**3. Otologic complications arising from treatment of NPC**

As NPC is highly radiosensitive, radiation treatment stands as the primary modality of management. The aim of treatment is eradication of tumor through targeted delivery of radiation to the tumor bed, at tolerable doses to minimize acute and late complications. It is a challenge to balance cure on one hand, and prevention of complications from treatment on the other. The focus in this section is to highlight the impact of treatment of NPC on ear structures.

#### **3.1 Radiation therapy**

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

Referred otalgia is pain felt in the ear but originating from a non-otologic source. Ear pain is a diagnostic dilemma when otoscopy reveals normal external ear and tympanic membrane. As the ear is innervated by sensory contributions of the the 5th, 7th, 9th and 10th cranial nerves as well as spinal nerves C2 and C3, lesions arising from areas supplied by these nerves may

Theoretically, NPC can present as referred otalgia by involving the 9th cranial nerve. We concur with the observation by van Hasselt & Gibb (1991) that otalgia is less common than one might expect. We agree with the view that the most common description of pain is not "sharp" but "aching, dull or pressing" (Epstein and Jones, 1993). This is illustrated by a case

A 48 year old man complained of a sensation of fullness in the left peri-auricular region, just antero-inferior to the tragus lasting for a month. Examination by manual palpation failed to reveal any mass in the region. CT scan of the parotid was normal. Nasal-endoscopy however, revealed a discrete mass in the left side of the post-nasal space. Biopsy of this nasopharyngeal mass showed undifferentiated nasopharyngeal carcinoma. His symptom

It is common for patients to consult the Otologist for the complaint of tinnitus in the absence of other ear symptoms or signs. If unilateral, the Otologist often considers the possibility of an early acoustic neuroma and investigates as such. It is however, highly unlikely that NPC presents as tinnitus as an isolated symptom in the absence of other features relating to the ear, a view shared by van Hasselt & Gibb (1991). If present, it is normally a result of Eustachian tube, middle ear or auditory nerve involvement with the resulting associated

Although NPC metastasizing to the parotid is rare with only 14 cases reported in the literature (Wanamaker et al., 1994), this possibility should be considered in high-risk patients presenting with parotid masses. Batsakis and Bautina (1990) cautioned that some cases of 'primary undifferentiated carcinoma of nasopharyngeal type' in the major salivary glands might in fact be metastatic nasopharyngeal carcinoma. Low (2002) reported a case of

A 50-year-old man was treated for nasopharyngeal carcinoma overseas. Two years later, he exhibited complete left lower motor neuron facial nerve palsy. Examination revealed a hard mass in the left parotid over the region of the facial trunk in addition to multiple swollen cervical nodes (figure 3). The postnasal space was clinically free of tumor, and the appearance of the ears was unremarkable. Chest x-ray showed multiple metastases. Analysis of a fine-needle aspiration sample of the parotid mass identified an undifferentiated carcinoma consistent with metastatic nasopharyngeal carcinoma. The

metastatic NPC to the parotid and presenting with facial palsy as follows.

patient refused further treatment and died 3 months later.

**2.3 Referred otalgia** 

result in pain referred to the ear.

report by Low & Goh (1999**):** 

resolved after radiation therapy.

aural manifestations as well.

**2.5 Peri-auricular mass** 

**2.4 Tinnitus** 

Megavoltage external beam radiotherapy is the primary treatment of choice. There are two lateral opposing and one anterior field beams. This is meant to cover the sides of the neck and entire nasopharynx. Radiotherapy is given prophylactically to the neck assuming there is occult disease.

A typical convention technique used by us involves patients treated with six megavolt (6MV) X-rays from linear accelerators. Chemotherapy was not part of the protocol for any patient. The primary volume covered the nasopharynx including the Eustachian tube, adjacent parapharynx to the level of the inferior border of C2, and posterior third to half of the nasal cavity and maxillary antra (Figures 2 and 3). As shown, the brainstem was shielded throughout on the lateral fields and the inner ear would be at the edge of this shield. A total dose of 66 – 70 Gys in 2 Gy daily increments was prescribed. The neck received 60 Gy electively, with palpable nodes boosted to 70 Gy.

