Incidence and Factors Associated with the Development of Calvarial Osteoradionecrosis in Patients Treated for Cutaneous Malignancies

Abstract

Study Design: Retrospective cohort study. Objective: Calvarial osteoradionecrosis (ORN) is a rare but devastating complication of radiotherapy. The aim of this study was to describe the cumulative incidence of Calvarial ORN in patients in patients treated for cutaneous malignancy of the scalp. Methods: Data was compiled from patient records of a large tertiary hospital Plastic Surgery department and radiotherapy records of an affiliated cancer Center. We included all patients that were treated for cutaneous malignancies of the scalp that received radiotherapy. Patient demographics, cancer stage, treatment modalities, intraoperative details, and patient outcome data were recorded. Patients with incomplete radiotherapy data were excluded. Results: We analyzed 105 radiotherapy treatments to the scalp administered to 84 patients and recorded 7 cases of calvarial ORN resulting in a gross incidence of 6.67% per radiotherapy treatment. The parietal bone was the most frequently targeted site of radiotherapy and accordingly the most common site of ORN (85.7%). Median time from radiotherapy dose to the development of ORN was 846 days. Higher number of radiotherapy fractionation (p = 0.038), cumulative radiotherapy dose (p = 0.035), prolonged radiotherapy duration (p = 0.022) and skin grafting (p = 0.003) were associated with the development of ORN. Conclusions: Our findings suggest radiotherapy variables, such as prolonged radiotherapy duration, increased cumulative dose and higher radiotherapy fractions were strongly associated with the development of ORN. In addition, skin grafting following surgical resection was associated with the development of ORN. Further studies with larger sample sizes are required to further explore this relationship.

Introduction

Osteoradionecrosis (ORN) is a rare but serious complication of radiotherapy characterized by ischemic necrosis of bone in the absence of tumor recurrence [1]. Previously irradiated bone is devitalized and exposed through the underlying skin and mucosa [2]. ORN is defined by exposed bone for at least 2 months without the recurrence of local neoplastic tissue [1].

ORN is most commonly observed in bones with a low intrinsic blood supply, most notably the mandible. Although much rarer, ORN can also affect the calvarium which may present clinically with recurrent severe headaches, pain, and discharges from the wound site [3]. Given the advanced age and high burden of comorbidity of patient’s presenting with calvarial ORN, management is particularly challenging due to increased perioperative risk.

Risk factors for the development of ORN include the total dose of radiation [3,4], location and radiation modality, and tumor invasion [5]. Additionally, patient factors such as alcohol consumption and smoking [6] were also associated with the development of ORN.

Marx proposed the renowned “3H” model of ORN, in which hypoxia, hypocellularity, and hypovascularity, secondary to radiation, lead to the breakdown of skin and connective tissues [7]. Firstly, high dose ionizing radiation results in chromosomal breakage and disintegration leading to either DNA repair or cell death. On a tissue level, hypovascularity results from vessel thrombosis, hyalinization, and endothelial death. Periosteum, skin, and mucosa become fibrotic with diminished cellularity. Osteoblasts and osteocytes undergo necrosis and there is fibrosis of the bone marrow. Thus, the mainstay of ORN is poor wound healing, in that radiation results in a degree of cell damage that is beyond the ability of the underlying tissue to repair and support.

This model was later expanded by Delanian and Lefaix [8], who elaborated on the role of radiation-induced fibroatrophy (RIF) in the pathophysiology of ORN. Following radiotherapy, myofibroblasts are persistently activated resulting in the secretion of inflammatory cytokines and growth factors such as TGF-β1. Additionally, exposure to ionizing radiation generates reactive oxidative species (ROS) from the initial inflammatory response. The resulting oxidative stress overwhelms the tissues mechanisms for cellular repair and the exacerbates the fibrogenic response.

The clinical presentation of ORN affecting the calvaria is scant in the literature. One case study by Nguyen et al. noted that the patient presented with recurrent severe headaches, pain, pus, and accompanying foul odor from the wound site [3]. Additionally, untreated, and aggressive ORN of the calvarium may raise a nidus for intracranial infection such as cerebritis and meningitis.

The aim of this study was to describe the incidence of ORN of the calvarium in patients who underwent radiotherapy for cutaneous malignancies of the scalp. This is followed by a review of the management principles for ORN in these patients.

