Search

Purpose: The purpose of this study was to evaluate the radiotherapy planning feasibility of dose escalation with intensity-modulated proton therapy (IMPT) to hypoxic tumor regions identified on 18F-Fluoromisonidazole (FMISO) positron emission tomography and computed tomography (PET-CT) in NPC., Materials and Methods: Nine patients with stages T3-4N0-3M0 NPC underwent 18F-FMISO PET-CT before and during week 3 of radiotherapy. The hypoxic volume (GTVhypo) is automatically generated by applying a subthresholding algorithm within the gross tumor volume (GTV) with a tumor to muscle standardized uptake value (SUV) ratio of 1.3 on the 18F-FMISO PET-CT scan. Two proton plans were generated for each patient, a standard plan to 70 Gy and dose escalation plan with upfront boost followed by standard 70GyE plan. The stereotactic boost was planned with single-field uniform dose optimization using two fields to deliver 10 GyE in two fractions to GTVhypo. The standard plan was generated with IMPT with robust optimization to deliver 70GyE, 60GyE in 33 fractions using simultaneous integrated boost technique. A plan sum was generated for assessment., Results: Eight of nine patients showed tumor hypoxia on the baseline 18F-FMISO PET-CT scan. The mean hypoxic tumor volume was 3.9 cm 3 (range .9-11.9cm 3 ). The average SUVmax of the hypoxic volume was 2.2 (range 1.44-2.98). All the dose-volume parameters met the planning objectives for target coverage. Dose escalation was not feasible in three of eight patients as the D0.03cc of temporal lobe was greater than 75GyE., Conclusions: The utility of boost to the hypoxic volume before standard course of radiotherapy with IMPT is dosimetrically feasible in selected patients. Clinical trials are warranted to determine the clinical outcomes of this approach., (© 2023 John Wiley & Sons Australia, Ltd.)

Objectives: To characterize longitudinal changes in Epstein-Barr virus (EBV) DNA post-radiotherapy in nasopharyngeal carcinoma (NPC) patients, and investigate whether an early (0-2 weeks) or delayed (8-12 weeks) EBV DNA result better predicts for disease-free survival (DFS)., Materials and Methods: Histologically-confirmed NPC patients with ≥1 EBV DNA test quantified using the harmonized BamHI-W polymerase chain reaction-based assay at 0-2 and 8-12 weeks post-radiotherapy were included., Results: We identified 302 patients with EBV DNA measured at 0-2 weeks post-radiotherapy; of which, 110 (36.4 %) underwent a repeat test at 8-12 weeks post-treatment. Patients harboring a detectable EBV DNA at 0-2 weeks experienced an inferior DFS (adjusted HR 1-264 copies 1.72 [95 %CI: 1.05-2.83], P = 0.031; AHR ≥265 copies 4.39 [95 %CI: 1.68-11.44], P = 0.002 relative to 0 copies/mL). At 8-12 weeks, we observed substantial shifts in EBV DNA readings from 0 to 2 weeks; 76/110 (69.1 %) and 34/110 (30.9 %) patients at 0-2 weeks versus 90/110 (81.8 %) and 20/110 (18.2 %) at 8-12 weeks recorded undetectable and detectable EBV DNA, respectively. Positive EBV DNA at 8-12 weeks was strongly associated with relapse (73.3 % [11/15] for 1-264; 80.0 % [4/5] for ≥265 subgroups had relapses versus 15.6 % [14/90] for 0 copies/mL). Area under receiver operating curve values for 2-year relapse rates were 0.817 (95 %CI: 0.725-0.909) for stage + EBV DNA 8-12w versus 0.654 (95 %CI: 0.542-0.765) for stage + EBV DNA 0-2w. CONCLUSION: EBV DNA is dynamic post-radiotherapy, and delayed EBV DNA testing better enriched for higher-risk NPC patients. This implicates trials investigating adjuvant chemotherapy intensification based on early EBV DNA testing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose or Objective: The COVID-19 pandemic has resulted in significant healthcare implications, with care for cancer patients compromised due to resource diversion towards battling the pandemic. We aim to investigate the impact of the peak wave of the pandemic in 2020 on the delivery of cancer care in Singapore, specifically via our nasopharyngeal carcinoma (NPC) treatment data. This study applies real world numbers to the impact of COVID-19 on cancer care delivery in Singapore. The choice of nasopharyngeal cancer allows a good direct estimate of common treatment measures such as time to biopsy, time