]. Preliminary results for 12 patients suffering from progressive ORN and treated with combined PTX–Vit.E have been very satisfactory, including 6 cases of complete healing in 3 months out of 7 patients with exteriorized ORN of the mandible and 5 cases of a 50% objective response after 6 months of treatment in 5 patients with chronic aseptic ORN [11].
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Conclusion
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Continuous treatment with combined PTX–Vit.E and clodronate proved able to completely reverse the progressive septic ORN characterized by defective healing combined with severe radiation-induced fibrosis associated with excessive healing, until tissue condition returned to normal.
Received for publication November 2, 2001.
Revision received February 1, 2002.
Accepted for publication February 6, 2002.
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References
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Abstract
Introduction
