**3.2 Prevention**

For NPC and other tumours that are treated mainly by radiation, improved radiotherapy techniques such as intensity modulated RT help to reduce unnecessary radiation exposure to the ear. This may be facilitated by early detection when the tumours are still small and situated away from ear structures.

Accurate delineation of the middle and inner ear is a prerequisite to achieve dose constraint to those structures. The size and proximity of the middle and inner ear to the tumor, renders it susceptible to damage. As deviation during contouring can have a profound impact on post treatment sequelae **(**Wang et al., 2011), Pacholke et al. (2005) established guidelines for contouring the middle ear and the two major components of the inner ear. These guidelines have been of practical help to radiation oncologists.

Ear-Related Issues in Patients with Nasopharyngeal Carcinoma 169

There are specific issues related to cochlear implantation in post-irradiated ears that one

Adhesions in middle ear could complicate surgery, including posing difficulties during identification of the round window niche. Post radiation obliteration of the cochlea lumen is possible, which could compromise smooth insertion of electrode array during implantation

In cochlear implantation of patients who had been irradiated for NPC, two aspects ought to be highlighted. Firstly, these patients not infrequently have perforated eardrums and middle ear infections, with the Eustachian tube openings in the nasopharynx completely obliterated. For these patients, conventional techniques of cochlear implantation do not apply and modified techniques such as subtotal petrosectomy, fat obliteration and blind sac closure become necessary. Secondly, NPC has a racial predilection and is common in the Chinese. Racial differences in mastoid morphology exist and such differences had even been used in race identification during forensic and anthropology investigations. Indeed, a study of Chinese temporal bones had revealed differences in the course of the facial nerve in the mastoid and in the origin of the chorda tympani, as compared to those described in Western textbooks (Low, 1999). Knowledge of such racial anatomical variations may reduce the risk of facial nerve injury during mastoid surgery, especially in irradiated ears where the bone is

A part of the internal component of the cochlear implant is a small magnet, which is required to secure the external component to the skin of the patient. In an NPC patient who had been treated previously, magnetic resonance imaging is sometimes required to exclude the possibility of tumor recurrence. Should magnetic resonance imaging be indicated in a patient who is already a cochlear implant recipient, there may be a need to remove the

In recurrent tumors, further radiotherapy may be indicated. Fortunately, the internal device had been shown to be resistant to damage by radiation (Ralston et al., 1999). However, cumulative radiation doses from further radiotherapy could inflict severe damage to the

Conventional hearing aids may effectively address conductive hearing loss resulting from MEE. However, they may aggravate otorrhea, and ear moulds traumatize osteoradionecrosis ulcers in the ear canal. An alternative for patients is the bone-anchored hearing aids (BAHA). BAHA has been shown to have successful osseointegration in postirradiated NPC patients (Soo et al., 2009). Improved subjective hearing clarity, reduced ear discharge rates, and extended BAHA usage times accounted for high patient satisfaction with the BAHA hearing system. Soo et al (2009) therefore, recommended the BAHA hearing

auditory nerve, which could compromise the post-implant hearing outcome.

should consider: **3.3.1.1 Surgery** 

(Formanek et al., 1998).

usually more friable than normal.

magnet from the internal device before the scan.

**3.3.2 Bone-anchored hearing aids** 

**3.3.1.2 Surveillance imaging** 

**3.3.1.3 Re-irradiation** 

Improving tumor control rate is the aim, but another important goal is to reduce radiationinduced complications and to improve the quality of life of survivors. The application of 3D conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT) signified a major improvement over conventional 2D radiation therapy. A randomized controlled clinical study showed that at 12 months post-radiation therapy, quality of life scores were significantly higher in the IMRT group than the conventional radiation therapy group for patients with NPC (86.5 versus 58.3; P <0.001) (Pow et al., 2006). The incidence of chronic otitis media and abnormal vestibular evoked myogenic potentials in NPC patients treated by IMRT were significantly lower when compared with those treated by 2DRT, demonstrating the superiority of IMRT in decreasing unwanted otologic complications. However, occurrence of MEE, which was related with advanced T stage, cannot be reduced by IMRT (Hsin et al., 2010).

