**5. Acknowledgement**

We thank Dr Fong Kam Weng, Senior Consultant of the Therapeutic Radiology Department, Singapore National Cancer Centre, for the illustrations

## **6. References**


Ear-Related Issues in Patients with Nasopharyngeal Carcinoma 175

Leong JL, Fong KW, Low WK. Factors contributing to delayed diagnosis in nasopharyngeal

Lim BY, Pang KP, Low WK, Tan HM. CSF otorrhea complicating temporal bone

Lim LH, Goh YH, Chan YM, Chong VF, Low WK. Malignancy of the temporal bone and external auditory canal. Otolaryngol and Head Neck Surg. 2000 Jun;122(6):882-86. Loong HH, Ma BB, Chan AT. Update on the management and therapeutic monitoring of

Lou PJ, Chen WP, Tai CC. Delayed irradiation effects on nasal epithelium in patients with

Low WK. Facial palsy from metastatic nasopharyngeal carcinoma at various sites: Three

Low WK. Surgical anatomy of the facial nerve in Chinese mastoids. ORL J Otorhinolaryngol

Low WK. Middle ear pressures in patients with nasopharyngeal carcinoma and their clinical significance. Journal of Laryngology and Otology. 1995 May; 109:390-93. Low WK, Burgess R, Fong KW, Wang DY. Effect of radiotherapy on retro-cochlear

Low WK, Fong KW, Chong VF. Cerebellopontine angle involvement by nasopharyngeal

Low WK, Fong KW. Long-term hearing status after radiotherapy for nasopharyngeal

Low WK, Goh YH, Uncommon otological manifestations of nasopharyngeal carcinoma, J

Low WK, Gopal K, Goh LK, Fong KW. Cochlear implantation in postirradiated ears:

Low Wk, Lim TA, Fan YF, Balakrishnan A, Pathogenesis of middle ear effusion in

Low WK, Sun L, Tan MG, Chua AW, Wang DY. L-N-Acetylcysteine protects against

Low WK, Tan MG, Chua AW, Sun L, Wang DY. 12th Yahya Cohen Memorial Lecture: The

Low WK, Tan MG, Sun L, Chua AW, Goh LK, Wang DY. Dose- dependant radiationinduced apoptosis in a cochlear cell-line. Apoptosis 2006a Dec; 11:2127-36. Low WK, Toh ST, Wee J, Fook-Chong SM, Wang DY. Sensorineural hearing loss after

Merchant TE, Gould CJ, Xiong X, Robbins N, Zhu J, Pritchard DL, Khan R, Heideman RL,

nasopharyngeal carcinoma: a new perspective. J Laryngol Otol. 1997 May; 111(5):

radiation-induced apoptosis in a cochlear cell line. Acta Otolaryngol. 2008 Apr;

cellular and molecular basis of radiation-induced sensori-neural hearing loss. Ann

radiotherapy and chemoradiotherapy: a single, blinded, randomized study. J Clin

Krasin MJ, Kun LE. Early neuro-otologic effects of three-dimensional irradiation in

outcomes and challenges.Laryngoscope; 2006b Jul; 116(7):1258-62.

osteoradionecrosis in a patient with nasopharyngeal carcinoma. Ear Nose Throat J.

advanced nasopharyngeal cancer. Hematol Oncol Clin North Am. 2008 Dec; 22(6):

nasopharyngeal carcinoma. An ultrastructural study. Ann Otol Rhinol Laryngol.

carcinoma. J Laryngol Otol. 1999 Jul; 113(7):633-36.

reports. Ear, Nose Throat J. Feb. 2002; 81(2):99-101.

pathways. Laryngoscope; 2005 Oct; 115:1823-26.

carcinoma. Am J Otol. 2000 Nov; 21(6):871-76.

Laryngol Otol. 1999 Jun; Vol.113, 558-60.

Acad Med Singapore. 2009 Jan; 38(1):91-94.

Oncol. 2006c Apr; 20;24(12):1904-09.

carcinoma. Aurus Nasus Larynx; 1998 Jan; 25:21–24.

Relat Spec. 1999 Nov-Dec; 61(6):341-44.

2005 Jan; 84(1):39-40.

1999 May; 108(5):474-80.

1267-78

431-34.

128(4):440-45.


