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Adaptive radiotherapy (ART) has recently been introduced to restore the planned dose distribution by accounting for the anatomic changes during treatment. By quantifying the anatomic changes in nasopharyngeal carcinoma (NPC) patients, this study aimed to establish an ART strategy for NPC cases. A total of 30 NPC patients treated with helical tomotherapy were recruited. In the pretreatment megavoltage CT images, the anatomic changes of the posterolateral wall of nasopharynx (P-NP), neck region and parotid glands were measured and assessed. One-way repeated measure ANOVA was employed to define threshold(s) at any time-point. The presence of a threshold(s) would indicate significant anatomical change(s) such that replanning should be suggested. A pragmatic schedule for ART was established by evaluating the threshold for each parameter. Results showed the P-NP, parotid gland and neck volumes demonstrated significant regressions over time. Respectively, the mean loss rates were 0.99, 1.35, and 0.39 %/day, and the mean volume losses were 35.70, 47.54 and 11.91% (all P < 0.001). The parotid gland shifted medially and superiorly over time by a mean of 0.34 and 0.24 cm, respectively (all P < 0.001). The neck region showed non-rigid posterior displacement, which increased from upper to lower neck. According to the threshold occurrences, three replans at 9th, 19th and 29th fractions were proposed. This ART strategy was able to accommodate the dosimetric consequences due to anatomic deviation over the treatment course. It is clinically feasible and would be recommended for centers where an adaptive planning system was not yet available.

Adaptive radiotherapy (ART) has been introduced to correct the radiation-induced anatomic changes in head and neck cases during a treatment course. This study evaluated the potential dosimetric benefits of applying a 3-phase adaptive radiotherapy protocol in nasopharyngeal carcinoma (NPC) patients compared with the nonadaptive single-phase treatment protocol. Ten NPC patients previously treated with this 3-phase radiation protocol using Hi-Art Tomotherapy were recruited. Two new plans, PII-ART and PIII-ART, were generated based on the up-to-date computed tomography (CT) images and contours and were used for treatment in phase two (PII; after 25th fraction) and phase three (PIII; after 35th fraction), respectively. To simulate the situation of no replanning, 2 hybrid plans denoted as PII-NART and PIII-NART were generated using the original contours pasted on the PII- and PIII-CT sets by CT-CT fusion. Dosimetric comparisons were made between the NART plans and the corresponding ART plans. In both PII- and PIII-NART plans, the doses to 95% of all the target volumes (D₉₅) were increased with better dose uniformity, whereas the organs at risk (OARs) received higher doses compared with the corresponding ART plans. Without replanning, the total dose to 1% of brainstem and spinal cord (D₁) significantly increased 7.87 ± 7.26% and 10.69 ± 6.72%, respectively (P = 0.011 and 0.001, respectively), in which 3 patients would have these structures overdosed when compared with those with two replannings. The total maximum doses to the optic chiasm and pituitary gland and the mean doses to the left and right parotid glands were increased by 10.50 ± 10.51%, 8.59 ± 6.10%, 3.03 ± 4.48%, and 2.24 ± 3.11%, respectively (P = 0.014, 0.003, 0.053, and 0.046, respectively). The 3-phase radiotherapy protocol showed improved dosimetric results to the critical structures while keeping satisfactory target dose coverage, which demonstrated the advantages of ART in helical tomotherapy of NPC., (Copyright © 2012 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Epstein Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is endemic in Southeast Asia, and the plasma level of EBV DNA is a highly sensitive marker of disease recurrence following radiotherapy. Leptomeningeal recurrence from NPC is extremely rare and difficult to diagnose; only 4 cases have been reported in the literature. We report a case of leptomeningeal recurrence in NPC that was diagnosed using imaging and plasma and cerebrospinal fluid EBV DNA assays, followed by a review of the literature., (Copyright 2008 S. Karger AG, Basel.)

The aim of this study is to evaluate the deficiencies in target coverage and organ protection of 2-dimensional radiation therapy (2DRT) in the treatment of advanced T-stage (T3-4) nasopharyngeal carcinoma (NPC), and assess the extent of improvement that could be achieved with intensity modulated radiation therapy (IMRT), with special reference to of the dose to the planning organ-at-risk volume (PRV) of the brainstem and spinal cord. A dosimetric study was performed on 10 patients with advanced T-stage (T3-4 and N0-2) NPC. Computer tomography (CT) images of 2.5-mm slice thickness of the head and neck were acquired with the patient immobilized in semi-extended-head position. A 2D plan based on Ho's technique, and an IMRT plan based on a 7-coplanar portals arrangement, were established for each patient. 2DRT was planned with the field borders and shielding drawn on the simulator radiograph with reference to bony landmarks, digitized, and entered into a planning computer for reconstruction of the 3D dose distribution. The 2DRT and IMRT treatment plans were evaluated and compared with respect to the dose-volume histograms (DVHs) of the targets and the organs-at-risk (OARs), tumor control probability (TCP), and normal tissue complication probabilities (NTCPs). With IMRT, the dose coverage of the target was superior to that of 2DRT. The mean minimum dose of the GTV and PTV were increased from 33.7 Gy (2DRT) to 62.6 Gy (IMRT), and 11.9 Gy (2DRT) to 47.8 Gy (IMRT), respectively. The D(95) of the GTV and PTV were also increased from 57.1 Gy (2DRT) to 67 Gy (IMRT), and 45 Gy (2DRT) to 63.6 Gy (IMRT), respectively. The TCP was substantially increased to 78.5% in IMRT. Better protection of the critical normal organs was also achieved with IMRT. The mean maximum dose delivered to the brainstem and spinal cord were reduced significantly from 61.8 Gy (2DRT) to 52.8 Gy (IMRT) and 56 Gy (2DRT) to 43.6 Gy (IMRT), respectively, which were within the conventional dose limits of 54 Gy for brainstem and of 45 Gy for spinal cord. The mean maximum doses deposited on the PRV of the brainstem and spinal cord were 60.7 Gy and 51.6 Gy respectively, which were above the conventional dose limits. For the chiasm, the mean dose maximum and the dose to 5% of its volume were reduced from 64.3 Gy (2DRT) to 53.7 Gy (IMRT) and from 62.8 Gy (2DRT) to 48.7 Gy (IMRT), respectively, and the corresponding NTCP was reduced from 18.4% to 2.1%. For the temporal lobes, the mean dose to 10% of its volume (about 4.6 cc) was reduced from 63.8 Gy (2DRT) to 55.4 Gy (IMRT) and the NTCP was decreased from 11.7% to 3.4%. The therapeutic ratio for T3-4 NPC tumors can be significantly improved with IMRT treatment technique due to improvement both in target coverage and the sparing of the critical normal organ. Although the maximum doses delivered to the brainstem and spinal cord in IMRT can be kept at or below their conventional dose limits, the maximum doses deposited on the PRV often exceed these limits due to the close proximity between the target and OARs. In other words, ideal dosimetric considerations cannot be fulfilled in IMRT planning for T3-4 NPC tumors. A compromise of the maximal dose limit to the PRV of the brainstem and spinal cord would need be accepted if dose coverage to the targets is not to be unacceptably compromised. Dosimetric comparison with 2DRT plans show that these dose limits to PRV were also frequently exceeded in 2DRT plans for locally advanced NPC. A dedicated retrospective study on the incidence of clinical injury to neurological organs in a large series of patients with T3-4 NPC treated by 2DRT may provide useful reference data in exploring how far the PRV dose constraints may be relaxed, to maximize the target coverage without compromising the normal organ function.

Background and Purpose: To define the dose-response relationship of nasopharyngeal carcinoma (NPC) above the conventional tumoricidal dose level of 66 Gy when the basic radiotherapy (RT) course was given by the 2D Ho's technique., Patients and Methods: Data from all five regional cancer centers in Hong Kong were pooled for this retrospective study. All patients (n = 2426) were treated with curative-intent RT with or without chemotherapy between 1996 and 2000 with the basic RT course using the Ho's technique. The primary endpoint was local control. The prognostic significance of dose-escalation ('boost') after 66 Gy, T-stage, N-stage, use of chemotherapy, sex and age (< or =40 years vs >40 years) was studied. Both univariate and multivariate analyses were performed., Results: On multivariate analysis, T-stage (P < 0.01; hazard ratio [HR], 1.58) and optimal boost (P = 0.01; HR, 0.34) were the only significant factors affecting local failure for the whole study population, and for the population of patients treated by radiotherapy alone, but not for patients who also received chemotherapy. The following were independent determinants of local failure for patient groups with different T-stages treated by radiotherapy alone: use of a boost in T1/T2a disease (P = 0.01; HR, 0.33); use of a boost (P < 0.01; HR, 0.60) and age (P = 0.01; HR, 1.02) in T3/T4 tumors. Among patients with T2b tumors treated by radiotherapy alone and given a boost, the use of a 20 Gy-boost gave a lower local failure rate than a 10 Gy-boost. There was no apparent excess mortality attributed to RT complications., Conclusions: Within the context of a multi-center retrospective study, dose-escalation above 66 Gy significantly improved local control for T1/T2a and T3/4 tumors when the primary RT course was based on the 2D Ho's technique without additional chemotherapy. 'Boosting' in NPC warrants further investigation. Caution should be taken when boosting is considered because of possible increase in radiation toxicity.