Clinically effective preventive measures can potentially be applied based on the above proposed ROS-linked p-53 dependent apoptotic model of radiation-induced ototoxicity. It also provides a basis for the use of anti-oxidants and anti-apoptotic factors in its prevention. Antioxidants look promising as effective agents to prevent radiation-induced ototoxicity; they target upstream processes leading to different cell death mechanisms that may co-exist in the population of damaged cells (Low et al., 2009). An anti-oxidant, L-N-Acetylcysteine (L-NAC), was demonstrated in the same cell line to have a protective effect (Low et al., 2008). With its track record of safety in humans and efficacy as an anti-oxidant, L-NAC appears promising as an agent to prevent radiation-induced SNHL in the near future. High doses can potentially be delivered trans-tympanically into the middle ear with minimal systematic side effects, and entry to the inner ear is facilitated by its low molecular weight.

#### **3.3 Treatment**

Efforts to regenerate hair cells represent a large and important field of research and appear promising in animal studies. However, integrating transplanted stem cells into damaged epithelium and generating the correct number of cells in the correct parts of the Organ of Corti will be a challenge. Given that much of cochlear function depends on the precise mechanical properties of the Organ of Corti, excess or inappropriately placed cells are likely to cause problems. Moreover, the possible effects of radiation on the supporting and vascular structures of the Organ of Corti, may also complicate regenerative efforts.

For now, the best therapeutic strategy would be effective rehabilitation of SNHL after RT.

#### **3.3.1 Cochlear implantation**

In patients with profound SNHL, cochlear implants may be effective if the retro-cochlear auditory pathways remained intact. To substantiate that the retro-cochlear auditory pathways remained intact after RT (Low et al., 2005), a case-control study of cochlear implant recipients who had prior irradiation for NPC was conducted in our clinic (Low et al 2006b). They received their RT 11-28 years prior to cochlear implantation and the postimplant follow-up period ranged from 9 to 46 months. The implanted ear of each patient had favourable pre-operative promontory stimulation results. Post-implant, all patients were satisfied with their hearing outcomes and the improvement in speech discrimination scores was comparable to the controls.

There are specific issues related to cochlear implantation in post-irradiated ears that one should consider:

#### **3.3.1.1 Surgery**

168 Carcinogenesis, Diagnosis, and Molecular Targeted Treatment for Nasopharyngeal Carcinoma

Improving tumor control rate is the aim, but another important goal is to reduce radiationinduced complications and to improve the quality of life of survivors. The application of 3D conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT) signified a major improvement over conventional 2D radiation therapy. A randomized controlled clinical study showed that at 12 months post-radiation therapy, quality of life scores were significantly higher in the IMRT group than the conventional radiation therapy group for patients with NPC (86.5 versus 58.3; P <0.001) (Pow et al., 2006). The incidence of chronic otitis media and abnormal vestibular evoked myogenic potentials in NPC patients treated by IMRT were significantly lower when compared with those treated by 2DRT, demonstrating the superiority of IMRT in decreasing unwanted otologic complications. However, occurrence of MEE, which was related with advanced T stage, cannot be reduced

Clinically effective preventive measures can potentially be applied based on the above proposed ROS-linked p-53 dependent apoptotic model of radiation-induced ototoxicity. It also provides a basis for the use of anti-oxidants and anti-apoptotic factors in its prevention. Antioxidants look promising as effective agents to prevent radiation-induced ototoxicity; they target upstream processes leading to different cell death mechanisms that may co-exist in the population of damaged cells (Low et al., 2009). An anti-oxidant, L-N-Acetylcysteine (L-NAC), was demonstrated in the same cell line to have a protective effect (Low et al., 2008). With its track record of safety in humans and efficacy as an anti-oxidant, L-NAC appears promising as an agent to prevent radiation-induced SNHL in the near future. High doses can potentially be delivered trans-tympanically into the middle ear with minimal systematic side effects, and entry to the inner ear is facilitated by its low molecular weight.

