CLINICAL OUTCOMES OF 174 NASOPHARYNGEAL CARCINOMA PATIENTS WITH RADIATION-INDUCED TEMPORAL LOBE NECROSIS

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1 doi: /j.ijrobp Int. J. Radiation Oncology Biol. Phys., Vol. 82, No. 1, pp. e57 e65, 2012 Copyright Ó 2012 Elsevier Inc. Printed in the USA. All rights reserved /$ - see front matter CLINICAL INVESTIGATION Head and Neck Cancer CLINICAL OUTCOMES OF 174 NASOPHARYNGEAL CARCINOMA PATIENTS WITH RADIATION-INDUCED TEMPORAL LOBE NECROSIS TAI-CHUNG LAM, F.R.C.R., z FRANK C. S. WONG, F.R.C.R., z TO-WAI LEUNG, M.D.,* S. H. NG, F.R.C.P., y AND STEWART Y. TUNG, F.R.C.R. z z Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong, People s Republic of China *Department of Clinical Oncology, Queen Mary Hospital, Hong Kong, People s Republic of China; and y Department of Medicine and Geriatrics, Tuen Mun Hospital, Hong Kong, People s Republic of China Purpose: To retrospectively study the clinical outcomes of nasopharyngeal carcinoma patients with radiationinduced temporal lobe necrosis (TLN) treated with steroids, surgery, or observation only. Methods and Patients: We performed a retrospective analysis of 174 consecutive patients diagnosed with TLN between 1990 and Before 1998, symptomatic patients were treated with oral steroids, while asymptomatic patients were treated conservatively. After 1998, most symptomatic and asymptomatic patients with a large volume of necrosis were treated by intravenously pulsed-steroid therapy with a standardized protocol. We examined factors affecting grade 4 complication-free survival and overall survival. Outcomes of the three treatment groups, those receiving conservative treatment, those receiving oral steroid, and those receiving intravenous pulse steroid, were compared. Results: The mean follow-up time was 115 months. Rates of grade 4 complication-free survival at 2 years and at 5 years after diagnosis of TLN were 72.2% and 54.1%, respectively. The 2-year and 5-year overall survival rates were 57.5% and 35.4%, respectively. Multivariate analysis revealed that being symptomatic at diagnosis (relative risk [RR], 4.5; p = ), re-irradiation of the nasopharynx (NP) (RR, 1.56; p = 0.008), salvage brachytherapy to the NP (RR, 1.75; p = 0.012), and a short latency period before the diagnosis of TLN (RR, 0.96, p < ) were independent prognosticators of poor grade 4 complication-free survival. Patients with all four factors had a 100% risk of developing grade 4 complications within 5 years; whereas if no factor was present, the risk was 12.5%. Intravenous pulse steroid therapy was associated with a higher clinical response rate compared with conventional steroid therapy (p <0.0001); however, it did not affect complication-free survival in multivariate analysis. Conclusions: TLN patients with good prognosticators could be observed without active treatment. Although treatment with intravenously pulsed steroid was associated with better clinical response than conventional steroid delivery, it did not affect the complication-free survival rate of TLN patients. Ó 2012 Elsevier Inc. Nasopharyngeal carcinoma, Radiotherapy, Temporal lobe necrosis, Neurosurgery, Pulsed steroid. INTRODUCTION Radiotherapy is an important curative treatment modality for nasopharyngeal carcinoma (NPC) (1). Due to the proximity of the nasopharynx (NP) to the skull base, part of the temporal lobe is inevitably included in the radiation field. Radiationinduced temporal lobe necrosis (TLN) has been a wellrecognized late complication, with a reported incidence ranging from 4.6% in 10 years (with conventional fractionation to 66 Gy) to 35% in 3.5 years (with accelerated hyperfractionation to 71.2 Gy) (2, 3). The incidence is particularly high among patients who have received re-irradiation for local recurrence, with an unsatisfactory 5-year central nervous system (CNS) complication-free rate ranging from 47.8% to 55.7% (4, 5). Patients with TLN usually present with mild symptoms of dizziness, forgetfulness, or temporal lobe epilepsy. Severe and even fatal complications of TLN, including convulsion, intracranial hemorrhage, mass effect causing herniation, and death, have occasionally been seen (6) (Fig. 1). A literature review retrieved a total of 308 cases of TLN after radiation for extracranial malignancy, 228 of which were NPC patients (7). The largest series of TLN patients reported dated back to 1988, in which 102 NPC patients treated with radiotherapy from 1964 to 1983 developed Reprint requests to: Tai-chung Lam, F.R.C.R., Department of Clinical Oncology, Tuen Mun Hospital, 15 Tsing Chung Koon Road, Tuen Mun, Hong Kong, People s Republic of China. Tel: ; Fax: ; lamtaichung@gmail. com e57 Presented at the 17th Annual Scientific Meeting of the Hong Kong College of Radiologists, Hong Kong, ROC, Oct Conflict of interest: none. Received June 21, 2010, and in revised form Nov 7, Accepted for publication Nov 22, 2010.