Casselbrandt ML, Cantekin EI, Dirkmat Dc, Doyle WJ, Bluestone CD. Experimental

Choa GB, Nasopharyngeal carcinoma. In: Otolaryngology, Vol. 5 ed. G.M. Philadelphia:

Cundy LR, Sando I, Hemingway WG. Middle ear extension of nasopharyngeal carcinoma

Epstein JB, Jones CK. Presenting signs and symptoms of nasopharyngeal carcinoma. Oral

Formanek M, Czerny C, Gstoettner W, Kornfehl J. Cochlear implantation as a successful

Goh J, Lim K. Imaging of nasopharyngeal carcinoma. Ann Acad Med Singapore. 2009 Sep;

Goh YH, Chong VF, Low WK. Temporal bone tumours in patients irradiated for nasopharyngeal neoplasm. J Laryngol Otol. 1999 Mar; 113(3):222-28. Gouliamos AD, Athanassopoulou A, Moulopoulou L, et al. MRI nasopharyngeal carcinoma

Grontved A, Moller A, Jorgenson L. Studies on gas tension in the normal middle ear. Acta

Hao SP, Tsang NM, Chang KP, Chen CK, Chao WC. Osteoradionecrosis of external auditory

Hao SP, Chen HC, Wei FC, Chen CY, Yeh AR, Su JL. Systematic management of osteoradionecrosis in the headand neck. Laryngoscope; 1999 Aug; 109:1324-27. Hergils L, Magnuson B. Human ear gas composition studied by mass spectrometry. Acta

Ho, WK, Wei WI, Kwong DL, Sham JS, Tai PT, Yuen AP, Au DK. Long-term sensorineural

Honjo, I. Nasopharyngeal Carcinoma on Otitis Media with Effusion in Eustachian Tube and

Hsin CH, Chen TH, Young YH, Liu WS. Comparison of otologic complications between

carcinoma patients. Otolaryngol Head Neck Surg. 2010 Nov;143(5):662-68. John DG, Porter MJ, van Hasselt CA. Beware bleeding from the ear. J Laryngol Otol 1993

Kwong DLW, Wei WI, Sham JST, Ho WK, Yuen PW, Chua DTT, Au DKK, Wu PM, Choy

Leist M, Jaattela M. Caspase-independent cell death. In: Grimm S, editor. Genetics of

Lederman M. Malignant tumours of the ear. J Laryngol Otol. 1965 Feb: 79: 85-119.

Apoptosis. UK: BIOS Scientific Publishers Ltd,Trowbridge, 2003.

carcinoma: a prospective study. Head Neck; 1999 Sep; 21, 547–53.

canal in nasopharyngeal carcinoma. Chang Gung Med J. 2007 Mar-Apr; 30(2): 116-

hearing deficit following radiotherapy in patients suffering from nasopharyngeal

Middle Ear Diseases. Springer-Verlag, Tokyo-Berlin-Heidelberg-New York-

intensity-modulated and two-dimensional radiotherapies in nasopharyngeal

DTK. Sensorineural hearing loss in patients treated for nasopharyngeal carcinoma: A prospective study of the effect of radiation and cisplatin treatment. Int J Rad

to the cerebellopontine angle. Neuroradiol. 1996 May; 38:375–77.

Otolaryngologica (Stockholm)1990 Mar; 109:271-77.

Otolaryngologica (Stockholm) 1990 Jul-Aug; 110:92-99.

rehabilitation for radiation-induced deafness. Eur Arch Otorhinolaryngol. 1998;

via eustachian tube. Arch Otolaryngol. 1973 Aug; 98: 131-33.

Surg Oral Med Oral Pathol. 1993 Jan; 75(1):32-36.

Sep-Oct; 106:178-85

255:175–78.

38(9):809-16.

21.

Harper & Row,1981; 1-35.

London-Paris, 1988; 91-111.

Oncol Biol Phys. 1996 Sep; 36: 281-89.

Feb; 107:137-9.

paralysis of tensor veli palatini muscle, Acta Otolaryngologica ( Stolkholm) 1988


children with primary brain tumors. Int J Radiat Oncol Biol Phys. 2004 Mar 15; 58(4): 1194-207.

Ear-Related Issues in Patients with Nasopharyngeal Carcinoma 177

Seidman MD, Vivek P. Intratympanic treatment of hearing loss with novel and traditional

Sha SH, Taylor R, Forge A, Schacht J. Differential vulnerability of basal and apical hair cell is based on intrinsic susceptibility to free radicals. Hear Res. 2001 May; 155(1-2):1-8. Sham, JSI, Weis I, Lau SK, Yau CC, Choy D. Serous otitis media and paranasopharyngeal

Shibahara Y, Sando I. Congenital anomalies of the Eustachian tube in Down Syndrome. Histopathologic case report. Ann Otol Rhinol Laryngol. 1989Jul; 98: 543-7. Shinomiya N. New concepts in radiation-induced apoptosis: 'premitotic apoptosis' and

Singh IP, Slevin NJ. Late audio-vestibular consequences of radical radiotherapy to the

Skinner DW, van Hasselt CA. A study of the complications of grommet insertion for

Skinner DW, van Hasselt CA, Tsao SY. Nasopharyngeal carcinoma: modes of presentation.