Efforts to regenerate hair cells represent a large and important field of research and appear promising in animal studies. However, integrating transplanted stem cells into damaged epithelium and generating the correct number of cells in the correct parts of the Organ of Corti will be a challenge. Given that much of cochlear function depends on the precise mechanical properties of the Organ of Corti, excess or inappropriately placed cells are likely to cause problems. Moreover, the possible effects of radiation on the supporting and

vascular structures of the Organ of Corti, may also complicate regenerative efforts.

For now, the best therapeutic strategy would be effective rehabilitation of SNHL after RT.

In patients with profound SNHL, cochlear implants may be effective if the retro-cochlear auditory pathways remained intact. To substantiate that the retro-cochlear auditory pathways remained intact after RT (Low et al., 2005), a case-control study of cochlear implant recipients who had prior irradiation for NPC was conducted in our clinic (Low et al 2006b). They received their RT 11-28 years prior to cochlear implantation and the postimplant follow-up period ranged from 9 to 46 months. The implanted ear of each patient had favourable pre-operative promontory stimulation results. Post-implant, all patients were satisfied with their hearing outcomes and the improvement in speech discrimination

by IMRT (Hsin et al., 2010).

**3.3 Treatment** 

**3.3.1 Cochlear implantation** 

scores was comparable to the controls.

Adhesions in middle ear could complicate surgery, including posing difficulties during identification of the round window niche. Post radiation obliteration of the cochlea lumen is possible, which could compromise smooth insertion of electrode array during implantation (Formanek et al., 1998).

In cochlear implantation of patients who had been irradiated for NPC, two aspects ought to be highlighted. Firstly, these patients not infrequently have perforated eardrums and middle ear infections, with the Eustachian tube openings in the nasopharynx completely obliterated. For these patients, conventional techniques of cochlear implantation do not apply and modified techniques such as subtotal petrosectomy, fat obliteration and blind sac closure become necessary. Secondly, NPC has a racial predilection and is common in the Chinese. Racial differences in mastoid morphology exist and such differences had even been used in race identification during forensic and anthropology investigations. Indeed, a study of Chinese temporal bones had revealed differences in the course of the facial nerve in the mastoid and in the origin of the chorda tympani, as compared to those described in Western textbooks (Low, 1999). Knowledge of such racial anatomical variations may reduce the risk of facial nerve injury during mastoid surgery, especially in irradiated ears where the bone is usually more friable than normal.

#### **3.3.1.2 Surveillance imaging**

A part of the internal component of the cochlear implant is a small magnet, which is required to secure the external component to the skin of the patient. In an NPC patient who had been treated previously, magnetic resonance imaging is sometimes required to exclude the possibility of tumor recurrence. Should magnetic resonance imaging be indicated in a patient who is already a cochlear implant recipient, there may be a need to remove the magnet from the internal device before the scan.

#### **3.3.1.3 Re-irradiation**

In recurrent tumors, further radiotherapy may be indicated. Fortunately, the internal device had been shown to be resistant to damage by radiation (Ralston et al., 1999). However, cumulative radiation doses from further radiotherapy could inflict severe damage to the auditory nerve, which could compromise the post-implant hearing outcome.

