Aga - Mac - Dati - PS - Tumori 1/03 - Rosenblatt - S.

Tumori, 89: 68-74, 2003

LATE VISUAL AND AUDITORY TOXICITY OF RADIOTHERAPY FOR NASOPHARYNGEAL CARCINOMA Edward Rosenblatt1,2, Olga R Brook1, Nurit Erlich3, Benjamin Miller2,3, Henry Z Joachims2,4, and Abraham Kuten1,2 1

Department of Oncology, Rambam Medical Center, Haifa; 2The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa; 3Department of Ophthalmology, Rambam Medical Center, Haifa; 4Department of Otolaryngology, Rambam Medical Center, Haifa, Israel

Aims and background: Classical irradiation of carcinoma of the nasopharynx involves large fields and high doses; therefore, significant late toxicity and late side effects are to be expected. Given the fact that nasopharyngeal carcinoma (NPC) is a relatively radiosensitive disease and a significant proportion of patients are long-term survivors, late visual and auditory complications of treatment are of utmost concern for patients and radiation oncologists. The aim of this study was to evaluate the long-term visual and auditory toxicity in patients treated with radiotherapy for NPC. Methods and study design: Forty-three long-term survivors (including 11 children), following definitive radiotherapy for NPC, underwent a thorough visual and auditory evaluation 2-22 years after their treatment. Ophthalmological examination consisted of anamnesis of dry eye syndrome and visual acuity, visual acuity testing, slit-lamp examination, Schirmer test, fundus examination, and intraocular pressure measurement, as well as fluo-

rescein angiography in patients with pathological vascular findings in the fundus examination. Audiological evaluation included anamnesis of hearing loss, tinnitus or vertigo, examination of the ears and nasopharynx, audiogram, and tympanogram. Results: Radiation retinopathy was found in 16% of patients by fundus examination, with one patient (2.3%) developing blindness. Severe dry eye syndrome was present in 26%. Fifty-six percent had some degree of hearing impairment, with 74% showing severe sensorineural hearing loss. Fifty-eight percent of patients reported tinnitus and 26% reported suffering from dizziness. Radiation retinopathy as well as all manifestations of auditory toxicity were found to bear a direct correlation with dose per fraction. Conclusions: Unless there is tumor involvement, the orbital contents should be completely excluded from the target volume. Auditory toxicity is significant when treating NPC with two-dimensional techniques.

Key words: auditory, nasopharynx, ocular, radiotherapy, toxicity.

Introduction

Classical irradiation of carcinoma of the nasopharynx involves large fields and high doses; therefore, significant late toxicity and late side effects are to be expected. Given the fact that nasopharyngeal carcinoma (NPC) is a relatively radiosensitive disease and a significant proportion of patients are long-term survivors, late visual and auditory complications of treatment are of utmost concern for patients and radiation oncologists. The rate of late visual and auditory complications after radiation therapy is not clearly established, particularly in children. Israel is located in the intermediate risk zone for NPC, with an incidence of 1.3 cases per 100,000 population 1. The epidemiology and treatment results in Northern Israel have been reported previously2. The following is an evaluation of 43 patients considered cured of nasopharyngeal carcinoma and an assessment of the potential long-term impact of radiation therapy on their visual and auditory function. Material and methods

Fifty-one long-term survivors considered disease-free were identified from the follow-up files of our outpatient clinic. Three were lost to follow-up, two were hos-

pitalized in psychiatric and geriatric facilities, and four declined to participate in the study. Forty-three patients agreed to participate in the visual-auditory assessment and constitute the study group. This population’s characteristics are presented in Table 1. There were 32 male (72%) and 11 female (28%) patients. The mean age at diagnosis was 36 years (range, 9-68 years). The group included 11 children treated with radiation therapy for NPC. Treatment technique All patients were irradiated with curative intent. Radiotherapy was given 2-22 years before the present evaluation. It consisted of a mean dose of 6645 cGy (range, 5000-7440 cGy) to the nasopharyngeal tumor and clinically positive lymph nodes, and 4875 cGy (range, 4500-7000 cGy) to the clinically negative neck, in 180-200 cGy fractions over seven weeks. The treatment technique consisted of two lateral coaxial ports, including the nasopharyngeal tumor and its extensions as well as the upper neck lymph nodes. A lower anterior field treated the lower neck and both supraclavicular regions. In patients without base of skull involvement, the upper border of the lateral fields was placed at the level of or immediately below the pituitary fossa. In patients with known or suspected base of skull involvement, the upper border of the lateral fields was placed 1.5 cm

Correspondence to: Dr Edward Rosenblatt, Department of Oncology, Rambam Medical Center, POB 9602, 31096 Haifa, Israel. Tel +972-4-8543154; fax +972-4-8542929; e-mail [email protected] Received May 5, 2002; accepted August 22, 2002.

