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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.

Supplementary materials including supplementary figures and tables Supplementary Figure S1. Flowchart of randomized controlled trial selection. AC, adjuvant chemotherapy; CCRT, concurrent chemoradiotherapy; GZ, Guangzhou; HeCOG, Hellenic Cooperative Oncology Group; IC, induction chemotherapy; NCCS, National Cancer Centre Singapore; NPC, nasopharyngeal carcinoma; PWH, Prince of Wales Hospital; RCT, randomized controlled trial Supplementary Figure S2. Forest plots for (A) progression-free survival and (B) overall survival. The estimated hazard ratio (HR) for each individual trial is indicated by the center of the square and the horizontal line gives the 95% confidence interval (CI). The closed diamonds show the overall HR and 95% CI. HR < 1 and 95% CI excluding 1 indicate improved survival for the experimental versus control arm. A fixed effect model was used. CCRT, concurrent chemoradiotherapy; GZ, Guangzhou; HeCOG, Hellenic Cooperative Oncology Group; IC, induction chemotherapy; NCCS, National Cancer Centre Singapore; NPC, nasopharyngeal carcinoma; O-E, observed minus expected deaths or events; PWH, Prince of Wales Hospital. Supplementary Figure S3. Multiple treatment comparison network. Each treatment area is proportional to the cumulative number of patients (in parentheses). Solid lines between treatments represent direct comparisons. AC, adjuvant chemotherapy; CCRT, concurrent chemoradiotherapy; CEP, cisplatin, epirubicin and paclitaxel; GCP, gemcitabine, carboplatin and paclitaxel; IC, induction chemotherapy; PF, cisplatin and fluorouracil; PX, cisplatin and capecitabine; TP, docetaxel and cisplatin; TPF, TP and fluorouracil. Supplementary Table S1. Description of the Two Trials Included in the Supplementary Analysis Supplementary Table S2. Description of Patient Characteristics Supplementary Table S3. Disease Status and Pattern of FailureSupplementary Table S4. Compliance with Induction Chemotherapy and Concurrent Chemoradiotherapy Supplementary Table S5. Summary of Major Grade 3-4 Adverse Events*

A feasibility study was performed to determine if CT-based radiomics could play an augmentative role in predicting neoadjuvant rectal score (NAR), locoregional failure free survival (LRFFS), distant metastasis free survival (DMFS), disease free survival (DFS) and overall survival (OS) in locally advanced rectal cancer (LARC). The NAR score, which takes into account the pathological tumour and nodal stage as well as clinical tumour stage, is a validated surrogate endpoint used for early determination of treatment response whereby a low NAR score ( 16) has been correlated with poorer outcomes. CT images of 191 patients with LARC were used in this study. Primary tumour (GTV) and mesorectum (CTV) were contoured separately and radiomics features were extracted from both segments. Two NAR models (NAR > 16 and NAR 16 and NAR 16 and NAR

Purpose: Reirradiation for locally recurrent nasopharyngeal carcinoma (NPC) is challenging because prior radiation dose delivered in the first course is often close to the tolerance limit of surrounding normal structures. A delicate balance between achieving local salvage and minimizing treatment toxicities is needed. However, high-level evidence is lacking because available reports are mostly retrospective studies on small series of patients. Pragmatic consensus guidelines, based on an extensive literature search and the pooling of opinions by leading specialists, will provide a useful reference to assist decision-making for these difficult decisions. Methods and Materials: A thorough review of available literature on recurrent NPC was conducted. A set of questions and preliminary draft guideline was circulated to a panel of international specialists with extensive experience in this field for voting on controversial areas and comments. A refined second proposal, based on a summary of the initial voting and different opinions expressed, was recirculated to the whole panel for review and reconsideration. The current guideline was based on majority voting after repeated iteration for final agreement. Results: The initial round of questions showed variations in clinical practice even among the specialists, reflecting the lack of high-quality supporting data and the difficulties in formulating clinical decisions. Through exchange of comments and iterative revisions, recommendations with high-to-moderate agreement were formulated on general treatment strategies and details of reirradiation (including patient selection, targets contouring, dose prescription, and constraints). Conclusion: This paper provides useful reference on radical salvage treatment strategies for recurrent NPC and optimization of reirradiation through review of published evidence and consensus building. However, the final decision by the attending clinician must include full consideration of an individual patient's condition, understanding of the delicate balance between risk and benefits, and acceptance of risk of complications. (C) 2021 Elsevier Inc. All rights reserved.