#### **3.3.2 Bone-anchored hearing aids**

Conventional hearing aids may effectively address conductive hearing loss resulting from MEE. However, they may aggravate otorrhea, and ear moulds traumatize osteoradionecrosis ulcers in the ear canal. An alternative for patients is the bone-anchored hearing aids (BAHA). BAHA has been shown to have successful osseointegration in postirradiated NPC patients (Soo et al., 2009). Improved subjective hearing clarity, reduced ear discharge rates, and extended BAHA usage times accounted for high patient satisfaction with the BAHA hearing system. Soo et al (2009) therefore, recommended the BAHA hearing

Ear-Related Issues in Patients with Nasopharyngeal Carcinoma 171

significantly worse for patients in the chemo-RT arm at all the post-treatment time points

Osteo-radionecrosis (ORN) is an uncommon complication of radiation treatment. In postirradiated NPC patients, it may occur in the temporal bone and presents as chronic or recurrent ear discharge. To the unwary Clinician, this can potentially be misdiagnosed as the symptoms of chronic suppurative otitis media and otitis externa, both of which are

Radiation may result in hypoxia, hypovascularity and hypocellularity of canal skin. These impair normal collagen synthesis and cell production and lead to tissue breakdown and eventual ORN (Hao et al., 2007). Obliterative vasculitis also causes a direct radiation-induced avascular necrosis of the bone (Schuknecht & Karmody, 1966). This is more likely to occur in the presence of tumor involvement (Lederman, 1965). There is a positive relationship between

Fig. 4. Endoscopic view of the left external and middle ear showing osteo-radionecrosis. This 60 year old woman had radiotherapy for NPC 15 years ago and had remained disease free since. She presented with chronic left ear discharge 12 years after radiotherapy.

Examination showed necrotic in the external ear canal and middle ear. CT scan showed that the bony lesions did not involve the rest of the temporal bone. She was closely followed up with regular aural toilet and topical antibiotics. She was not keen for other treatment options

studied and were more severely affected than those at lower frequencies.

the size of the radiation dose and the degree of necrosis (Thornley et al., 1979).

**3.4 Osteo-radionecrosis** 

common in post-irradiated NPC patients.

like hyperbaric oxygen and sequestrectomy.

system for the treatment of chronic suppurative otitis media-related hearing problems in NPC patients.

#### **3.3.3 Active middle ear implants**

Compared to conventional hearing aids, active middle ear implants such as the Vibrant Soundbridge provide more mechanical energy into the inner ear. However, they still rely on viable cochlear hair cells in order to convert mechanical energy into electrical energy for onward transmission through the auditory nerve to the brain. In radiation-induced SNHL, there may be progressive cochlear hair cell loss. Patients with post-radiotherapy SNHL affecting only the higher frequencies may initially be suitable for middle ear implants. However, it's use should be cautioned as the natural progressive nature of radiationinduced SNHL might affect the effectiveness of these devices in the longer term.

#### **3.3.4 Chemo-radiation and their combined ototoxic effects**

Combined chemo-radiotherapy is increasingly being used clinically to treat advanced head and neck cancers. In radiotherapy of tumours in the head and neck region, the auditory pathways are often included in the radiation fields and radiation-induced SNHL may result. Cisplatin (CDDP), widely used as an effective anti-neoplastic drug for these cancers, is also well known to cause ototoxicity. Therefore, in combined therapy, the synergistic ototoxic effects of CDDP and radiation could theoretically be catastrophic for the patient and is a clinical issue that deserves more attention.

Skinner et al. (1990) remarked that previous or concurrent use of other ototoxic agents with CDDP, may increase toxicity by more than simple algebric summation. Indeed, there have been a number of reports that described enhanced radiatiation-induced ototoxicity when used with CDDP. In a study by Schnell et al (1989) it was found that children and young adults treated with CDDP suffered an additional 20-30dB SNHL if they had received prior cranial RT. In a study on children and adolescents who had received CDDP for the treatment of solid tumours, Skinner et al. (1990) reported more severe CDDP ototoxicity in patients who had previously received RT encompassing the ear. Similarly, Merchant et at (2004) observed enhanced ototoxicity in a study on children with brain tumours who were treated by pre-RT ototoxic chemotherapy. Miettinen et al (1997) also found that radiotherapy enhanced the ototoxicity of CDDP in the higher speech frequencies. The results of these studies were consistent with those from case reports, which supported the idea that RT should be considered cautiously in children treated with CDDP for intracranial malignancies (Sweetow & Will, 1993; Walker et al, 1989)

