Prognostic model for survival of local recurrent nasopharyngeal carcinoma with intensity-modulated radiotherapy.

BACKGROUND: Intensity-modulated radiotherapy (IMRT) is the main salvage treatment for advanced locally recurrent nasopharyngeal carcinoma (NPC); however, survival outcomes vary. We aimed to construct a prognostic-score model to identify patients who could benefit from salvage IMRT. METHODS: This retrospective study involved 251 patients with locally recurrent NPC. The following parameters were analysed following IMRT: patient performance status, age, gender, late complications, T-stage of recurrence, synchronous nodal recurrence, primary gross tumour volume (GTV-nx), disease-free interval, re-irradiation dose and chemotherapy. The model was based on the hazard ratio coefficients of six significantly negative prognostic factors for survival. RESULTS: Significantly negative prognostic factors included Karnofsky Performance Status ≤70, age >50 years, late complications, recurrent T(3-4) stage, synchronous nodal recurrence and GTV-nx >30 cm(3). Three subgroups were defined according to model scores: low risk (0-4), intermediate risk (5-8) and high risk (9-15). The 5-year overall survival rates were 64.3%, 32.2% and 7.7%, respectively. The main cause of death was radiation-induced complications. CONCLUSION: The prognostic-score model demonstrated that re-irradiation with IMRT is suitable for low-risk and intermediate-risk patients but may be unsuitable for high-risk patients. Further research into the protection of critical adjacent organs to reduce late complications in these patients is warranted.

Late toxicities after intensity-modulated radiotherapy for nasopharyngeal carcinoma: patient and treatment-related risk factors.

BACKGROUND: The objective of this study is to analyse the factors affecting late toxicity for nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiotherapy (IMRT). METHODS: Seven hundred and eighty-nine consecutive NPC patients treated with IMRT at our centre from January 2003 to February 2008 were retrospectively analysed. Radiotherapy-related complications were categorised using the RTOG Late Radiation Morbidity Scoring Criteria and the Common Terminology Criteria for Adverse Events (Version 3.0). Two hundred and thirty-three patients were treated with IMRT alone (group 1) and 556 patients underwent cisplatin-based chemotherapy (group 2). RESULTS: Median follow-up was 65 months (range, 4-106 months). The 5-year major late toxicity rate was significantly greater in group 2 than group 1 (63.2% vs 42.0%, P<0.001). Multivariate analyses showed that N category, T category and chemotherapy were significant factors. The maximal dose (Dmax) to the temporal lobe was a significant factor affecting temporal lobe injury (TLI), with a hazard ratio of 1.26 (95% confidence interval (CI), 1.18-1.35; P<0.001) per 1-Gy increase. The 5-year TLI rate increased from 0.8% for 284 lobes with Dmax <65.77 Gy to 27.1% for 176 lobes with greater doses (P<0.001). Logistic regression showed that the hazard ratio attributed to the parotid gland mean dose was 1.36 (95% CI, 1.21-1.53; P<0.001) per 1-Gy increase. Chemotherapy was not a significant factor (P=0.211). CONCLUSION: With the application of IMRT, the incidence of radiation-related complications has been reduced except for TLI. The significant factors affecting the risk of TLI included T category, chemotherapy and Dmax.

Results of a prospective randomized trial comparing neoadjuvant chemotherapy plus radiotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma.