## **3.1.1 Post-irradiation otitis media**

#### **3.1.1.1 Middle ear effusion**

MEE is a common finding among patients who have been irradiated for NPC patients and is generally attributed to Eustachian tube dysfunction. Post-irradiated ultra-structural findings of the Eustachian tubal mucosa showed ciliary loss, intercellular and intracellular vacuolation and ciliary dysmorphism (Lou et al., 1999). Most of these pathologic findings were observed to be persistent and did not resolve with time suggesting that radiation had caused long-term damage to the Eustachian tube epithelium. The Eustachian tube could grossly manifest in differing ways ranging from patulous Eustachian tube, adhesion, incomplete and complete obstruction (Zhou et al., 2003).

MEE could be present in the early post-radiotherapy period and some persist in the longterm. Low & Fong (1998) studied the factors, which could possibly influence the development of long-term middle ear effusion in patients irradiated for NPC. Thirty-five patients (70 ears) were studied for 2-8 years (mean 5.5 years) post-radiotherapy. The factors studied were (a) sex (b) age (c) tumour size and (d) presence of pre-radiotherapy MEE. Only

Ear-Related Issues in Patients with Nasopharyngeal Carcinoma 165

Fig. 3. Axial CT scan of the nasopharynx showing a computer generated isodose plan. This shows the distribution of radiation dose as determined by the specific beam arrangement.

Therefore, hearing loss resulting from post-radiotherapy MEE should preferably be addressed by amplification with hearing aids rather than drainage with ventilation tubes

Chronic Suppurative Otitis Media (CSOM) was found in 24.5% of NPC patients who developed otological complications after radiotherapy (Yuen and Wei, 1994). Perforation of the eardrum may occur after ventilation tube insertion for MEE or spontaneously as a result

Some Otologists in managing CSOM in post-irradiated NPC patients prefer a conservative approach, presumably because of the belief that impaired healing is more likely in irradiated tissues and radiation-induced Eustachian tube dysfunction may lead to lesser chance of successful repair. Yuen and Wei (1994) however, recommended tympanomastoidectomy for NPC patients with active CSOM who fail to respond to conservative treatment, citing a

Radiotherapy of head and neck cancers including NPC is well known to result in sensorineural hearing loss (SNHL), when the ear structures are included in the radiation fields. The

of radiotherapy-induced spontaneous Eustachian tube dysfunction (Wei et al, 1988).

The dose to the target volume and various structures of interest can be assessed.

(Skinner & van Hasselt, 1991).

**3.1.1.2 Chronic suppurative otitis media** 

nearly 70% chance of success after surgery.

**3.1.2 Post-irradiation sensorineural hearing loss** 

Fig. 2. Beam's Eye View (BEV) of lateral post-nasal space field.

The field (yellow box) is superimposed on a digitally reconstructed radiograph (DRR) by the planning computer. The solid red area represents the target volume where a uniform high dose is deposited. Critical structures are shielded to reduce exposure. These structures include the brain stem and spinal cord, optic chiasma (blue), and the inner ear as much as is feasible.

the presence of pre-radiotherapy MEE was found to be statistically significant (P = 0.004, Fisher's exact test). Stepwise multiple regression analysis showed the presence of preradiotherapy MEE was a predictor of post-radiotherapy MEE with an odds ratio of 0.67. Hence, an ear with pre-irradiation MEE was almost seven times more likely to have longterm post-irradiation MEE than an ear without pre-irradiation MEE. It was postulated that irreversible Eustachian tube dysfunction occurred only when the tube that had been damaged by tumour was further damaged by irradiation. It may well be that tumour and irradiation had induced change in the compliance of the Eustachian tube resulting in the development of long-term post-radiotherapy MEE.

As the mechanism of post-radiotherapy MEE is likely to be different from MEE commonly found in children, its principles of management are also different. Unlike in children, the use of ventilation tubes has the tendency to result in chronic infection, which was are often persistent and troublesome. They also tend to be associated with persistent perforations.

Fig. 2. Beam's Eye View (BEV) of lateral post-nasal space field.

development of long-term post-radiotherapy MEE.

feasible.

