Potential pitfalls in incorporating plasma Epstein-Barr virus DNA in the management of nasopharyngeal carcinoma.

BACKGROUND: This study identifies potential pitfalls in incorporating plasma Epstein-Barr virus (EBV) DNA into the management of nasopharyngeal carcinoma (NPC). METHODS: A total of 208 NPC patients without distant metastasis who received radical treatment and had measurements of EBV DNA at baseline, 8 weeks and 26 weeks postradiotherapy were analyzed. Prognostic and predictive values at each time-point were compared. RESULTS: Risk stratification by pretreatment level failed to identify a poor prognostic group. Detectable EBV DNA at 8 weeks and 26 weeks postradiotherapy were both associated with significantly poorer 5-year disease-free survival (HR 0.30, P < .001 and HR 0.03, P < .001, respectively) and overall survival (HR 0.27, P = .009 and HR 0.03, P < .001, respectively). Eighty percentage had detectable EBV DNA at recurrence (53.3% for local only, 100% for regional only, and 100% for distant failure). CONCLUSIONS: Posttreatment EBV DNA, particularly at 26 weeks post-radiotherapy, has high prognostic and predictive values. Surveillance endoscopy/imaging are recommended for the detection of local recurrence.

Analysis of Plasma Epstein-Barr Virus DNA in Nasopharyngeal Cancer After Chemoradiation to Identify High-Risk Patients for Adjuvant Chemotherapy: A Randomized Controlled Trial.

Purpose The contribution of adjuvant chemotherapy after chemoradiation therapy (CRT) in nasopharyngeal cancer (NPC) remains controversial. Plasma Epstein-Barr virus (EBV) DNA is a potential biomarker of subclinical residual disease in NPC. In this prospective, multicenter, randomized controlled trial, we used plasma EBV DNA to identify patients with NPC at a higher risk of relapse for adjuvant chemotherapy. Patients and Methods Eligible patients with histologically confirmed NPC of Union for International Cancer Control stage IIB to IVB, adequate organ function, and no locoregional disease or distant metastasis were screened by plasma EBV DNA at 6 to 8 weeks after radiotherapy (RT). Patients with undetectable plasma EBV DNA underwent standard surveillance. Patients with detectable plasma EBV DNA were randomly assigned to either adjuvant chemotherapy with cisplatin and gemcitabine for six cycles (arm 1) or observation (arm 2). Patients were stratified for primary treatment (RT v CRT) and stage (II/III v IV). The primary end point was relapse-free survival (RFS). Results Seven hundred eighty-nine patients underwent EBV DNA screening. Plasma EBV DNA was undetectable in 573 (72.6%) and detectable in 216 (27.4%); 104 (13.2%) with detectable EBV DNA were randomly assigned to arms 1 (n = 52) and 2 (n = 52). After a median follow-up of 6.6 years, no significant difference was found in 5-year RFS rate between arms 1 and 2 (49.3% v 54.7%; P = .75; hazard ratio for relapse or death, 1.09; 95% CI, 0.63 to 1.89). The level of post-RT plasma EBV DNA correlated significantly with the hazards of locoregional failure, distant metastasis, and death. Conclusion In patients with NPC with detectable post-RT plasma EBV DNA, adjuvant chemotherapy with cisplatin and gemcitabine did not improve RFS. Post-RT plasma EBV DNA level should be incorporated as the selection factor in future clinical trials of adjuvant therapy in NPC.

Current management of nasopharyngeal cancer.

Management of nasopharyngeal carcinoma is one of the greatest clinical challenges. Appropriate detection is not easy because of its anatomical location; sensitive biomarkers in addition to endoscopic and radiological examinations would be valuable. One useful biomarker (particularly for nonkeratinizing carcinoma) is the plasma level of Epstein-Barr viral deoxyribonucleic acid, and its role as a tool for prognostication and monitoring disease progress is presented. Radiotherapy is the primary treatment modality, and using radiation therapy in combination with chemotherapy is recommended for the treatment of locoregionally advanced tumors. Intensity-modulated radiotherapy techniques with image guidance to ensure setup precision are recommended if resources allow; adaptive replanning should be considered if major deviations from the intended dose distribution occur during the treatment course. Most contemporary series have reported encouraging results, with locoregional control exceeding 90%; the key problem is distant failure. The therapeutic margin is extremely narrow. Although significant reduction of some toxicities (eg, xerostomia) and better quality of life is now achievable especially for early stages, the risk of major late toxicities remains substantial. This review will focus on the primary treatment: the current consensus and controversies in the treatment strategy for different stages, the choice of chemotherapy regimen, and the key factors for improving the therapeutic ratio of radiotherapy will be discussed. Summary of the current achievement and direction for future improvement will be presented.

Parapharyngeal extension of nasopharyngeal carcinoma: still a significant factor in era of modern radiotherapy?