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.

Purpose: Target delineation in nasopharyngeal carcinoma (NPC) often proves challenging because of the notoriously narrow therapeutic margin. High doses are needed to achieve optimal levels of tumour control, and dosimetric inadequacy remains one of the most important independent factors affecting treatment outcome. Method: A review of the available literature addressing the natural behaviour of NPC and correlation between clinical and pathological aspects of the disease was conducted. Existing international guidelines as well as published protocols specified by clinical trials on contouring of clinical target volumes (CTV) were compared. This information was then summarized into a preliminary draft guideline which was then circulated to international experts in the field for exchange of opinions and subsequent voting on areas with the greatest controversies. Results: Common areas of uncertainty and variation in practices among experts experienced in radiation therapy for NPC were elucidated. Iterative revisions were made based on extensive discussion and final voting on controversial areas by the expert panel, to formulate the recommendations on contouring of CTV based on optimal geometric expansion and anatomical editing for those structures with substantial risk of microscopic infiltration. Conclusion: Through this comprehensive review of available evidence and best practices at major institutions, as well as interactive exchange of vast experience by international experts, this set of consensus guidelines has been developed to provide a practical reference for appropriate contouring to ensure optimal target coverage. However, the final decision on the treatment volumes should be based on full consideration of individual patients' factors and facilities of an individual centre (including the quality of imaging methods and the precision of treatment delivery). (C) 2017 Elsevier B.V. All rights reserved.

Purpose: The treatment of nasopharyngeal carcinoma requires high radiation doses. The balance of the risks of local recurrence owing to inadequate tumor coverage versus the potential damage to the adjacent organs at risk (OARs) is of critical importance. With advancements in technology, high target conformality is possible. Nonetheless, to achieve the best possible dose distribution, optimal setting of dose targets and dose prioritization for tumor volumes and various OARs is fundamental. Radiation doses should always be guided by the As Low As Reasonably Practicable principle. There are marked variations in practice. This study aimed to develop a guideline to serve as a global practical reference.Methods and Materials: A literature search on dose tolerances and normal-tissue complications after treatment for nasopharyngeal carcinoma was conducted. In addition, published guidelines and protocols on dose prioritization and constraints were reviewed. A text document and preliminary set of variants was circulated to a panel of international experts with publications or extensive experience in the field. An anonymized voting process was conducted to rank the proposed variants. A summary of the initial voting and different opinions expressed by members were then recirculated to the whole panel for review and reconsideration. Based on the comments of the panel, a refined second proposal was recirculated to the same panel. The current guideline was based on majority voting after repeated iteration for final agreement.Results: Variation in opinion among international experts was repeatedly iterated to develop a guideline describing appropriate dose prioritization and constraints. The percentage of final agreement on the recommended parameters and alternative views is shown. The rationale for the recommendations and the limitations of current evidence are discussed.Conclusions: Through this comprehensive review of available evidence and interactive exchange of vast experience by international experts, a guideline was developed to provide a practical reference for setting dose prioritization and acceptance criteria for tumor volumes and OARs. The final decision on the treatment prescription should be based on the individual clinical situation and the patient's acceptance of optimal balance of risk. (C) 2019 Elsevier Inc. All rights reserved.