to staging scans, time to treatment commencement, due to its clear protocol and algorithms for staging and treatment; thus serving as an excellent surrogate for the effectiveness and timeliness of the different aspects of cancer care delivery., Materials and Methods: In this retrospective study, we included all patients with newly diagnosed NPC from 1st January to 31st May from 2017 to 2020 at our centre. This time period was chosen as it coincided with the period in 2020 during the COVID-19 pandemic where there was the most strain on healthcare resources and the most restrictions on population movement within Singapore, which may impact on healthcare seeking behaviour. Narrowing down the time period to the first 5 months of the 4 respective years also allowed us to reduce the effect of annual seasonal variation in patient numbers seen as a result of holidays and festive periods such as the Lunar New Year and scheduled school holidays. Electronic medical records (EMR) were accessed. Only newly diagnosed NPC cases were included in our analysis. Patients with second synchronous primary malignancies or NPC disease recurrence were excluded. Data analysis was carried out using a combination of SPSS and Microsoft Excel., Results: Significantly, there was a reduction of 37-46.3% in newly diagnosed NPC cases during the peak of the COVID-19 pandemic from January to end May 2020 compared to the preceding three years. Despite the reduction in numbers of newly diagnosed NPC, there was no statistically significant differences in delay from biopsy to the first radiation oncology visit and from biopsy to the first day of treatment in 2020 compared to the preceding years. All the patients treated in our centre also received the standard NPC treatment for their disease stage as per international guidelines., Conclusion: We recommend a heightened awareness of the dangers of delaying cancer presentation and care in healthcare policies and resource allocation and at the same time, encourage patient's confidence in their ability to seek care. With the resurgence of new COVID-19 variants and case numbers worldwide and in Singapore, this study focuses upon the need to be aware of the exigencies of other clinical groups in resource utilization. It would be instructive to compare this study with future long term follow up to investigate the trajectory of our cancer care delivery, as well as survival outcomes., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2023.)

Background: There is no standard-of-care for recurrent, metastatic nasopharyngeal carcinoma (rmNPC) after first-line chemotherapy. Here, we report the efficacy and safety data of apatinib in rmNPC patients., Methods: Thirty-five biopsy-proven rmNPC patients received apatinib at 500 mg/day under a compassionate access programme. Primary end-point was objective response rate (ORR; RECIST v1.1). Kaplan-meier method was used to estimate progression-free survival (PFS) and overall survival (OS). Toxicity was assessed by CTCAE v4.0., Results: 82.9% (29 of 35) of patients had poly-metastatic rmNPC. All patients, except five, were platinum-refractory; 37.1% (13 of 35) received ≥ 2 lines. Median number of apatinib cycles was 4.0 (IQR: 2.0-8.0). ORR was 31.4% (11 of 35 [95% CI: 16.9-49.3]) and disease control rate was 74.3% (26 of 35 [95% CI: 56.7-87.5]); 11 (31.4%) and 4 (11.4%) patients demonstrated response for ≥ 6 and ≥ 12 months, respectively. Median PFS and OS was 3.9 (95% CI: 3.1-5.5) months and 5.8 (95% CI: 4.5-8.0) months, respectively. Among the ≥ 12-month responders, all patients had pre-apatinib EBV DNA titer of <700 (range: 353-622) copies/ml; this was consistent with the association of PFS with pre-apatinib EBV DNA titer (adjusted HR 3.364 [95% CI: 1.428-7.923] for ≥ 4000 copies/ml, P = 0.006). 42.9% (15 of 35) of patients required dose reduction. Nonetheless, only five (14.3%) patients suffered from G3 toxicities (two haematological, one hypertension, one hand-foot syndrome and one elevated aminotransferases)., Conclusion: Our data suggests potential efficacy of apatinib in rmNPC patients. Although incidence of severe toxicities was low, dose modification was required in 42.9% of patients., (Copyright © 2021. Published by Elsevier Ltd.)