2 e58 I. J. Radiation Oncology d Biology d Physics Volume 82, Number 1, 2012 were treated with salvage brachytherapy with or without external beam radiotherapy (4). If radiological features of TLN were present at the time of diagnosis of the local recurrence, re-irradiation of the NP was not performed. All NPC patients had life-long regular clinical follow-up visits. TLN was diagnosed on the basis of magnetic resonance imaging (MRI) or computed tomography (CT) scanning of the brain, if they developed symptoms typical of TLN. TLN was also sometimes incidentally found during imaging studies performed to exclude local recurrence. Fig. 1. TLN presented as an emergency with increased intracranial pressure. TLN. Various treatment strategies for TLN were reported in the literature, including hyperbaric oxygen (8), antiplatelet (9), anticoagulant (9) and corticosteroid therapy (6), and neurosurgery(10). However, all reports were largely in the form of case series, while studies with large sample sizes of optimal treatments and outcomes were lacking. The Department of Clinical Oncology at Tuen Mun Hospital of Hong Kong treats more than 100 new cases of NPC each year. Treatment results have been published previously (4, 5, 11 14). In 1998, a neurooncology clinic was established in the department, and pulse steroid treatment for TLN patients was initiated. pulse steroid treatment was believed to be beneficial because it minimized long-term glucocorticoid-induced side effects and was better tolerated. Severe complications, including bradycardia, arrhythmia, and sudden death, have been rare (15, 16). The aim of this study was to summarize the clinical outcomes of patients with TLN, with special emphasis on the efficacy and safety of steroid treatment. METHODS AND MATERIALS Patients with NPC who have been treated or followed in our unit from 1990 to 2008 were included in this study. From 1990 to 1998, a two-dimensional radiotherapy technique was used to treat NPC (11). Conformal radiotherapy was introduced in the department in 1998 and intensity-modulated radiotherapy (IMRT) in Patients with persistent disease of the NP after radical radiotherapy underwent salvage high-dose-rate brachytherapy (13). Patients with an isolated local recurrence were salvaged by either reirradiation of the NP or nasopharyngectomy (4, 5). Patients with a short time to recurrence or with a small-volume recurrence Treatment protocol for TLN in Tuen Mun Hospital, Before 1998, patients with symptomatic TLN were treated with continuous oral corticosteroid (dexamethasone) therapy (6). The dosage was titrated according to the severity of symptoms. The usual dosage was 4 to 16 mg, daily, for 4 6 weeks, and then titrated off within 3 4 months. Asymptomatic TLN patients were treated by observation. After the establishment of a neurology clinic in the department in 1998, all TLN patients were treated and followed in the clinic, with joint assessment by oncologists and neurologists. Generally, all TLN patients were treated with pulse steroid, unless 1) the patient developed uncontrolled local, regional, or distant recurrence of NPC; 2) MRI with no contrast enhancement showed the TLN had undergone cystic change and no vasogenic edema, which implied late manifestation in TLN (17); 3) the patient was asymptomatic, and MRI showed small-sized TLN (classified as small if the tumor did not extend beyond a 60-Gy isodose line or was <1 cm); or 4) the patient was too old and frail and had poor performance status. In these exceptions, patients were followed by observation. Patients who were received pulse steroid therapy were followed with MRI at 6- to 12-month intervals. For asymptomatic, stable patients receiving conservative treatment or patients with metastatic NPC, follow-up radiological studies would be performed only if clinically indicated. Administration of pulsed steroid Pulse steroid, methylprednisolone, was administered by intravenous infusion over 3 consecutive days (18). Three grams of methylprednisolone was given in each cycle. Administration of 1 g was infused over 1 h daily for 3 days on an in-patient basis, which then tailed off in 10 days with administration of oral prednisolone. During intravenous infusion of steroid, patients were monitored with a cardiac monitor. For older patients or patients with known cardiovascular diseases, pulse steroid was given as 0.5 g daily for 6 days. If no complication was noted, further cycles of pulse steroid would be given every three to six months. If both the patient s symptoms and edema, as shown on MRI, were significant, pulse steroid would be given on a 3-month cycle. If the patient s condition and MRI findings showed stable improvement, pulse steroid would be given on a 6-month cycle. Patients were seen at 3 months for clinical assessment, and follow-up MRI was done yearly to assess the progress of TLN (Fig. 2). Pulse steroid therapy was stopped if 1) TLN was noted to undergo cystic change with no contrast enhancement; 2) TLN was noted to have completely resolved on MRI scan; or 3) the patient developed recurrence or metastases of NPC. Patients were given anticonvulsants if clinically indicated, as assessed by the neurologist. Patients were also referred to a neurosurgeon if TLN caused a potentially life-threatening mass effect.