69

TOXICITY OF RADIOTHERAPY IN NASOPHARYNGEAL CARCINOMA

Results

Total number of patients Males/females Mean age (range) Number of pediatric patients Mean age of pediatric patients (range) No. at NPC Stage I* No. at NPC Stage II No. at NPC Stage III No. at NPC Stage IV Mean total dose to nasopharyngeal tumor Mean total dose to the clinically negative neck Number of patients receiving chemotherapy

43 32/11 36 (9-68) 11 14 (9-18) 2 1 6 34 6645 cGy 4875 cGy 32 (74%)

*The staging classification used for this series of patients was the AJCC/UICC 1992 edition. NPC, nasopharyngeal carcinoma.

above the pituitary fossa for the first 50 Gy, and then a cone-down boost was given to the nasopharyngeal tumor, with the upper border moved below the level of the pituitary fossa but still covering the base of the skull; the total dose was taken to 66-70 Gy in this reduced target volume. Radiation therapy doses to the posterior retina, optic nerve, lacrimal gland, and auditory apparatus were retrospectively estimated from simulation films, portal films, and isodose distributions. Before 1997, 32 patients (74%) received two or three courses of induction chemotherapy with cisplatin and 5-fluorouracil prior to definitive radiotherapy. Ophthalmologic examination consisted of anamnesis of dry eye syndrome (keratoconjunctivitis sicca) and visual acuity, visual acuity testing, slit lamp examination, Schirmer test, fundus examination, and intraocular pressure measurement, as well as fluorescein angiography in patients with pathological vascular findings in the fundus examination. The Amoaku classification of radiation retinopathy (RR) was used3,4. Dry eye syndrome was defined as “severe” if the Schirmer test was 0 mm in any eye and “moderate” if the test value was between 0 and 10 mm. Above 10 mm, the test was considered normal. Audiological evaluation included anamnesis of hearing loss, tinnitus or vertigo, examination of the ears and nasopharynx, tympanogram, and audiogram. Objective hearing loss was defined as a sound reception threshold of more than 25 dB in the audiogram. Significant sensorineural hearing loss (SNHL) was defined as a ≥20 dB increase in bone conduction threshold at one given frequency, as recommended by the American Speech and Hearing Association. Statistical analysis All results are expressed as means. Comparisons between two means were performed using two-sample dtest (t-distribution). Comparisons between several groups’ means were done using one-way analysis of variance (F distribution). Comparison of two proportions was done with the z-test and tested under normal distribution. Comparison of several proportions was performed with the use of the chi-square test and tested under contingency tables. Statistical significance was set at P <0.05 (by two-tailed testing).

Median follow-up was 64 months. Ocular toxicity Radiation retinopathy. In seven of the 43 patients (16%) fundus examination revealed objective signs of RR, with one of them (2.3%) developing bilateral blindness. These included six adult males and one 14-yearold girl, who had received radiation therapy for a mean period of 111 months (9.2 years) prior to assessment. There was a trend to develop RR for patients treated at a younger age (mean, 37 years of age at diagnosis of NPC) compared with patients without RR (mean, 45 years of age at diagnosis). The radiotherapy dose given to the nasopharyngeal tumor was greater for patients with RR (6917 cGy) than for patients without RR (6700 cGy) (P = 0.08). The dose received by the posterior orbit was higher for patients with RR (6660 cGy) than for patients without RR (5464 cGy) (P = 0.01) (Figure 1). Dose per fraction was larger for patients with RR (194 cGy) than for patients without RR (188 cGy) (P = 0.14). Dry eye syndrome. Eleven patients (26%), eight males and three females, with severe dry eye syndrome were identified. Sixteen patients (38%) had moderate dry eye syndrome. Overall, 64% of the patients had an impaired (“moderate” plus “severe”) Schirmer test: 18 of 32 males and nine of 11 females. Patients with a Schirmer test of 0 mm were older at diagnosis (50 years) as compared with patients with a Schirmer test of between 0 and 10 mm (41 years) (P = 0.08), not including pediatric patients. When pediatric patients were included, the difference was more striking. The dose to the lacrimal gland compartment was retrospectively calculated from simulation and portal films. Patients with a pathological Schirmer test were found to have received a mean dose of 34.2 Gy, while those with a normal test received a mean of 24 Gy (P = 0.001) (Figure 2). No significant difference in elapsed time from treatment, total dose to the nasopharynx, or fraction size was found between these two groups. Auditory toxicity Hearing deficit. Twenty-four of the 43 patients (56%), 16 males and eight females, had some degree of