Purpose: The aim of this joint guideline is to provide evidence-based recommendations to practicing physicians and other healthcare providers on definitive-intent chemoradiotherapy for patients with stage II-IVA nasopharyngeal carcinoma (NPC)., Methods: The Chinese Society of Clinical Oncology (CSCO) and ASCO convened an expert panel of radiation oncology, medical oncology, surgery, and advocacy representatives. The literature search included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2020. Outcomes of interest included survival, distant and locoregional disease control, and quality of life. Expert panel members used this evidence and informal consensus to develop evidence-based guideline recommendations., Results: The literature search identified 108 relevant studies to inform the evidence base for this guideline. Five overarching clinical questions were addressed, which included subquestions on radiotherapy (RT), chemotherapy sequence, and concurrent, induction, and adjuvant chemotherapy options., Recommendations: Evidence-based recommendations were developed to address aspects of care related to chemotherapy in combination with RT for the definitive-intent treatment of stage II to IVA NPC.Additional information is available at www.asco.org/head-neck-cancer-guidelines.

Background: Lactate dehydrogenase (LDH) is a known prognostic biomarker for the endemic variant of nasopharyngeal carcinoma (NPC). Here, we investigate whether serial changes in LDH level between chemotherapy (CT) cycles are associated with tumour response to CT., Methods: Patients with biopsy-proven, recurrent or treatment-naïve metastatic NPC (mNPC) were recruited. All patients had received at least two cycles of platinum-based doublet or triplet CT, with serial assessment of LDH prior to every cycle of chemotherapy (CT1-6). Patients harbouring conditions that affect LDH levels (IU/L) were excluded. Tumour response was assessed after every two cycles of CT by RECIST v1.1., Results: A total of 158 patients were analysed, including 77 with recurrent and 81 with treatment-naïve mNPC. High pre-CT LDH was associated with an inferior overall survival [hazard ratio 1.93 for ⩾240 versus <240 (1.34-2.77), p  < 0.001], which is consistent with published literature. We found that both absolute LDH levels and LDH ratios (LDH CTn : LDH CTn-1 ) were associated with tumour response [partial response versus progressive disease: median value across CT1-6 = 168-190 versus 222-398 (absolute); 0.738-0.988 versus 1.039-1.406 (ratio)], albeit LDH ratio had a tighter variance between patients. Finally, we showed that an LDH ratio cut-off of 1.0 at CT1, CT3 and CT5 was predictive of progressive disease at CT2, CT4, CT6 [area under the curve of 0.73 (0.65-0.80)]., Conclusion: Herein, we characterised the longitudinal variation of LDH in response to CT in mNPC. Our findings suggest the potential utility of interval LDH ratio to predict subsequent tumour response to CT., Competing Interests: Conflict of interest statement: MC reports personal fees from Astellas, Janssen, Bayer, Pfizer, MSD, personal fees and non-financial support from AstraZeneca, personal fees and grants from Ferring, personal fees and non-financial support from Varian, non-financial support from Decipher Biosciences, non-financial support from Medlever, and consults for immunoSCAPE Inc., outside the submitted work., (© The Author(s), 2020.)