3 Outcomes of temporal lobe necrosis in NPC patients d T.-C. LAM et al. e59 Fig. 2. Radiological improvement of TLN is shown after four cycles of pulsed steroid. Patient data retrieval All case notes (from 1 Jan 1990 to 31 Oct 2008) for patients with NPC who had been treated in Tuen Mun Hospital were retrieved through the clinical data analysis system of the Hospital Authority, Hong Kong. Progress notes and CT/MRI reports of every case were screened manually for the diagnosis of cerebral radionecrosis/temporal lobe necrosis. Demographic data, disease status, and treatment details of NPC and TLN, survival, complications of disease and treatment, and causes of death were recorded. Diagnosis of TLN relied on clinical features and radiological imaging as described in detail by Lee et al. (3). Due to the limitation of this retrospective study, data for quality of life and symptomatology were not analyzed, as it had not been routinely graded and recorded. The severity of TLN at diagnosis was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) under the category CNS necrosis/cystic progression, as follows: grade 1, asymptomatic, radiographic findings only; grade 2, symptomatic, not interfering with activities of daily living (ADL); medical intervention indicated; grade 3, symptomatic and interfering with ADL; hyperbaric oxygen therapy indicated; grade 4, life-threatening, disabling; operative intervention indicated to prevent or treat CNS necrosis/cystic progression; and grade 5, death. The severity of medical comorbidities of TLN patients was measured by using the Charlson Comorbidity Index (CCI) (19), a weighted index that takes into account the number and severity of comorbid diseases. It has been shown that different scores predict the risk of dying from comorbid disease in 10 years. The index has been validated in many patient groups including oncology patients (20). Definition of primary outcome Complications of TLN, including brain abscess formation and intracranial hemorrhage at the temporal lobe, were recorded. Complication-free survival of TLN patients was defined as the period between the starting date of primary radiotherapy to the NP and the onset of grade 4 TLN-associated complications or the patient s last follow-up date before 1 November Definition of secondary outcomes and complications Overall survival for TLN patients was defined as the period between the diagnosis of TLN and the death of the patient or the patient s last follow-up date before 1 November The efficacy of various treatments was assessed by radiological progress and posttreatment TLN severity grading. The former was classified as deteriorated, stable, or improved and was recorded according to the formal CT/MRI report made by radiologists. The latter was defined as the worst grade of TLN occurring during the follow-up period. Severe complications from oral steroid and pulse steroid therapy were reported. Causes of death were determined retrospectively after case notes were studied. The ethics committee of Tuen Mun Hospital had approved the study protocol. Statistical analysis All TLN patients were divided into three subgroup for further statistical analysis: 1) patients who received conservative treatment, 2) patients who received conventional oral steroid treatment with dexamethasone, and 3) patients who received pulse steroid treatment. Normally distributed data were expressed as means standard deviations (SD), and other continuous data were expressed as median values. Continuous variables were compared by using the Mann-Whitney U test. Categorical variables were compared using the chi-square test. Overall survival was analyzed by Kaplan-Meier survival curves, and comparisons among patient groups receiving different treatments were made by the log-rank test. Univariate analysis of factors predictive of survival was performed. Significant factors, determined as having a p value of <0.01, were recruited as independent factors in multivariate analysis using the Cox proportional hazard model. All reported p values were 2-tailed, and a p value of <0.05 was considered statistically significant. All analyses were performed using JMP IN version 5.1 software (SAS Institute Inc., Carey, NC). RESULTS Patient demographics and treatment of NPC During the period from Jan 1990 to Oct 2008, 174 TLN patients were identified and treated in the department. The