Methods

Study Design

This retrospective study utilized data collected from patient records at a tertiary hospital in Melbourne, Australia.

Patients who underwent radiotherapy treatment between 1st June 2013 and 30th September 2019, either as a primary treatment or adjuvant treatment post-surgery, were included in the study. We allowed for a minimum follow-up of 3 years as ORN may not developed in the early post treatment period. Patient demographics, including age, gender, and comorbidities, were recorded. Cancer stage, treatment modalities, intraoperative details, and patient outcome data were also collected. Patients with incomplete cancer, surgery, and/or radiotherapy data were excluded. The primary outcome of interest was the incidence and risk factors associated with calvarial ORN. Cases of ORN were identified through a comprehensive review of patient records, including clinical notes, imaging reports, and surgical records.

Radiotherapy Treatment

Patients who had primary radiotherapy and adjuvant radiotherapy were included in the analysis. In general, radiotherapy followed national radiotherapy guidelines for the management of cutaneous malignancy (eviQ.org.au/radiation-oncology/skin) in terms of prescribed dose and prescription point, tumor delineation, and elective nodal coverage. Orthovoltage radiotherapy and simple electron techniques utilized clinical mark up with manual dose calculation. The principle of radiotherapy field specification in these cases was to include the gross tumor plus a margin for sub-clinical extension including risk of peri-neural spread, setup uncertainty, and beam penumbra considerations. This allowed for standard risk-adapted margins utilizing eviQ guidelines [9]. For patients referred for postoperative cases, the treatment field consisted of the base of the operative bed and at least a 1 cm margin on the scar (modified for peri-neural or in-transit disease), and then a margin for setup uncertainty and beam penumbra. All electron and megavoltage photon cases were treated with overlying tissue equivalent bolus to ensure adequate skin dose. A thermoplastic mask was used for patient immobilization for cases with megavoltage photon or electron treatments. For cases with complex anatomy (e.g., overlying air-filled sinuses and high patient curvature), CT-based planning was used to plan either electron beam or inverse-planned intensity modulated radiotherapy (IMRT) with dynamic sliding window or volumetric arc therapy where appropriate, delivered via linear accelerator (Elekta Agility or Versa HD, Elekta Inc, Stockholm), with either 2D kilovoltage or cone-beam CT treatment verification images taken daily prior to treatment and a zero-tolerance iso-move policy. In all cases, Monte Carlo dose calculation was used (Monaco™ treatment planning system, Elekta Inc, Stockholm) and was also available for electrons available in the latter part of the study period. All orthovoltage treatments were delivered on Pantak Therapax 225 SXRT machine (Pantak, Inc, USA).

Surgical Treatment for ORN

When patients present with suspected ORN, the first priority is to exclude tumor recurrence and identify if there is superimposed soft tissue infection and/or osteomyelitis. The ulcerated area was biopsied and swabbed for microscopy and culture to rule out cancer recurrence and concurrent infection, respectively. If microscopy and culture identify a specific pathogen, sensitivities would be obtained, and the patient would be commenced on appropriate antibiotic therapy with consultation with the infection disease unit. If there is any evidence of tumor recurrence, this will be managed with approximate surgical resection margins and reconstruction. Imaging such as CT and MRI scan will also help to delineate the extent of soft tissue and bone involvement. Once the diagnosis of ORN is established, the patient will either be managed conservatively or offered potential surgical management based on their clinical symptoms, extent of soft tissue and bone necrosis. This will be discussed in a multidisciplinary setting with the neurosurgical service. If there is minimal bone necrosis, patient may be offered serial debridement and soft tissue reconstruction. If there is significant bone necrosis, patient will be offered a craniectomy, followed by bone and soft tissue reconstruction. Soft tissue reconstruction may involve the use of local flap or free tissue transfer depending on the donor site availability. In the setting of free tissue transfer, further imaging may be required to identify suitable recipient in the temporal and neck region to aid for surgical planning.