Purpose: Improved antitumor responses have been observed in patients after combination radiation therapy (RT) and immune checkpoint blockade (ICB). Whether these clinical responses are linked to the host systemic immune system has not been elucidated., Methods and Materials: In this single-institution prospective observational study, peripheral blood was longitudinally collected from 10 patients with metastatic disease who had responded to anti-PD-1/anti-PD-L1 ICB and received RT (8-50 Gy in 1-5 fractions) upon disease progression at the following timepoints: baseline (pre-RT), 1 to 2 weeks post-RT, and post-ICB (cycle 1) on reintroduction post-RT. To thoroughly characterize the interaction between combined RT-ICB and the host immune system, we performed high-dimensional, mass cytometry-based immunophenotyping of circulating lymphocytes using a 40-marker panel addressing lineage, differentiation, activation, trafficking, cytotoxicity, and costimulatory and inhibitory functions. Phenotypic expression of circulating lymphocytes was compared across patients and time points and correlated with post-RT tumor responses., Results: Foremost, we demonstrated excellent posttreatment clinical responses, including 4 local responses with >50% reduction in radiated tumor size, 1 out-of-field response, and 4 patients who resumed ICB for >1 year. Baseline and post-RT immune states were highly heterogeneous among patients. Despite this interindividual heterogeneity in baseline immune states, we observed a systemic immune reaction to RT-ICB common across patients, histology, and radiation sites; a subset of pre-existing Ki-67+ CD8+ T cells were increased post-RT and further expanded upon reintroduction of ICB post-RT (2.3-fold increase, P = .02). Importantly, RT did not alter the phenotypic profile of these Ki-67+ CD8+ T cells, which was characterized by a distinct activated and differentiated effector phenotype., Conclusions: Collectively, these findings point toward a sustained reinvigoration of host antitumor immunity after RT-ICB and suggest an expansion in activated Ki-67+ CD8+ T cells as a possible demonstration of this synergy, thereby providing new insights that may support the development of optimal sequencing strategies., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Current guideline recommends a uniform method of delineation of subclinical disease within the primary clinical target volume (CTVp) for all stages of nasopharyngeal carcinoma (NPC). We performed a prospective observational study to investigate the outcomes with a reduced CTVp and radiation dose for early-stage NPC., Methods and Materials: Patients with newly diagnosed, biopsy-proven World Health Organization type II-III and American Joint Committee on Cancer/Union for International Cancer Control sixth edition stage T1-2N0-1 disease were enrolled. All patients were treated with intensity modulated radiation therapy alone. We categorized CTVp into CTVp1 (high risk) and CTVp2 (low risk). CTVp1 comprised of gross tumor (on magnetic resonance imaging or contrast-enhanced computed tomography) plus a 5-mm margin (3-mm posteriorly) and was prescribed to 60 Gy in 30 fractions (fr). CTVp2 was generated from CTVp1 plus a 5-mm margin (3 mm posteriorly), excluding the maxillary and cavernous sinuses, and was prescribed to 54 Gy in 30 fr. The prescribed doses to the primary and nodal gross tumor volume (GTVp and GTVn) were 68 Gy in 30 fr and 60 to 66 Gy in 30 fr, respectively. Primary endpoint was local recurrence-free survival. This study was registered in ClinicalTrials.gov, number NCT03839602., Results: From May 2001 to August 2006, 103 patients were recruited and completed IMRT. With a median follow-up of 15.2 years (range, 2.1-18.1 years), only 1 patient had local failure. Ten-year local recurrence-free survival, regional recurrence-free survival, distant metastasis-free survival, and overall survival were 90.3%, 88.3%, 90.3%, and 91.2%, respectively. Among late IMRT-related adverse events, we recorded 2 patients with G1 cranial nerve injury, 3 patients with G3 hearing loss, and 3 patients with G3 subcutaneous fibrosis. No patients had temporal lobe necrosis, brain stem injury, or trismus., Conclusions: Decreased CTV margins and radiation doses can achieve long-term tumor control with mild late toxicities for patients with early-stage NPC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Purpose: To compare physician and patient reported xerostomia and correlate xerostomia with dosimetric and clinical parameters for nasopharyngeal cancer (NPC) patients treated with intensity modulated radiotherapy (IMRT) and chemotherapy., Patients and Methods: We analyzed the data of 172 patients with locally advanced NPC. Xerostomia