4 e60 I. J. Radiation Oncology d Biology d Physics Volume 82, Number 1, 2012 Table 1. Disease status at diagnosis and radiotherapy details Disease status No. of patients (%) NPC stage at initial diagnosis I 17 (9.9) II 57 (32.7) III 70 (40.1) IV 30 (17.3) T stage of NPC at initial diagnosis I 34 (19.5) II 68 (39.0) III 50 (28.9) IV 22 (12.6) TLN grade at diagnosis 1 78 (44.8) 2 48 (27.6) 3 34 (19.5) 4 14 (8.1) Re-irradiation of NP 89 (51.1) Primary RT technique 2D 157 (90.2) Conformal 15 (8.6) IMRT 2 (1.2) Second course of external RT technique 2D 41 onformal 12 IMRT 12 Stereotactic RT 16 Other/unknown 8 crude incidence rate of TLN was 5.6%. One hundred thirtytwo patients were male and 42 were female. Mean follow-up time was 115 months. Median age at diagnosis of TLN was 52.9 years old (SD, 10.9 years). Nearly half of the patients (45.3%) were asymptomatic for TLN on diagnosis, while 8% of the patients presented with grade 4 severity. The mean latency period of diagnosis of TLN since primary RT was 80.5 months (SD, 48.9). Local recurrence was diagnosed in 108 (62.1%) patients, and 89 (51.1%) of these patients received re-irradiation. The primary radiotherapy technique for all 174 patients was relatively homogeneous. Of the total, 90.2% of patients were given conventional two-dimensional primary treatment (11); and 86% of patients received radiotherapy in 2- to 2.5-Gy fractions. The mean biologically effective dose (BED) of external radiotherapy was 112 Gy (SD, 4.8 Gy) for a mean overall treatment time of 42.8 days (SD, 4.3 days). Eighteen (10.3%) patients received brachytherapy to the NP. Ten of these patients received brachytherapy for persistent disease at 6 weeks after the first course of radiotherapy (13). Seven patients received brachytherapy as part of the re-irradiation treatment (4). One patient received brachytherapy for both indications. About 40% of the cohort had received some form of chemotherapy at some time. Approximately 11% of patients received concurrent chemoradiotherapy: 21.6% of patients received induction chemotherapy, and 5.3% of patients received an adjuvant chemotherapy. Twenty-seven (15.5%) patients received neurosurgery for TLN involving a lobectomy, in all except 3 patients. Details of the cohort are shown in Tables 1 and 2. Table 2. Treatment of TLN and treatment results Treatment No. of patients (%) Steroid treatment Conservative 96 (55.2) Conventional oral steroid 28 (16.1) Pulsed steroid 50 (28.7) Neurosurgery 27 (15.3) 34 lobectomies done on 26 patients 8 patients received bilateral lobectomies 5 patients had drainage of intracranial abscess 3 shunt procedures on 1 patient Median no. of months of complication-free survival (95% CI) Since primary RT 160 ( ) Since TLN diagnosis 68 (52 not reached) Median no. of months of overall survival (95% CI) Since primary RT 118 ( ) Since TLN diagnosis 36 (24 45) TLN radiological progress Improved 13 (7.5) Stable 39 (22.4) Deteriorated 40 (23.0) Not reassessed 82 (47.1) Posttreatment TLN severity grade 1 67 (38.5) 2 27 (15.5) 3 24 (13.8) 4 43 (24.7) 5 13 (7.5) Abbreviation: CI = confidence interval. Overall complications of TLN Thirty-two percent of TLN patients developed grade 4 5 complications during the follow-up period. Among them, 4%, 11.6%, and 27.7% of patients developed brain abscess, intracranial hemorrhage, and fatal sepsis, respectively. Notably, sepsis was a common cause of death in all three groups. Even in the conservative group, the chance of dying from sepsis reached 21.8%. Administration of pulse steroid was not associated with a statistically higher risk of developing sepsis (p = 0.92). Details are shown in Tables 2 and 4. Nearly 70% of patients in this cohort had perfect health except for NPC and TLN, as their CCIs were zero. Predictive factors for complication-free (grade 4) survival Median complication-free (grade 4) survival was 160 months after the first course of radiotherapy and 68 months after diagnosis of TLN (Table 2). Seven factors, as listed in Table 5, were found to be associated with complicationfree survival of this cohort by univariate analysis (Fig. 3 5). Among these factors, being symptomatic at diagnosis of TLN (relative risk [RR], 4.5, p = ), re-irradiation of the NP (RR, 1.56, p = 0.008), undergoing salvage brachytherapy to the NP (RR, 1.75, p = 0.012), and a short latency period to TLN diagnosis (RR, 0.96, p < ) were independent predictors of poor outcome by multivariate analysis. Although intravenous pulse steroid therapy was associated