cGy

Table 1 - Patient and treatment characteristics

7000 6000 5000 4000 3000 2000 1000 0

6660 5464 Radiation retinopathy No radiation retinopathy

P = 0.01 Figure 1 - Total dose to the posterior orbit received by patients with and without radiation retinopathy.

E ROSENBLATT, OR BROOK, N ERLICH ET AL

clinical hearing deficit in either ear. Eighteen of these patients (75%) were found to have objective bilateral hearing loss; six patients (25% of those with hearing loss) had unilateral impairment. The average age at diagnosis was higher for adult patients with hearing loss (47 years) than for adult patients without this deficit (36 years) (P = 0.001, SD = 9.57). When pediatric patients were included, the difference was even larger. Mean elapsed time from radiotherapy was longer for the group with hearing loss (108 months) than for the group without hearing loss (61 months) (P = 0.017). Mean total dose delivered to the nasopharynx was not significantly different between the two groups: 6761 cGy in the hearing-impaired group vs 6718 cGy in the nonhearing-impaired group. Fraction size was larger for patients with hearing impairment compared with those without (191 cGy vs 185 cGy) (P = 0.03). Fewer patients with hearing impairment received cisplatin-containing chemotherapy (67% vs 84%, P = 0.19). SNHL. Significant SNHL was found in 32 of the 43 patients (74%), 20 males and 12 females. In 26 of these (81%) the SNHL was bilateral. Six other patients (19%) had unilateral SNHL. The mean age at diagnosis was higher for patients with SNHL (45 years) than for patients without this abnormality (31.5 years) (P = 0.001). Mean elapsed time from radiotherapy was 88 months for patients with SNHL and 84 months for patients without SNHL (P = 0.85). Mean total dose to the nasopharynx was not found to be significantly different between the two groups. Fraction size was larger in the group with SNHL than in the group without SNHL (193 cGy/fraction vs 186 cGy/fraction, P = 0.084) (Figure 3). Fewer patients received cisplatin-containing chemotherapy in the group with SNHL (69%) than in the group without SNHL (91%) (P = 0.15). Tinnitus. Twenty-five of the 43 patients (58%) reported tinnitus. Patients with tinnitus had an average age at diagnosis of 46 years compared with 40 years for patients without this symptom. Mean time interval from radiotherapy was 102 months for patients with tinnitus compared with 67 months for patients without tinnitus (P = 0.08). Four percent of patients with tinnitus reported being exposed to noise as compared with 16.7% of patients without tinnitus (P = 0.16).

cGy

4000 3000

3424 Impaired Schirmer 2404

2000

Normal Schirmer

1000 0 P <0.001 Figure 2 - Total dose of radiation received by patients with a normal and impaired Schirmer test.

Percentage of patients

70 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

dizziness P = 0.03

tinnitus P = 0.22

impaired SRT P = 0.04

175,180cGy

SNHL P = 0.54

200cGy

Figure 3 - Dose per fraction relative to all four forms of auditory toxicity (dizziness, tinnitus, sound reception threshold (SRT) and sensorineural hearing loss (SNHL)). A significant correlation was found for dizziness, SRT and SNHL.