was evaluated via physician-rated xerostomia based on RTOG morbidity score (E1), patient-rated dry mouth (E2) and patient-rated sticky saliva (E3) based on EORTC QLQ-HN35 questionnaire. Primary endpoint was the presence of moderate to severe xerostomia at 2-year after completion of IMRT., Results: The levels of physician reported xerostomia (E1) were consistently lower than patient reported dry mouth (E2) over time. The incidence of patients with xerostomia at 3-month post RT was 58% based on E1, 70% based on E2, and 51% based on E3. The corresponding incidence rates at 2-year post RT was 26% (E1), 36% (E2) and 21% (E3). The incidence of patients with xerostomia at 1-year post RT was close to that at 2-year post RT for all the 3 endpoints. The average Dmean of parotid glands was 41.5 Gy (range: 31.0 Gy-65.9 Gy, median: 40.7 Gy). No dosimetric parameters were significantly associated with xerostomia., Conclusion: Significant proportion of patients still experienced long term xerostomia with IMRT. Dose-effect relationships between xerostomia and the parotid glands were not observed in this study., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background Nasopharyngeal carcinoma (NPC) may be cured with radiation therapy. Tumor proximity to critical structures demands accuracy in tumor delineation to avoid toxicities from radiation therapy; however, tumor target contouring for head and neck radiation therapy is labor intensive and highly variable among radiation oncologists. Purpose To construct and validate an artificial intelligence (AI) contouring tool to automate primary gross tumor volume (GTV) contouring in patients with NPC. Materials and Methods In this retrospective study, MRI data sets covering the nasopharynx from 1021 patients (median age, 47 years; 751 male, 270 female) with NPC between September 2016 and September 2017 were collected and divided into training, validation, and testing cohorts of 715, 103, and 203 patients, respectively. GTV contours were delineated for 1021 patients and were defined by consensus of two experts. A three-dimensional convolutional neural network was applied to 818 training and validation MRI data sets to construct the AI tool, which was tested in 203 independent MRI data sets. Next, the AI tool was compared against eight qualified radiation oncologists in a multicenter evaluation by using a random sample of 20 test MRI examinations. The Wilcoxon matched-pairs signed rank test was used to compare the difference of Dice similarity coefficient (DSC) of pre- versus post-AI assistance. Results The AI-generated contours demonstrated a high level of accuracy when compared with ground truth contours at testing in 203 patients (DSC, 0.79; 2.0-mm difference in average surface distance). In multicenter evaluation, AI assistance improved contouring accuracy (five of eight oncologists had a higher median DSC after AI assistance; average median DSC, 0.74 vs 0.78; P < .001), reduced intra- and interobserver variation (by 36.4% and 54.5%, respectively), and reduced contouring time (by 39.4%). Conclusion The AI contouring tool improved primary gross tumor contouring accuracy of nasopharyngeal carcinoma, which could have a positive impact on tumor control and patient survival. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Chang in this issue.

Background: The aim of this study was to investigate the effect of treatment with the saliva biomimetic, casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) and SnF 2 /NaF compared with SnF 2 /NaF alone on coronal surface caries progression in head-and-neck cancer patients undergoing radiotherapy., Methods: Twenty-four participants were randomized into two groups. Both groups used 0.4% SnF 2 gel and a 0.32% NaF toothpaste; the test group also applied a crème containing 10% CPP-ACP three times daily while the control group used an identical crème without CPP-ACP (placebo). Resting saliva flow rate and saliva fluoride concentrations were determined. Caries status was assessed using ICDASII at baseline and 12-weeks postradiotherapy. Data were statistically analysed using a linear mixed effects model., Results: Both groups showed significantly reduced resting saliva flow rate (P < 0.001) postradiotherapy. There were no significant differences in flow rates and fluoride concentration between groups. The CPP-ACP group exhibited a significant (P < 0.05) 51% reduction in coronal surface caries progression compared with the placebo group., Conclusion: Resting salivary flow rate was significantly reduced in head-and-neck cancer patients following radiotherapy and use of CPP-ACP with SnF 2 /NaF significantly lowered caries progression compared with SnF 2 /NaF alone., (© 2018 Australian Dental Association.)