The field (yellow box) is superimposed on a digitally reconstructed radiograph (DRR) by the planning computer. The solid red area represents the target volume where a uniform high dose is deposited. Critical structures are shielded to reduce exposure. These structures include the brain stem and spinal cord, optic chiasma (blue), and the inner ear as much as is

the presence of pre-radiotherapy MEE was found to be statistically significant (P = 0.004, Fisher's exact test). Stepwise multiple regression analysis showed the presence of preradiotherapy MEE was a predictor of post-radiotherapy MEE with an odds ratio of 0.67. Hence, an ear with pre-irradiation MEE was almost seven times more likely to have longterm post-irradiation MEE than an ear without pre-irradiation MEE. It was postulated that irreversible Eustachian tube dysfunction occurred only when the tube that had been damaged by tumour was further damaged by irradiation. It may well be that tumour and irradiation had induced change in the compliance of the Eustachian tube resulting in the

As the mechanism of post-radiotherapy MEE is likely to be different from MEE commonly found in children, its principles of management are also different. Unlike in children, the use of ventilation tubes has the tendency to result in chronic infection, which was are often persistent and troublesome. They also tend to be associated with persistent perforations.

Fig. 3. Axial CT scan of the nasopharynx showing a computer generated isodose plan. This shows the distribution of radiation dose as determined by the specific beam arrangement. The dose to the target volume and various structures of interest can be assessed.

Therefore, hearing loss resulting from post-radiotherapy MEE should preferably be addressed by amplification with hearing aids rather than drainage with ventilation tubes (Skinner & van Hasselt, 1991).

#### **3.1.1.2 Chronic suppurative otitis media**

Chronic Suppurative Otitis Media (CSOM) was found in 24.5% of NPC patients who developed otological complications after radiotherapy (Yuen and Wei, 1994). Perforation of the eardrum may occur after ventilation tube insertion for MEE or spontaneously as a result of radiotherapy-induced spontaneous Eustachian tube dysfunction (Wei et al, 1988).

Some Otologists in managing CSOM in post-irradiated NPC patients prefer a conservative approach, presumably because of the belief that impaired healing is more likely in irradiated tissues and radiation-induced Eustachian tube dysfunction may lead to lesser chance of successful repair. Yuen and Wei (1994) however, recommended tympanomastoidectomy for NPC patients with active CSOM who fail to respond to conservative treatment, citing a nearly 70% chance of success after surgery.

#### **3.1.2 Post-irradiation sensorineural hearing loss**

Radiotherapy of head and neck cancers including NPC is well known to result in sensorineural hearing loss (SNHL), when the ear structures are included in the radiation fields. The

Ear-Related Issues in Patients with Nasopharyngeal Carcinoma 167

SNHL occur within hours or days after completion of RT, whereas late-onset radiationinduced SNHL may manifest months or years after exposure. Hence, "late"-onset radiationinduced SNHL may possibly represent the later stages of the progression in hair cell degeneration initiated by direct cellular injury during irradiation. Alternatively, the initial radiation-induced injury could have rendered the cells more susceptible to apoptosis following subsequent exposure to insults such as noise and ototoxic medications (Low et al.,

There has been compelling evidence in animal models, implicating reactive oxygen species (ROS) in the damage associated with non-radiation causes such as cochlear ischemia, noise trauma, presbycusis, meningitis-associated hearing loss and aminoglycoside and cisplatin

In radiation-induced apoptosis in the OC-k3 inner ear cell line, Low et al., (2006a), demonstrated dose-dependant intracellular generation of ROS at 1 hour post-irradiation and was believed to be an important triggering factor in the apoptotic process. ROS could explain the observation that high frequency hearing is preferentially damaged by radiation (Rybak & Whitworth 2005). In an animal study on aminoglycoside ototoxicity, outer haircell death in the Organ of Corti was observed to follow a base-to-apex gradient, which was eliminated by the addition of antioxidants (Sha et al., 2001). This was attributed to the outer hair cells in the basal coil (respond to higher frequency sounds) having much lower levels of glutathione than those in the apical region (respond to lower frequency sounds) and

In the OC-k3 inner ear cell line, Low et al., (2006a) found up- regulation of p53 related genes from micro-array studies. Western blotting confirmed up-regulation of p53 at 72 hours and phosphorylation at 3, 24, 48 and 72 hours after irradiation. It is well known that p53 can

Nevertheless, a number of different mechanisms leading to cell deaths may also be involved in radiation-induced ototoxicity. These include necrotic cell death, p53-independent mechanisms and caspase-independent programmed cell death. Multiple cellular organelles may trigger several pathways that may act independently or in concert (Leist & Jaattela

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

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

therefore, a lower antioxidant capacity (Rybak & Whitworth 2005).