This phase III randomized study compared concurrent cisplatin-radiotherapy (CRT) versus radiotherapy (RT) alone in patients with locoregionally advanced nasopharyngeal carcinoma. A total of 350 patients were randomly assigned to receive external RT alone or concurrently with cisplatin at a dosage of 40 mg/m(2) weekly. The primary endpoint was overall survival, and the median follow-up was 5.5 years. The 5-year overall survival was 58.6% (95% confidence interval [CI] = 50.9% to 66.2%) for the RT arm and 70.3% (95% CI = 63.4% to 77.3%) for the CRT arm. In Cox regression analysis adjusted for T stage, age, and overall stage, the difference in overall survival was statistically significantly in favor of concurrent CRT (P = .049, hazard ratio [HR] = 0.71 [95% CI = 0.5 to 1.0]). Subgroup analysis demonstrated that there was no difference between overall survival in the arms for T1/T2 stage (P = .74, HR = 0.93 [95% CI = 0.59 to 1.4]), whereas there was a difference between the arms for T3/T4 stage (P = .013, HR = 0.51 [95% CI = 0.3 to 0.88]), favoring the CRT arm. The regimen of weekly concurrent CRT is a promising standard treatment strategy for locoregionally advanced nasopharyngeal carcinoma patients.

Purpose: To analyze the treatment results achievable for nasopharyngeal carcinoma in the modern era to identify the key failures for future improvement and to provide an updated baseline for future trials., Methods and Materials: The results of 2687 consecutive patients treated at all public oncology centers in Hong Kong during 1996-2000 were retrospectively analyzed. The stage distribution (by American Joint Committee on Cancer and International Union Against Cancer staging system, 1997) was 7% Stage I, 41% Stage II, 25% Stage III, and 28% Stage IVA-B. All patients were irradiated with 6-MV photons and the median total dose was 66 Gy. Only 23% of patients had additional treatment with chemotherapy., Results: The 5-year local, nodal, and distant failure-free rates were 85%, 94%, and 81%, respectively; patients with local failure had significantly higher risk of nodal and distant failures. The 5-year progression-free, overall, and cancer-specific survival rates were 63%, 75%, and 80%, respectively. The presenting stage was the most important prognostic factor for all endpoints: with overall survival decreasing from 90% for Stage I to 58% for Stage IVA-B. The results achieved by the 2070 patients treated by radiotherapy alone were almost identical to that of the whole series, the distant failure-free rate among patients with locoregional control was 89% for Stage I-II and 75% for Stage III-IVB. The 860 patients (32%) staged with magnetic resonance imaging achieved significantly better results than those staged by computed tomography, the overall survival being 93% vs. 83% for Stages I-II, and 72% vs. 63% for Stages III-IVB (p = 0.001)., Conclusions: Treatment results for nasopharyngeal carcinoma have substantially improved in the modern era; future trials should be based on updated baseline results. Further reduction of distant failure is important for future breakthrough, particularly for patients with advanced disease.

Purpose: To evaluate the efficacy of using intensity-modulated radiotherapy (IMRT) in the primary treatment of nasopharyngeal carcinoma (NPC), including the role of dose escalation above 66 Gy level., Methods and Materials: Between July 2000 and September 2002, 63 newly diagnosed NPC patients were treated with IMRT. The disease was Stage I in 9 (14%), Stage II in 18 (29%), Stage III in 22 (35%), and Stage IV in 14 (22%). The prescribed dose was 66 Gy to the gross tumor volume (GTV) and positive neck nodes, 60 Gy to the planning target volume (PTV), and 54-60 Gy to the clinically negative neck. All 20 (100%) patients with T1-2a tumors received intracavitary brachytherapy (ICB) boost, and 15/42 (36%) patients with T2b-T4 tumors received conformal boost (8 Gy/4 fractions). Nineteen patients with advanced stage disease also received either neoadjuvant or concurrent chemotherapy. Acute and late normal tissue effects were graded according to the Radiation Therapy Oncology Group (RTOG) radiation morbidity scoring criteria. Local relapse-free survival (LRFS), nodal relapse-free survival (NRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were estimated using the Kaplan-Meier method., Results: With a median follow-up of 29 months (range 8-45 months), 4 patients developed local in-field failure, 1 patient developed regional relapse, and 13 patients developed distant metastases. All 4 patients with local failure had either T3 or T4 disease before primary treatment and did not have ICB or conformal boost. The 3-year actuarial LRFS, NRFS, DMFS, and OS were 92%, 98%, 79%, and 90%, respectively. Multivariate analysis showed that dose escalation above 66 Gy was significantly associated with better PFS and DMFS, whereas GTV size was a significant adverse factor for OS. The worst acute mucositis was Grade 1 or 2 in 36 (59%), and Grade 3 in 25 (41%) patients. Acute dysphagia requiring tube feeding occurred in 5 (8%) patients. The proportion of patients with Grade 2-3 xerostomia was 57% at 3 months, and 23% at 2 years after IMRT. Within the subset of patients with a mean parotid dose of <31 Gy, the proportions with Grade 2-3 xerostomia were 30% and 17% at 3 months and 2 years, respectively., Conclusion: Our experience of using IMRT in the primary treatment of NPC showed a very high rate of locoregional control and favorable toxicity profile. Furthermore, we found that dose escalation above 66 Gy of IMRT-based therapy was a significant determinant of progression-free survival and distant metastasis-free survival for advanced T-stage tumors. Distant metastases represent the predominant mode of treatment failure.

Nasopharyngeal carcinoma (NPC), an endemic tumor in southern China, has three unique etiologic factors, including genetic susceptibility, chemical carcinogens, and association with Epstein-Barr virus (EBV) infection. Recent identification of critical genetic changes in this cancer has allowed the description of a multistep model for the pathogenesis of NPC. NPC is highly radiosensitive and chemosensitive. Attempts have been made to improve treatment results by integrating radiotherapy with some form of chemotherapy. Here, we review the current evidence available on the various chemotherapy-radiotherapy sequencing approaches and seek to define the optimal integration of radiotherapy and chemotherapy. Despite consistently high response rates to platinum-based neoadjuvant chemotherapy, none of six randomized studies of neoadjuvant and/or adjuvant chemotherapy showed any improvement in overall survival, although two did demonstrate significant improvement in local control rates and progression-free survival. However, three randomized studies of concurrent cisplatin-radiotherapy one with, and two without, adjuvant chemotherapy demonstrated significant improvement in progression-free survival and two of these have demonstrated improvement in overall survival. Preliminary data on the use of neoadjuvant chemotherapy followed by concurrent chemoradiation have been highly encouraging. Concurrent cisplatin-radiation with or without adjuvant chemotherapy should be considered as standard practice for locoregionally advanced NPC. The addition of neoadjuvant chemotherapy warrants further investigation and appears to be the most likely approach to further improve treatment results.

This review describes the clinical background that underlies the transition from two-dimensional to three-dimensional (3D) planning techniques in the treatment of nasopharyngeal cancer (NPC). A systematic search of the Medline was performed using 'nasopharyngeal carcinoma', 'radiotherapy', '3-dimensional conformal radiotherapy', 'stereotactic radiosurgery/radiotherapy' and 'intensity-modulated radiotherapy' as keywords. Citing evidence from the published literature and their own institutional experience, the authors critically examined the positive impact of 3D methods--with emphasis on intensity-modulated radiotherapy (IMRT)--on target coverage and geometric accuracy, sparing of normal organs, and dosimetric homogeneity. Potential problems related to the widespread practice of IMRT such as quality assurance, utilization of medical resources and the risk of developing radiation-induced secondary cancers were highlighted. Application of IMRT within the context of altered fractionation, dose escalation and concurrent chemotherapy were discussed. The article concluded with a suggested treatment approach and research direction for different stages of NPC.

Purpose: To assess the efficacy of neoadjuvant paclitaxel and carboplatin (TC) followed by concurrent cisplatin and radiotherapy (RT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and to monitor treatment response with plasma Epstein-Barr virus (EBV) DNA., Patients and Methods: Thirty-one patients with International Union Against Cancer stages III and IV undifferentiated NPC had two cycles of paclitaxel (70 mg/m2 on days 1, 8, and 15) and carboplatin (area under the curve 6 mg/mL/min on day 1) on a 3-weekly cycle, followed by 6 to 8 weeks of cisplatin (40 mg/m2 weekly) and RT at 66 Gy in 2-Gy fractions. Plasma EBV DNA was measured serially using the real-time quantitative polymerase chain reaction method. Results All patients completed planned treatment. Response to neoadjuvant TC was as follows: 12 patients (39%) achieved partial response (PR) and 18 achieved (58%) complete response (CR) in regional nodes; five patients (16%) achieved PR and no patients achieved CR in nasopharynx. At 6 weeks after RT, one patient (3%) achieved PR and 30 patients (97%) achieved CR in regional nodes, and 31 patients (100%) achieved CR in nasopharynx; 29 patients (93%) had EBV DNA level of less than 500 copies/mL. Neoadjuvant TC was well tolerated, and the most common acute toxicity of cisplatin plus RT was grade 3 mucositis (55%). At median follow-up of 33.7 months (range, 7 to 39.3 months), six distant and three locoregional failures occurred. Plasma EBV DNA level increased significantly in eight of nine patients who experienced treatment failure but did not increase in those who did not. The 2-year overall and progression-free survival rates were 91.8% and 78.5%, respectively. CONCLUSION This strategy was feasible and resulted in excellent local tumor control. Serial plasma EBV DNA provides a noninvasive method of monitoring response in NPC., (Copyright 2004 American Society of Clinical Onocology)

Aims: To evaluate the current UICC/AJCC Staging System for nasopharyngeal carcinoma and to search for ways of improving the system., Materials and Methods: This is a retrospective analysis of 2687 consecutive patients treated in five public centres in Hong Kong during the period 1996-2000. All patients were staged by computed tomography, magnetic resonance imaging, or both. The prognostic significance of the current stage assignment on various aspects of tumour control was evaluated., Results: T-category, N-category and stage-group were all significant prognostic factors for major end points (P < 0.01). However, the distinction of prognosis between Stage I and II was insignificant (5-year cancer-specific survival being 92% vs 95%; P = 0.13). Multivariate analyses (corrected for age and sex) revealed lack of significance between T2a and T1 in hazards of local and distant failures, N3a and N2 in distant failure and subgroups of T1-2N0 in cancer-specific deaths. Corresponding down-staging of T2a to T1, N3a to N2, and subgroup T2N0 to stage I, resulted in more even and orderly increase in the hazard ratio of cancer-specific deaths (from 1 for stage I to 1.98 for II, 3.5 for III, 6.08 for IVA and 8.62 for IVB), better hazard consistency among subgroups of the same stage and more balanced stage distribution., Conclusions: The current UICC/AJCC Staging System could be further improved by the modifications suggested; validation of the current proposal by external data is urgently awaited.