Skinner R, Pearson ADJ, Amineddine HA, Mathias DB, Craft AW. Ototoxicity of cisplatinum in children and adolescent. Br J Cancer. 1990 Jun; 61(6):927-31. Soo G, Tong MC, Tsang WS, Wong TK, To KF, Leung SF, van Hasselt CA. The BAHA

Su CY, Hsu SP, Lui CC. Computed tomography, magnetic resonance imaging and

Sweetow RW, Will TI . Progression of hearing loss following the completion of

Takahara T, Sando I, Bluestone CD, Myers EM. Lymphoma invading the anterior Eustachian

Thornley GD, Gullane PJ, Ruby RR, Heeneman H. Osteoradionecrosis of the temporal bone.

van Hasselt AC, Gibb AG. Nasopharyngeal Carcinoma, Chinese University Press, Hong

van Hasselt, A, Woo JKS. Nasopharyngeal carcinoma. Scott Brown's otorhinolaryngology

Verheij M, Bartelink H. Radiation-induced apoptosis. Cell Tissue Res 2000 Jul; 301 (1):133-42. Walker DA, Pillow J, Waters KD, et al. Enhanced Cis-platinum ototoxicity in children with

Wanamaker JR, Kraus DH, Biscotti CV, Eliachar I. Undifferentiated nasopharyngeal carcinoma presenting as a parotid mass. Head Neck. 1994 Nov-Dec; 16(6):589-93. Wang X, Hu C, Eisbruch A. Organ-sparing radiation therapy for head and neck cancer. Nat

brain tumours who have received simultaneous or prior cranial irradiation. Med

and head and neck surgery, 7th ed., 2008; vol-2: ch188: 2445-74..

Rev Clin Oncol. 2011 Jul 26. doi: 10.1038/nrclinonc.2011;106.

patients: a new indication. Otol Neurotol. 2009 Jun; 30(4):496-501.

nasopharyngeal carcinoma. Laryngoscope; 1993 Jun; 103(6): 673-78.

secretory otitis media in the presence of nasopharyngeal carcinoma. Clin

hearing system for hearing-impaired post-irradiated nasopharyngeal cancer

electromyographic studies of tensor veli palatini muscles in patients with

chemotherapy and radiation therapy: case report. J Am Acad Audiol. 1993 Nov;

tube. Temporal bone histopathology of functional tubal obstruction. Ann Otol

'postmitotic apoptosis'. J Cell Mol Med. 2001 Jul-Sep; 5(3):240-53.

Singapore Cancer Registry Interim Report 2001-2005

4:360-63.

Kong, 1991; 105-44.

Pedia Oncol. 1989; 17:48-52.

parotid. Clin Oncol. 1991 Jul; 3 (4):217–19.

Otolaryngol Allied Sci. 1991 Oct; 16(5):480-82

Rhinol Laryngol. 1986 Jan-Feb; 95: 101-105.

J Otolaryngol. 1979 Oct; 8 (5):396-400.

Ann Otol Rhinol Laryngol. 1991 Jul; 100(7): 544–51

extension of nasopharyngeal carcinoma. Head and Neck. 1992 Jan-Feb; 14(1): 19-23.

agents. Otolaryngol Clin North Am. 2004 Oct; 37(5): 973-90.


Miettinen S, Laurikainen E, Johansson R, Minn H, Laurell G, Salmi TT. Radiotherapy

Miura T, Hirabuki N, Nishiyama K, Hashimoto T, Kawai R, Yoshida J, Sasaki R, Matsunaga

Pacholke HD, Amdur RJ, Schmalfuss IM, Louis D, Mendenhall WM. Contouring the middle

Pow EH, Kwong DL, McMillan AS, Wong MC, Sham JS, Leung LH, Leung WK. Xerostomia

Pringle MB, Jefferis AF, Barrett GS. Sensorineural hearing loss caused by metastatic prostatic

Proud GO, Odoi H, Toledo PS. Bullar pressure changes in eustachian tube dysfunction. Ann

Raaijmakers E, Engelen AM. Is sensorineural hearing loss a possible side effect of

Ralston A, Stevens G, Mahomudally E, Ibrahim I, Leckie E. Cochlear implants: response to therapeutic irradiation. Int. J Radiat Oncol Biol Phys 1999 Apr; 44(1):227–31. Ramsden RT. Acoustic neuroma. In: Booth JB, Kerr AG. Scotts-Brown otolaryngology:

Ramsden RT, Bulman CH, Lorigan BP. Osteoradionecrosis of the temporal bone. J Laryngol

Rudge FW.Osteoradionecrosis of the temporal bone: Treatment with hyperbaric oxygen

Rybak L. P, Whitworth C. A. Ototoxicity:therapeutic opportunities. Drug Discov Today;

Sadé J. The nasopharynx, Eustachian tube and otitis media. J Laryngol Otol. 1994 Feb; 108:

Sadé J, Luntz M. Gas diffusions in the middle ear. Acta Otolaryngologica (Stockholm); 1991;

Schell M, McHaney VA, Green AA, Kun LE, Hayes FA, Horowitz M, Meyer WH. Hearing

Schuknecht HF, Karmody CS. Radionecrosis of the temporal bone. Laryngoscope; 1966 Aug;

loss in children and young adults receiving cisplatin with and without prior cranial

nasopharyngeal and parotid irradiation? A systematic review of the literature.

carcinoma: a case report. J Laryngol Otol. 1993 Oct; 107(10):933-4.

