Hai Qiang Mai

Long-Term Survival After Cisplatin-Based Induction Chemotherapy and Radiotherapy for Nasopharyngeal Carcinoma: A Pooled Data Analysis of Two Phase III Trials

5524 Background: To evaluate the long-term treatment outcome in patients with advanced stage nasopharyngeal carcinoma (NPC) treated by cisplatin-based induction chemotherapy and radiotherapy (CRT) versus radiotherapy alone (RT). METHODS The updated records of two previously reported phase III studies (the Asian-Oceania Clinical Oncology Association trial and the Guangzhou trial). testing the benefit of adding induction chemotherapy to radiotherapy in NPC were reviewed and the data were pooled together for analysis. A total of 784 patients were included for analysis, with equal number of patients in both the CRT and RT arms. The induction chemotherapy consisting of 2-3 cycles of cisplatin 100 mg/m2 day 1, bleomycin 10 mg/m2 day 1 & 5, and fluorouracil 800 mg/m2 day 1-5, or cisplatin 60 mg/m2 day 1 and epirubicin 110 mg/m2 day 1. Radiotherapy was given to the nasopharynx and neck using megavoltage radiation, with a median dose of 70 Gy. Treatment compliance was 92.6% in the CRT arm and 98% in the RT arm. The median follow-up time for surviving patients was 67 months. Analysis was done by intention to treat. RESULTS The addition of induction chemotherapy to radiotherapy was associated with a decrease in relapse by 14.3% and cancer deaths by 12.9% at 5 years. The 5-year relapse-free survival rate was 50.9% in the CRT arm and 42.7% in the RT arm (p=0.014), and the 5-year disease-specific survival rate was 63.5% in the CRT arm and 58.1% in the RT arm (p=0.029). The median disease-specific survival was not yet reached in the CRT arm and it was 82 months in the RT arm. The incidence of loco-regional failure and distant metastases were reduced by 18.3% and 13.3% at 5 years respectively with induction chemotherapy. There was no significant difference in the failure patterns between the 2 arms. CONCLUSIONS The addition of cisplatin-based induction chemotherapy to radiotherapy was associated with a modest but significant improvement in survival in advanced stage NPC. No significant financial relationships to disclose.

Epstein-barr virus-encoded LMP2A induces an epithelial- mesenchymal transition and increases the number of side population stem-like cancer cells in nasopharyngeal carcinoma

It has been recently reported that a side population of cells in nasopharyngeal carcinoma (NPC) displayed characteristics of stem-like cancer cells. However, the molecular mechanisms underlying the modulation of such stem-like cell populations in NPC remain unclear. Epstein-Barr virus was the first identified human tumor virus to be associated with various malignancies, most notably NPC. LMP2A, the Epstein-Barr virus encoded latent protein, has been reported to play roles in oncogenic processes. We report by immunostaining in our current study that LMP2A is overexpressed in 57.6% of the nasopharyngeal carcinoma tumors sampled and is mainly localized at the tumor invasive front. We found also in NPC cells that the exogenous expression of LMP2A greatly increases their invasive/migratory ability, induces epithelial–mesenchymal transition (EMT)-like cellular marker alterations, and stimulates stem cell side populations and the expression of stem cell markers. In addition, LMP2A enhances the transforming ability of cancer cells in both colony formation and soft agar assays, as well as the self-renewal ability of stem-like cancer cells in a spherical culture assay. Additionally, LMP2A increases the number of cancer initiating cells in a xenograft tumor formation assay. More importantly, the endogenous expression of LMP2A positively correlates with the expression of ABCG2 in NPC samples. Finally, we demonstrate that Akt inhibitor (V) greatly decreases the size of the stem cell side populations in LMP2A-expressing cells. Taken together, our data indicate that LMP2A induces EMT and stem-like cell self-renewal in NPC, suggesting a novel mechanism by which Epstein-Barr virus induces the initiation, metastasis and recurrence of NPC.