Background: Inter-patient heterogeneity in radiation-induced DNA damage responses is proposed to reflect intrinsic variations in tumour and normal tissue radiation sensitivity, but the prediction of phenotype by a molecular biomarker is influenced by clinical confounders and assay reproducibility. Here, we characterised the intrapatient and inter-patient heterogeneity in biomarkers of DNA damage and repair and radiation-induced apoptosis., Methods: We enrolled 85 of 172 patients with locally advanced nasopharynx cancer from a randomised controlled phase II/III trial of induction chemotherapy added to chemo-radiotherapy. G 0 blood lymphocytes were harvested from these patients, and irradiated with 1, 4, and 8 Gy ex vivo. DNA damage induction (1 Gy 0.5 h) and repair (4 Gy 24 h) were assessed by duplicate γH2AX foci assays in 50-100 cells. Duplicate FLICA assays performed at 48 h post-8 Gy were employed as surrogate of radiation-induced apoptosis; %FLICA-positive cells were quantified by flow cytometry., Results: We observed limited intrapatient variation in γH2AX foci and %FLICA readouts; median difference of duplicate foci scores was - 0.37 (IQR = - 1.256-0.800) for 1 Gy 0.5 h and 0.09 (IQR = - 0.685-0.792) for 4 Gy 24 h; ICC of ≥0.80 was observed for duplicate %FLICA 0Gy and %FLICA 8Gy assays of CD4+ and CD8+ T lymphocytes. As expected, we observed wide inter-patient heterogeneity in both assays that was independent of intrapatient variation and clinical covariates, with the exception of age, which was inversely correlated with %FLICA background-corrected (Spearman R = - 0.406, P < 0.001 [CD4+]; R = - 0.220, P = 0.04 [CD8+]). Lastly, an exploratory case-control analysis indicates increased levels of γH2AX foci at 4 Gy 24 h in patients with severe late radiotherapy-induced xerostomia (P = 0.05)., Conclusion: Here, we confirmed the technical reproducibility of DNA damage response assays for clinical implementation as biomarkers of clinical radiosensitivity in nasopharynx cancer patients.

Paranasal sinus and skull base tumors are rare aggressive head and neck cancers, and typically present in the locally advanced stages. As a result, achieving wide surgical resection with clear margins is a challenge for these tumors, and radiotherapy is thus usually indicated as an adjuvant modality following surgery to optimize local control. Given the integral role of radiotherapy in the management of this subgroup of head and neck tumors, the advent of intensity-modulated radiotherapy (IMRT) has led to substantial improvement of clinical outcomes for these patients. This is primarily driven by the improvement in radiation dosimetry with IMRT compared to conventional two dimensional (2D)- and 3D-techniques, in terms of ensuring dose intensity to the tumor target coupled with minimizing dose exposure to critical organs. Consequently, the evident clinical benefits of IMRT have been in reduction of normal tissue toxicities, ranging from critical neurological symptoms to less debilitating but bothersome symptoms of eye infections and radiation-induced skin changes. Another domain where IMRT has potential clinical utility is in the management of a subset of non-resectable T4 paranasal sinus and skull base tumors. For these inoperable lesions, the steep dose-gradient between tumor and normal tissue is even more advantageous, given the crucial need to maintain dose intensity to the tumor. Innovative strategies in this space also include the use of induction chemotherapy for patient selection. In this review, we summarized the data for the aforementioned topics, including specific discussions on the different histologic subtypes of paranasal sinus and skull base tumors., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Importance: Modern precision radiotherapy is an innovative and effective treatment of cancer, yet it is unclear how radiotherapy trials are affected by expanding targeted and immune therapies and declining National Institutes of Health funding., Objective: To analyze and compare the characteristics of radiotherapy trials with other oncological trials registered on ClinicalTrials.gov., Design, Setting, and Participants: This is a cross-sectional analysis of trials registered on ClinicalTrials.gov between June 1, 2007, and May 8, 2017. Records of all 243 758 clinical studies registered