Conservative management of advanced mandibular osteoradionecrosis with mild clinical presentation after 17 years of oncological treatment: A case report

Osteoradionecrosis (ORN) of the jaws is a late complication of RT in head and neck cancer, with an approximate incidence of 4–7%, which has been described in recent studies [1],[2]. Moreover, there is a higher prevalence of ORN in the mandible, commonly manifested in the first three years after treatment [3],[4]. At clinical assessment, ORN is found to be a painful exposure of necrotic bone in the irradiated region, which does not heal spontaneously within 3–6 months, and may be associated with purulent drainage, orocutaneous fistulae, and pathological fracture [3],[5]. However, there have been reports of advanced cases of the lesion that might clinically exhibit an intact mucosa or mild exposure in association with extensive destruction of the bone cortical, which were detected by imaging analysis of computed tomography (CT) scans [6]. From imaging exams, areas of multilocular bone raaction, mixed osteolytic regions, bone sequestration, and/or pathological fractures could be identified [3].

The physiopathology of ORN is still controversial, and it has been associated mostly with the total dose received during RT (>50 Gy), or tissue volume irradiated and techniques used. In addition, there are external agents, for example, bone trauma resulting from highly invasive surgical procedures such tooth extractions or dental implant placements [1],[2]. Numerous theories have endeavored to explain the physiopathology of ORN; however, two of these have a larger domain in the literature, and these probably guide the current therapy of the condition [3]. Marx et al. (1983) proposed that the development of ORN was associated with cellular and extracellular changes caused by RT such as hypovascularization, hypoxia, and hypocellularity of tissues, which promote cell death, collagen lysis, and of a chronic non-healing wound [5]. Moreover, Delanian and Lefaix (2004) proposed the fibro-atrophy theory, according to which ionizing radiation would be able to promote the dysregulation of fibroblastic activity, damaging vascular endothelial cells, leading to the consequent radiation induced fibrosis (RIF) [7].

Osteoradionecrosis treatments have improved in the last few years, including conservative management based on conventional drug therapy with antibiotics, adequacy of oral hygiene, hyperbaric oxygen therapy (HBOT), photobiomodulation (PBM), antimicrobial photodynamic therapy (aPDT), use of PENTO and pentoxifylline-tocopherol-clodronate (PENTOCLO) drug protocols, and superficial surgical management [3],[8]. Advanced lesions are commonly treated by performing extensive surgical resections, associated with subsequent reconstruction with microvascularized free flaps [6]. It has being reported that isolated therapies are unable to promote total regression of lesions, and require the combination of adjuvant techniques in order to obtain better results [4].

The PENTO protocol, based on the fibro-atrophy theory and characterized as the use of pentoxifylline (PTX) associated with tocopherol (TCF), is being widely used at present. Both drugs have shown effects such as tissue oxygenation, antifibrotic and antioxidant action on irradiated bone, and act synergistically in decreasing RIF. Clodronate, an antiresorptive drug of the bisphosphonate group, when added completes the PENTOCLO triad, with effectiveness in inhibiting osteoclastic bone destruction [9]. In the last five years, the management of ORN with PENTO has shown satisfactory results in stabilizing for both, advanced or ractory cases, probably used more often of its mechanism of postponing or avoiding the need for extensive surgical management [10].

The present case report aims to describe the conservative management of an advanced ORN lesion, with a mild clinical presentation, by using PENTO protocol associated with adjuvant therapies.

A 62-year-old Afro-descendent woman, with a history of cancer treatment 17 years ago due to oral squamous cell carcinoma (OSCC) in the left side of the floor of the mouth, whose clinical and pathological stage was pT1N0M0 that did not involve the bone/periosteum/cortex or medullary portion of mandible. She underwent surgery for tumor resection and locoregional control associated with radiotherapy, by means of the three-dimensional conformal technique with a total dose of 54 Gy was given to the primary lesion and 45 Gy to the homolateral lymphatic neck drainage plus concomitant chemotherapy. Her complaints started in January 2020, with toothache in tooth 47 and possibility of having prosthetic rehabilitation performed with dental implants in the left edentulous region of the residual alveolar bone, which had previously been irradiated. At extraoral clinical examination, slight facial edema was observed on the left side (Figure 1A), and at intraoral evaluation, the buccal mucosa of the residual alveolar ridge with an aspect of integrity was visualized; however, on palpation, there was a slight purulent drainage associated with tooth 33, without previous symptoms (Figure 1B). On imaging studies, orthopantomography (OP) an extensive destruction of the cortical bone in the left mandible was observed, with mixed areas compatible with bone sequestration (Figure 1C) and CT identified a pathological fracture of mandibular baseline (Figure 1D).

