Yoke Lim Soong

Comparison of Circulating Tumour Cells and Circulating Cell-Free Epstein-Barr Virus DNA in Patients with Nasopharyngeal Carcinoma Undergoing Radiotherapy

Quantification of Epstein-Barr virus (EBV) cell-free DNA (cfDNA) is commonly used in clinical settings as a circulating biomarker in nasopharyngeal carcinoma (NPC), but there has been no comparison with circulating tumour cells (CTCs). Our study aims to compare the performance of CTC enumeration against EBV cfDNA quantitation through digital PCR (dPCR) and quantitative PCR. 74 plasma samples from 46 NPC patients at baseline and one month after radiotherapy with or without concurrent chemotherapy were analysed. CTCs were captured by microsieve technology and enumerated, while three different methods of EBV cfDNA quantification were applied, including an in-house qPCR assay for BamHI-W fragment, a CE-IVD qPCR assay (Sentosa ®) and a dPCR (Clarity™) assay for Epstein-Barr nuclear antigen 1 (EBNA1). EBV cfDNA quantitation by all workflows showed stronger correlation with clinical stage, radiological response and overall survival in comparison with CTC enumeration. The highest detection rate of EBV cfDNA in pre-treatment samples was seen with the BamHI-W qPCR assay (89%), followed by EBNA1-dPCR (85%) and EBNA1-qPCR (67%) assays. Overall, we show that EBV cfDNA outperforms CTC enumeration in correlation with clinical outcomes of NPC patients undergoing treatment. Techniques such as dPCR and target selection of BamHI-W may improve sensitivity for EBV cfDNA detection.

Surrogate End Points for Overall Survival in Loco-Regionally Advanced Nasopharyngeal Carcinoma: An Individual Patient Data Meta-analysis

Background: Our objective was to evaluate progression-free survival (PFS) and distant metastasis–free survival (DMFS) as surrogate end points for overall survival (OS) in randomized trials of chemotherapy in loco-regionally advanced nasopharyngeal carcinomas (NPCs). Methods: Individual patient data were obtained from 19 trials of the updated Meta-Analysis of Chemotherapy in Nasopharyngeal Carcinoma (MAC-NPC) plus one additional trial (total = 5144 patients). Surrogacy was evaluated at the individual level using a rank correlation coefficient &rgr; and at the trial level using a correlation coefficient R2 between treatment effects on the surrogate end point and OS. A sensitivity analysis was performed with two-year PFS/DMFS and five-year OS. Results: PFS was strongly correlated with OS at the individual level (&rgr; = 0.93, 95% confidence interval [CI] = 0.93 to 0.94) and at the trial level (R2 = 0.95, 95% CI = 0.47 to 1.00). For DMFS, too, the individual-level correlation with OS was strong (&rgr; = 0.98, 95% CI = 0.98 to 0.98); at trial level, the correlation was high but the regression adjusted for measurement error could not be computed (unadjusted R2 = 0.96, 95% CI = 0.94 to 0.99). In the sensitivity analysis, two-year PFS was highly correlated with five-year OS at the individual level (&rgr; = 0.89, 95% CI = 0.88 to 0.90) and at the trial level (R2 = 0.85, 95% CI = 0.46 to 1.00); two-year DMFS was highly correlated with five-year OS at the individual level (&rgr; = 0.95, 95% CI = 0.94 to 0.95) and at the trial level (R2 = 0.78, 95% CI = 0.33 to 1.00). Conclusions: PFS and DMFS are valid surrogate end points for OS to assess treatment effect of chemotherapy in loco-regionally advanced NPC, while PFS can be measured earlier.

An assessment of the magnitude of intra-fraction movement of head-and-neck IMRT cases and its implication on the action-level of the imaging protocol

BACKGROUND AND PURPOSE A planning margin ⩽3 mm is employed in some head-and-neck IMRT cases due to the proximity of critical structures. This study aims to explore the need to redefine the action-level in the head-and-neck imaging protocol in consideration of the intra-fraction movement. MATERIAL AND METHODS This is a local study of 18 patients treated using the same immobilisation system and setup protocol. Post-treatment orthogonal pair of kilovoltage X-ray images was acquired on the first three days of treatment. 106 sets of pre- and post-treatment kV X-ray images acquired over 53 fractions were analysed against the treatment planning DRR for calculation of intra-fraction movement. RESULTS Individual mean intra-fraction movement in all directions ranged from -1.8 to 1.1 mm. Population mean (median) intra-fraction movement in the x-, y-, and z-planes were -0.1 mm (0 mm), -0.3 mm (-0.3 mm) and -0.2 mm (-0.2 mm) respectively. Intra-fraction movement in all three dimensions, x-, y- and z-planes were considered statistically significant (p<0.05). 7 out of 53 fractions (13.2%) were highlighted as the combined magnitude of the intra-fraction motion with the uncorrected pre-treatment setup errors had exceeded the boundaries of given margins. CONCLUSIONS 3 mm-AL was not adequate to account for intra-fraction movement when the CTV-PTV margin was ⩽3 mm and should be excluded from the routine imaging protocol and daily image-guided radiotherapy should be employed. Adjusting the action-level to 2 mm would allow a more confident approach in delivery of the prescribed dose in head-and-neck IMRT cases.