Background and Purpose: This pilot study assesses the psychosocial impact of different modalities of breast cancer surgery in Chinese patients and their husbands., Methods: Thirty-six patients who underwent conservative breast therapy (BCT) for breast cancer were compared with 36 women who underwent total mastectomy (TM) on four aspects of psychosocial adjustment. They were matched in pairs in terms of stage of disease, age and time since surgery. Where available, their husbands were also consented for similar assessment., Results: Women who underwent BCT showed a significantly better response to their body and sexual image than those who underwent TM. This difference did not translate into any significant difference in terms of emotional and symptomatic aspects, daily activities, or fear of recurrences. The husbands of patients in the TM group showed significantly more emotional and symptomatic distress and greater change in the perception of their wives' body and sexual images., Conclusion: This is the first of such study conducted in a Chinese population. The lack of differences in certain psychosocial aspects may indicate a generally good adjustment in the TM patients after their surgery. It may also relate to the fact that volunteers for the study were themselves representative only of the patient population who adapted well to the surgery, and those patients who were emotionally distressed tended to decline to participate. Psychosocial disruption in the patients' families is reflected in our study where patients' husbands in the TM group were significantly more disturbed. However, due to the limited number of patients studied, the findings are not yet conclusive and require further studies for confirmation., (Copyright 2003 John Wiley & Sons, Ltd.)

Deletion of 11q23 is a common genetic aberration in nasopharyngeal carcinoma (NPC). Multiple candidate tumor suppressor genes (TSG) were mapped to this region but few of them were investigated in NPC. TSLC1 (tumor suppressor in lung cancer) is recently reported to be a putative TSG on 11q23. This gene was found to be inactivated by promoter hypermethylation in non-small cell lung carcinoma (NSCLC), liver cancer, and breast cancer. To study the role of TSLC1 gene in NPC tumorigenesis, we screened for mutations and aberrant methylation of TSLC1 gene in 5 NPC cell lines, 3 NPC xenografts, and 38 primary NPC cases. No somatic mutations of TSLC1 were detected in the NPC samples, but a 9-bp (CCACCACCA) deletion in exon 8 was found in a primary NPC and its corresponding blood sample. Bisulfite sequencing revealed aberrant methylation of TSLC1 promoter in four NPC cell lines. Loss of TSLC1 gene expression was found in two cell lines (HK-1 and CNE-2) with dense methylation. Expression of this gene was restored in these cell lines after treatment with demethylating agent 5-aza-2'-deoxycytidine. Our results showed that silencing of TSLC1 gene expression in NPC was associated with promoter hypermethylation. Promoter hypermethylation of TSLC1 gene was further illustrated in 34.2% (13/38) of primary NPCs. No aberrant promoter methylation was found in any of the four investigated normal nasopharyngeal epithelia. Frequent epigenetic inactivation of TSLC1 gene in NPC suggested that this gene is one of the target tumor suppressor genes of this endemic cancer., (Copyright 2003 Wiley-Liss, Inc.)

Background: This study prospectively examines the prognostic role of p53 oncoprotein (p53), Ki67-antigen (Ki67), tumor angiogenesis (MVD), epidermal growth factor receptor (EGFR), and HER2 receptor protein (HER2) expression in Chinese with undifferentiated nasopharyngeal carcinoma (NPC)., Methods: Seventy-eight Chinese were recruited from October 1995 to July 1997 at the Prince of Wales Hospital, Hong Kong. Pretreatment immunohistochemical preparations of the primary tumor were made, and clinical data were collected prospectively until October 30, 2000. The markers were correlated with overall survival (OS), disease-free survival (DFS), time to progression (TTP), and UICC stage., Results: On univariate analysis, EGFR expression correlated with poorer OS (p =.0001), DFS (p =.01), shorter TTP (p =.0001), and advanced T stage (p =.036). Strong EGFR expression, when compared with weak or moderate, was associated with poorer OS (p =.04) and shorter TTP in a subgroup of patients with UICC stage III-IV disease. HER2 expression was associated with advanced UICC stage (p =.006). The presence of p53 expression correlated with poorer DFS (p =.01) and a trend toward shorter TTP (p =.06). No correlation was found with Ki67-antigen or MVD. On multivariate analysis, only EGFR expression was significantly linked to shorter OS and TTP., Conclusions: EGFR expression in undifferentiated NPC is associated with a poor clinical outcome. A prognostic role of p53 and HER2 expression is suggestive but not consistently defined in this study. The relatively high prevalence of positive staining for EGFR supports the use of molecular targeted therapy in this disease., (Copyright 2003 Wiley Periodicals, Inc.)

Background and Purpose: To study pre-treatment cell kinetics and their clinical correlations in nasopharyngeal carcinoma (NPC)., Materials and Methods: Ninety newly diagnosed NPC patients were studied using in vivo Bromodeoxyuridine (BrdU) labeling and flow cytometric analysis. Immunohistochemical staining for BrdU and Ki 67 was also performed., Results: The median S-phase duration (Ts) was 6.2 h (range 3.5-18.7 h), median flow cytometric labeling index (FCM-LI) was 7.4% (1.3-37.6%), and median potential doubling time (Tpot) was 3.6 days (0.5-19.9 days). The median histologic labeling index (H-LI) was 12.4% (1.2-43.3%), and median histologic Tpot (H-Tpot) was 2.1 days (0.5-33.3 days). FCM-LI and H-LI were both positively correlated with Ki67 whereas Tpot and H-Tpot were both negatively correlated with Ki67 and N-stage. In univariate analysis, Tpot and H-Tpot showed a trend for progression free survival. Tpot was significantly associated with local relapse free survival, but lost its significance in multivariate analysis. N-stage was the only significant prognostic factor for all radiotherapy outcomes in both univariate and multivariate analyses., Conclusions: Tpot was the only pre-treatment cell kinetic parameter for which some evidence was found for an association with survival in NPC patients. Future studies should aim to combine cell kinetic parameters together with other biological markers and clinical parameters to provide more useful prognostic information to guide individual patient's therapy.

Purpose: To compare intensity-modulated radiotherapy (IMRT) with two-dimensional RT (2D-RT) and three-dimensional conformal radiotherapy (3D-CRT) treatment plans in different stages of nasopharyngeal carcinoma and to explore the feasibility of dose escalation in locally advanced disease., Materials and Methods: Three patients with different stages (T1N0M0, T2bN2M0 with retrostyloid extension, and T4N2M0) were selected, and 2D-RT, 3D-CRT, and IMRT treatment plans (66 Gy) were made for each of them and compared with respect to target coverage, normal tissue sparing, and tumor control probability/normal tissue complication probability values. In the Stage T2b and T4 patients, the IMRT 66-Gy plan was combined with a 3D-CRT 14-Gy boost plan using a 3-mm micromultileaf collimator, and the dose-volume histograms of the summed plans were compared with their corresponding 66-Gy 2D-RT plans., Results: In the dosimetric comparison of 2D-RT, 3D-CRT, and IMRT treatment plans, the T1N0M0 patient had better sparing of the parotid glands and temporomandibular joints with IMRT (dose to 50% parotid volume, 57 Gy, 50 Gy, and 31 Gy, respectively). In the T2bN2M0 patient, the dose to 95% volume of the planning target volume improved from 57.5 Gy in 2D-RT to 64.8 Gy in 3D-CRT and 68 Gy in IMRT. In the T4N2M0 patient, improvement in both target coverage and brainstem/temporal lobe sparing was seen with IMRT planning. In the dose-escalation study for locally advanced disease, IMRT 66 Gy plus 14 Gy 3D-CRT boost achieved an improvement in the therapeutic ratio by delivering a higher dose to the target while keeping the normal organs below the maximal tolerance dose., Conclusions: IMRT is useful in treating all stages of nonmetastatic nasopharyngeal carcinoma because of its dosimetric advantages. In early-stage disease, it provides better parotid gland sparing. In locally advanced disease, IMRT offers better tumor coverage and normal organ sparing and allows room for dose escalation.