Dizziness. Eleven of the 43 patients (26%) reported suffering from dizziness following radiotherapy. Mean time interval from radiotherapy was 117 months for patients with dizziness compared with 77 months for patients without this symptom (P = 0.16). Mean dose per fraction was 195 cGy for patients with dizziness compared with 187 cGy for patients without dizziness (P = 0.03) (Figure 3). Pediatric patients Eleven of the 43 patients were children, with a mean age of 14 years (range, 9-18 years). One child (9%) had RR grade 1, and in another three (27%) visual acuity was mildly impaired. Two children (18%) had an abnormal Schirmer test, one of them severe. Hearing function was impaired in two pediatric patients (18%), one of them being totally deaf. Four patients (37%) developed SNHL, and five (46%) reported tinnitus. Discussion

The established treatment modality for NPC is definitive radiation therapy5-7. Some recently published series have corroborated the benefit of adding chemotherapy, particularly in advanced stage disease8,9. The incidence of mild or moderate late complications after radiation therapy is difficult to evaluate from the literature, as usually only severe complications are reported10. The classical 2-D technique of radiotherapy for NPC11 emphasized inclusion of the nasopharynx proper, the posterior 2 cm of the nasal cavity, the posterior ethmoid sinuses, the entire sphenoid sinus and basiocciput, the cavernous sinus, the base of the skull, the pterygoid fossae, the posterior third of the orbits, the posterior third of the maxillary sinuses, the lateral and posterior oropharyngeal wall to the level of the midtonsillar fossa, and the retropharyngeal nodes. The anterior margin of the lateral field was drawn from the external canthus inferiorly until the upper neck posterior to the submandibular gland, clearly including the posterior third of the orbital cavity. The patients analyzed in the present study were treated according to these guidelines.

TOXICITY OF RADIOTHERAPY IN NASOPHARYNGEAL CARCINOMA

Since 1998 the upper and anterior margins of the field have been modified, completely excluding the orbital contents from the initial treatment volume. Fletcher and Million11 and Mendenhall et al.12 include the posterior fourth of the orbit in the initial treatment volume. However, the standard fields used at the Mallinckrodt Institute of Radiology do not include the orbit because orbital recurrence has not been observed13. The tolerance of the eye and optic pathway is dose-limiting in radiotherapy for patients with neoplasms located in the vicinity of the orbit. Clearly, knowledge of the radiation dose-response characteristics of the various tissues of the visual pathways is essential for making rational decisions regarding the total radiation dose and the choice of treatment portals. Parsons et al.14 published a detailed analysis of radiation damage to the retina in a series of 64 patients treated with radiotherapy for a variety of head and neck cancers, including three patients with NPC. Their results indicated that doses in the 45-55 Gy range delivered to half or more of the retina produced a 53% rate (eight of 15 eyes) of retinopathy, with the risk being increased by diabetes mellitus (two eyes), chemotherapy (two eyes), and a higher-than-standard dose per fraction (two eyes received more than 3 Gy/fraction). If these six eyes with unusual risk factors were excluded from the analysis, the rate of occurrence of retinopathy in the 45-55 Gy range would be 22% (2/9 eyes). RR was not observed at doses below 45 Gy to the retina in 64 treated patients, but increased steadily in incidence at doses in excess of 45 Gy. In the present series 16% of 43 patients showed objective signs of RR, with one patient (2.3%) developing blindness. A number of reports have implicated diabetes mellitus as a factor increasing the risk for retinopathy. There were no patients with diabetes in the present series. A trend toward increased incidence of RR was observed in patients treated with a mean dose per fraction of 1.94 Gy as compared with those who received mean doses of 1.88 Gy/fraction. The series reported by Parsons et al.14 showed a correlation between dose per fraction and the development of radiation damage to the optic pathways. In their guidelines for the prevention of radiation-induced eye injury, Million and Parsons15 recommended the routine use of doses of less than 1.9 Gy/fraction. In a total of 215 optic nerves irradiated in 131 patients16, optic neuropathy was observed in 17 (8%). Anterior ischemic optic neuropathy developed in five nerves, and retrobulbar optic neuropathy in 12 nerves. No injuries were observed in 106 optic nerves that received a total dose of less than 59 Gy. Among nerves that received doses higher than 60 Gy, the dose per fraction was more important than the total dose in producing optic neuropathy. The 15-year actuarial risk of optic neuropathy after doses higher than 60 Gy was 11% when treatment was administered in fraction sizes of less than 1.9 Gy compared with 47% when treatment was given in fraction sizes of higher than 1.9 Gy.