5 Outcomes of temporal lobe necrosis in NPC patients d T.-C. LAM et al. e61 Table 3. Baseline characteristics of subgroups according to steroid treatment received Characteristics No steroid group (n =96 [55%]) Oral steroid group (n =28 [16%]) Pulsedsteroid group (n =50 [29%] p value Mean age of < TLN Dx %ofnpc recurrence % of re-irradiation of NP Months of latency of TLN diagnosis since RT Severity of TLN < grade at diagnosis Mean oral dexamethasone dosage given (mg) < Abbreviation: Dx = diagnosis. with a less-severe posttreatment TLN grade, according to CTCAE, than conventional steroid therapy (Tables 3 and 4), it was not independently associated with complicationfree survival by multivariate analysis. CCI and chemotherapy or concurrent chemoradiotherapy history were not associated with complication-free survival of TLN patients. Dosimetric factors, including the radiation dose and BED received during primary radiotherapy or re-irradiation, the technique used for re-irradiation (e.g., two-dimensional [2D], conformal RT, IMRT, stereotactic radiotherapy), the fraction size, Table 4. Outcomes of subgroups according to steroid treatment received Outcome No steroid (n = 96) Oral steroid (n = 28) Pulse steroid (n = 50) p value Radiological progress (n) < Improved Stable Deteriorated Not reassessed Posttreatment severity < grade (n) % undergoing neurosurgery < % with brain abscess % with intracranial hemorrhage % who died of sepsis Table 5. Regression analyses of complication-free survival (grade 4) Variable 10-year complication-free survival Univariate Multivariate Relative risk (95% CI) Symptomatic at < ( ) diagnosis Asymptomatic: 87.7% Symptomatic: 47.8% Steroid treatment < Conservative: 0.86 ( ) 77.2% Conventional 1.35 ( ) steroid: 22.9% Pulsed steroid: Reference 56.1% Re-irradiation of < ( ) NP 1 course of RT: 80.1% 2 courses of RT: 49.8% Dose of oral < ( ) dexamethasone given Salvage ( ) brachytherapy to NP Yes: 31.5% No: 70.4% Latency of TLN < < ( ) diagnosis since RT Age at TLN diagnosis ( ) Abbreviation: CI = confidence interval. and the overall treatment time were not associated with complication-free survival. The later the year that TLN was diagnosed was not associated with better complication-free survival. Using the four independent predictors identified by multivariate analysis given above, a predictive model was constructed to estimate the risk that TLN patients would develop grade 4 complications in 5 years. The risk was 12.5% if no factor was present, 26.5% if one factor was present, 52.7% if two factors were present, 77.9% if three factors were present, and 100% if four factors were present (p < ) (Fig. 6). Overall survival after TLN diagnosis Median overall survival of TLN patients was 118 months after the first course of radiotherapy and 36 months after diagnosis of TLN. Five factors, as listed in Table 6, were found to be associated with overall survival. Two factors were independent predictors of poor outcome by multivariate analysis, including initial late T staging of NPC (p = 0.018) and recurrence of NPC (RR, 1.69, p = 0.015), while neurosurgery

6 e62 I. J. Radiation Oncology d Biology d Physics Volume 82, Number 1, 2012 Fig. 3. Effects of complication-free survival and being symptomatic at presentation. was associated with better prognosis (RR, 0.53, p = ). Medical comorbidities as measured by CCI were not associated with overall survival. CCI of patients receiving neurosurgery was not statistically different from those who did not receive neurosurgery. The later the year of diagnosis of TLN was not associated with longer overall survival. Subgroups according to steroid treatment received Baseline characteristics of the three groups are summarized in Table 3. In total, 209 cycles of pulse steroid were given to 50 patients. The range of the number of cycles given to patients was 1 to 15; the median number was 3 cycles. The Fig. 4. Effects of complication-free survival and steroid treatments. Fig. 5. Effects of complication-free survival and radiotherapy to NP. group receiving conventional oral steroids had a shorter latency period between primary radiotherapy and diagnosis of TLN than the conservatively treated group (mean, 28 months vs months, respectively; p = 0.01). As expected, the latter group had the highest proportion of asymptomatic presentations of TLN (grade 1, 64.0%; p < ). Outcome and complications of the three groups About 20% of the patients receiving intravenous pulse steroid therapy demonstrated radiological improvement of TLN compared to 0% and 3.2% of patients treated conservatively and those receiving conventional oral steroid, respectively (p < ). However, it should