Nasopharyngeal carcinoma (NPC) is highly radiosensitive and patients presenting with early disease have a high cure rate after radiotherapy. For patients presenting with locoregionally advanced disease, despite a high initial control rate with radiotherapy, the subsequent failure rates are significant. Concurrent cisplatin-radiotherapy with or without adjuvant chemotherapy have been demonstrated to significantly improve survival and is currently the standard treatment strategy for patients with locoregionally advanced disease. Encouraging phase II trials have been reported on the use of neoadjuvant chemotherapy followed by concurrent chemotherapy-radiotherapy, which may provide the optimal way to deliver chemoradiation in NPC. Improved radiotherapy techniques using intensity modulated methods or three-dimensional conformal methods may further improve local control by reducing geographical misses while preserving normal organ functions., (Copyright 2002 Elsevier Science Ltd.)

Objectives/hypothesis: Nasopharyngectomy is a well-established treatment option for recurrent nasopharyngeal carcinoma. Over a period of 4 years and 3 months, in a total of 43 patients, 45 nasopharyngectomies were performed. Thirty-one patients with follow-up ranging from 12 to 58 months were studied. Twenty-two patients (58%) survived; of these, 18 patients (82%) remained disease free. All patients who developed repeat recurrence or died (n = 12) had a high recurrent T-stage tumor, skull base involvement, multiple recurrences, positive surgical margins, or concurrent neck node metastasis. These factors are poor prognostic parameters and might mitigate the indications for aggressive salvage surgery. However, low recurrent T-stage tumor without neck metastasis carries a good prognosis. Modern minimally invasive surgery carries minimal morbidity. STUDY DESIGN A retrospective study was made to determine prognostic indicators in patients treated with salvage surgery for recurrent nasopharyngeal carcinoma., Methods: Medical records were analyzed for all patients who had received nasopharyngectomy for recurrent nasopharyngeal carcinoma from March 1997 to June 2001. They were followed up from March 1997 to January 2002. Recurrent T stage, nodal metastasis, surgical approach, surgical margins, and pathological nodal status, together with surgical mortality, morbidity, and the delivery of postoperative irradiation, were compared with survival., Results: In all, 43 patients underwent 45 nasopharyngectomies over a period of 4 years and 3 months. Patients with less than 1 year of follow-up were excluded. Four patients with residual disease, who represent a more favorable group, and five patients with planned debulking, nasopharyngectomy, and postoperative stereotactic irradiation were also excluded. The study group comprised 25 men and 6 women (ratio of 4:1) with age ranging from 26 to 69 years (mean age, 49.5 y). In 28 patients (90.3%), the recurrence of nasopharyngeal carcinoma was their first recurrence; in 3 patients (9.7%), the recurrences were second recurrences. Twenty-two patients (71%) survived, achieving a mean survival of 28.5 months. Nine patients died with a mean interval of 7.8 months (range, 1-14 mo). Of the nine patients who died, six (67%) had T3 or T4 tumor, four (44.4%) had concurrent recurrent neck disease, and five (55.5%) had positive surgical margins. Two patients died of perioperative meningitis. Fifteen (83.3%) of the 18 disease-free survivors had a low recurrent T-stage tumor. Mean intervals for development of repeat recurrence or distant metastasis were 16 and 7.9 months, respectively., Conclusions: High recurrent T stage, skull base involvement, repeated recurrence before surgery, nodal metastasis, and positive surgical margins carry a poor prognosis. This is particularly evident with high T stage and concurrent nodal metastasis. However, patients with low T stage have a survival advantage and benefit most from surgical treatment.

Purpose: Tumor hypoxia is known to be associated with resistance to chemotherapy, radiotherapy, and poorer survival. Recently, it is shown that hypoxia induces the expression of hypoxia-inducible factor-1alpha and 2alpha (HIF-1alpha and HIF-2alpha), which then up-regulates the expression of downstream genes such as carbonic anhydrase IX (CA IX) and vascular endothelial growth factor (VEGF)., Experimental Design: We examined the expression of HIF-1alpha, HIF-2alpha, CA IX, and VEGF by immunohistochemistry in nasopharyngeal carcinoma (NPC) biopsies from 90 consecutive patients recruited between 1994 and 1997 in a randomized controlled trial of chemoradiation in locally advanced NPC and investigated their relationship with survival., Results: HIF-1alpha was expressed in 52 of 90 (58%), HIF-2alpha in 6 of 89 (7%), CA IX in 51 of 90 (57%), and VEGF in 54 of 90 (60%) of tumors. Tumor HIF-1alpha expression correlated significantly with that of CA IX (P = 0.008) and VEGF (P = 0.003). High tumor HIF-1alpha expression was associated with a trend for poor overall survival (P = 0.06). Tumors with a positive hypoxic profile (defined as high expression of both HIF-1alpha and CA9) were associated with worse progression-free survival (P = 0.04). Tumors with both hypoxic and angiogenic profile (defined as high VEGF expression) were associated with a worse progression-free survival (P = 0.0095)., Conclusion: Overexpression of HIF-1alpha, CA IX, and VEGF is common in NPC, which is probably related to hypoxia up-regulated expression involving a HIF-dependent pathway, and is associated with poor prognosis. Targeting the hypoxia pathway may be useful in the treatment of NPC.

Nasopharyngeal carcinoma (NPC) is endemic in southern China where genetic abnormalities and Epstein-Barr virus (EBV) infection are critical in the pathogenesis of the disease. Circulating EBV-DNA has been shown to improve prognostication and monitoring of NPC patients. Radiotherapy is the mainstay treatment for early disease and concurrent cisplatin/radiotherapy has been demonstrated to prolong survival in locoregionally advanced disease. Ongoing studies of targeting agents and immunotherapeutic approaches may further improve treatment results.

Purpose: To study the factors affecting the risk of symptomatic temporal lobe necrosis after different fractionation schedules., Methods and Materials: One thousand thirty-two patients with T1-2 nasopharyngeal carcinoma treated with radical radiotherapy in Hong Kong during 1990-1995 were studied. They were treated at four different centers with similar techniques but different fractionation schedules: 984 patients were given 1 fraction daily throughout (q.d.), and 48 patients were irradiated twice daily (b.i.d.) for part of the course. The median total dose was 62.5 Gy (range 50.4-71.2), dose per fraction was 2.5 Gy (range 1.6-4.2), and overall treatment time (OTT) was 44 days (range 29-70). In addition, 500 patients received supplementary doses for parapharyngeal extension, 113 received booster doses by brachytherapy, and 114 received sequential chemotherapy using cisplatin-based regimes., Results: Altogether, 24 patients developed symptomatic temporal lobe necrosis: 18 from the q.d. group and 6 from the b.i.d. group. The 5-year actuarial incidence ranged from 0% (after 66 Gy in 33 fractions within 44 days) to 14% (after 71.2 Gy in 40 fractions within 35 days). Multivariate analyses showed that the risk was significantly affected by the fractional effect of the product of total dose and dose per fraction (hazard ratio [HR] = 1.04, 95% confidence interval [CI] 1.02-1.05), OTT (HR 0.88, 95% CI 0.80-0.97), and b.i.d. scheduling (HR 13, 95% CI 3-54). Repeating the analyses for patients treated with the q.d. schedules confirmed the independent significance of OTT in addition to the product of total dose and dose per fraction., Conclusion: The tentative results suggest that in addition to fractional dose, the OTT also had significant impact on the risk of temporal lobe necrosis, and b.i.d. scheduling increased the hazard further.

Purpose: Nasopharyngeal carcinoma (NPC) is highly sensitive to both radiotherapy (RT) and chemotherapy. This randomized phase III trial compared concurrent cisplatin-RT (CRT) with RT alone in patients with locoregionally advanced NPC., Patients and Methods: Patients with Ho's N2 or N3 stage or N1 stage with nodal size > or = 4 cm were randomized to receive cisplatin 40 mg/m(2) weekly up to 8 weeks concurrently with radical RT (CRT) or RT alone. The primary end point was progression-free survival (PFS)., Results: Three hundred fifty eligible patients were randomized. Baseline patient characteristics were comparable in both arms. There were significantly more toxicities, including mucositis, myelosuppression, and weight loss in the CRT arm. There were no treatment-related deaths in the CRT arm, and one patient died during treatment in the RT-alone arm. At a median follow-up of 2.71 years, the 2-year PFS was 76% in the CRT arm and 69% in the RT-alone arm (P =.10) with a hazards ratio of 1.367 (95% confidence interval [CI], 0.93 to 2.00). The treatment effect had a significant covariate interaction with tumor stage, and a subgroup analysis demonstrated a highly significant difference in favor of the CRT arm in Ho's stage T3 (P =.0075) with a hazards ratio of 2.328 (95% CI, 1.26 to 4.28). For T3 stage, the time to first distant failure was statistically significantly different in favor of the CRT arm (P =.016)., Conclusion: Concurrent CRT is well tolerated in patients with advanced NPC in endemic areas. Although PFS was not significantly different between the concurrent CRT arm and the RT-alone arm in the overall comparison, PFS was significantly prolonged in patients with advanced tumor and node stages.