We conducted a single blinded randomized trial to investigate the true differences in extent, onset and clinical course of SNHL between newly diagnosed nasopharyngeal carcinoma (NPC) patients treated by RT alone and by combined chemo-RT (Low et al 2006c). Bone conduction thresholds were performed before treatment and at 1 week, 6 months, 1 year and 2 years after completion of RT. Statistical analysis was performed using the Mann-Whitney test. Hearing thresholds averaged over 0.5, 1 and 2kHz were found to be poorer in the chemo-RT group (116 ears) compared to the radiotherapy group (114 ears), at 1 year (p=0.001) and 2 years (p=0.03) post-treatment. Hearing thresholds at 4kHz were significantly worse for patients in the chemo-RT arm at all the post-treatment time points studied and were more severely affected than those at lower frequencies.

#### **3.4 Osteo-radionecrosis**

170 Carcinogenesis, Diagnosis, and Molecular Targeted Treatment for Nasopharyngeal Carcinoma

system for the treatment of chronic suppurative otitis media-related hearing problems in

Compared to conventional hearing aids, active middle ear implants such as the Vibrant Soundbridge provide more mechanical energy into the inner ear. However, they still rely on viable cochlear hair cells in order to convert mechanical energy into electrical energy for onward transmission through the auditory nerve to the brain. In radiation-induced SNHL, there may be progressive cochlear hair cell loss. Patients with post-radiotherapy SNHL affecting only the higher frequencies may initially be suitable for middle ear implants. However, it's use should be cautioned as the natural progressive nature of radiation-

Combined chemo-radiotherapy is increasingly being used clinically to treat advanced head and neck cancers. In radiotherapy of tumours in the head and neck region, the auditory pathways are often included in the radiation fields and radiation-induced SNHL may result. Cisplatin (CDDP), widely used as an effective anti-neoplastic drug for these cancers, is also well known to cause ototoxicity. Therefore, in combined therapy, the synergistic ototoxic effects of CDDP and radiation could theoretically be catastrophic for the patient and is a

Skinner et al. (1990) remarked that previous or concurrent use of other ototoxic agents with CDDP, may increase toxicity by more than simple algebric summation. Indeed, there have been a number of reports that described enhanced radiatiation-induced ototoxicity when used with CDDP. In a study by Schnell et al (1989) it was found that children and young adults treated with CDDP suffered an additional 20-30dB SNHL if they had received prior cranial RT. In a study on children and adolescents who had received CDDP for the treatment of solid tumours, Skinner et al. (1990) reported more severe CDDP ototoxicity in patients who had previously received RT encompassing the ear. Similarly, Merchant et at (2004) observed enhanced ototoxicity in a study on children with brain tumours who were treated by pre-RT ototoxic chemotherapy. Miettinen et al (1997) also found that radiotherapy enhanced the ototoxicity of CDDP in the higher speech frequencies. The results of these studies were consistent with those from case reports, which supported the idea that RT should be considered cautiously in children treated with CDDP for intracranial

We conducted a single blinded randomized trial to investigate the true differences in extent, onset and clinical course of SNHL between newly diagnosed nasopharyngeal carcinoma (NPC) patients treated by RT alone and by combined chemo-RT (Low et al 2006c). Bone conduction thresholds were performed before treatment and at 1 week, 6 months, 1 year and 2 years after completion of RT. Statistical analysis was performed using the Mann-Whitney test. Hearing thresholds averaged over 0.5, 1 and 2kHz were found to be poorer in the chemo-RT group (116 ears) compared to the radiotherapy group (114 ears), at 1 year (p=0.001) and 2 years (p=0.03) post-treatment. Hearing thresholds at 4kHz were

induced SNHL might affect the effectiveness of these devices in the longer term.

**3.3.4 Chemo-radiation and their combined ototoxic effects** 

clinical issue that deserves more attention.

malignancies (Sweetow & Will, 1993; Walker et al, 1989)

NPC patients.

