Laryngeal chondroradionecrosis following radiotherapy

Objective: to study larynx chondroradionecrosis related to radiotherapy and chemotherapy treatment and provide a treatment flowchart. Methods: retrospective study with clinical data analysis of all larynx cancer patients admitted in a two tertiary hospital in a five years period. Results: from 131 patients treated for larynx cancer, 28 underwent chemoradiotherapy with curative intent and three of them presented chondroradionecrosis. They were treated with hiperbaric oxigen therapy and surgical debridment following our flowchart, preserving the larynx in all. Conclusions: the incidence of chondroradionecrosis as a complication of chemoradiotherapy in our series was 10,7% and the treatment with hiperbaric oxigen therapy, based in our flowchart, was effective to control this complication.

Current forms of treatment for the patient with laryngeal carcinoma include surgery, radiotherapy and chemotherapy, associated or not.Radiotherapy is a treatment modality for several neoplasms, and can be indicated for three purposes: curative, palliative and symptomatic, the latter being less indicated.Compared with surgery, radiotherapy alone or in combination with chemotherapy was effective for the treatment of laryngeal cancer in its early stages, with similar diseasefree survival, which in the 1990s gave rise to the organ-preservation protocol that was widely used, including for advanced stages (III and IV) of the tumor.However, new evidence in the literature has shown that there is no benefit of radiotherapy at these advanced stages, both in overall survival and local control.On the contrary, there was an increase in treatment complications of a dysfunctionalized organ 11,12 .
In particular for laryngeal cancer, radiotherapy causes damage and complications in almost 100% of irradiated patients, which are major or minor, transient or permanent, and may occur during the application or even months or years after the end of treatment [13][14][15] .Isolated or associated radiotherapy inflicts alterations on the perilaryngeal and laryngeal tissues that cause local hypoxia, decrease the vascularization and the cellular population, with consequent decrease in the production of collagen and fibrin, favoring the appearance of fissures, fistulas and chronic wounds that do not heal.These changes, if left untreated and resolved, lead to the loss of the organ, with continuous broncho-aspiration, requiring rescue surgery, even in the absence of neoplasia 12,13,16 .Thus, with the increase in the indication of radiotherapy, there was also an increase in the rate of its complications, including laryngeal edema with hoarseness, dyspnea and bronchoaspiration, radiodermatitis (grades I and II), skin necrosis (grade III), simple chondritis, chondritis with necrosis (chondroradionecrosis) and cartilage exposure to the airway.
Chondroradionecrosis as a complication has a variable incidence, ranging from 1% to 5.3%, resulting in rescue laryngectomies in up to 25% of cases [17][18][19] .It clinically progresses to dysphagia, odynophagia, fistula formation, hoarseness, partial or total dysfunction of the larynx, loss of airway protection with airway obstruction and bronchospasm.Deemed a severe complication, it can lead to death if untreated, a complete recovery being rare 19,20 .The main risk factors for onset of chondroradionecrosis are persistence of smoking, postoperative infection, atherosclerosis, laryngopharyngeal reflux, diabetes and local trauma 15,21,22 .
To guide treatment, some authors proposed a classification of the laryngeal radionecroses based on symptoms, showing a direct relation between the amount of radiation and the severity of tissue reaction 23,24 .They noted that for grades I and II the treatment was eminently clinical and that for grades III and IV, where chondritis was severe or chondroradionecrosis had already ensued, treatment was usually surgical (Tables 1 and 2).Some older articles postulate that once chondroradionecrosis occurs, treatment will always be surgical, through total laryngectomy, since there is no way to partially preserve the larynx 20,22 .However, recently other authors have described conservative management of chondroradionecrosis with hyperbaric chamber (or oxygen therapy) air humidifiers, systemic antibiotics and corticosteroids 21,[24][25][26] .According to Abe et al. 27 , the use of the hyperbaric chamber was effective to maintain larynx function, being an option for the treatment of chondroradionecrosis. Dequanter et al. 28 demonstrated that of 16 patients who underwent rescue surgery and who used oxygen therapy, 14 displayed success and considered hyperbaric oxygen therapy as a powerful and effective ally for the treatment of postoperative fistulas.Allen et al. 29 , in their review of patients with laryngeal cancer treated with radiotherapy, propose a follow-up with positron emission tomography (PET-CT) to avoid local trauma and include oxygen therapy as a non-surgical alternative to larynx preservation.This article aims to study laryngeal condroradionecrosis as a complication of radiotherapy for the treatment of laryngeal cancer and to propose a treatment flow chart with the use of hyperbaric chamber.