71

In an analysis of 219 patients treated for various cancers of the nasal cavity and paranasal sinuses, Jiang et al. 17 found symptomatic retinopathy in seven of 77 (9%) patients who received irradiation to a relatively large retinal surface. It is noteworthy that most cancers arising in this region are diagnosed at an advanced stage, and orbital structures are often within the target volume of high-dose irradiation. None of the patients receiving a dose of less than 50 Gy developed optic neuropathy or chiasm injury. In contrast, the 10-year actuarial incidences of optic nerve chiasm injury were 5% and 30% for patients receiving 50-60 Gy and 61-78 Gy, respectively. Here again, a 30% rate of optic neuropathy was reported in patients receiving total doses of 61-78 Gy, clearly exceeding the known tolerance of the optic nerve. In the MD Anderson series17, the Cox proportional hazards model was applied to fit the linear-quadratic model to their data. The aim was to estimate the α/β ratios for radiation injury to the various components of the visual pathway. The low values found suggested that these structures should behave as late-responding tissues and have a relatively high sensitivity to dose per fraction. This has important implications when considering possible strategies to avoid late radiation damage to these structures15. The results of the present series are in agreement with the results reported by Jiang et al.17 The posterior orbit, including at least part of the optic nerve and the retina, may have received doses in the order of 54-66 Gy in 1.8-2.0 Gy/fraction, as retrospectively estimated from simulation films, portal films, and isodose distributions. Midena et al.18 reported that four of 11 (36%) patients with NPC who were treated with 70 Gy developed symptomatic RR, 24-108 months after treatment. Fluorescein angiography demonstrated widespread areas of retinal ischemia and neovascularization. In the present series the posterior third of both eyes received progressively increasing doses, from 50 to 65 Gy. Retinopathy is a rare condition resulting from blood vessel proliferation in response to some insult. Its most common causes are diabetes and radiation. No patients in this series had diabetes; thus, the presence of retinopathy is probably attributable to the radiation effect. Considering the results of this and previous investigations, it becomes apparent that the inclusion of the posterior orbit should not be considered standard practice in radiotherapy of NPC. The dose to the lacrimal gland at which dry eye syndrome begins to occur is about 30 Gy, and the incidence increases to 100% at 55-60 Gy.15 In a series by Parsons et al.19, 20 of 33 (60%) patients treated to the entire orbit developed severe dry eye syndrome. All 17 patients who received doses higher than 57 Gy developed this complication. Three of 16 patients (19%) who received doses of less than 45 Gy developed severe dry eye syndrome. The authors described a sigmoid dose-response curve for dry eye syndrome that increased dramatically between 30 and 57 Gy. The present results are in accordance with the findings of Parsons: patients with a

72

pathological Schirmer test were found to have received a mean dose of 34.2 Gy to the lacrimal gland as compared with those with a normal test, who received a mean of 24 Gy (P = 0.001). The dose per fraction in the present series was not found to be significantly different between these two groups. In early tumors of the nasopharynx (T1, T2) the upper border of the radiation field is classically placed splitting the pituitary fossa and extending anteriorly along the sphenoidal plate11. When drawing the blocks for radiation therapy, an attempt is made to shield the pituitary gland and the bony auditory canal as seen in the simulation radiographs. This is done without compromising a 1.5 to 2.0 cm margin from the known nasopharyngeal tumor and its extensions. Therefore, in some cases the edge of the irradiation field will fall at the level of the bony auditory canal, meaning that the middle and inner ear may lie at least at the edge of the field. For lesions with any base of skull involvement (T3, T4), the superior border should be at least 1.0-1.5 cm above the pituitary fossa. In these patients no attempt is made to protect the pituitary gland or the ear structures for the first 45-50 Gy. In patients treated with two-dimensional techniques the incidence of otitis has been reported to be from 3% to 14%12, with a 45% binaural hearing disability20. The reported incidence of deafness ranges from 1% to 7%, with 8% of patients having significant hearing impairment and 3% having bilateral deafness12. In the present series the dose per fraction was found to be an adverse factor for the development of dizziness, impaired sound reception threshold (SRT), and sensorineural hearing loss (SNHL). (We are aware of the fact that these patients did not have a baseline audiogram before therapy, which was a major limitation, as deficits could have been due either to natural aging or to the disease itself.) Patients treated with doses of 175-180 cGy/fraction had a 79% incidence of late auditory complications, while in patients who received 200 cGy/fraction the incidence of late auditory complications was 94.7% (P = 0.14). Grau et al. 21, reporting on 22 patients evaluated after external irradiation for NPC, observed a significant correlation between decreased hearing and radiation doses. When the regression lines for each frequency were plotted against the cochlear dose, all slopes were significantly different from zero, including correction for age. SNHL was more pronounced at high frequencies with values up to 35 dB. The latency period for this complication appeared to be 12 months or longer. A relatively high incidence (58%) of tinnitus was recorded in the present series. It is difficult to conclude that this and other auditory symptoms were radiationinduced, because patients did not have a consistent auditory assessment before radiotherapy. It is well known that patients with NPC frequently present with hearing loss and tinnitus due to eustachian tube dysfunction22. Lau et al.23 described prolonged tinnitus in 14 of 49 patients treated with irradiation for NPC. However, before radiation therapy 11 of 49 patients complained of tinni-