**3.3.3 Active middle ear implants** 

Osteo-radionecrosis (ORN) is an uncommon complication of radiation treatment. In postirradiated NPC patients, it may occur in the temporal bone and presents as chronic or recurrent ear discharge. To the unwary Clinician, this can potentially be misdiagnosed as the symptoms of chronic suppurative otitis media and otitis externa, both of which are common in post-irradiated NPC patients.

Radiation may result in hypoxia, hypovascularity and hypocellularity of canal skin. These impair normal collagen synthesis and cell production and lead to tissue breakdown and eventual ORN (Hao et al., 2007). Obliterative vasculitis also causes a direct radiation-induced avascular necrosis of the bone (Schuknecht & Karmody, 1966). This is more likely to occur in the presence of tumor involvement (Lederman, 1965). There is a positive relationship between the size of the radiation dose and the degree of necrosis (Thornley et al., 1979).

Fig. 4. Endoscopic view of the left external and middle ear showing osteo-radionecrosis. This 60 year old woman had radiotherapy for NPC 15 years ago and had remained disease free since. She presented with chronic left ear discharge 12 years after radiotherapy. Examination showed necrotic in the external ear canal and middle ear. CT scan showed that the bony lesions did not involve the rest of the temporal bone. She was closely followed up with regular aural toilet and topical antibiotics. She was not keen for other treatment options like hyperbaric oxygen and sequestrectomy.

Ear-Related Issues in Patients with Nasopharyngeal Carcinoma 173

specimens obtained under local anesthesia. It was only upon larger and deeper specimens

RATs may be uncommon, but with refinement in radiotherapy techniques and the resultant increase in patient survival, there may be more patients with radiation-associated tumours in the future. It remains imperative for clinicians to be vigilant when patients previously irradiated for NPC present with otological symptoms as the key to the successful management of this condition lies in the early detection and expedient treatment of this

Because of the close relation between the nasopharynx and ear structures, NPC frequently has Otological manifestations. Attending Physicians must be mindful of these manifestations as they may aid early diagnosis with consequently better treatment

Treatment of NPC with radiotherapy or chemo-radiation also has great impact on the practice of Otology. Improved RT techniques have reduced unnecessary radiation exposure to ear structures, with lesser chances of developing ear complications. Nevertheless, it is inevitable in many instances. With greater emphasis in the use of chemo-RT in advanced head and neck cancers, chemo-radiation-induced SNHL has also assumed greater significance. Although recent technology such as cochlear implants have been highly successful in rehabilitating profound hearing loss, prevention is still the best practice in the management of radiation-induced SNHL. A proposed ROS-dependent apoptotic model of hair-cell damage offers the prospect of prevention at a molecular level in the near future.

We thank Dr Fong Kam Weng, Senior Consultant of the Therapeutic Radiology Department,

Atar O, Avraham KB. Therapeutics of hearing loss: expectations vs reality. Drug Discov

Awwad HK. Late reacting tissues: radiation damage to central nervous system. Radiation Oncology: The Netherlands: 1990 Nov; Kluger Academic Publishers. Batsakis JG, Bautina E. Metastases to major salivary glands. Ann Otol Rhinol Laryngol. 1990

Bergstrom L, Baker, BB, Sando I. Sudden deafness and facial palsy from metastatic

Bluestone CD. Current concepts in Eustachian tube function as related to otitis media.

Bluestone CD.Eustachian tube function: physiology, pathophysiology, and role of allergy in pathogenesis of otitis media. J allergy Clin. Immunol. 1983 Sep; 72:242-51. Bohne BA, Marks JE, Glasgow GP. Delayed effects of ionizing radiation on the ear.

bronchogenic carcinoma. J Laryngol Otol. 1977 Sep; 91: 787-89.