METHODS
We reviewed the clinical data of all patients with laryngeal and hypopharyngeal carcinomas consecutively admitted to the Head and Neck Surgery services of two tertiary hospitals, with histological confirmation, in the five-year period from January 2009 to January 2014.There was authorization from the Hospital Ethics in Research Committee to carry out this work, registered at Plataforma Brasil under number 37230414.4.0000.5483.
We gathered data on epidemiology, stage of the neoplasia, date of initial and rescue surgeries, initial treatment proposed and treatment for recurrence when applicable, treatment complications, data regarding treatment of complications and the date of the last visit.Inclusion criteria were patients with laryngeal or hypopharyngeal SCC.Exclusion criteria were patients already suffering from larynx or hypopharynx local recurrence with biopsy confirmation and patients referred for palliative care.

RESULTS
In the analyzed period, 131 patients with larynx or hypopharynx SCC were treated in both institutions.Of these, 28 (21.4%) were referred for radiotherapy associated or not with chemotherapy as the first treatment, due to refusal of surgery, clinical comorbidities or high surgical risk.Of the 28 patients, three (10.7%)developed laryngeal chondroradionecrosis, clinically proven and with biopsy, none of them with tumor recurrence.Table 3 shows these three patients' clinical data.All were submitted to neck computed tomography (NCT) to rule out local recurrences.NCT also revealed alterations in all patients, such as persistent edema of the laryngeal mucosa after the end of treatment and cartilage changes such as displacement, collapse or resorption of one or more of them (Figure 1).Computed tomography of the thorax showed no metastases in any patient.
Videolaryngoscopy demonstrated intense edema of the laryngeal scaffold, with purulent exudate and fibrin, areas of necrosis to a greater or less degree, with cartilage exposure, and glottis lumen decrease of more than 70%, which determined the indication of tracheostomy in one patient (Figure 2).In all three patients, we performed suspension laryngoscopy in the operating room, with biopsies of the affected site, which were negative for neoplasia recurrence, both in the frozen section and in the final anatomopathological examination.PET-CT was performed in all three patients and showed local edema with laryngeal cartilage alteration and a maximum Standardized Uptake Value (SUV) of less than 3.5, rendering a negative or unlikely recurrence result, and suggestive of inflammatory process, which was confirmed by the negative guided biopsies (Figure 3).
The treatment consisted of antibiotic therapy with Gram positive, Gram negative and anaerobic coverage with a third generation cephalosporin and clindamycin, corticosteroids, analgesics, proton pump inhibitors, air humidification and local care with adequate oxygen supply.We also performed suspension laryngoscopies to remove endolaryngeal exposed cartilage in patient 1 and an external surgical approach for removal of exposed cartilage and skin necrosis with pectoral flap rotation for coverage in patient 2 (Figure 4).All underwent hyperbaric chamber oxygen therapy with 100% O 2 at 2 ATM pressure, one hour per session, in 20 to 40 sessions, depending on the case and after re-evaluation in the postoperative period.
There were no deaths in the postoperative period or related to the clinical treatment and we performed a weekly follow-up with videolaryngoscopy.We observed healing with complete epithelization of the necrotic area and remission of edema in all patients, within two months.We found no evidence of local recurrence.The larynx was preserved in all patients and only one patient had the tracheostomy maintained.We performed no total laryngectomy due to complications or aspiration.by radiotherapy in combination with chemotherapy, with similar results in local control and survival.Recent studies demonstrate local control with radiotherapy for T1 glottis neoplasias ranging from 82% to 93%, preserving the larynx in 89% to 96% of cases, and for T2 tumors, 57% to 82% for local control, and preservation of the larynx in 73% to 82% 30 .The rate of relapse with surgical treatment is small and depends on factors such as: involvement of the anterior commissure due to its difficult access site for adequate resection; the ideal laryngeal exposure during the surgical procedure for the various open laryngectomy techniques and for endolaryngeal or trans-oral laser resections; and conditions inherent to the patient 31 .From 1998 on, there was a change in the treatment of laryngeal cancer, with the institution of radiotherapy associated or not with chemotherapy, with the intention of preserving organs, indicated mainly for stages III (T3) 11,32 .However, the extension of the indication to the other stages increased the radiotherapy complication rates 33,34 .Despite the current guidelines, there is still no consensus on the best treatment strategy 12,35 .Radiation as a therapy induces an environment with local hypoxic alterations, stimulating the formation of tissue fibrosis, endarteritis with blood vessel obliteration, local lymphatic vessels obstruction and tissue and neoplastic necrosis 36 .Edema then develops by lymphatic obstruction and increased reactive lymphovascular permeability, promoting an increase in local tissue pressure and decreasing blood flow.Microfissures of the perichondrium (both internal and external) appear, exposing the cartilage in its deep face to the bacteria of the aero-digestive tract.Infection sets in, leading to chondroradionecrosis, which is then considered a late complication 18,25,37 .