To identify the epigenetic changes in nasopharyngeal carcinoma (NPC), we performed methylation-sensitive restriction fingerprinting (MSRF) analysis on NPC cell lines and xenografts. A 190 bp sequence methylated in NPC tumors was isolated and showed high homology to the 5' CpG island of the endothelin receptor B (EDNRB) gene. Since the EDNRB gene is commonly inactivated in prostate and bladder cancers, it may be a candidate target gene involved in NPC tumorigenesis. By bisulfite sequencing, we have confirmed that hypermethylation of the 5' CpG island of EDNRB occurred in both xenografts and all 4 cell lines but not in 2 normal nasopharyngeal outgrowths. RT-PCR demonstrated that only original EDNRB transcripts, but not the splicing transcripts, were expressed in normal nasopharyngeal epithelial cells. Loss of the original EDNRB expression was consistently found in 2 xenografts and 3 cell lines with dense methylation patterns. Treatment of these 3 cell lines with 5'-aza-2'-deoxycytidine led to re-expression of the EDNRB transcript and demethylation of its promoter regions. Our results demonstrate that silencing of EDNRB gene expression in NPC is associated with promoter hypermethylation. Using methylation-specific PCR, we also detected methylation of the 5' CpG island of EDNRB in 19/21 (90.5%) primary tumors, while no methylation was found in all 6 normal nasopharyngeal epithelia. The high frequencies of promoter hypermethylation suggest that repression of the EDNRB gene may play a role in the development of NPC., (Copyright 2002 Wiley-Liss, Inc.)

We have applied the method of genomic microarray to investigate amplification of oncogenes throughout the genome of nasopharyngeal carcinoma (NPC). Array based comparative genomic hybridization (array CGH) allows simultaneous examination of 58 oncogenes commonly amplified in various human cancers. In the present study, we have examined 15 NPC samples including five cell lines, two xenografts and eight primary tumours with array CGH to reveal the particular oncogenes associated with this cancer. This is the first genome wide survey of multiple oncogene amplifications involved in the development of NPC. Non-random gene amplifications were identified for the first time in NPC on MYCL1 in 1p34.3 and on TERC and PIK3CA at 3q26.3. Other high level amplified oncogenes included NRAS, RAF1, MYB, EGFR, FGF4, EMS1, and D17S167. Highest frequencies of gain of novel oncogenes were detected on MYCL1 (66.7%), TERC (46.7%), ESR (46.7%), PIK3CA (40%), LAMC2 (33.3%), and CSE1L (33.3%).

Purpose: The methylation profile of nasopharyngeal carcinoma (NPC) has been investigated by a candidate gene approach., Experimental Design: Four NPC cell lines, 4 NPC xenografts, 33 NPC primary tumors, and 6 samples of normal nasopharyngeal epithelium were subjected to methylation-specific PCR for analysis of promoter methylation of eight cancer-related genes. These eight genes were RASSF1A, RARbeta2, DAP-kinase, p16, p15, p14, MGMT, and GSTP1. The correlation between methylation status of these genes and clinical features such as stage, local-regional recurrence, distant metastasis, and survival has been analyzed., Results: The incidence of promoter methylation in NPC samples was 84% for RASSF1A, 80% for RARbeta2, 76% for DAP-kinase, 46% for p16, 17% for p15, 20% for p14, 20% for MGMT, and 3% for GSTP1. No methylation of these genes was detected in the six normal nasopharyngeal epithelium samples. All NPC tumor samples in this study displayed aberrant methylation in at least one of these eight genes. No significant correlation between methylation status of these genes and clinical parameters of the patients was found., Conclusions: A high frequency of aberrant methylation of the 5' CpG island of the RASSF1A, RARbeta2, DAP-kinase, and p16 genes in the present study was noted. Our findings suggest that methylation of the genes in the critical pathways is common in NPC.

Background: It has been proposed that nasopharyngeal carcinoma (NPC) has an early noninvasive stage, designated nasopharyngeal intraepithelial neoplasia (NPIN). Hence, the detection and treatment of NPIN will prevent NPC from developing, and this would be similar to the strategies used for cervical cancer prevention. We wanted to ascertain the feasibility of using a brush sampler to collect cells for the cytologic diagnosis of NPIN and NPC. If successful, the technique could be used as a screening test in endemic areas., Methods: A disposable sampler (Uterobrush) was used to collect nasopharyngeal mucosal brushings from 546 patients for cytologic examination. After this, most patients had biopsies, and this allowed histologic-cytologic correlation to be undertaken., Results: In 528 patients (96.7%) there were satisfactory cytologic and biopsy specimens for evaluation. There were 149 cases with positive histology and 103 had positive cytology (specificity was 100% and the sensitivity was 69.1%). One case of NPC with concurrent NPIN was seen among the biopsy specimens, but no case of NPIN was detected cytologically., Conclusions: The cytologic pickup of NPC was substantially lower than that obtained on biopsy. More importantly, NPIN was uncommon. Therefore, a screening test that depends on the collection of cells for the microscopic diagnosis of NPIN and NPC is unlikely to have a major impact on the incidence of NPC. Furthermore, obtaining a good cytologic specimen from the nasopharynx is not simple, and this further limits this technique for mass screening purposes. The concept of a cytologic test for NPC, similar to the Pap test for the prevention of uterine cervix cancer, has still to be realized.

We have investigated the genetic and epigenetic changes of a newly isolated tumor suppressor gene on 3p21.3, RASSF1A, in nasopharyngeal carcinoma (NPC). Four xenografts, four cell lines and 21 primary tumors were examined. Promoter hypermethylation of the 5'CpG island of RASSF1A was detected in 4 of 4 (100%) xenografts, in 3 of 4 (75%) cell lines, and in 14 of 21 (66.7%) primary tumors but not in the normal nasopharyngeal epithelia. Mutations were found in 2 of 21 (9.5%) primary tumors. In the cell lines and xenografts with extensive methylation, no RASSF1A gene expression was found. After treatment with 5'-aza-2'deoxycytidine, reexpression and demethylation of the RASSF1A gene were detected in a NPC cell line. These findings suggest that promoter hypermethylation may participate in the transcriptional inactivation of the RASSF1A gene in NPC. The high incidence of RASSF1A alterations suggest that it is the critical target gene on chromosome 3p21.3 involved in the development of NPC.

Background and Purpose: The aim of this study is to evaluate and delineate the deficiencies in conventional two-dimensional (2-D) radiotherapy planning of nasopharyngeal carcinoma (NPC) treatment and to explore the means for improvement of the existing treatment technique aiming at enhancing local tumor control and reducing treatment complications., Methods and Materials: Ten patients with NPC sparing the skull base and without intracranial extension or cranial nerve(s) palsy were chosen in the present study. Two sets of CT images for Phases I and II of the radiotherapy treatment were taken with patient immobilized in the flexed-head and the extended-head positions, respectively. Based on the CT images and endoscopic findings, the gross tumor volume (GTV) was defined. The clinical target volume (CTV) circumscribing the GTV was defined according to Ho's (Halnan, K.E. (ed.) Treatment of Cancer. London: Chapman and Hall, 1982. pp. 249-268) description of the organs at risk of tumor infiltration. The planning target volume (PTV) was defined by adding a margin to the CTV which catered for geometrical inaccuracies. The field borders and shields were set at standard distances from certain bony landmarks and were drawn on the simulator radiograph. Data on the beams and shield arrangements were then transferred to the planning computer via a digitizer. By applying 3-D volumetric dose calculation using a commercial three-dimensional (3D) treatment planning computer, the dose-volume-histograms (DVHs) of GTV, CTV, PTV and critical normal organs were generated for both phases of Ho's treatment technique. The same patients were re-planned using a modified Ho's technique which used 3-D beams-eye-view (BEV) in placing the shielding blocks and the same set of DVHs were generated and compared with those obtained from Ho's technique., Results: The median volumes of GTV, CTV and PTV covered by the 95% isodose in Ho's phase I treatment were around 60%. The dose coverage was unsatisfactory in the superior and inferior and the posterolateral regions. In phase II treatment, the median volume of GTV, CTV and PTV covered by the 95% isodose were 99, 96 and 72%, respectively. Even though the dose coverage of the PTV in both phases of treatment were unsatisfactory, radiotherapy with the original Ho's technique had consistently produced good local control for NPC. However, there is potential room for enhancing the local control further because after modifying Ho's technique by using 3-D BEV customization of the treatment portals, the median volume of the target covered by the 95% isodose was defined as V(95). The V(95) of the PTV during the Phase II treatment was improved by 13%. The 90% of the volume of temporo-mandibular joints and parotid glands were both irradiated to 53 Gy and 43.6 Gy of the total prescribed dose of 66 Gy, respectively, in phase I and II treatments. With the addition of a hypothalamus-pituitary shield to Ho's technique, 50% of the volume of optic chiasma and temporal lobes received, respectively, 19.3 Gy and 4.5 Gy. However, small volume of the temporal lobes received a maximum dose (D(max)) of 62.8 Gy (95.2% of 66Gy). Most of the brainstem was shielded from the lateral portals but 5% of its volume received a dose ranging from 25.4 to 50.4Gy. The spinal cord (at C1/C2 level) received a D(max) of 40.8 Gy in phase I and of 4.8 Gy in phase II. After modifying Ho's technique by 3-D BEV customization of the treatment portals, the D(max) to the brainstem, the optic chiasma and the temporal lobes could be reduced by 8, 12 and 5%, respectively., Conclusions: Our study indicated that the dose-coverage of the PTV in Ho's radiotherapy technique for the early T-stage NPC was less than satisfactory in the superior and inferior and the posterolateral regions. However, in view of the excellent historical local tumor control with Ho's technique, we have to postulate that the present definition of CTV (and hence the PTV after adding margins to the CTV) lacks clinical significance and can be improved. It appears that the inclusion of the entire sphenoid sinus floor and both medial and lateral pterygoid muscles in the CTV is not necessary for maximal tumor control in the absence of clinical/radiological evidence of tumor infiltration of these organs. Ho's technique can be improved by using 3-D BEV to customize the treatment portals with multileaf collimators or blocks.

