Is Radiation the Only Culprit? Understanding Osteoradionecrosis in Current Era and the Implications of Free Flap

Introduction

Osteoradionecrosis (ORN) is a late complication of head and neck radiation therapy characterized by non-healing exposed bone causing significant discomfort, pain and an overall poor quality of life. Radiotherapy (RT) for head and neck carcinoma has evolved from two dimensional (2D RT) to three dimensional conformal RT (3DCRT) to Intensity modulated radiotherapy (IMRT) and image-guided radiation therapy (IGRT) that may reduce the incidence of ORN by increasing treatment accuracy1. Surgery is the initial treatment of choice for operable oral squamous cell carcinoma (OSCC). Adjuvant radiation or chemoradiation are indicated as per presence of adverse risk factors. Flap reconstruction is one of the major treatment components for locally invasive oral cancers involving the mandible to maintain functional and cosmetic integrity. The gold standard for mandibular reconstruction is free fibular ossteocutaneous flap with titanium plate fixation. Despite extensive flap reconstruction, development of flap necrosis as a later side effect can significantly impair the functional outcomes. However, there is a dearth of literature to suggest whether reconstructed mandible carries an increased risk of subsequent necrosis.

Inspite of recent advances in treatment, ORN occurs in 5-35% of head and neck cancers treated with IMRT.

What is ORN?

Osteoradionecrosis (ORN) is a late complication of head and neck radiation therapy characterized by non-healing exposed bone causing significant discomfort, pain and an overall poor quality of life.

Factors leading to ORN

Other than surgery itself, factors leading to development of ORN can include but are not limited to high radiation dose (>60 Gray [Gy]), fractionation scheme, type of radiation and its energy, radiation field size, older age, addiction history, poor oral and dental hygiene, performance status, compromised blood flow in the pedicle, oral cavity tumour site, mandibular surgery etc.

Clinical symptoms and treatment interventions

Patients can present with severe pain, trismus, dysphagia, or the formation of oro-cutaneous fistula. Various treatment modalities include pain killers, antibiotics, hyperbaric oxygen therapy, segmental resection of the mandible/maxilla and flap reconstruction

Stages of ORN

The Schwartz and Kagan classification system is used to grade ORN as follow:

Stage 1: Superficial involvement of mandible with only soft tissue ulceration and exposed cortical bone

Stage 2: Exposed cortical bone and underlying medullary bone necrotic

Stage 3: Full diffuse involvement.

Literature review

PORT leads to a decrease in the autologous flap vascularity, tissue hypoxia, delayed bone healing and tissue atrophy causing breakdown of tissue and thereby non healing wound and ORN2. In a study conducted by Wang et al. a 47% incidence of ORN was reported in 15 patients treated with osteocutaneous fibula flap following PORT3. The limitation of this study was that it did not take into account the radiation dose or type of carcinoma. A retrospective study conducted by Wu et al. between January 2000 and December 2019 evaluated ORN in reconstructed mandible and native mandible (defined by those who had any non-osseous free tissue transfer)4. RN as follow:

38 out of 155 oral cavity SCC patients undergoing free flap surgery and PORT had a fibular free flap for mandibular reconstruction, whereas 117 (75%) patients did not have mandibular reconstruction. Of the 117 patients without mandibular reconstruction, 63 (41%) received radial forearm free flap, 43 (28%) had anterolateral thigh, and 10 had latissimus dorsi free flap surgery at tumour resection followed by postoperative IMRT to a dose of 60 Gy in 30 fractions. 3 (7.9%) of 38 patients with mandibular reconstruction developed ≥ Grade 2 ORN, as compared to 11 (9.4%) of 117 patients with no mandibular reconstruction, which was not significantly different (p = 0.813). This study concluded that mandibular reconstruction does not escalate the risk of developing ORN.

Dosimetric parameters to the native mandible and oral cavity were not different between patients with and without mandibular reconstruction, with the exception of mandibular V60 (volume of mandible receiving 60Gy or higher dose), which was higher in patients with reconstructed mandibles (44.9% vs. 19.2%, p = 0.002)

Another study by Tsai et al. aimed to establish an association between radiation doses to the mandible and ORN in patients treated with 3-dimensional (3D) conformal radiation therapy or IMRT5. A total of 402 patients of oropharyngeal carcinoma treated between 2000 and 2008 were included in the study out of which 30 patients (7.5%) developed ORN during a median follow-up time of 31 months. The median time to develop ORN was 8 months. Dose volumes were noted for ORN patients and ORN free patients and a statistically significant difference was observed in the volumes of mandible in the 2 groups receiving doses between 50 Gy (V50) and 60 Gy (V60) with V50 having a P value of 0.02 after adjustment for the matching variables and dental status, thereby suggesting that minimizing the percent mandibular volume exposed to 50 Gy may reduce the risk of ORN. Apart from this, it was observed that dental extraction before radiation treatment was associated with increased risk for ORN. A large number of ORN patients were edentulous from baseline as compared to ORN free control, this could be explained by the fact that edentulous patients may have poor dental hygiene, poor blood supply leading to inadequate healing post procedure

The type of flap used for mandibular reconstruction can also influence the development of ORN. A retrospective study by Gazyakan et al. studied the incidence of ORN in patients with osteocutaneous fibular flap (OSC) and osteomyocutaneous peroneal artery-based combined (OPAC) fibula flap used for mandibular reconstruction6. It consists of a fibula bone segment, a single or two independent skin paddles, and a soleus muscle component. It offers more soft tissue replacement components as compared to the traditional fibula OSC flap. The extra soft tissue volume can be used to obliterate large dead spaces and provide additional soft tissue support, which can aid in preventing soft tissue contractions. PORT can cause wound contracture and may result in plate exposure in later stages. The study demonstrated a significant lower incidence of ORN and plate exposure rates in patients treated with the OPAC flap than the fibula OSC flap which could be due to the additional soft tissue bulk due to soleus muscle component and the fasciocutaneous skin paddle elements. This provides an additional support for the reconstruction plate and reconstructed fibula making the reconstructed mandible more resistant towards tissue breakdown post radiotherapy by maintaining vascularity thereby concluding that the OPAC flap may be a reliable alternative in the reconstruction of mandibular defects.

If dental extraction is needed, it should be completed at least 2 weeks prior to the start of RT.