Initial carcinomas of the larynx and hypopharynx can be treated equally by surgery or
The first report of larynx chondronecrosis due to radiotherapy was by Goodrich and Lenz, in 1948 38 , and since then not many cases have been reported, up to the present time a total of seventyseven patients, without including those of the present study.There was also no consensus for the creation of a prospective study involving the treatment of chondroradionecrosis.The incidence of 10.7% of chondroradionecrosis in our cases is somewhat elevated when compared with the literature data, but can be explained by differences in the radiotherapy techniques of the different services [17][18][19] .
Since the clinical signs and symptoms of chondroradionecrosis can be many, it was necessary to create severity ratings to guide treatment 23,24 .However, these classifications failed because they did not distinguish chondroradionecrosis from local recurrence with greater clarity.Symptoms of chondroradionecrosis are most often indistinguishable from the symptoms of local relapses (or persistence), and control should be done periodically through videolaryngoscopy, biopsies and imaging tests, such as NCT, magnetic resonance imaging, and more recently PET-CT 21,25 .
The tomographic findings of laryngeal changes during or shortly after radiotherapy are not able to rule out local recurrence.The findings are often nonspecific and the data in the literature are confusing, except for citing that the likelihood of relapse is greater within one year and that after this period the chance of chondroradionecrosis is higher 37,[39][40][41] .According to Hermans et al. 40 , the local recurrence rate after radiotherapy is about 10% to 20% for T1 / T2 lesions and 40% to 50% for T3 / T4 lesions.Since recurrences are much more frequent than chondroradionecrosis, deep biopsies should be performed for restaging, although they may worsen the infection and local necrosis (14, 37).Currently, this diagnostic dilemma can be resolved through PET-CT, in which tumor activity is evident in the larynx if relapse occurs, but examination should be done only three months after the end of radiotherapy to eliminate the interference of actinic inflammation [42][43][44] .All our three chondroradionecrosis patients underwent PET-CT, with a negative result for tumor recurrence, a fact evidenced by the performed biopsies.
Although this is a small sample, given the rarity of chondroradionecrosis, we can verify that PET-CT has been highly accurate, in accordance with findings of a recent systematic review of 1,476 articles on imaging exams, of which eight focused on PET-CT.The authors demonstrated a sensitivity of 89% and specificity of 74% of the PET-CT to differentiate between tumor recurrence and local actinic late alterations.It should therefore be the exam of choice to avoid unnecessary CT scans and laryngoscopies with biopsies 42,43,45 .
The various treatments proposed for chondroradionecrosis included the use of antibiotic therapy, air humidifiers, corticosteroids, antireflux drugs (proton pump blockers, prokinetics) and hyperbaric chamber (HBC), the latter being in varied regimens.The use of HBC is approved for the treatment of complications of radiotherapy by the American Society of Diving and Hyperbaric Medicine and by the Brazilian Society of Hyperbaric Medicine.The first report of its use for the treatment of necrosis by radiotherapy was in 1976 and, in 1987, its use was first described for laryngeal necrosis [46][47][48] .The principle of HBC is to increase the partial pressure of O 2 from 21% present in ambient air to 100% in a pressurized chamber, transferring this oxygenation to the tissues and promoting healing 49 .A common fear concerning the use of HBC refers to the possibility of tumor growth during treatment, which is why we have to rule out disease relapse, although some studies fail to demonstrate this characteristic 50,51 .The review of the literature demonstrates the effectiveness of the treatment of laryngeal chondroradionecrosis with HBC, with fistula closure, high index of laryngeal preservation (without laryngectomies) and eventually decannulation of patients, despite reports of HBC failure in up to 22% of cases classified as Chandler IV 24,25,41,46 .In our patients, there was no HBC failure, achieving 100% success for clinical treatment, with epithelization of the cartilage necrotic or exposed area and avoiding rescue laryngectomy.The HBC regimen applied 100% O 2 , at a 2-ATM pressure, of one hour per session, in 20 to 40 sessions, with results comparable to those of other authors 19,24,52 .
To date, there is no randomized trial comparing the treatment of laryngeal chondroradionecrosis by HBC with other clinical forms of treatment, unlike what exists for mandible bone necrosis 53 .We did not find any randomized study with the key words "larynx chondronecrosis", "laryngeal chondroradionecrosis", "laryngeal necrosis", "laryngeal radionecrosis".Most of the current literature is composed of case reports or series of cases, describing, to date, only 77 patients.
With this small series of three cases, we attempt to contribute with the scarce literature to understand this disease, which seems to be more common than we imagine.We propose an algorithm (Figure 5) to guide the treatment of laryngeal chondroradionecrosis with the use of the hyperbaric chamber, based on the data of the current literature.We emphasize, however, that one should apply it with caution, evaluating the different clinical characteristics of each case.

Table 3 .
Clinical data of the study patients with laryngeal chondronecrosis post radio and chemotherapy.