be noted that radiological follow-up was not provided equally among the three treatment groups: 72.9% of patients in the group receiving pulse steroid were followed radiologically, while follow-up scanning was used in 55.5% and 42.5% of patients in the conventional steroid and conservative treatment groups, respectively. Patients receiving conventional steroid treatment had the worst posttreatment grade according to CTCAE v3.0 (p < ): more than 60% of the patients in the conventional steroid group developed grade 4 or grade 5 complications (Table 4). Compared to patients on pulse steroid and patients on conservative treatment, patients in the conventional steroid group also had the highest rate of neurosurgical interventions (39% vs. 26% [pulse steroid group] vs. 3.1% [conservative group]; p < ), the highest rate of brain abscess (11% vs. 4% [pulse steroid group] vs. 2% [conservative group]; p = 0.19) and intracranial hemorrhage (21% vs. 12% vs. 8%; p = 0.2), and the greatest chance of dying of sepsis (35% vs. 26% [pulse steroid group] vs. 26% [conservative group]; p = 0.24), although the last three complications were not statistically significant (Table 4). Patients receiving intravenous pulse had a lower rate of developing grade 4 or higher complications (38%) than

7 Outcomes of temporal lobe necrosis in NPC patients d T.-C. LAM et al. e63 Table 6. Regression analyses of overall survival Variable 3-year overall survival Univariate Multivariate Relative risk (95% CI) T stage at NPC diagnosis T1: 63.0% Reference T2: 54.2% 1.29 ( ) T3: 29.3% 2.12 ( ) T4: 65.0% 0.82 ( ) Recurrence of NPC < ( ) Yes: 36.6% No: 71.6% Re-irradiation of NP ( ) Yes: 37.7% No: 62.1% Steroid treatment Conservative: 1.04 ( ) 47.6% Conventional 1.40 ( ) steroid: 35.3% Pulsed steroid: Reference 61.9% Neurosurgery ( ) Yes: 72.9% No: 45.7% Abbreviation: CI = confidence interval. Fig. 6. Model for predicting grade 4 complications of TLN. those in the conventional steroid group, but the lowest rate was seen in the conservative treatment group (20.8%). This was expected, as the conservative treatment group, compared with the other two groups, had the lowest rate of re-irradiation (40%), the highest rate of being asymptomatic at diagnosis (64% presented with grade 1 severity), and the longest latency period of TLN diagnosis (mean, 96 months). Concerning the safety profile of steroid treatment, severe steroid side-effects such as symptomatic avascular necrosis of the hip and/or bradycardia/arrhythmia were not detected in this cohort. DISCUSSION Treatment strategies for TLN Complication-free survival (grade 4) was chosen as the primary endpoint because it was clinically important for determining treatment plans in TLN patients. The conditions of patients in this group were commonly complicated by local recurrence, metastases, or other radiation-induced late side effects; so, it was not surprising to find that 5-year complication-free survival rate was higher than the overall survival rate (54.1% vs. 35.4%, respectively) (Table 2). This implied that a significant proportion of TLN patients would not suffer from major, life-threatening complications during their lifetime. Independent factors and the predictive model of severe complications, as found in this study, would help the clinicians to treat those who most needed treatment. More than half of the patients (55%; n = 96) received conservative treatment. Most of this select group of patients had asymptomatic TLN, a long latency period of TLN development, favorable MRI findings (17), and had received only one course of RT. This group of patients had better outcomes than patients in the steroid treatment group. This implied that a significant proportion of TLN patients might not need treatment. Although some patients had a benign course of TLN, a significant proportion developed major symptoms and disabilities. Fatal TLN cases were commonly seen (7.5% in our cohort) for patients who presented with severe symptoms of increased cranial pressure and those for whom control by steroid therapy had failed. Neurosurgery was indicated in these emergency situations. Previous reports of neurosurgery outcome in TLN patients were conflicting. Good recovery and symptom control had been reported (11), but there was also a series of patients who ended with poor outcome (6). Our series of 27 patients was one of the largest series ever presented. Multivariate analysis of overall survival indicated that neurosurgery was a strong and significant protective factor with hazard ratio of Thus, contrary to a previous comment that neurosurgery was hazardous (6), we found that neurosurgery could not only be