E ROSENBLATT, OR BROOK, N ERLICH ET AL

tus as a presenting symptom of NPC. In addition, four of 49 patients also had hearing loss due to the tumor. Tinnitus developed during or after completion of radiation therapy in 24 patients (49%) who did not have this symptom prior to treatment. Fourteen (29%) continued to complain of intermittent tinnitus 12 months after treatment. The influence of chemotherapy on auditory toxicity is problematic. Most recent chemotherapy combinations have included cisplatin, in itself a known ototoxic drug. Since cisplatin is also a radiosensitizer, its synergistic effect on the auditory apparatus when given concomitantly with radiotherapy cannot be excluded. Ototoxicity is a cumulative and irreversible side effect of cisplatin treatment that has been reported in approximately 31% of treated patients. The initial audiographic manifestation is loss of high-frequency range acuity (4000 to 8000 Hz). Choi et al.24 observed significant SNHL in 17 of 24 patients (71%) treated with radiotherapy and cisplatinbased chemotherapy. The mean radiation dose to the cochlea was 6814 cGy, with a positive correlation between the radiation dose to the cochlea and the degree of SNHL. In the present series a correlation between cisplatin therapy and auditory toxicity was not found. This coincides with the results of Kwong et al. 25, who found that a low dose of preirradiation cisplatin did not increase the risk of SNHL. Most information regarding ocular toxicity of radiation therapy in pediatric patients derives from the treatment of retinoblastoma. This is a very different clinical scenario, in which the eye itself is the main target of radiation. In this context the incidence of radiation cataract is 85-100%26 and can be reduced to about 28% with the use of lens-sparing techniques27. Keratitis as a late effect of irradiation for retinoblastoma has been reported with varying frequency: 28% by Imhof et al.28 and 13% by Fontanesi et al.26. In the present study the radiation dose received by the posterior orbit may explain retinal changes seen in one patient and mild visual deterioration in three. The auditory apparatus is frequently irradiated in children treated for brain tumors. Cranial irradiation alone rarely has a significant effect on hearing. However, the combination of radiation and cisplatin, or radiation followed by cisplatin, may produce a significant hearing impairment29. In the present study we identified one child with clinical deafness, another with hearing impairment, and four with SNHL. Innovative techniques of radiation delivery may prove beneficial in reducing the overall incidence of visual and auditory toxicity in the treatment of NPC. A brachytherapy boost to the nasopharyngeal cavity can be given either with cesium-137 sources30 or with iodine-125 seeds31 following 60 Gy of external irradiation. Three-dimensional conformal radiotherapy and intensity-modulated radiation therapy are innovative tools which have been shown to reduce the potential for toxicity32,33.

73

The findings in the present study suggest that an attempt should be made to completely exclude the visual apparatus during radiotherapy when using classical twodimensional techniques. An incidence close to 50% of late hearing deficit is to be expected, as the middle and inner ears are usually included in the target volume when using this technique. Visual toxicity and some forms of auditory toxicity appear to be dependent on fraction size (Figure 4). Thus, the use of a fraction size of 1.8 Gy rather than 2.0 Gy is warranted. Future investigative efforts to minimize visual and auditory toxicity should include radiation-protective agents and organ sparing using intensity-modulated radiation therapy (IMRT).

Percentage of patients

TOXICITY OF RADIOTHERAPY IN NASOPHARYNGEAL CARCINOMA

100% 95% 90% 85% 80% 75% 70% Any auditory complication, P = 0.14 175-180cGy

200cGy

Figure 4 - Dose per fraction relative to the rate of all forms of auditory toxicity.

