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Nasopharyngeal carcinoma of the undifferentiated histologic subtype is endemic and prevalent in southeast Asia. The dramatic improvement of treatment outcomes and overall prognosis during the past few decades has been attributed to advances in disease screening and diagnosis, diagnostic imaging, radiotherapy techniques, use of combination systemic therapy, and dedicated clinical and biomarker surveillance. The current practice of treating patients with advanced locoregional disease using cisplatin concurrent with conventional fractionated radiotherapy, followed by adjuvant cisplatin and fluorouracil, was established in 1998 when the landmark Intergroup-0099 Study demonstrated a survival benefit with the addition of systemic therapy. There is little doubt regarding the need for concurrent chemotherapy, but there has been uncertainty about the magnitude of the benefit attributed to the adjuvant phase. Furthermore, instead of one-size-fits-all recommendations, it will be ideal if we can tailor adjuvant therapy to high-risk patients only to avoid unnecessary toxicities. In addition, recent evidence suggests that induction chemotherapy before concurrent chemoradiation can achieve better outcomes, especially in distant control, even in the modern era of intensity-modulated radiation therapy. This article provides a comprehensive review of key literature on the current management of locoregionally advanced nasopharyngeal carcinoma and highlights future research directions to unravel these controversies.

BACKGROUND Surgery is the mainstay of meningioma treatment, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. DNA methylation profiling, copy number variants (CNVs), exome sequencing, and RNA sequencing have improved understanding of meningioma biology, but have not superseded histologic grading, or revealed biomarkers for radiotherapy responses. To address these unmet needs, we optimized and validated a targeted gene expression biomarker predicting meningioma outcomes and responses to radiotherapy. METHODS Targeted gene expression profiling was performed on a discovery cohort of 173 meningiomas (median follow-up 8.1 years) and a validation cohort of 331 meningiomas (median follow-up 6.1 years) treated with surgery (n=504) and postoperative radiotherapy (n=73) at independent, international institutions (70% WHO grade 1, 24% WHO grade 2, 6% WHO grade 3). Optimized targeted gene expression models predicting clinical outcomes (34 genes) or radiotherapy responses (12 genes) were developed from the discovery cohort, and compared to histologic and molecular classification systems by performing DNA methylation profiling, CNV analysis, exome sequencing, and RNA sequencing on the same meningiomas. RESULTS Targeted gene expression profiling achieved a concordance-index of 0.75 ± 0.03 (SEM) for local freedom from recurrence (LFFR) and 0.72 ± 0.03 for overall survival (OS) in the validation cohort, outperforming WHO grade (5-year LFFR delta-AUC 0.15, 95% CI 0.076-0.229, p=0.001) and DNA methylation grouping (delta-AUC 0.075, 95% CI 0.006-0.130, p=0.01) for LFFR, disease-specific survival, and OS. The biomarker was independently prognostic after accounting for WHO grade, extent of resection, primary versus recurrent presentation, CNV status, DNA methylation group, and Ki67 labeling index, and identified meningiomas benefiting from radiotherapy (interaction p-value=0.0008), suggesting postoperative radiotherapy could be refined in 30.2% of cases. CONCLUSIONS Targeted gene expression profiling of 504 meningiomas improves discrimination of meningioma local recurrence, disease-specific survival, and overall survival, and predicts radiotherapy responses.

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