Concurrent Chemoradiotherapy vs Radiotherapy Alone in Stage II Nasopharyngeal Carcinoma: Phase III Randomized Trial

BACKGROUND Concurrent chemoradiotherapy (CCRT) has been shown to improve outcomes for stage III-IV nasopharyngeal carcinoma (NPC) patients compared with radiotherapy (RT) alone, but the effectiveness of the combined therapy for stage II NPC patients is unknown. METHODS Patients with Chinese 1992 stage II NPC were randomly assigned to receive either RT alone (n = 114) or CCRT (n = 116). The CCRT patients were given concurrent cisplatin (30 mg/m(2) on day 1) weekly during RT. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), distant metastasis-free survival, and locoregional relapse-free survival. All patients were analyzed by the intent-to-treat principle. The Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) and in multivariable analyses to test the independent statistical significance of treatment intervention. Toxic effects and the response to treatment were analyzed using the χ(2) test. All statistical tests were two-sided. RESULTS With a median follow-up of 60 months, adding chemotherapy statistically significantly improved the 5-year OS rate (94.5% vs 85.8%; HR of death = 0.30, 95% CI = 0.12 to 0.76; P = .007), PFS (87.9% vs 77.8%; HR of progression = 0.45, 95% CI = 0.23 to 0.88; P = .017), and distant metastasis-free survival (94.8% vs 83.9%; HR of distant relapse = 0.27, 95% CI = 0.10 to 0.74; P = .007); however, there was no statistically significant difference in the 5-year locoregional relapse-free survival rate (93.0% vs 91.1%; HR of locoregional relapse = 0.61, 95% CI = 0.25 to 1.51; P = .29). Multivariable analysis showed that the number of chemotherapy cycles was the only independent factor that was associated with OS, PFS, and distant control in stage II NPC. The CCRT arm experienced statistically significantly more acute toxic effects (P = .001), although the rate of late toxic effects did not increase statistically significantly. CONCLUSION Concurrent chemotherapy and radiotherapy is associated with a considerable survival benefit for patients with stage II NPC.

Elevated Beclin 1 expression is correlated with HIF-1α in predicting poor prognosis of nasopharyngeal carcinoma

Recent studies have suggested that autophagy plays a pivotal role in regulation of cancer development and progression. High expression of the autophagy-related Beclin 1 protein predicted favorable patient outcome in several tumors. Here, a randomized controlled trial (RCT)-derived 128 nasopharyngeal carcinoma (NPC) patients were subjected to analysis of Beclin 1 expression and survival probability. In this RCT, 61 patients treated with induction chemotherapy plus concurrent chemoradiotherapy were used as a training set to generate a Beclin 1 cutoff score for patient outcome by receiver operating characteristic (ROC) curve analysis. For validation, the ROC-derived cutoff point was subjected to analysis of the association of Beclin 1 expression with patient outcome and clinical characteristics in testing set. The testing set comprised of 67 patients received induction chemotherapy plus radiotherapy. In the testing set and overall patients, our univariate and multivariate analysis showed that higher Beclin 1 expression, defined by the training set ROC analysis-generated cutoff score, predicted poorer overall survival, progression-free survival and distant metastasis-free survival. However, we failed to detect a correlation between Beclin 1 and local failure-free survival. Moreover, a positive relationship between Beclin 1 and HIF-1α expression was found. Importantly, among patients with elevated HIF-1α expression, a subset with lower Beclin 1 expression displayed a significant overall survival advantage than those with higher expression (p = 0.036). Contrary to previous studies, our results demonstrated that high autophagic Beclin 1 expression was an inferior prognostic marker for NPC. HIF-1α-associated Beclin 1 high expression might facilitate NPC cells surviving from chemoradiotherapy, suggesting a novel therapeutic molecular target for NPC.

Emerging treatment options for nasopharyngeal carcinoma

Nasopharyngeal carcinoma is endemic in Asia and is etiologically associated with Epstein–Barr virus. Radiotherapy is the primary treatment modality. The role of systemic therapy has become more prominent. Based on multiple phase III studies and meta-analyses, concurrent cisplatin-based chemoradiotherapy is the current standard of care for locally advanced disease (American Joint Committee on Cancer manual [7th edition] stages II–IVb). The reported failure-free survival rates from phase II trials are encouraging for induction + concurrent chemoradiotherapy. Data from ongoing phase III trials comparing induction + concurrent chemoradiotherapy with concurrent chemoradiotherapy will validate the results of these phase II studies. Intensity-modulated radiotherapy techniques are recommended if the resources are available. Locoregional control exceeding 90% and reduced xerostomia-related toxicities can now be achieved using intensity-modulated radiotherapy, although distant control remains the most pressing research problem. The promising results of targeted therapy and Epstein–Barr virus-specific immunotherapy from early clinical trials should be validated in phase III clinical trials. New technology, more effective and less toxic chemotherapy regimens, and targeted therapy offer new opportunities for treating nasopharyngeal carcinoma.

Long-term treatment outcome of recurrent nasopharyngeal carcinoma treated with salvage intensity modulated radiotherapy.