References 1. Israel Cancer Registry, Jerusalem, 2000. 2. Kuten A, Cohen Y, Lavie R, Dale J, Ben Arush MB, Goldberg H, Stein M: Update on nasopharyngeal carcinoma in northern Israel. Strahlenther Onkol, 170: 565-570, 1994. 3. Amoaku WM, Archer DB: Fluorescein angiographic features, natural course and treatment of radiation retinopathy. Eye, 4: 657-667, 1990. 4. Gordon KB, Char DH, Sagerman RH: Late effects of radiation on the eye and ocular adnexa. Int J Radiat Oncol Biol Phys, 31: 1123-1139, 1995. 5. Laramore GE, Clubb B, Quick C, Amer MH, Ali M, Greer W, Mahboubi E, El-Senoussi M, Schultz H, Al-Ekkad SM: Nasopharyngeal carcinoma in Saudi Arabia: a retrospective study of 166 cases treated with curative intent. Int J Radiat Oncol Biol Phys, 15: 1119-1127, 1988. 6. Johansen LV, Mestre M, Overgaard J: Carcinoma of the nasopharynx: analysis of treatment results in 167 consecutively admitted patients. Head Neck, 14: 200-207, 1992 7. Lee AWM, Poon WF, Foo W, Law SCK, Cheung FK, Chan DKK, Tung SY, Thaw M, Ho JHC: Retrospective analysis of 5037 patients with nasopharyngeal carcinoma treated during 1976-1985: overall survival and patterns of failure. Int J Radiat Oncol Biol Phys, 23: 261-270, 1992. 8. International Nasopharynx Cancer Study Group: VUMCA I Trial. Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs radiotherapy alone in stage IV (>N2, M0) undifferentiated nasopharyngeal carcinoma: a positive effect on progression-free survival. Int J Radiat Oncol Biol Phys, 35: 463-469, 1996. 9. Al-Sarraf M, LeBlanc M, Giri S, Fu KK, Cooper J, Vuong T, Forastiere AA, Adams G, Sakr WA, Schuller DE, Ensley JF: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup Study 0099. J Clin Oncol, 16: 1310-1317, 1998. 10. Zhang EP, Lian PG, Cai KL, Chen YF, Cai MD, Zheng XF, Guang XX: Radiation therapy of nasopharyngeal carcinoma: prognostic factors based on a 10-year follow-up of 1302 patients. Int J Radiat Oncol Biol Phys, 16: 301-305, 1989. 11. Fletcher GH, Million RR: Nasopharynx. In: Textbook of radiotherapy, 3rd ed, Fletcher GH (Ed), pp 364-383, Lea & Febiger, Philadelphia, 1980. 12. Mendenhall WM, Million RR, Mancuso AA: Nasopharynx. In: Management of head and neck cancer: a multidisciplinary approach, 2nd ed, Million RR, Cassisi NJ (Eds), pp 599-623, Lippincott, Philadelphia, 1994. 13. Perez CA: Nasopharynx. In: Principles and practice of radiation oncology, 3rd ed, Perez CA, Brady LW (Eds), pp 897939, Lippincott-Raven, Philadelphia, 1997. 14. Parsons JT, Bova FJ, Fitzgerald CR, Mendenhall WM, Mil-

15.

16.

17. 18. 19.

20. 21.

22. 23. 24.

25.

26.

27.