6523 Background: Based on an individual patient data (IPD) network meta-analysis (NMA) of 20 randomized trials and 5,144 patients (pts), the MAC-NPC collaborative group has shown that the addition of adjuvant chemotherapy (AC) to chemo-radiotherapy (CRT) achieved the highest survival benefit in nasopharyngeal carcinoma (NPC; Ribassin-Majed JCO 2017). Here, we updated the meta-analysis with the addition of 8 trials. Methods: Trials of Radiotherapy (RT) with or without chemotherapy (CT) in patients with non-metastatic NPC were identified and updated IPD obtained. Both Western and Chinese medical literatures were searched. Overall Survival (OS) was the main endpoint. Fixed and random-effects frequentist NMA models were applied, network heterogeneity and consistency were evaluated. P-score was used to rank the treatments. R software - netmeta package was used to perform the analyses. Treatments were grouped in the following categories: RT alone (RT), induction chemotherapy followed by RT (IC-RT), induction chemotherapy without taxanes followed by concomitant chemoradiotherapy (ICtax(-)-CRT), induction chemotherapy with taxanes followed by concomitant chemoradiotherapy (ICtax(+)-CRT), concomitant chemoradiotherapy (CRT), concomitant chemoradiotherapy followed by adjuvant chemotherapy (CRT-AC) and RT followed by adjuvant chemotherapy (RT-AC). Results: Overall 28 trials and 8,214 pts were included. Median follow-up was 7.2 years. There was no heterogeneity in the NMA. There was inconsistency in the main analysis, which disappeared after the exclusion of 2 outlier trials. ICtax(+)-CRT ranked the best treatment for OS with a P-Score of 91%. Hazard ratio [HR, 95% Confidence Interval] for ICtax(+)-CRT was 0.75 [0.59-0.96] compared to CRT and 0.92 [0.69-1.24] compared to CRT-AC (second best treatment in raking with a P-Score of 85%; see league table below). When the 2 types of IC were merged, CRT-AC ranked the first followed by IC-CRT with P-Scores of 93% and 86% respectively, with a HR of 0.97 [0.84-1.14] for CRT-AC vs. IC-CRT. Conclusions: This IPD NMA of the treatment of locally advanced NPC demonstrates that the addition of IC or AC to CRT improves disease control probability and survival over CRT alone. Data on progression-free survival, locoregional and distant control will be presented at the meeting. [Table: see text]

Specific research foci: (1) Mouse models of gamma-herpes virus-68 (γHV-68) and polyomavirus (PyV) infections during neonatal versus adult life. (2) For human papilloma virus (HPV)-positive oropharyngeal carcinoma (OPC)—(a) Asking the question: Is oral sex a powerful carcinogen? (b) Examining the evidence for the vertical transmission of HPV infection. (c) Examining the relationship between HPV and Epstein–Barr virus (EBV) infections and nasopharyngeal cancer (NPC) in West European, East European, and East Asian countries. (d) Examining the association between HPV-positive OPC and human leukocyte antigen (HLA). (3) For non-smoking East Asian female lung adenocarcinoma—(a) Examining the incidence trends of HPV-positive OPC and female lung adenocarcinoma according to birth cohorts. (b) Examining the association between female lung adenocarcinoma and HPV. (c) Examining the associations of lung adenocarcinoma with immune modulating factors. (4) For triple-negative breast carcinoma (TNBC) in East Asians—(a) Examining the association between TNBC and HPV. (b) Examining the unique epidemiological characteristics of patients with TNBC. A summary “epidemiological” model tying some of these findings together.

The Epstein-Barr virus (EBV) has been definitively implicated in the development of nasopharyngeal cancer (NPC). However, little is known about how specifically EBV gains entry into the cells to effect carcinogenic change, and why this affects certain ethnic populations more than others. The current dogma regarding EBV infection in NPC has been that of late infection, followed by multiple postulated mechanisms for immune evasion of EBV against the host defences, leading to eventual trigger of carcinogenesis. This paper postulates that beta-integrin 6, which is primarily expressed during embryonic development and possibly in neonatal life, may play a role in the development of NPC by facilitating entry of EBV into cells within the nasopharynx during the perinatal period, and this, coupled with ethnic differences in cell—mediated and innate immunity, leads to latent infection within the nasopharynx. Subsequent accumulation of further environmental and/or oncogenic changes leads to the eventual development of NPC in the patient in later life.