PURPOSE: A prospective randomized trial was performed to evaluate the contribution of neoadjuvant chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma. PATIENTS AND METHODS: Patients with locoregionally advanced nasopharyngeal carcinoma were treated either with radiotherapy alone (RT group) or neoadjuvant chemotherapy plus radiotherapy (CT/RT group). Neoadjuvant chemotherapy consisting of two to three cycles of cisplatin (100 mg/m(2), day 1), bleomycin (10 mg/m(2), days 1 and 5), and fluorouracil (5-FU; 800 mg/m(2), days 1 through 5, continuous infusion) followed by radiotherapy was given to the CT/RT group. All patients were treated in a uniform fashion by definitive-intent radiation therapy in both groups. RESULTS: Between July 1993 and July 1994, 456 patients were entered onto the study, with 228 patients randomized to each treatment arm, and 449 patients (225 in the RT group and 224 in the CT/RT group) were assessable. All 456 patients were included in survival analysis according to the intent-to-treat principle. The 5-year overall survival (OS) rates were 63% for the CT/RT group and 56% for the RT group (P =.11). The median relapse-free survival (RFS) time was 50 months for the RT group and not reached for the CT/RT group. The 5-year RFS rate was 49% for the RT group versus 59% for the CT/RT group (P =.05). The 5-year freedom from local recurrence rate was 82% for the CT/RT group and 74% for the RT group (P =.04). There was no significant difference in freedom from distant metastasis between the two treatment groups (CT/RT group, 79%; RT group, 75%; P =.40). CONCLUSION: This randomized study failed to demonstrate any significant survival benefit with the addition of neoadjuvant chemotherapy for patients with locoregionally advanced nasopharyngeal carcinoma. Therefore, neoadjuvant chemotherapy for nasopharyngeal carcinoma should not be used outside of the context of a clinical trial.

Epstein-Barr virus (EBV) DNA in whole blood as a superior prognostic and monitoring factor than EBV-encoded small RNA in situ hybridization in diffuse large B-cell lymphoma.

Epstein-Barr virus (EBV) status was retrospectively analysed by the use of EBV-encoded small RNA (EBER) in situ hybridization (ISH) and EBV DNA analysis in whole blood with diffuse large B-cell lymphoma, to assess the clinical significance for diagnosis, prognostication, and monitoring of tumour burden. Three hundred and twenty-nine patients were retrospectively enrolled, with 232 patients being available for EBER ISH analysis, 189 patients for EBV DNA analysis, and 138 patients for both analyses. EBER was positive in 24 (10.3%) patients, and EBV DNA was positive in 18 (9.5%) patients; the two analyses had 92.8% concordance. Patients with pretreatment EBER positivity had worse overall survival (OS) than those without EBER positivity (p 0.03); the same pattern was observed for EBV DNA (p < 0.01). A significant p-value was also observed for OS when EBER and EBV DNA were combined (p < 0.01). On multivariate analysis, both EBV DNA (hazard ratio 3.71, 95% CI 1.78-7.74, p < 0.01) and EBER (hazard ratio 2.03, 95% CI 1.03-4.00, p 0.04) remained independent predictive factors for OS. Regarding the dynamic changes in copy number of elevated EBV DNA, the transformation from positive to negative after cycle 3 with chemotherapy may have the most capacity to distinguish a superior from an inferior outcome. These findings suggest that EBV DNA in whole blood has good concordance with EBER ISH, and that it may be a better prognostic and monitoring biomarker than EBER.

Is the 1997 AJCC staging system for nasopharyngeal carcinoma prognostically useful for Chinese patient populations?

PURPOSE: The 5th edition of the American Joint Committee on Cancer (AJCC) staging manual defines new rules for classifying nasopharyngeal carcinoma (NPC). The study was conducted to assess its effectiveness in predicting the prognosis for Chinese patient populations. METHODS AND MATERIALS: Between June 1993 and June 1994, 621 consecutively admitted patients with nondisseminated NPC were treated with definitive-intent radiation therapy alone. All had computed tomography of the nasopharynx, skull base, and the upper neck. A computer database containing all information for staging was formed on presentation. The extent of disease of each patient was restaged according to the 1997 AJCC system. RESULTS: Of the 621 patients, The 5-year overall survival (OS) rate was 60%. The 1997 AJCC system creates subgroups (Stages I to IV) that are assigned to 38 (6.1%), 270 (43.5%), 157 (25.3%), and 156 (25.1%) patients, respectively. The incidence of parapharyngeal extension was 74.1% (460/621). Of these patients (460) with parapharyngeal extension, 310 (67.4%) patients were classified as T2b disease. The 1997 AJCC system showed highly significant differences between the overall stages for both OS and relapse-free survival (RFS). The 1997 AJCC T classifications showed significant correlation with local failure, and N classification was accurate in predicting FDM. Multivariate analysis showed that paraoropharyngeal involvement was an independently significant prognostic factor for OS, freedom from local recurrence (FLR), and freedom form distant metastasis (FDM). CONCLUSION: The 1997 AJCC staging system for NPC is prognostically useful for Chinese patient populations. We proposed that subdivision of parapharyngeal extension should be included in future revisions of the staging system.