PURPOSE: To retrospectively analyze the prognostic value of parapharyngeal space (PPS) extension after conformal radiotherapy for nasopharyngeal carcinoma. PATIENTS AND METHODS: Between 1998 and 2005, 700 patients were treated with conformal radiotherapy at 2 Gy/fraction daily to a total of 70 Gy. All patients underwent staging with magnetic resonance imaging. The incidence of PPS was determined, and the extent of involvement was further subclassified regarding the presence or absence of carotid space (CS) involvement. The prognostic parameters, including age, gender, stage, chemotherapy, additional boosting, and extent of PPS involvement, were analyzed by univariate and multivariate analyses. RESULTS: The median duration of follow-up was 51 months, and the 5-year overall survival rate for the whole group was 73%. The overall incidence of PPS extension was high (74%), and 29% had additional extension to the CS. Multivariate analysis showed age, gender, chemotherapy, T stage, and N stage to be significant prognostic factors, but not PPS involvement with or without CS extension. In the subgroup of patients with Stage T2 disease (n = 242), the presence of PPS involvement alone or PPS plus CS extension had no statistically significant effect in terms of local control (p = 0.68), distant metastases (p = 0.34), or overall survival (p = 0.24) compared with those without PPS involvement (Stage T2a). CONCLUSIONS: With better tumor delineation by magnetic resonance imaging and improved coverage using modern radiotherapy techniques, PPS extension per se no longer predicts for disease outcome. Hence, subcategorizing Stage T2 disease is no longer important in future International Union Against Cancer/American Joint Committee on Cancer classifications.

N-staging by magnetic resonance imaging for patients with nasopharyngeal carcinoma: pattern of nodal involvement by radiological levels.

BACKGROUND AND PURPOSE: To study the pattern of lymphatic spread for patients with nasopharyngeal carcinoma (NPC), the significance of retropharyngeal node (RP-LN) involvement, and the possibility of replacing the supraclavicular fossa (SCF) by Levels IV and Vb (LL) as a demarcating criterion for N3-category. PATIENTS AND METHODS: The magnetic resonance imagings (MRI) of 202 consecutive patients with NPC treated during 2001-2002 were retrospectively reviewed. Distribution in terms of radiological level (using the same criteria as other head and neck cancers) was mapped, and the size of individual node measured. Prognostic significance of RP-LN and LL was analyzed. RESULTS: Only 4% of patients were node-negative on presentation. The nodal involvement occurred predominately at II (94%), III (85%) and RP-LN (80%). The presence of RP-LN affected the N-category in 3.5% of patients, and had no significant impact on tumor control. Replacing SCF by LL as one of the criteria for defining N3 is predictive for both distant control and overall survival. CONCLUSIONS: With sensitive detection by MRI, the incidence of nodal involvement was very high for patients with NPC. It was difficult to isolate the prognostic significance of RP-LN. The current criterion for defining N3-category by extension into SCF or nodal size > 6 cm is the recommended standard, however replacing SCF with LL could be potentially useful and further validation is warranted.

Melatonin slowed the early biochemical progression of hormone-refractory prostate cancer in a patient whose prostate tumor tissue expressed MT1 receptor subtype.

Melatonin inhibited the proliferation of hormone-independent LNCaP prostate cancer cells partly via MT1 receptor activation both in vitro and in nude mice xenograft model. In this study, the melatonin receptor expression in the prostate cancer tissue of a patient with bone metastases and the effect of melatonin on the biochemical progression of hormone-refractory prostate tumor which later developed in the same patient were reported. Saturation and competition 2-[125I]iodomelatonin binding assays were conducted on prostate tumor tissue obtained by transurethral resection of the prostate from the index patient. The receptor subtype identity of melatonin receptor expressed in the cancer tissue was determined by comparison of the rank order of inhibition constants (Ki) of various melatonergic ligands and the affinity of 4-phenyl-2-propionamidotetraline relative to melatonin in inhibiting 2-[125I]iodomelatonin binding to the tumor sample and to human cell lines stably transfected with MT1 or MT2 melatonin receptor subtype. MT1 receptor expression in the cancer tissue was also examined by immunohistochemistry. The surgically castrated patient later developed biochemical relapse of his disease. His serum total prostate-specific antigen (PSA) level was monitored before and during treatment with 5 mg/day oral melatonin at 20:00 hr. High-affinity (Kd = 103.7 pm) MT1 melatonin receptor subtype was expressed by the patient's prostate cancer. As indicated by his PSA levels, melatonin induced stabilization of his hormone-refractory disease for 6 wk. This report validates melatonin's oncostatic action on prostate cancer and the potential involvement of MT1 receptor subtype in the attendant antiproliferative signal transduction as suggested by recent preclinical laboratory findings in a human.