Follow-Up Procedures after Initial Treatment

Clinical follow-up varied based on treatment and was independently conducted by the Plastic Surgery and Radiation Oncology departments. Patients that received surgical treatment were typically followed up frequently postoperatively for a wound review on a weekly basis. Radiotherapy follow-up consisted of 2–4-week clinic appointments following the completion of treatment for acute toxicity management (and then subsequent depending on severity of reaction). For both plastic surgery and radiation oncology departments, patients with high-risk SCC (tumor size (>2 cm), depth of invasion (>4 mm), presence of peri-neural invasion, recurrent lesions, and immunosuppression) were followed for 2 years, every 3 months, then 4–6 monthly for up to 5 years. Low-risk SCC and BCC were followed 4– 6 monthly for at least 3 years. Patients that were not followed up or reviewed by clinicians at the treating hospital within a year of commencement of data collection were contacted for a phone review and screened for symptoms of calvarial ORN.

Endpoint Definition

The diagnosis of ORN was made by either a radiation oncologist or a plastic surgeon based on clinical findings and/or radiological diagnosis. Patients with soft tissue ulceration and exposed but intact calvarium were defined as stage I. Patients with radiological evidence of calvarial destruction were defined as stage II. Patients with full thickness osseous destruction and signs of intracranial infection (ie, meningitis and cerebritis) were defined as stage III.

The location of ORN within the calvarium was recorded to assess the distribution of affected sites. Clinical and technical data were used to correlate ORN with radiation fields, where multiple lesions were treated on the scalp. This data was used to calculate the cumulative and gross incidence of calvarial ORN. The secondary outcome was to identify risk factors for the development of calvarial ORN.

Statistical Methods

Statistical analysis was performed in IBM SPSS V28 (Armonk, NY: IBM Corp). To assess the association between potential risk factors and the development of ORN, appropriate statistical tests were employed. Fisher’s exact test was used for categorical variables, owing to small sample size. Continuous data was assessed for normality using the Shapiro–Wilk and Kolmogorov–Smirnov tests. Independent samples t test was utilized for normally distributed data whilst the Mann–Whitney U test was used for non-normally distributed data. Due to the small sample size (<10 events), logistic regression and proportional hazards regression model were not used in this study. A p-value of less than 0.05 was considered statistically significant. The Kaplan–Meyer method was utilized to calculate cumulative incidence curves depicted in Figure 1, utilizing the 1-survival function. Ethics approval for this study was obtained from Austin Health HREC (81743). Patient confidentiality and data protection were strictly maintained throughout the study. All data were anonymized and securely stored to ensure participant privacy.

Results

Out study analyzed 84 patients, 71 men and 13 women who received in a total of 105 radiotherapy treatments to the scalp. Twelve patients received multiple courses of radiotherapy; however, this was not significantly associated with the development of ORN (p = 0.259).

The median age of participants during their initial radiotherapy treatment was 79 years. Patient specific factors such as comorbidities, alcohol, tobacco, age, and sex were not associated with the development of ORN. The median time from final radiotherapy treatment to last follow-up or death was 911 days.

Table 1. Patient Characteristics.

Seven cases of calvarial osteoradionecrosis (ORN) were identified, resulting in a gross incidence of 8.33% or 6.67% per radiotherapy treatment. The cumulative incidence of ORN, as depicted in Figure 1, was 0% at 1 year, 1.61% at 2 years, and 6.98% at 3 years accounting for loss to follow-up.

Abbreviations: T2DM: type 2 diabetes mellitus, COPD: chronic obstructive pulmonary disease, PVD: peripheral vascular disease, IHD: ischemic heart disease, CKD: chronic kidney disease, BMI: body mass index, CVD: cardiovascular disease, AF: atrial fibrillation.

Table 2. Tumor Characteristics.

One patient presented with stage I ORN with non-healing ulcerated skin with exposed calvarial bone. Most patients (n = 5) presented as stage II calvarial ORN, with exposed bone and radiological changes of osseus destruction. Of these, one patient presented with intermittent intense headaches. One patient with severe calvarial ORN (stage III) presented with hemiparesis and seizures secondary to meningitis in the context of a chronic defect, which had broken down several years after initial oncological reconstruction.

The parietal bone was the most frequent treatment site accounting for 6 cases of ORN. Several radiotherapy variables were significantly associated with the development of ORN. Specifically, higher number of radiotherapy fractions (p = 0.038) and cumulative radiotherapy dose (p = 0.035) were found to be statistically significant risk factors. The median time from radiotherapy dose to the development of ORN was 846 days, ranging from 353 to 2064 days.