GRID or spatially fractionated radiation therapy was historically used in the orthovoltage era to deliver large single 15–20 Gy doses of radiotherapy to tumours greater than 6 cm by creating a dosimetric distribution that is comprised of intervening “hot” and “cold” spots within the tumour. However, despite impressive response rates of 70% with GRID at such non-tumoricidal doses, the technique quickly fell out of favour with the advent of megavoltage linear accelerators. With the introduction of modern techniques like stereotactic body radiation therapy (SBRT) that have produced comparable response rates, it is possible that a commonality between both modalities pertains to the influence on the adaptive immune response within the tumour microenvironment. Here, we review the clinical evidence and potential mechanisms underpinning the clinical efficacy of GRID; we also propose potential scenarios where GRID represents a cost-effective and safe measure of delivering profound hypo-fractionated radiation therapy in the contemporary setting.

OBJECTIVES AND IMPORTANCE: Cochlear implantation is an established, reliable, and safe procedure with a low complication rate. Electrode array extrusion through the posterior aspect of external ear canal is a potential major complication of cochlear implant surgery that may result in revision surgery or explantation. Although there have been previous case reports of such extrusions through the tympanic membrane, this is the first well-documented report of an extrusion through the posterior canal wall which was previously intact.In this case report, we present a case of electrode array extruding through an initially intact posterior canal wall presenting as a delayed post-operative complication in a 13-year old Asian boy.With reference to existing relevant literature, the case is discussed focusing on its management, possible contributing factors, and prevention strategies.Excessive thinning of the bony wall should be avoided as it can potentially break down. Abutment on the posterior canal wall by a coiled electrode array in the mastoid cavity exerting undue pressure on the bony wall can further contribute to additional stress. The implant surgeon must be cognizant of mastoid growth patterns in children. Life-long regular follow-up in implanted patients is crucial.

We thought it would be appropriate for us as editors to close this issue with some personal reflections on certain areas with respect to nasopharyngeal carcinoma (NPC).

Current proposed mechanisms implicate both early and latent Epstein–Barr virus (EBV) infection in the carcinogenic cascade, whereas epidemiological studies have always associated nasopharyngeal carcinoma (NPC) with early childhood EBV infection and with chronic ear, nose, and sinus conditions. Moreover, most patients with NPC present with IgA antibody titers to EBV capsid antigen (VCA-IgA), which can precede actual tumor presentation by several years. If early childhood EBV infection indeed constitutes a key event in NPC carcinogenesis, one would have to explain the inability to detect the virus in normal nasopharyngeal epithelium of patients at a high risk for EBV infection. It is perhaps possible that EBV resides within the salivary glands, instead of the epithelium, during latency. This claim is indirectly supported by observations that the East Asian phenotype shares the characteristics of an increased susceptibility to NPC and immature salivary gland morphogenesis, the latter of which is influenced by the association of salivary gland morphogenesis with an evolutionary variant of the human ectodysplasin receptor gene (EDAR), EDARV370A. Whether the immature salivary gland represents a more favorable nidus for EBV is uncertain, but in patients with infectious mononucleosis, EBV has been isolated in this anatomical organ. The presence of EBV-induced lymphoepitheliomas in the salivary glands and lungs further addresses the possibility of submucosal spread of the virus. Adding to the fact that the fossa of Rosen Müller contains a transformative zone active only in the first decade of life, one might be tempted to speculate the possibility of an alternative carcinogenic cascade for NPC that is perhaps not dissimilar to the model of human papillomavirus and cervical cancer.