Prognostic Model for Stratification of Radioresistant Nasopharynx Carcinoma to Curative Salvage Radiotherapy

Purpose To investigate for a prognostic index (PI) to personalize recommendations for salvage intensity-modulated radiotherapy (IMRT) in patients with locally recurrent nasopharyngeal carcinoma (lrNPC). Methods Patients with lrNPC from two academic institutions (Sun Yat-Sen University Cancer Center [SYSUCC-A; n = 251 (training cohort)] and National Cancer Centre Singapore [NCCS; n = 114] and SYSUCC-B [n = 193 (validation cohorts)]) underwent salvage treatment with IMRT from 2001 to 2015. Primary and secondary clinical end points were overall survival (OS) and grade 5 toxicity-free rate (G5-TFR), respectively. Covariate inclusion to the PIs was qualified by a multivariable two-sided P < .05. Discrimination and calibration of the PIs were assessed. Results The primary PI comprised covariates that were adversely associated with OS in the training cohort (gross tumor volumerecurrence hazard ratio [HR], 1.01/mL increase [ P < .001], agerecurrence HR, 1.02/year increase [ P = .008]; repeat IMRT equivalent dose in 2-Gy fractions [EQD2] ≥ 68 Gy HR, 1.42 [ P = .03]; prior radiotherapy-induced grade ≥ 3 toxicities HR, 1.90 [ P = .001]; recurrent tumor [rT]-category 3 to 4 HR, 1.96 [ P = .005]), in ascending order of weight. Discrimination of the PI for OS was comparable between training and both validation cohorts (Harrells C = 0.71 [SYSUCC-A], 0.72 [NCCS], and 0.69 [SYSUCC-B]); discretization by using a fixed PI score cutoff of 252 determined from the training data set yielded low- and high-risk subgroups with disparate OS in the validation cohorts (NCCS HR, 3.09 [95% CI, 1.95 to 4.89]; SYSUCC-B HR, 3.80 [95% CI, 2.55 to 5.66]). Our five-factor PI predicted OS and G5-TFR (predicted v observed 36-month OS and G5-TFR, 22% v 15% and 38% v 44% for high-risk NCCS and 26% v 31% and 45% v 46% for high-risk SYSUCC-B). Conclusion We present a validated PI for robust clinical stratification of radioresistant NPC. Low-risk patients represent ideal candidates for curative repeat IMRT, whereas novel clinical trials are needed in the unfavorable high-risk subgroup.

Nasopharyngeal carcinoma-past lessons and a glimpse into the future.

Nasopharyngeal carcinoma is a unique cancer with specific patterns of racial and geographical distribution, which may be linked to demographic-specific genetic susceptibility and viral-induced tumourigenesis by Epstein-barr virus (EBV) and human papilloma virus (HPV) (1).

Induction Chemotherapy plus Concurrent Chemoradiotherapy in Endemic Nasopharyngeal Carcinoma: Individual Patient Data Pooled Analysis of Four Randomized Trials

Purpose: Because of the uneven geographic distribution and small number of randomized trials available, the value of additional induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) remains controversial. This study performed an individual patient data (IPD) pooled analysis to better assess the precise role of IC + CCRT in locoregionally advanced NPC. Experimental Design: Four randomized trials in endemic areas were identified, representing 1,193 patients; updated IPD were obtained. Progression-free survival (PFS) and overall survival (OS) were the primary and secondary endpoints, respectively. Results: Median follow-up was 5.0 years. The HR for PFS was 0.70 [95% confidence interval (CI), 0.56–0.86; P = 0.0009; 9.3% absolute benefit at 5 years] in favor of IC + CCRT versus CCRT alone. IC + CCRT also improved OS (HR = 0.75; 95% CI, 0.57–0.99; P = 0.04) and reduced distant failure (HR = 0.68; 95% CI, 0.51–0.90; P = 0.008). IC + CCRT had a tendency to improve locoregional control compared with CCRT alone (HR = 0.70; 95% CI, 0.48–1.01; P = 0.06). There was no heterogeneity between trials in any analysis. No interactions between patient characteristics and treatment effects on PFS or OS were found. After adding two supplementary trials to provide a more comprehensive overview, the conclusions remained valid and were strengthened. In a supplementary Bayesian network analysis, no statistically significant differences in survival between different IC regimens were detected. Conclusions: This IPD pooled analysis demonstrates the superiority of additional IC over CCRT alone in locoregionally advanced NPC, with the survival benefit mainly associated with improved distant control. Clin Cancer Res; 24(8); 1824–33. ©2018 AACR.

Somatostatin receptor imaging in nasopharyngeal cancer

Somatostatin is a neuropeptide better known for its role in inhibiting the secretion of growth hormone, insulin and glucagon. There are five subtypes of somatostatin receptors (SSTRs) with varying tissue distribution and function. They have been reported to be expressed in the brain, pituitary gland, pancreas, gastrointestinal tract, adrenal glands, immune cells and several human tumors. Recently there have been several reports of the presence of somatostatin receptor type 2 in nasopharyngeal cancer (NPC). Somatostatin receptor imaging sheds new insight into the biology of NPC and opens up exciting and novel diagnostic and therapeutic opportunities in the management of NPC.