Important prognostic factors in patients with skull base erosion from nasopharyngeal carcinoma after radiotherapy.

PURPOSE: To evaluate the long-term outcome and prognostic factors in patients with skull base erosion from nasopharyngeal carcinoma after initial radiotherapy (RT). METHODS AND MATERIALS: From January 1985 to December 1986, 100 patients (71 males, 29 females) with a diagnosis of nasopharyngeal carcinoma were found on computed tomography (CT) to have skull base erosion. The mean age was 41 years (range 16-66). Ninety-six patients had World Health Organization type III undifferentiated carcinoma, and 4 had type I. The metastatic workup, including chest radiography, liver ultrasound scanning, and liver function test was negative. All patients underwent external beam RT (EBRT) alone to 66-80 Gy during 6-8 weeks. A daily fraction size of 2 Gy was delivered using 60Co or a linear accelerator. No patient received chemotherapy. All patients were followed at regular intervals after irradiation. The median follow-up was 22.3 months (range 2-174). Survival of the cohort was computed by the Kaplan-Meier method. The potential prognostic factors of survival were examined. Multivariate analyses were performed using the Cox regression model. RESULTS: The 1, 2, 5, and 10-year overall survival rate for the cohort was 79%, 41%, 27%, and 13%, respectively. However, the subgroup of patients with both anterior cranial nerve (I-VIII) and posterior cranial nerve (IX-XII) involvement had a 5-year survival of only 7.7%. A difference in the time course of local recurrence and distant metastasis was observed. Both local recurrence and distant metastasis often occurred within the first 2 years after RT. However, local relapse continued to occur after 5 years. In contrast, no additional distant metastases were found after 5 years. The causes of death included local recurrence (n = 59), distant metastasis (n = 21), both local recurrence and distant metastasis (n = 1), and unrelated causes (n = 5). After multivariate analysis, complete recovery of cranial nerve involvement, cranial nerve palsy, and headache after irradiation were found to be independent prognostic factors in this cohort. CONCLUSIONS: We present one of the longest follow-ups of patients with nasopharyngeal carcinoma invading the skull base. Our results demonstrate the importance of cranial nerve involvement, recovery of headache, and cranial nerve palsy. These factors should be carefully evaluated from the history, physical examination, and imaging studies. A subgroup of patients with skull base involvement had long-term survival after RT alone. The findings of this study are important as a yardstick against which more aggressive strategies, such as combined radiochemotherapy and altered fractionation RT can be compared.

MiR-375 is downregulated in epithelial cells after IL-13 stimulation and regulates an IL-13-induced epithelial transcriptome.

Interleukin 13 (IL-13)-induced epithelial gene and protein expression changes are central to the pathogenesis of multiple allergic diseases. Herein, using human esophageal squamous and bronchial columnar epithelial cells, we identified microRNAs (miRNAs) that were differentially regulated after IL-13 stimulation. Among the IL-13-regulated miRNAs, miR-375 showed a conserved pattern of downregulation. Furthermore, miR-375 was downregulated in the lung of IL-13 lung transgenic mice. We subsequently analyzed miR-375 levels in a human disease characterized by IL-13 overproduction--the allergic disorder eosinophilic esophagitis (EE)--and observed downregulation of miR-375 in EE patient samples compared with control patients. MiR-375 expression levels reflected disease activity, normalized with remission, and inversely correlated with the degree of allergic inflammation. Using a lentiviral strategy and whole-transcriptome analysis in epithelial cells, miR-375 overexpression was sufficient to markedly modify IL-13-associated immunoinflammatory pathways in epithelial cells in vitro, further substantiating interactions between miR-375 and IL-13. Taken together, our results support a key role of miRNAs, particularly miR-375, in regulating and fine-tuning IL-13-mediated responses.

Factors contributing to the efficacy of concurrent-adjuvant chemotherapy for locoregionally advanced nasopharyngeal carcinoma: combined analyses of NPC-9901 and NPC-9902 Trials.