Median tumor size was 20 mm, ranging from 1.2 mm to 75 mm, and majority of cases presented as either T1 or T2, however, neither tumor staging, nor size were associated with the development of ORN. Squamous cell carcinoma (SCC) accounted for the majority of tumors follow by basal cell carcinoma (BCC). Poor differentiation was the most common histological grade of SCC; however, we found an all cases ORN were associated with either well or moderately differentiated SCC. Other tumor specific factors such as malignancy type (ie, SCC and BCC) and depth of invasion were not associated with the development of ORN.

Regarding intraoperative variables, skin grafting following surgical resection was found to be a significant risk factor for ORN (p = 0.003)

Table 3. Treatment Characteristics.

. Of the 47 patients that received skin grafts for the oncological reconstruction following surgical resection, 14.9% (7 patients) developed ORN. Of these patients, 6 patients were treated with a split thickness skin graft (STSG) and 1 patient was treated with a full thickness skin graft (FTSG). There was no association between the type of graft used and the development of ORN. Other treatment variables such as calvarial burring, surgical margins, and locoregional or free flap reconstruction were not associated with the development of ORN.

Regarding the treatment of scalp defects secondary to ORN, as depicted in

Table 4. Management of ORN.

, craniectomy with subsequent cranioplasty using titanium mesh and free tissue transfer was the primary treatment modality. Of these, the latissimus dorsi myocutaneous flap was the most common free flap (n = 3) and one patient was treated with an anterolateral thigh free flap. One patient was managed with a locoregional flap initially. Unfortunately, there was delayed wound healing which require further debridement and reconstruction with dermal matrix. Two of the patients were managed conservatively with local wound care, and one of them received additional hyperbaric oxygen therapy (HBOT).

Discussion

Calvarial osteoradionecrosis (ORN) is a severe and debilitating complication of radiotherapy characterized by a chronic non-healing ulcer with exposed calvarium. It is a rare condition but it has a significant impact on the quality of life of affected individuals and can serve as a nidus for intracranial infection [3]. Most published studies for ORN are based on mandibular ORN with minimal data regarding calvarial ORN. Understanding the incidence and associated risk factors for calvarial ORN may be beneficial for identifying high-risk patients and implementing preventive strategies by modifying initial treatment to prevent the development of ORN in this population.

There are many proposed staging classifications for ORN based on clinical and radiological criteria [10,11,12,13]; however, they are almost exclusively describing the presentation of mandibular ORN. We proposed a staging classification specific to the calvarium, as depicted in

Table 5. Clinical Staging of Calvarial ORN.

, based on patients in our own cohort and case reports in the literature.

We identified a gross incidence of 8.33% of calvarial ORN among patients receiving radiotherapy for cutaneous malignancies of the scalp. There are no other cohort studies which have reported on the incidence of calvarial ORN; however, this figure is comparable to contemporary rates of mandibular ORN which is reported 5%–15% [6]. Despite the highly vascular nature of the scalp and thus its inherent resistance to devascularization, we observed comparable rates with other subsites of ORN. Notwithstanding, this may be due advances in perioperative planning and prophylactic treatment protocols which have dramatically reduced the historical incidence of mandibular ORN [14].

The median time to the development of ORN in our study was 846 days, ranging from 353 to 2064 days. This finding is consistent with the reported latency period of 1 to 2 years for the development of mandibular ORN [6] and case reports of calvarial ORN. The extended period between radiotherapy and ORN onset highlights the importance of long-term follow-up and vigilance in patients who have received radiotherapy to the scalp. Clinicians should remain attentive to potential late complications and provide extended surveillance and supportive care during this critical post-radiotherapy period.

Our results suggest an association between radiotherapy variables and the development of ORN. Specifically, larger cumulative radiotherapy doses were found to be a statistically significant risk factor. These findings are in line with previous studies that have reported a dose-response relationship and an increased risk of ORN with higher radiation doses, albeit using shorter fractionation intervals [4]. Unexpectedly, higher radiation fraction count was associated with the development of ORN despite typically being viewed as protective against late toxic effects of radiation. Clinically, larger skin areas are unlikely to tolerate shorter dose-fractionations due to the increased risk of skin failure. However, tumor size was similar in patients with or without ORN in our cohort.