Traditional approaches to nasopharyngectomy for the treatment of recurrent nasopharyngeal carcinoma carry considerable complications. This paper presents an innovative transnasal approach with stereotactic navigation guidance through a mid-face deglove incision which has been done for 15 patients with minimal morbidity. All patients had resumed their oral diet within a week, and were discharged within 10 days. The intraoral wound had healed within a week. The only complications were a mild degree of saddling of the nasal dorsum in one patient and temporary facial numbness that resolved within six weeks in three. Tumour had been resected with clear margins in 12/15, in the other three being stuck to the carotid artery.

Purpose: The aim of the present study was to compare the survival, local control and complications of conventional/accelerated-hyperfractionated radiotherapy and conventional radiotherapy in nonmetastatic nasopharyngeal carcinoma (NPC)., Methods and Materials: From February 1993 to October 1995, 159 patients with newly diagnosed nonmetastatic (M0) NPC with N0 or 4 cm or less N1 disease (Ho's N-stage classification, 1978) were randomized to receive either conventional radiotherapy (Arm I, n = 82) or conventional/accelerated-hyperfractionated radiotherapy (Arm II, n = 77). Stratification was according to the T stage. The biologic effective dose (10 Grays) to the primary and the upper cervical lymphatics were 75.0 and 73.1 for Arm I and 84.4 and 77.2 for Arm II, respectively., Results: With comparable distribution among the T stages between the two arms, the free from local failure rate at 5 years after radiotherapy was not significantly different between the two arms (85.3%; 95% confidence interval, 77.2-93.4% for Arm I; and 88.9%; 95% confidence interval, 81.7-96.2% for Arm II). The two arms were also comparable in overall survival, relapse-free survival, and rates of distant metastasis and regional relapse. Conventional/accelerated-hyperfractionated radiotherapy was associated with significantly increased radiation-induced damage to the central nervous system (including temporal lobe, cranial nerves, optic nerve/chiasma, and brainstem/spinal cord) in Arm II. Although insignificant, radiation-induced cranial nerve(s) palsy (typically involving VIII-XII), trismus, neck soft tissue fibrosis, and hypopituiturism and hypothyroidism occurred more often in Arm II. In addition, the complications occurred at significantly shorter intervals after radiotherapy in Arm II., Conclusion: Accelerated hyperfractionation when used in conjunction with a two-dimensional radiotherapy planning technique, in this case the Ho's technique, resulted in increased radiation damage to the central nervous system without significant improvement in efficacy.

Purpose: To study the efficacy of intracavitary brachytherapy (ICT) in early T-stage nasopharyngeal carcinoma (NPC)., Methods and Materials: All early T-stage (T1 and T2 nasal cavity tumour) NPC treated with a curative intent up to 1996 were analyzed (n=743), 163 from the Prince of Wales Hospital (PWH) and 25 from Tuen Mun Hospital (TMH) were given ICT after radical external radiotherapy (ERT; group A). They were compared with 555 patients treated with ERT alone (group B). The radiotherapy techniques were identical between the two hospitals. The ERT delivered the tumoricidal dose (uncorrected biological equivalent dose (BED)-10, > or = 75 Gy) to the primary tumour, and this did not differ in technique or dosage between the two groups. The ICT delivered a dose of 18-24 Gy in three fractions over 15 days to a point 1 cm perpendicular to the midpoint of the plane of the sources., Results: The local failure was significantly less (crude rates, 6.9 vs. 13.0%; 5-year actuarial rates, 5.8 vs. 11.7%) and the disease-specific mortality was significantly lower (crude rates, 13.8 vs. 18.9%; 5-year actuarial rates, 12.2 vs. 15.2%) in group A compared with group B. ICT was the only significant independent prognostic factor predictive of fewer local failures. When ICT was excluded from the Cox regression model, the total physical dose or the total BED-10 uncorrected for tumour repopulation became significant in predicting the ultimate local failure rate. The two groups were comparable in the rate of the chronic radiation complications. A significant dose-tumour-control relationship existed, plotting the local failure as a function of the total physical dose or the total BED., Conclusions: Supplementing ERT, which delivered the tumoricidal dose (uncorrected BED-10, > or = 75 Gy), with ICT significantly enhanced ultimate local control in early T-stage (T1/T2 nasal infiltration) NPC. A significant dose-tumour-control relationship exists above the conventional tumoricidal dose level.

Nasopharyngeal carcinoma (NPC) is a common cancer in South China but is rare in other parts of the world. To better understand the molecular basis of this cancer, we performed high-resolution allelotyping on 27 microdissected primary tumors using 382 microsatellite markers. We have detected high frequencies of allelic imbalance on 3p (96.3%), 9p (85.2%), 9q (88.9%), 11q (74.1%), 12q (70.4%), 13q (55.6%), 14q (85.2%), and 16q (55.6%). Nonrandom allelic changes of 12q and 16q were revealed for the first time. In addition, loss of heterozygosity on chromosomal arms 1p (37.0%), 5q (44.4%), and 12p (44.4%) were also common in NPC. Multiple minimally deleted regions, 7-40 cM, were identified at 3p14-24.2, 11q21-23, 13q12-14, 13q31-32, 14q24-32, and 16q22-23. Frequent deletions of these minimally deleted regions implied the presence of tumor suppressor genes that may be involved in the development of NPC. Consistent loss of heterozygosity on 3p, 9p, and 14q in almost all tumors suggested that such changes are critical events in NPC tumorigenesis.

Background: The incidence of recurrent nasopharyngeal carcinoma (NPC) after primary radiotherapy is considerable. The result of re-irradiation to the recurrent tumor is not satisfactory., Methods: Thirty-one patients who received nasopharyngectomy for treatment of their recurrent nasopharyngeal carcinoma (NPC) (rT1 to rT3) at the Prince of Wales Hospital during the period 1986 to 1997 were reviewed retrospectively. Eleven patients had nasopharyngectomy performed by the transoropalatal approach, 9 patients by the maxillary swing approach, and 11 patients by the mandibular approach., Results: Most recurrences (29 of 31) were rT1 and rT2 tumors. No hospital mortality occurred. The common complications of nasopharyngectomy were palatal defect (17 of 31), trismus (15 of 31), otitis media with effusion (20 of 31), dysphagia (12 of 31), and nasal regurgitation (8 of 31). Nine surgical specimens had microscopic invasion of the resection margins. The 5-year actuarial overall survival, actuarial disease-free survival, and tumor control were 47%, 42%, and 43%, respectively. The administration of postoperative radiotherapy significantly enhanced survival and tumor control after nasopharyngectomy., Conclusions: Nasopharyngectomy supplemented by postoperative radiotherapy achieved significant survival and tumor control with acceptable complications in selected recurrent NPC. It appears to be a better salvage treatment than re-irradiation alone for selected recurrent NPC.

Background and Purposes: Recent randomized studies from the West show that post-operative locoregional radiotherapy improves survival in lymph node (LN) positive pre-menopausal women with breast cancer but this benefit has not been established in the Chinese population. There is no published study on clinical outcomes (locoregional recurrence, survival and toxicities) of post-operative locoregional radiotherapy in Chinese women with breast cancer., Materials and Methods: We conducted a retrospective study of 399 female Chinese patients with breast cancer who had received post-mastectomy locoregional radiotherapy in our center between 1984 and 1990. The patients were stratified according to tumor size, menopausal and LN status. We analyzed the incidence and pattern of locoregional recurrence, distant recurrence, survival rates and toxicity related to radiotherapy., Results: Of the 399 patients 216 were pre-menopausal and 183 were post-menopausal. The mean age was 49.3 years (23-83). Distribution of tumor size and LN status of the two groups was similar. Median follow-up was 71.9 months. Locoregional recurrence occurred in 57 (14.3%) patients (pre-menopausal 24 (11.1%); post-menopausal 33 (18.3%) P=0.489). Recurrence was more common in LN positive patients (18.2%) than LN negative patients (9.2%). The pattern of locoregional recurrence was: chest wall 24, axilla LN 12, supraclavicular LN 10, chest plus LN 11. The distant recurrence rate was 39.6% for all patients and 75.4% for patients with locoregional recurrences. The overall 10-year survival rate for all patients was 54%. For LN positive patients the 10-year survival rate of pre-menopausal and post-menopausal women was 38 and 51%, respectively (P=0.207), and for LN negative patients the rate was 73 and 70%, respectively (P=0.603). Acute skin toxicity included redness (30.8%), dry desquamation (12.8%), and wet desquamation (6. 8%). Long-term toxicities included skin atrophy (0.3%), telangectasia (3.3%), pneumonitis (2.8%) and brachial plexus palsy (1.3%)., Conclusions: In our series Chinese patients with node-positive breast cancer have a relatively high locoregional recurrence rate in spite of mastectomy and post-operative radiotherapy. Limited use of adjuvant system chemotherapy may account, at least in part, for this finding. Clinical outcomes of post-operative radiotherapy in pre-menopausal and post-menopausal breast cancer patients are similar.