8 e64 I. J. Radiation Oncology d Biology d Physics Volume 82, Number 1, 2012 life-saving for TLN patients in emergency situation, but it might also provide the chance to control symptoms in a significant proportion of patients. For TLN patients with mild to moderate symptoms, steroid treatment may be considered. This study has suggested that intravenous pulse steroid might be a better option than conventional steroid delivery, as it was associated with better clinical and radiological outcome than that for the oral steroid group. One hypothesis was that patients taking pulse steroid were spared the chronically high dose of potent oral corticosteroid given to patients in the oral steroid group (mean dose, 140 mg, vs. 492 mg [492 mg vs. 140 mg], respectively; p < ) (Table 4). Pulse steroid therapy also had a good safety profile in our experience, but caution is warranted to avoid steroid use in patients with lower cranial nerve palsy, as they have higher risks of aspiration and sepsis. However, it must be stressed that the comparative results of steroid treatment should be interpreted with caution, as baseline characteristics of the different treatment groups and follow-up protocols were markedly different. More frequent radiological follow-up of patients in the pulse steroid group may detect more clinically insignificant improvements or deterioration. Moreover, although intravenously pulse steroid was associated with better clinical staging of TLN than conventional steroid therapy, it did not improve the rate of complication-free survival. It was likely that pulse steroid therapy produced only temporary symptomatic relief but did not change the underlying biological process of TLN, which caused severe complications. NPC treatment and TLN Salvage brachytherapy to the NP combined with external beam radiotherapy or brachytherapy used alone to treat locally persistent NPC or recurrent NPC was an effective method of dose escalation, and the reported 3-year local failure-free survival rate was up to 71% (4). However, reirradiation to the NP caused a high rate of CNS complications (4), and in this study, salvage brachytherapy to the NP was found to be an independent predictor of worse complication-free survival of TLN. It should be noted that salvage brachytherapy was a different treatment from adjuvant brachytherapy (12), as the dose of salvage treatment was much higher ( Gy/3 fractions vs Gy/2 fractions, respectively). Adjuvant high-dose-rate brachytherapy treatment was not associated with an increased rate of CNS complications (12). Improving local control of NPC by adjuvant brachytherapy or other methods, which would avoid the need for re-irradiation or other salvage treatments, would be one of the best ways to avoid complications of re-irradiation, including TLN. Limitations of the study Quality of life data and well-defined symptomatology data were not available for this cohort. Effects of pulse steroid on quality of life and cognitive function of TLN patients remained undefined. Future prospective studies with accounts of patient-reported outcomes will be important for improving the standard of care. The impact of IMRT on the incidence and severity of TLN will surface in coming years when follow-up periods are lengthened. With the help of a modern planning program, dosimetric parameters affecting TLN will be better delineated. CONCLUSIONS TLN is an important complication of radiotherapy for NPC patients, which can cause severe morbidity and may even be fatal; yet, the clinical course of TLN varies, and a significant proportion of patients with TLN do not develop severe complications, even without treatment. Factors including being symptomatic at presentation, re-irradiation of the NP, salvage brachytherapy to the NP, and a shorter latency period of TLN development will help to identify those patients who have a higher risk of developing grade 4 complications. Neurosurgery is an important modality of treatment in emergency situations. While pulse steroid treatment may lead to better clinical response than conventional steroid and has a good safety profile, it did not affect complication-free survival in TLN patients. REFERENCES 1. Ho JHC. An epidemiologic and clinical study of nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1978;4: Lee AWM, Foo W, Chappell R, et al. 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