BACKGROUND: The current standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) was conventional-fractionation radiotherapy plus concurrent-adjuvant chemotherapy as recommended by the Intergroup-0099 Study. This combined analysis of the NPC-9901 and the NPC-9902 Trials aims to provide more comprehensive data to evaluate the efficacy of the Intergroup-0099 regimen and the contributing factors. METHODS: Eligible patients with stage III-IVB non-keratinizing NPC were randomly assigned to radiotherapy-alone (RT(i) group: 218 patients) or chemoradiotherapy (CRT(i) group: 223 patients) using cisplatin (100mg/m(2)) for three cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m(2)) plus fluorouracil (1000 mg/m(2)/day for 4 days) for three cycles. The median follow-up was 6.1 years. FINDINGS: Comparison by intention-to-treat showed that the CRT(i) group achieved significant improvement in overall failure-free rate (FFR), locoregional-FFR and cancer-specific survival (p ≤ 0.019); but the improvements for distant-FFR and overall survival (OS) were statistically insignificant (p ≥ 0.14). Further exploratory studies based on actual treatment showed that an additional improvement achieved was a significant gain in OS (CRT(a) versus RT(a) group: 72% versus 63% at 5-year, p=0.037). Multivariate analyses showed that the dose of cisplatin during the concurrent phase had significant impact on locoregional-FFR and OS, while that of fluorouracil during the adjuvant phase was significant for distant-FFR. The 5-year locoregional-FFR for patients who received 0-1, 2 and 3 concurrent cycles were 79%, 88% and 88%, respectively; the corresponding distant-FFR by adjuvant cycles were 68%, 78% and 77%, respectively. INTERPRETATION: Our results support the current practice of adding concurrent cisplatin plus adjuvant cisplatin-fluorouracil to radiotherapy for treating patients with locoregionally advanced NPC. The concurrent phase is important for locoregional control and survival, cisplatin 200mg/m(2) in two concurrent cycles might be adequate. Additional chemotherapy using fluorouracil-containing combination contributed to improving distant control.

Treatment results and late complications of 556 patients with locally advanced nasopharyngeal carcinoma treated with radiotherapy alone.

The aim of this study was to investigate the outcome in 556 patients with locally advanced nasopharyngeal carcinomas treated by radiation therapy alone. We observed 556 patients with stage T3-4 and N0-3 carcinoma who were treated by conventional radiotherapy alone between January and December 1999. The total dose delivered to the nasopharynx was 66-80 Gy over 6.5-8 weeks and to the neck lymph nodes 60-70 Gy over 6-7 weeks. The 5-year actuarial overall survival rate (OS) reached 66.41%. The OS was higher among stage T3 patients than among stage T4 patients (69.12% vs 58.96%, p = 0.0359). Among patients with stage N0, N1, N2 and N3 disease, the OS was 73.98%, 65.96%, 57.58% and 29.39%, respectively (p = 0.0009). Differences in disease-free survival, locoregional control rate and metastasis-free survival rate among each N stage were statistically significant, although this was not true of differences between stage T3 and T4 disease. Multivariate analysis showed that gender, age, T stage and N stage were significant prognostic factors for 5-year overall survival, disease-free survival, locoregional control and metastasis-free survival. We found that N stage is the dominant prognostic indicator for patients with locally advanced nasopharyngeal carcinoma receiving conventional radiation therapy alone, and that T stage was only a secondary correlative factor.

[Significance of the involvement of parapharyngeal space cervical nodes and cranial nerves in nasopharyngeal carcinoma].

Two hundred cases of nasopharyngeal carcinoma (NPC) admitted to this department from Feb. 1985 to May. 1988 were analysed according to the CT scanning and clinical findings of the primary lesions prior to radiotherapy. The results showed that involvement of parapharyngeal space was very common in NPC, about 80% (160/200 cases); particularly unilateral or bilateral retro-styloid spaces, about 69.5% (139/200 cases). It was proposed that patients with NPC had a high incidence of ipsilateral cervical node metastasis. Contralateral cervical node metastasis was rare. The development of cervical node metastasis in NPC has to modes: one is direct infiltration of the retro-styloid space by the lesion; the other is along the nasopharyngeal lymphatic rete. The data also showed that patients with NPC who presented symptoms of IX-XII cranial nerve paralyses always had ipsilateral or bilateral retro-styloid space infiltrations.