Skin grafting is a common reconstructive technique after cancer resection in the scalp. Skin grafts can be categorized as full thickness (FTSG), involving the epidermis and full dermis, or split thickness (STSG), involving the epidermis and partial dermis. FTSG are thought to be more prone to necrosis but offer better cosmesis and are typically utilized for the closure of small defects. STSG are utilized to cover larger defects but are more prone to scar contracture [15]. Our findings suggest an association between skin grafting following tumor resection and the development on ORN. Indeed, all cases of ORN were limited to patients treated with a skin graft (STSG or FTSG). Notably, 6 out of 7 instances of ORN received a STSG; however, due to low event numbers, it was not possible to demonstrate whether STSG was associated with a higher rate of ORN compared to FTSG. Given skin graft does not have the same propriety and intact blood supply compared to the scalp tissue, it may have a lower tolerance of ischemic injury associated with radiotherapy [16]. In contrast, direct closure or locoregional flap reconstruction carries a more robust blood supply and is likely to better tolerate the ischemic injury associated with radiotherapy. This is reflected in our study in which none of the patients who had an initial locoregional or free tissue reconstruction for their cancer treatment developed ORN. Whilst the total number does not have sufficient power to confirm an association, if a patient is anticipated to require adjuvant radiotherapy due to the tumor characterizes, it may be important to consider reconstruction using locoregional or free flaps to minimize the risk of developing ORN in the future.

As with other case reports of calvarial ORN [17,18], flap reconstruction was the definitive management for closure of calvarial ORN defects. However, given the advanced age, comorbidities, and patient’s preference for non-surgical management, alternative treatment modalities are required. The PENTCLO (potentiation by clodronate) protocol is a recent development in medical treatment of ORN which addresses the underlying pathophysiology of disease. The first phase of treatment involves a 4-6 week treatment regime of antibiotic, antifungal and anti-inflammatory agents to reduce tissue infiltration. The second phase consists of ongoing treatment with pentoxifylline, tocopherol, clodronate, and prednisolone. The combination of pentoxifylline and tocopherol increase oxygenation of tissues and reduce radiation-induced fibrosis. The addition of clodronate reduces osteoclastic bone destruction [19]. Whilst no patients in our cohort or case reports in the current literature report the treatment of calvarial ORN with the PENTCLO protocol, it remains a promising avenue for adjuvant therapy in combination with surgical treatment or a viable alternative in patients not suitable for surgery. It may be particularly suitable for patients with stage 1 calvarial ORN, and this again highlight the importance of long-term surveillance and early identification.

The limitations of our study include the retrospective study design and low gross event rate which violates assumptions necessary for some statistical tests such as regression analysis. It is also possible that unobserved covariates could have driven the rate of ORN in this retrospective cohort. Furthermore, our study focused on patients treated at a single institution, which may limit the generalizability of the findings to other populations and settings. Multi-center collaborations and larger patient cohorts are necessary to validate our results and ensure the applicability of the findings to a broader patient population. Finally, as ORN typically develops years after initial radiotherapy treatment, future studies should incorporate even longer-term follow-up periods to ensure cumulative incidence remains accurate over extended time periods.

Future prospective studies with larger patient cohorts and comprehensive data collection are needed to confirm our findings and provide more robust evidence regarding the risk factors for calvarial ORN.

Conclusion

In summary, calvarial ORN is a rare but serious complication of radiotherapy, and its incidence and risk factors in patients undergoing radiotherapy for cutaneous malignancies of the scalp have been explored in this study. Our findings suggest that cumulative radiotherapy dose, higher radiotherapy fractions, prolonged radiotherapy duration, and skin grafting may be potential risk factors for the development of ORN. Additionally, most of the episodes of ORN were found in patients with STSG, and notably, no patient treated with primary closure or primary radiotherapy developed ORN in our study. These results highlight the importance of individualized treatment planning, careful monitoring, and the implementation of preventive strategies in high-risk patients. Continued research in this field is necessary to expand our knowledge and improve patient outcomes in the management of calvarial ORN.