lion RR: Radiation retinopathy after external-beam irradiation: analysis of time-dose factors. Int J Radiat Oncol Biol Phys, 30: 765-773, 1994. Million RR, Parsons JT: Radiation-induced eye injury from head and neck therapy. In: Radiation injury: advances in management and prevention, Meyer JL (Ed), pp 21-33, S Karger, Basel, 1999. Parsons JT, Bova FJ, Fitzgerald CR, Mendenhall WM, Million RR: Radiation optic neuropathy after megavoltage external-beam irradiation: analysis of time-dose factors. Int J Radiat Oncol Biol Phys, 30: 755-763, 1994. Jiang GL, Tucker SL, Guttenberger R, Peters LJ, Morrison WH, Garden AS, Ha CS, Ang KK: Radiation-induced injury to the visual pathway. Radiother Oncol, 30: 17-25, 1994. Midena E, Segato T, Piermarocchi S, Corti L, Zorat PL, Moro F: Retinopathy following radiation therapy of paranasal sinus and nasopharyngeal carcinoma. Retina, 7: 142-147, 1996. Parsons JT, Bova FJ, Fitzgerald CR, Mendenhall WM, Million RR: Severe dry-eye syndrome following external beam irradiation. Int J Radiat Oncol Biol Phys, 30: 775-780, 1987. Low WK, Fong KW: Long-term hearing status after radiotherapy for nasopharyngeal carcinoma. Auris Nasus Larynx, 25: 21-24, 1998. Grau C, Møller K, Overgaard J, Overgaard J, Elbrønd O: Sensori-neural hearing loss in patients treated with irradiation for nasoharyngeal carcinoma. Int J Radiat Oncol Biol Phys, 21: 723-728, 1991. Young YH, Hsieh T: Eustachian tube dysfunction in patients with nasopharyngeal carcinoma pre- and post-irradiation. Eur Arch Otorhinolaryngol, 249: 206-208, 1992. Lau SK, Wei WI, Sham JS, Hui Y, Choy D: Effect of irradiation on middle ear effusion due to nasopharyngeal carcinoma. Clin Otolaryngol, 17: 246-250, 1992. Choi SL, Wolden SL, Pfister DG, Budnick AS, Levegrun S, Jackson A, Hunt MA, Zelefsky MJ, Singh B, Boyle JO, Kraus DH: Ototoxicity following combined modality therapy for nasopharyngeal carcinoma (abst). Int J Radiat Oncol Biol Phys, 48 (Suppl 3): 261, 2000. Kwong DLW, Wei WI, Sham JST, Ho WK, Yuen PW, Chua DTT, Au DKK, Wu PM, Choy DTK: Sensorineural hearing loss in patients treated for nasopharyngeal carcinoma: a prospective study of the effect of radiation and cisplatin treatment. Int J Radiat Oncol Biol Phys, 36: 281-289, 1996. Fontanesi J, Pratt CB, Kun LE, Hustu HO, Coffey D, Meyer D: Treatment outcome and dose-response relationship in infants younger than 1 year treated for retinoblastoma with primaryirradiation. Med Pediatr Oncol, 26: 297-304, 1996. Hernandez JC, Brady LW, Shields JA, Shields CL, DePotter P, Karlsson UL, Markoe AM, Amendola BE, Sing A: Exter-

74 nal beam radiation for retinoblastoma: results, patterns of failure, and a proposal for treatment guidelines. Int J Radiat Oncol Biol Phys, 35: 125-132, 1996. 28. Imhof SM, Hofman P, Tan KEWP: Quantification of lacrimal function after D-shaped field irradiation for retinoblastoma. Br J Ophthalmol, 77: 482-484, 199329. 29. McHanley V, Kavnar E, Meyer W: The effects of radiation therapy and chemotherapy on hearing. In: Late effects of treatment for childhood cancer, Green DM, D’Angio GJ (Eds), pp 7-10, John Wiley & Sons, New York, 1992. 30. Wang CC: Improved local control of nasopharyngeal carcinoma after intracavitary brachytherapy boost. Am J Clin Oncol, 14: 5-8, 1991.

E ROSENBLATT, OR BROOK, N ERLICH ET AL

31. Vikram B, Mishra S: Permanent iodine-125 (I-125) boost implants after external radiation therapy in nasopharyngeal cancer. Int J Radiat Oncol Biol Phys, 28: 699-701, 1994. 32. Kutchner GJ, Fuks Z, Brenner H, Brown AP, Burman C, Cheng E, Coia L, Krippner K, Manolis JM, Mohan R, Simpson JR, Urie M, Vikram B, Wallace R: Three-dimensional photon treatment planning for carcinoma of the nasopharynx. Int J Radiat Oncol Biol Phys, 21: 169-182, 1991. 33. Leibel SA, Kutcher GJ, Harrison LB,Fass DE, Burman CM, Hunt MA, Mohan R, Brewster LJ, Ling CC, Fuks ZY: Improved dose distributions for 3D conformal boost treatmentsin carcinoma of the nasopharynx. Int J Radiat Oncol Biol Phys, 20: 823-833, 1991.