Objectives: To investigate the failure patterns and the prognostic factors following postoperative radiotherapy for salivary gland carcinoma., Design: Retrospective study., Setting: University teaching hospital, Hong Kong., Patients: Fifty patients who had non-disseminated salivary gland carcinoma and who received primary treatment from 1984 through 1993., Main Outcome Measures: Demographic data, cancer T- and N-stages, histological type, site of origin, completeness of surgery, whether postoperative radiotherapy was given, and the clinical outcome., Results: Two (4%) patients had been treated with radiotherapy alone, six (12%) had undergone radical resection alone, and 42 (84%) had been radically treated by using both modalities. The 5-year overall survival and relapse-free survival rates were 78.4% and 63.1%, respectively. The free from local failure and free from distant metastasis rates at 5 years were 77.2% and 72.8%, respectively. The N-stage was a significant prognostic factor. The site of the primary tumour, T-stage, completeness of surgery, and use of postoperative radiotherapy were not significant independent prognosticators; however, among the T-stage tumours, the b-substage carcinomas had significantly fewer local failures (P=0.040) and better survival rates (P=0.038) than the a-substage carcinomas. There were seven (14%) locoregional failures without distant metastasis, seven (14%) cases of distant metastasis without locoregional failures, and four (8%) locoregional failures preceding distant metastasis; isolated regional relapse was rare (1/50; 2%). All regional failures (5/50; 10%) occurred ipsilateral to the primary lesion. There were no deaths due to lymphoepithelioma-like carcinoma or acinic cell carcinoma., Conclusions: The N-stage is the main prognostic factor of overall survival, relapse- and metastasis-free recovery, and success of treatment for salivary gland carcinoma. Optimal locoregional treatment can help reduce distant metastasis, and the maximal use of postoperative radiotherapy may contribute to improved locoregional control. Elective ipsilateral neck radiotherapy is indicated for lymphoepithelioma-like carcinoma.

Purpose: To study the efficacy of intracavitary brachytherapy (ICT) in early T-stage nasopharyngeal carcinoma (NPC)., Methods and Materials: All T1 and T2 (nasal infiltration) NPC treated with a curative intent from 1984 to 1996 were analyzed (n = 509). One hundred sixty-three patients were given ICT after radical external radiotherapy (ERT) (Group A). They were compared with 346 patients treated by ERT alone (Group B). The ERT delivered the tumoricidal dose (uncorrected BED-10 > or =75 Gy) to the primary tumor and did not differ between the two groups in technique or dosage. The ICT delivered a dose of 18-24 Gy in 3 fractions over 15 days to a point 1 cm perpendicular to the midpoint of the plane of the sources. ICT was used to treat local persistence diagnosed at 4-6 weeks after ERT (n = 101) or as an adjuvant for the complete responders to ERT (n = 62)., Results: The two groups did not differ in patients' age or sex, rate of distant metastasis, rate of regional failure, overall survival, or the follow-up duration. However, Group A had significantly more T2 lesions and Group B had significantly more advanced N-stages. Local failure was significantly less (crude rates 6.75% vs. 13.0%; 5-year actuarial rates 5.40% vs. 10.3%) and the disease-specific mortality was significantly lower (crude rates 14.1% vs. 21.7%; 5-year actuarial rates 11.9% vs. 16.4%) in Group A compared to Group B. Multivariate analysis showed that the ICT was the only significant prognostic factor predictive for fewer local failures (Cox regression p = 0.0328, risk ratio = 0.49, 95% confidence interval (95% CI) = 0.256-0.957). However, when ICT was excluded from the Cox regression model, the total physical dose or the total BED-10 uncorrected for tumor repopulation during the period of radiotherapy became significant in predicting ultimate local failure rate. The two groups were comparable in the incidence rates of each individual chronic radiation complication and the actuarial cumulative rate of the chronic radiation complications, with the exception of chronic radiation nasopharyngeal ulceration/necrosis which occurred in 10 patients in Group A and 1 patient in Group B. Headache (n = 4) and foul smell (n = 8) consequential to ulceration/necrosis were mild and manageable by conservative means. A significant dose-tumor-control relationship existed when local failure was studied as a function of the total physical dose or the total biological equivalent dose (linear quadratic equation, alpha/beta = 10) uncorrected for tumor repopulation during the time course of the radiotherapy., Conclusions: Supplementing ERT which delivered tumoricidal dose (uncorrected BED-10 > or =75 Gy), ICT significantly enhanced ultimate local control and avoided the necessity for morbid salvage treatments in early T-stage (T1/T2 nasal infiltration) NPC. The slight increase in chronic radiation ulceration/necrosis after ICT was acceptable with mild and manageable symptoms. Other late complications were not increased. A significant dose-tumor-control relationship exists above the conventional tumoricidal dose level.

The purpose of this work is to study the efficacy and limitations of using standard multileaf collimators (MLCs) and micro-multileaf collimators (mMLCs) in the treatment of nasopharyngeal carcinoma (NPC) by conventional and conformal radiotherapy techniques. The penumbra characteristics of MLC, mMLC, and customized block collimated beams are measured with respect to leaf edge angle, beam energy, treatment depth, and field size and compared with those generated by a commercial three-dimensional planning computer system. Upon verification of the planning system, it is used to evaluate the treatment plans generated with these beam shapers for conventional and conformal NPC treatments. The effective penumbra of a MLC beam is strongly influenced by its edge angle, leaf width, and treatment depth. The suitability of standard MLCs in conventional NPC treatments is determined mainly by the edge angle to be used. For conformal NPC treatments involving six or more fields, dose volume histograms comparable to those of customized beam blocks are obtained with a standard MLC. The mMLC does not have the same restrictions as those on standard MLC but is limited to phase II treatment by its small usable field size. Both standard MLCs and mMLCs can be used to replace customized divergent beam blocks in both conventional and conformal NPC treatments. However, a MLC, due to its larger effective penumbra, may be unsuitable for use in cases when the tumor volumes extend very close to the critical normal structures. A mMLC, on the other hand, is limited by its small maximum field size and can only be used for collimating the facial portals in the second phase treatment.

Aim: Lymphoepithelioma is principally a tumour of the nasopharynx with only sporadic cases arising elsewhere in the head and neck. We describe the clinical and imaging features of a group of rare lymphoepitheliomas related to the palate., Patients and Methods: Four patients with lymphoepithelioma of the palate are described. In each case we retrospectively reviewed the clinical records, laboratory results, and imaging which consisted of computed tomography (CT) and ultrasound in all four cases and magnetic resonance imaging (MRI) in two patients., Results: All four patients were ethnic Chinese (non-smokers, non-drinkers). All cases were Epstein-Barr virus (EBV) related. Tumour was related to the palate in two cases and extended into the nasal cavity in one patient. The fourth patient had a tumour in the floor of the nasal cavity with invasion of the palate on biopsy but not imaging. Cervical lymphadenopathy was seen in two cases, and the nasopharynx was normal in all the four patients., Conclusion: Lymphoepitheliomas occur in the region of the palate, where they are also EBV related in southern Chinese. Compared with the keratinizing squamous cell carcinomas, patients with lymphoepitheliomas have a better prognosis and these tumours are not tobacco or alcohol related. They should not be misdiagnosed as metastatic nasopharyngeal carcinoma (NPC), particularly since the nasopharynx is invariably normal on imaging and adequate nasopharyngeal biopsy is negative for malignancy.

The aim of this study was to define the risk of tongue and other aerodigestive tract cancers developing after primary radiation therapy for nasopharyngeal carcinoma (NPC). A cohort of 903 patients with non-disseminated NPC given radical radiotherapy between 1984 and 1989 was studied for the incidence of tongue cancer and other malignancies during follow-up. A contemporary cohort of 87 patients with tongue cancer, without a history of NPC, was studied for demographic data, cigarette smoking and alcohol consumption habits. These were then compared with all the NPC patients and with the NPC patients who later developed tongue cancers. There was a significantly increased number of tongue cancers following radiotherapy for NPC. The risk of developing tongue cancer after radiotherapy for NPC was 0.13% per patient per year. There was no increase in the number of other malignancies. The association between NPC and tongue cancer was that of a non-random temporal sequence with tongue cancers following NPC but not in the reverse order. The demographic data and smoking and alcohol consumption history of the 7 NPC patients who subsequently developed tongue cancer were significantly different from the de novo tongue cancer patient population. The absence of common aetiological factors between NPC and tongue cancer and the non-random sequence of tongue cancers occurring after NPC suggests that these seven tongue cancers could be radiation induced. The estimated radiation dose received by the part of the tongue developing cancer was substantial and significantly higher than the dose to the cancer-free tongue. An increase of tongue cancers after radiotherapy for NPC is reported and arguments are made in support of the hypothesis that these were radiation-induced malignancies. We suggest a decrease in the volume of tongue included within the planning target volume of NPC in the absence of oropharyngeal and/or parapharyngeal infiltration. Awareness of the association should make early diagnosis of this likely radiation-induced cancer possible.