Auris-Nasus-Larynx (Tokyo) 1985; 12 (Suppl 1): 1-4.

obtained under general anesthesia from the mastoid that revealed the true diagnosis.

difficult disease.

**4. Conclusion** 

**5. Acknowledgement** 

Jun; 99:501-03.

**6. References** 

Singapore National Cancer Centre, for the illustrations

Today; 2005 Oct 1;10 (19):1323-30.

Laryngoscope 1985 Jul; 95:818-28.

outcomes.

Ramsden et al (1975) classified osteoradionecrosis of the temporal bone as either localized or diffuse. In localized osteoradionecrosis, the disease is generally confined to the external auditory canal, and symptoms manifest according to the site and stage of the disease. In diffuse osteoradionecrosis it extends beyond the temporal bone to the base of the skull and its surrounding structures. The affected patients presented with more severe symptoms of profuse and pulsatile otorrhea and significant pain. The diffuse form is associated with a greater likelihood of complications, including trismus, intracranial infection, facial nerve palsy, labyrinthitis, chronic mastoiditis, CSF leak, and internal carotid artery aneurysm. (John et al., 1993)

The type that is more commonly seen is the localized type where the ORN is heralded by unhealed ulcer, foul discharge, exposed bone and accompanying granuloma. It is typically seen in the lower external canal skin, an area predisposed to downward pressure-induced trauma from wearing hearing aids or iatrogenically traumatized during aural toileting or ear-picking. Sometimes, it involves the middle ear (Figure 4). As suggested by Hao et al, treatment ranges from thorough aural toilet, otic drops, hyperbaric oxygen (Rudge 1993) that reverses the ill effects of radiation induced skin changes, and finally sequestrectomy. Most important though rare, high degree of suspicion and awareness is the key in detection and early management of this condition before serious complication ensues. Lim et al (2005) reported an interesting case of a 44-year-old Chinese man with a history of nasopharyngeal carcinoma that was treated with radiotherapy presented with fluid in the middle ear. A myringotomy was performed and subsequently a diagnosis of cerebrospinal fluid leakage secondary to osteoradionecrosis of the temporal bone was made.

#### **3.5 Radiation-associated tumors**

Radiation-associated tumours (RATS) are rare complications of radiotherapy. Goh et al (1999) studied RATs in the temporal bones of patients who were previously irradiated for cancers of the nasopharynx. Of the 7 patients studied, 5 had squamous cell carcinomas, 1 osteogenic sarcoma and 1 chondrosarcoma. This distribution of the type of cancer is interesting as radiation-induced cancers are more associated with sarcoma than with squamous cell carcinoma. A possible reason for this observation may be related to the chronic ear infections that are commonly present in post-irradiated ears. The combined long-term effects of radiation and chronic infections may well predispose the ear to squamous cell carcinoma. In another study of patients with malignant tumors of the external auditory canal and temporal bone, the 1-year cumulative recurrence for the RAT group was 100%, but there was no recurrence in the non-RAT group (P = 0.001) suggesting a poorer prognosis in RATS patients (Lim et al 2000)

Delayed diagnosis is not uncommon in this condition. Almost two thirds of the patients in the series reported by Lim et al. (2000) had T3 disease at the time of presentation. One reason could be that otorrhea, the most common presentation, was often mistaken to be due to chronic otitis externa.

Another reason for misdiagnosis is difficulty in getting histological confirmation in the Clinic. Lim et al (2000) gave the example of a patient with an initial diagnosis of pseudoepitheliomatous hyperplasia. This was based on superficial small punch biopsy specimens obtained under local anesthesia. It was only upon larger and deeper specimens obtained under general anesthesia from the mastoid that revealed the true diagnosis.

RATs may be uncommon, but with refinement in radiotherapy techniques and the resultant increase in patient survival, there may be more patients with radiation-associated tumours in the future. It remains imperative for clinicians to be vigilant when patients previously irradiated for NPC present with otological symptoms as the key to the successful management of this condition lies in the early detection and expedient treatment of this difficult disease.