Otol Rhinol Laryngol. 1971 Dec; 80(6):835-7.

otology, 5th ed. London: Butterworth, 1987; 500–33

Radiother Oncol. 2002 Oct; 65(1): 1-7.

therapy. Mil Med. 1993 Mar; 158(3):196-8.

irradiation. J Clin Oncol. 1989 Jun; 7(6):754-60.

Otol. 1975 Sep; 89:941-55.

2005 Oct; 10(9):1313-21.

95-100.

111(2): 354-57.

76(8):1416-28.

skull base and intracranial involvement. Cancer. 1990 Jan; 65(1): 29-37. Myers EN, Beery QC, Bluestone CD, Rood SR, Sigler BA. Effect of certain head and neck

Ann Otol Rhinol Laryngol Suppl. 1984 Nov-Dec; 114:3-16.

58(4): 1194-207.

94.

143-47.

981-91.

children with primary brain tumors. Int J Radiat Oncol Biol Phys. 2004 Mar 15;

enhanced ototoxicity of cisplatin in children. Acta Otolaryngol Suppl. 1997; 529:90-

T, Kozuka T. Computed tomographic findings of nasopharyngeal carcinoma with

tumors and their management on the ventilatory function of the eustachian tube.

and inner ear on radiotherapy planning scans. Am J Clin Oncol. 2005 Apr; 28(2):

and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys. 2006 Nov; 66(4):


Wei WL., Lund VJ, Howard, DJ. Serious otitis media in malignancies of the nasopharynx and maxilla. Journal of Laryngol and Otol. 1988 Feb; 102(2): 129-32.

**10** 

**Update on Medical Therapies of** 

Nasopharyngeal carcinoma (NPC) is a common head and neck cancer in most of the countries of the Mediterranean Area (MA) and North Africa (NA). Its incidence is variable from <1 in sporadic areas to 2-7/100000 in NA and MA to 20-30/100000 in Southern China and Southeast Asia (Boussen et al,2010; Lee et al, 1992). It's different from other head and neck cancers due to its particular epidemiology, natural history and therapeutic

It's highly radiosensitive and chemosensitive. Loco-regional radiotherapy (RT) remains the primary treatment for early stage disease (T1-T2, N0, N1), while combined chemotherapyradiotherapy became the gold therapeutic standard in locally advanced disease i.e T3-T4, N2-N3 (Boussen et al, 2010; Lee et al, 1992; Baujat et al, 2006). Combined treatment leads to a significant improvement on overall and disease-free survivals, but NPC remains at a high metastatic risk, requiring the search for new salvage therapeutic protocols (Boussen et al, 2010; Lee et al, 1992: Xu et al, 2010). This paper will focus on recent data on epidemiology

NPC represents 2 to 5% of all cancers in males, it is second to laryngeal cancer in most of the Mediterranean countries ant its incidence varying from 1 in Lebanon, Egypt, Greece, Turkey to 2-5/100000 in North Africa (NA), where it's characterized by a bimodal age repartition with a first peak at adolescence (Boussen et al, 2010; Ben Abdallah M, 2010). This high frequency of children and adolescents affected by NPC in Tunisia open the discussion to reach the maximum cure rate with minimal late aftereffects (Boussen et al, 2010). Endemic NPC is highly frequent in south-east Asia with an incidence > 20/100000 compared to NA (Tse et al, 2006). During the last 10 years, authors from Singapore reported a decrease of NPC incidence especially for UCNT type. This epidemiologic transition could be attributed to a socio-economic level increase as well as diet modification, such as salted fish (rich in nitrosamines) consumption decrease (Tse et al, 2006). The same trend have been observed

**1. Introduction**

considerations (Boussen et al, 2010; Lee et al, 1992).

and progresses on medical therapies in NPC.

**2. Transitional epidemiology of NPC** 

**Nasopharyngeal Carcinoma** 

Soumaya Labidi, Selma Aissi, Samia Zarraa,

Farouk Benna and Hamouda Boussen

Said Gritli, Majed Ben Mrad,

*Faculty of Medicine of Tunis,* 

*University of Tunis* 

*Tunisia* 