PURPOSE To evaluate the long-term treatment outcome in patients with recurrent nasopharyngeal carcinoma (NPC) treated with salvage intensity modulated radiotherapy (IMRT). MATERIALS AND METHODS One hundred and fifty one previously irradiation NPC patients with recurrent disease and re-irradiated by IMRT between 2001 and 2006 had been reviewed. The disease was re-stage I in 7, re-stage II in 21, re-stage III in 50 and re-stage IV in 73. Thirty-seven patients received concurrent chemotherapy, 39 had induction chemotherapy and 75 had radiotherapy alone. RESULTS All patients completed the planned IMRT. The median volume of the recurrent gross target volume of nasopharynx (rGTVnx) was 42.2 cm(3) (range 1.5-146.3 cm(3)). The median mean re-irradiation dose to the rGTVnx was 70.4Gy (range 62.1-77.6Gy). The median follow-up time after re-irradiation was 40.0 months (range 1.9-116.9 month). The 5-year local control rate (LCR) and overall survival rate (OS) for re-stage I, II, III, IV were 80.0%, 85.0%, 80.0%, 78.7% and 71.4%, 62.9%, 35.5%, 30.2%, respectively. Multivariate analysis indicated that rT classification (hazard ratio (HR), 2.02; 95%confidence interval (CI), 1.03-3.97; P=0.04) and the volume of rGTVnx (HR, 2.05; 95%CI, 1.31-3.22; P<0.01) were independent predictors for OS. Patients (39.0%) with re-stage III or IV disease experienced Grade 3 or 4 late toxicities. CONCLUSION Re-irradiation by IMRT for recurrent NPC resulted in encouraging local control. The clinical outcome for patients with early re-stage diseases was satisfactory. Further investigations, focus on optimising radiation dose and establishing effective treatment strategies, are warranted for advanced recurrent disease in order to improve overall survival and minimise late toxicity.

Prospective Study of Tailoring Whole-Body Dual-Modality [18F]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography With Plasma Epstein-Barr Virus DNA for Detecting Distant Metastasis in Endemic Nasopharyngeal Carcinoma at Initial Staging

PURPOSE To evaluate which patients with nasopharyngeal carcinoma (NPC) obtained the greatest benefits from the detection of distant metastasis with [(18)F]fluorodeoxyglucose positron emission tomography and computed tomography (PET/CT) combined with plasma Epstein-Barr virus (EBV) DNA levels. PATIENTS AND METHODS Consecutive patients with NPC were prospectively enrolled. PET/CT, conventional work-up (CWU), and quantification of plasma EBV DNA were performed before treatment. The accuracy of these strategies for distant metastases was assessed. The costs of the diagnostic strategies were compared. RESULTS Eighty-six (14.8%) of the 583 eligible patients were found to have distant metastases; 71 patients (82.6%) by PET/CT and 31 patients (36.0%) by CWU. In the multivariable analysis, advanced N stage (odds ratio, 2.689; 95% CI, 1.894 to 3.818) and pretreatment EBV DNA level (odds ratio, 3.344; 95% CI, 1.825 to 6.126) were significant risk factors for distant metastases. PET/CT was not superior to CWU for detecting distant metastases in very low-risk patients (N0-1 with EBV DNA < 4,000 copies/mL; P = .062), but was superior for the low-risk patients (N0-1 with EBV DNA ≥ 4,000 copies/mL and N2-3 with EBV DNA < 4,000 copies/mL; P = .039) and intermediate-risk patients (N2-3 disease with EBV DNA ≥ 4,000 copies/mL; P < .001). The corresponding patient management changes based on PET/CT were 2.9%, 6.3%, and 16.5%, respectively. The costs per true-positive case detected by PET/CT among these groups were ¥324,138 (≈

Centromere Protein H Is a Novel Prognostic Marker for Nasopharyngeal Carcinoma Progression and Overall Patient Survival

47,458), ¥96,907 (≈

What Is the Best Treatment of Locally Advanced Nasopharyngeal Carcinoma? An Individual Patient Data Network Meta-Analysis

14,188), and ¥34,182 (≈

Pretreatment body mass index as an independent prognostic factor in patients with locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy: Findings from a randomised trial

5,005), respectively. CONCLUSION PET/CT detects more distant metastases than conventional staging in patients with NPC. The largest benefit in terms of cost and patient management was observed in the subgroup with N2-3 disease and EBV DNA ≥ 4,000 copies/mL.