2009**).**

induce apoptosis.

**3.2 Prevention** 

situated away from ear structures.

have been of practical help to radiation oncologists.

2003).

ototoxicity (Seidman and Vivek, 2004).

reported post-radiation therapy hearing loss rates based on audiometric evaluation varied between 0% and 54% (Ho et al., 1999; Kwong et al., 1996; Raajmakers et al., 2002). This is attributed to radiation-induced damage to the sensorineural auditory pathways.

It is important to know whether the auditory nerve, the central nervous pathways or both, are damaged by radiotherapy. This is important in the context of treating profound hearing loss in post-irradiated ears using the cochlear implant. The cochlear implant works by stimulating the auditory nerve fibres directly, without the need for functioning cochlear hair cells. Its success therefore, depends largely on a functional auditory nerve and its central nervous pathways.

If the auditory nerve and central nervous structures are indeed spared and that damage occurs primarily in the cochlea, it will then be useful to understand the cellular and molecular processes involved in radiation-induced cochlear hair-cell damage. This is because it has relevance in preventive measures where medications are used to target the cellular and molecular pathways involved.

#### **3.1.2.1 Pathogenesis**

It was demonstrated in chinchillas that cochlear nerve fiber degeneration occurred after exposure to high radiation doses. In ears exposed to 40 to 50Gy and 60 to 90Gy of radiation, the incidence rates were 31% and 62% respectively, (Bohne et al., 1985) confirming that radiation induced damage is dose dependent.

To find out if radiation damages retro-cochlear auditory pathways, we prospectively studied newly diagnosed NPC patients treated by radiotherapy alone (Low et al., 2005). Audiograms including evoked response audiometry which could assess the integrity of retro-cochlear auditory pathways, were carried out prior to and after radiotherapy (at 3, 18 and 48 months). There was no statistically significant difference in inter-waves latencies recorded before and after RT (p >0.05, Wilcoxon Signed Ranks Test), suggesting that the retro-cochlear auditory pathways were functionally intact. Analysis of dose-volume histograms confirmed that the cochlea and internal auditory meatus received significant doses of radiation, ranging from 24.1-62.2 and 14.4 – 43.4 Gy respectively.

It is believed that etiologies of SNHL such as ageing and drug toxicity, share similar cell death mechanisms leading to a final common apoptotic pathway (Atar et al., 2005). Radiation-induced apoptosis has been well demonstrated in non-cochlear cell systems and is generally accepted as an important mechanism of radiation-induced cell death in vivo (Shinomiya 2001; Verheij & Bartelink 2000) Therefore, by relating our findings to what is already known, it is not unreasonable to expect radiation-induced apoptosis occurring in cochlear hair-cells in vivo.

It is well accepted that radiation-induced SNHL is progressive in nature. The integrity of normal tissues or organs depends on the maintenance of a certain number of normally functioning mature cells. When the depletion of functioning cells reaches a critical level, a clinically detectable effect becomes apparent (Awwad 1990). In the case of radiationinduced SNHL the cochlea consists of a finite number of post-mitotic non-regenerating hair cells. A patient may experience hearing loss when a critical mass of hair cells is lost and it may take several months or years after radiation exposure before this stage is reached. Radiation-induced SNHL has been described to have either early or late-onset. Early-onset

reported post-radiation therapy hearing loss rates based on audiometric evaluation varied between 0% and 54% (Ho et al., 1999; Kwong et al., 1996; Raajmakers et al., 2002). This is

It is important to know whether the auditory nerve, the central nervous pathways or both, are damaged by radiotherapy. This is important in the context of treating profound hearing loss in post-irradiated ears using the cochlear implant. The cochlear implant works by stimulating the auditory nerve fibres directly, without the need for functioning cochlear hair cells. Its success therefore, depends largely on a functional auditory nerve and its central

If the auditory nerve and central nervous structures are indeed spared and that damage occurs primarily in the cochlea, it will then be useful to understand the cellular and molecular processes involved in radiation-induced cochlear hair-cell damage. This is because it has relevance in preventive measures where medications are used to target the