Based on the clinical, imaging data and the patient's oncological record, the diagnosis of an advanced stage of ORN was established, without a proven biopsy. Osteoradionecrosis lesion stage for this case was III (advanced) according to the classification proposed by He et al. (2015) [6]. A conservative approach was initiated with conventional drug therapy, including antibiotic therapy with Amoxicillin + Clavulanic acid 500 mg every 8 hours for 15 days, 100 mg Nimesulide every 12 hours for 4 days, and antifibrotic therapy based on the PENTO protocol. Treatment with PENTO initially consisted of 400 mg of pentoxifylline twice daily plus 500 IU tocopherol administered twice daily initially for 4 months. After 3 months of using therapy with PENTO, a new evaluation by OP examination was performed, in which an area of greater radiopacity was observed, when compared with the initial OP (Figure 2); this would mean stabilization of the advanced ORN condition. In addition, the extraction of tooth 33 and superficial sequestrectomy were performed, associated with antimicrobial photodynamic therapy (aPDT) during the perioperative phase (Figure 3A), and primary wound closure was performed (Figure 3B).

The aPDT was performed in order to decrease the local bacterial load related to purulent drainage that still remained in the region. Initially, the area was washed with abundant saline solution, followed by surgical removal of necrotic bone, and subsequent application of Methylene Blue dye (Chimiolux, DMC, Sao Carlos, Sao Paulo, Brazil) at a concentration of 0.02% for 5 minutes. Then, low-level laser therapy (LLLT) (Therapy EC, DMC, São Carlos, São Paulo, Brazil) was applied with a beam output power of 100 mW, a wavelength of 660 nm and the energy per point of 6 Joules (J). The application points were distributed around the entire oral cavity, which resulted in a total of 6 points. Then, the remaining dye was removed by washing with abundant serum, in order to be able to proceed to the primary wound closure with Nylon 4/0 suture. Postoperative controls were performed for 7 days and 15 days after surgical treatment, accompanied by photobiomodulation sessions (PBM) (Therapy EC, DMC, São Carlos, São Paulo, Brazil) with application of 3 J per point (6 points in total in the bed of the operating wound area), with a wavelength of 660 nm and beam output power of 100 mW. The patient kept PENTO drug intake during 11 months and a half (also December 2020). Finally, after 12 months of follow-up, on clinical and imaging exams, showed an improvement in the healing process (Figure 4A) and continuous bone regeneration in the region initially compromised by ORN (Figure 4B). At present, the patient uses a removable partial denture (PPR) (Figure 5A) primarily in order to improve the esthetic and function (Figure 5B) and after 12 months of follow-up it was obtained a complete response observed through imaging analysis (OP) (Figure 5C).

Various therapy combinations have been used in the treatment of ORN [3]. The emergence of this complication has been reported in the literature ranging from 6 months to 5 years after cancer treatment, with rare occasions of subsequence development [1],[6]. In this case, however, an atypical presentation was described: the developmental of ORN after 17 years of cancer treatment with adjuvant RT, and specifically without bone exposure and orocutaneous fistula that are the main clinical signs that corresponded to an advanced stage of the disease. Currently, there is a classification based on imaging findings of ORN lesions, which covers cases in which the mucosa could be found intact during the intraoral clinical examination, but there was presence of an advanced stage of ORN observed at CT or other imaging exams [6].

Advanced or ractory cases of ORN are treated radically, with extensive surgical resections followed by reconstructions with different microvascularized free flaps such as the osteomyocutaneous or musculocutaneous grafts, which have become the most effective alternatives for stabilizing and decreasing progression of the condition [6]. Whereas the PENTO protocol, based on its antifibrotic, angiogenic, and potent antioxidant properties, has shown satisfactory clinical results and when used in conjunction with other adjuvant techniques, favoring the healing process with stabilization of and improvement in the initial clinical condition [4].

PENTO protocol is well tolerated by the majority of patients, although in some cases treatment must be adequate due to its acute toxicity. The dosage of the PENTO protocol recommended is based on 400 mg of pentoxifylline twice per day and 1000,000 IU of tocopherol whose undesirable secondary effects related were nausea or vomiting [4],[9].

Recent studies have demonstrated the ability of PENTO, either associated with clodronate (PENTOCLO), or not, for obtaining complete resolution of cases in early to advanced stages of ORN. Kolokythas et al. (2019) [10], in a recent systematic review and meta-analysis, demonstrated that in the treatment of ractory, moderate, and advanced ORN lesions, the PENTO therapy has a success rate of 62.7% (SD 3.4%, 95% CI, 55, 8–69.1%), avoiding the need for further surgical or medication approaches. However, the role of PENTO used alone continues to be controversial with respect to complete resolution of the disease itself, since some studies have shown associations of this therapy with other drugs, surgical techniques, and adjuvant therapies and these have produced different results [4]. In this case, there was a significant improvement in the advanced ORN lesion with the use of PENTO, with an initial dosage for three months after diagnosis was established, based on the clinical and imaging assessment. The interval between diagnosis and initial dosage was three months. Conservative management was performed with local control of infection and a superficial surgical removal of the necrotic bone and the application of aPDT and PBM as adjuvant therapies to improve local conditions, such as tissue repair, healing process, and maintenance or regression of the established advanced lesion, with favorable bone repair.

Therapy with the PENTO protocol proved to be effective in stabilizing the lesion in an advanced stage of ORN with onset after 17 years of oncological treatment of a primary tumor in the head and neck region. Adjuvant therapies for conventional management with surgical removal of the affected bone can be associated with improvements of local condition, stimulating tissue repair with consequent optimization of the healing process. However, longitudinal cohort studies with PENTO and these therapies must be conducted in order to clarify the role of each protocol in the control of the disease.