Purpose: To determine the efficacy of chemotherapy adjunctive to radical radiotherapy (neoadjuvant +/- adjuvant) in patients with node-positive nasopharyngeal carcinoma (NPC)., Methods and Materials: All the node-positive patients given adjunctive chemotherapy between 1984-1989 (n = 209, CHEMO) were compared with all the node-positive patients treated by radical radiotherapy alone during the same period (n = 409, NCHEMO). The CHEMO group had significantly more bulky nodes, lower cervical/supraclavicular nodes, and more advanced overall stages than the NCHEMO group because nodal size (> or =24 cm) was used as a selection criterion for chemotherapy (1984-1988 departmental protocol and 1988-1989 prospective randomized trial). The chemotherapy consisted of two courses of neoadjuvant cisplatin (100 mg/m2 D1) and 5-fluorouracil (5-FU) (1 gm/m2 D1-D3) in 191 patients. In addition to the two courses of neoadjuvant, four courses of adjuvant chemotherapy, of the same combination, were given after radical radiotherapy in a further 18 patients. Radical radiotherapy delivered a nasopharyngeal dose of 60-62.5 Gy. In addition, parapharyngeal booster external radiotherapy (20 Gy) was given in the presence of parapharyngeal involvement, and intracavitary brachytherapy (24 Gy) was used to treat any local residual tumor diagnosed at 4-6 weeks after external radiotherapy. Both crude and actuarial rates were compared (survival, distant metastases, and local failures) between CHEMO and NCHEMO for all patients, for individual Ho's overall stage, for patients with nodes of different sizes (< or =3 cm, >3-< or =6 cm, >6 cm), for individual T-stage and individual N-stage, and for patients belonging to different gender and different age groups (<40 years, > or =40 years). Multivariate analyses using the Cox Regression Model were performed to identify significant prognostic factors., Results: With a median follow-up of 5.5 years (range 0.7 to 10 years), CHEMO had significantly less local failures overall than NCHEMO; this was especially true for patients with advanced stages (III + IV). Additionally, in all nodal-size subgroups, in all node-positive T3, and in node-positive T3-Stage IV, there was a significant reduction in local failures after chemotherapy. There was a trend toward fewer local failures in favor of chemotherapy in Stage III, Stage IV, and T3-Stage III (0.05

Background: Lymphoepithelioma-like carcinoma (LELC) of the lung occurs at a higher frequency in Asian compared with Western patients. Its association with Epstein-Barr virus varies among different ethnic groups., Methods: Nine patients with primary LELC of the lung treated at a single institution with a multimodality approach comprised of surgery, chemotherapy, and radiotherapy are reported. Chemotherapy was comprised of cisplatin, 100 mg/m2, on Day 1 and 5-fluorouracil, 1 g/m2, on Days 2, 3, and 4., Results: Five male and 4 female patients were treated over a 3-year period. Eight patients were non-smokers. Three patients had operable disease. Two of these patients received adjuvant radiotherapy or chemotherapy and remained free of recurrence at 18 and 20 months, respectively; 1 patient received no adjuvant treatment, and palliative chemotherapy was given for subsequent recurrent disease. Six patients had inoperable disease and received palliative chemotherapy +/- radiotherapy. Five patients had distant metastatic disease at presentation. Of the 7 patients who were evaluable for response to chemotherapy, 71.4% had a partial response and 28.6% had progressive disease. One patient who was evaluable for response to radiotherapy achieved a partial response., Conclusions: Primary LELC of the lung has a high rate of systemic metastasis and is highly chemosensitive. A multimodality approach to the management of this disease is recommended.

In patients with locoregionally advanced nasopharyngeal carcinoma the results of treatment with conventional radiotherapy are unsatisfactory, with significant rates of both distant metastases and local recurrences. The use of neoadjuvant and adjuvant chemotherapy has resulted in consistently high response rates, but no randomized trial has yet demonstrated an improvement in overall survival. Altered-fractionation radiation techniques have not been proven to improve survival in locoregionally advanced nasopharyngeal carcinoma, and extreme caution is required to minimize unpredicted neurological toxicities. An interim analysis of a Head and Neck Intergroup study randomly assigning patients to receive concurrent chemotherapy and radiotherapy and adjuvant chemotherapy or radiotherapy alone has demonstrated significant benefit in overall survival favoring the use of concurrent chemotherapy and radiotherapy. Whether this regimen is applicable to all ethnic and histological groups, however, remains to be proven.

Background: Nasopharyngeal carcinoma (NPC) is a radiosensitive tumor for which there is a high local control rate after radical radiotherapy (RT). However, for patients with locoregionally advanced disease, the rate of distant metastasis is high and the 5-year overall survival rate is poor., Methods: A review of retrospective and prospective clinical studies was performed to assess the role of chemotherapy in three settings: metastatic disease; neoadjuvant and/or adjuvant; and concurrent chemotherapy with radiotherapy., Results: Cisplatin-based combination chemotherapy results in a high response rate in patients with metastatic NPC, and a subgroup may achieve long term disease free survival. The use of neoadjuvant and adjuvant chemotherapy to treat locoregionally advanced disease has resulted in consistently high response rates, but no randomized trial to date has demonstrated an improvement in overall survival. A recent Head and Neck Intergroup study randomized patients in the United States to receive concurrent chemotherapy (cisplatin) and radiotherapy or radiotherapy only. Although this approach demonstrated significant benefit in overall survival favoring the use of concurrent chemotherapy and radiotherapy, its applicability in geographic areas of high NPC incidence remains to be proven., Conclusions: NPC is a chemosensitive tumor, and patients with metastatic disease have a high response rate. Further prospective studies will define the standard approach to treating locoregionally advanced NPC, which is likely to incorporate into the primary treatment some form of systemic chemotherapy.

Purpose: To evaluate the efficacy of high-dose (> or = 60 Gy) reirradiation using mainly external beams in salvaging local failures of nasopharyngeal carcinoma (NPC) after modern primary radical radiotherapy that delivered radical dose-to-target volumes defined by CT scan., Methods and Materials: Nine hundred and three patients with nondisseminated NPC whose primary radical radiotherapy was administered between 1984 and 1989 inclusive were studied. One hundred and seventy-six had local failures comprising 9 persistences and 167 recurrences. In 10 patients the local failures were preceded or accompanied by (within 2 months) distant metastases, and these were given supportive treatment or palliative radiotherapy in low dose (< 60 Gy) if symptomatic. Most of the rest (123 of 166) were treated with either reirradiation to high dose (> or = 60 Gy) using mainly external photon beams (n = 103) or nasopharyngectomy with/without radical neck dissection with/without postoperative radiotherapy (n = 20). The remainder (n = 43) received only palliative treatments because of poor general condition and/or patients' refusal of radical treatments. The primary radiotherapy was planned on the basis of target volumes defined by CT scan and given to a standard nasopharyngeal dose of 62.5 Gy/29 fractions/6 weeks. In the presence of parapharyngeal involvement, an additional boost of 20 Gy/10 fractions/2 weeks was given via a posterior oblique photon beam. If local residual tumors were diagnosed at 4-6 weeks after the completion of external radiotherapy, an additional boost of 24 Gy/3 fractions/15 days was given by intracavitary intubation. For the local failures given high-dose reirradiation, the target volume was defined by CT scan and treated by a two-field or a three-field photon arrangement with or without additional dose supplement by intracavitary intubation. Nasopharyngectomy was performed via the transcervico-mandibulo-palatal approach or the maxillary swing approach. Radical neck dissection was only performed for the clinically evident nodal failures., Results: With a median follow-up of 20 months (range 2.5-81 months) since the diagnosis of local failure, the actuarial 5-year overall survival, further relapse-free survival and free-from-local-tumor rates were 9.4, 11.5, and 18.7%, respectively, for the 123 patients treated by either high-dose reirradiation (n = 103) or nasopharyngectomy (n = 20). Palliatively treated patients (n = 43) had a survival comparable to patients whose local failures were preceded or accompanied by distant metastasis (n = 10). Reirradiation to high dose (> or = 60 Gy) mainly by external photon beams achieved a 5-year overall survival of 7.6% and 5-year local control of 15.2% with significant complications. Radiation-induced temporal lobe encephalopathy was radiologically evident in 21 patients (20.4%), and 13 of these 21 patients were symptomatic. It could have been the cause of death in three patients who also suffered from uncontrolled local tumor. Significant morbidity was also associated with the other frequent radiation complications, including xerostomia, trismus, and deafness. Uni- and multivariate analyses indicated that brief initial disease-free interval between completion of primary radiotherapy and diagnosis of local failures and advanced recurrent T-stage and recurrent N-stage were significant prognosticators predicting poor survival and/or further local failure after reirradiation. These patients were unlikely to benefit from the treatment. Nasopharyngectomy (+/- neck dissection +/- postoperative radiotherapy) was associated with earlier recurrent T-stages (mostly rT1 and rT2) and better survival and local control than reirradiation. However, restricting the comparison to rT1 and rT2 still demonstrated the superior results in favor of nasopharyngectomy, which could not be explained by the selection of less advanced lesions or patients with better performance status for surgery. (ABSTRACT TRUNCATED)

Background: Breast-conserving surgery combined with radiotherapy has emerged as an alternative to mastectomy for women with early breast cancer, and cosmetic outcome has correlated closely with the psychosocial and physical well-being of the patient. Cosmetic outcome assessment after breast-conserving therapy in Chinese patients has so far not been conducted among the clinicians, the patients or their spouses., Methods: The cosmetic results from breast-conserving therapy were evaluated in a group of 33 patients who had been selected as suitable for undergoing local excision, axillary dissection and postoperative radiation therapy for early stage breast cancer. The success of the procedures was assessed by the patients, the clinicians and the patient's spouse, and their ratings were compared with each other., Results: Eighty per cent of the patients and their spouse were satisfied with the cosmetic outcome. Using McNemar's test, when the groups were evaluated on a case-by-case basis, there was a good level of concordance between the patients and their spouses, and that of the patients and the clinicians., Conclusions: Evaluation of the cosmetic and psychosocial sequelae of breast cancer patients is essential when new approaches to treatment are introduced; our data suggest that cosmetically successful breast conservation is feasible in a selected group of Chinese women with early breast cancer.