It was demonstrated in chinchillas that cochlear nerve fiber degeneration occurred after exposure to high radiation doses. In ears exposed to 40 to 50Gy and 60 to 90Gy of radiation, the incidence rates were 31% and 62% respectively, (Bohne et al., 1985) confirming that

To find out if radiation damages retro-cochlear auditory pathways, we prospectively studied newly diagnosed NPC patients treated by radiotherapy alone (Low et al., 2005). Audiograms including evoked response audiometry which could assess the integrity of retro-cochlear auditory pathways, were carried out prior to and after radiotherapy (at 3, 18 and 48 months). There was no statistically significant difference in inter-waves latencies recorded before and after RT (p >0.05, Wilcoxon Signed Ranks Test), suggesting that the retro-cochlear auditory pathways were functionally intact. Analysis of dose-volume histograms confirmed that the cochlea and internal auditory meatus received significant

It is believed that etiologies of SNHL such as ageing and drug toxicity, share similar cell death mechanisms leading to a final common apoptotic pathway (Atar et al., 2005). Radiation-induced apoptosis has been well demonstrated in non-cochlear cell systems and is generally accepted as an important mechanism of radiation-induced cell death in vivo (Shinomiya 2001; Verheij & Bartelink 2000) Therefore, by relating our findings to what is already known, it is not unreasonable to expect radiation-induced apoptosis occurring in

It is well accepted that radiation-induced SNHL is progressive in nature. The integrity of normal tissues or organs depends on the maintenance of a certain number of normally functioning mature cells. When the depletion of functioning cells reaches a critical level, a clinically detectable effect becomes apparent (Awwad 1990). In the case of radiationinduced SNHL the cochlea consists of a finite number of post-mitotic non-regenerating hair cells. A patient may experience hearing loss when a critical mass of hair cells is lost and it may take several months or years after radiation exposure before this stage is reached. Radiation-induced SNHL has been described to have either early or late-onset. Early-onset

doses of radiation, ranging from 24.1-62.2 and 14.4 – 43.4 Gy respectively.

attributed to radiation-induced damage to the sensorineural auditory pathways.

nervous pathways.

**3.1.2.1 Pathogenesis** 

cochlear hair-cells in vivo.

cellular and molecular pathways involved.

radiation induced damage is dose dependent.

SNHL occur within hours or days after completion of RT, whereas late-onset radiationinduced SNHL may manifest months or years after exposure. Hence, "late"-onset radiationinduced SNHL may possibly represent the later stages of the progression in hair cell degeneration initiated by direct cellular injury during irradiation. Alternatively, the initial radiation-induced injury could have rendered the cells more susceptible to apoptosis following subsequent exposure to insults such as noise and ototoxic medications (Low et al., 2009**).**

There has been compelling evidence in animal models, implicating reactive oxygen species (ROS) in the damage associated with non-radiation causes such as cochlear ischemia, noise trauma, presbycusis, meningitis-associated hearing loss and aminoglycoside and cisplatin ototoxicity (Seidman and Vivek, 2004).

In radiation-induced apoptosis in the OC-k3 inner ear cell line, Low et al., (2006a), demonstrated dose-dependant intracellular generation of ROS at 1 hour post-irradiation and was believed to be an important triggering factor in the apoptotic process. ROS could explain the observation that high frequency hearing is preferentially damaged by radiation (Rybak & Whitworth 2005). In an animal study on aminoglycoside ototoxicity, outer haircell death in the Organ of Corti was observed to follow a base-to-apex gradient, which was eliminated by the addition of antioxidants (Sha et al., 2001). This was attributed to the outer hair cells in the basal coil (respond to higher frequency sounds) having much lower levels of glutathione than those in the apical region (respond to lower frequency sounds) and therefore, a lower antioxidant capacity (Rybak & Whitworth 2005).

In the OC-k3 inner ear cell line, Low et al., (2006a) found up- regulation of p53 related genes from micro-array studies. Western blotting confirmed up-regulation of p53 at 72 hours and phosphorylation at 3, 24, 48 and 72 hours after irradiation. It is well known that p53 can induce apoptosis.

Nevertheless, a number of different mechanisms leading to cell deaths may also be involved in radiation-induced ototoxicity. These include necrotic cell death, p53-independent mechanisms and caspase-independent programmed cell death. Multiple cellular organelles may trigger several pathways that may act independently or in concert (Leist & Jaattela 2003).