by May 8, 2017, were downloaded, but only 25 907 interventional oncological trials registered between June 1, 2007, and May 8, 2017, and whose primary purpose was "treatment" were included in the final analysis. Trials were categorized according to cancer type and other registration information., Main Outcomes and Measures: Characteristics of radiotherapy trials were compared with characteristics of other oncological trials. Chronological shifts in radiotherapy trials were also analyzed., Results: Of the 25 907 trials selected, 1378 (5.3%) were radiotherapy trials and 24 529 (94.7%) were other oncological studies. The number of radiotherapy trials increased gradually from 94 (June 1, 2007, through May 31, 2008) to 192 (June 1, 2015, through May 31, 2016). Radiotherapy trials were less likely than other oncological studies to be registered before participant enrollment (763 of 1370 [55.7%] vs 16 105 of 24 434 [65.9%]; P < .001), to be blinded (45 of 1378 [3.3%] vs 2784 of 24 529 [11.3%]; P < .001), or to involve multiple geographic regions (2.4% vs 9.5%; P < .001), but they were more likely to be phase 2 to 3 (773 of 1124 [68.8%] vs 12 910 of 22 300 [57.9%]; P < .001) and to have a data-monitoring committee (839 of 1264 [66.4%] vs 11 728 of 21 060 [55.7%]; P < .001). Only a minority of radiotherapy trials were industry sponsored, which was significantly lower than for other oncological trials (80 of 1378 [5.8%] vs 10 651 of 24 529 [43.4%]; P < .001; adjusted odds ratio, 0.08; 95% CI, 0.06-0.10). The number of National Institutes of Health-sponsored radiotherapy trials decreased from 80 of 544 trials (14.7%) from 2007 to 2012 to 72 of 834 trials (8.6%) from 2012 to 2017 (P < .001). Radiotherapy trials with a sample size of more than 100 patients decreased from 155 of 543 trials (28.5%) from 2007 to 2012 to 157 of 833 trials (18.8%) from 2012 to 2017 (P < .001)., Conclusions and Relevance: The limited number of and the scarcity of funding for radiotherapy trials is concerning given the integral role of radiotherapy in the clinical management of patients with cancer worldwide. A multidisciplinary collaboration to promote and fund more radiotherapy research is warranted.

Modern standards of precision radiotherapy, primarily driven by the technological advances of intensity modulation and image guidance, have led to increased versatility in radiotherapy planning and delivery. The ability to shape doses around critical normal organs, while simultaneously "painting" boost doses to the tumor have translated to substantial therapeutic gains in head and neck cancer patients. Recently, dose adaptation (or adaptive radiotherapy) has been proposed as a novel concept to enhance the therapeutic ratio of head and neck radiotherapy, facilitated in part by the onset of molecular and functional imaging. These contemporary imaging techniques have enabled visualisation of the spatial molecular architecture of the tumor. Daily cone-beam imaging, besides improving treatment accuracy, offers another unique angle to explore radiomics - a novel high throughput feature extraction and selection workflow, for adapting radiotherapy based on real-time tumor changes. Here, we review the existing evidence of molecular and functional imaging in head and neck cancers, as well as the current application of adaptive radiotherapy in the treatment of this tumor type. We propose that adaptive radiotherapy can be further exploited through a systematic application of molecular and functional imaging, including radiomics, at the different phases of planning and treatment., (Copyright © 2018 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Immunotherapy and radiation therapy (RT) have each demonstrated clinical success in the treatment of nasopharyngeal carcinoma (NPC) when utilized independently. Several characteristics of NPC make it particularly well suited for immunotherapeutic strategies, such as the association with viral infections like EBV and human papilloma virus (HPV), upregulation of PD-L1 expression, and the high number of tumor infiltrating lymphocytes. Immune checkpoint blockade is one such immunotherapeutic strategy that is gaining popularity rapidly. However, clinical benefit of immunotherapy using immune checkpoint inhibitors has been limited to only a small subset of patients with existing T cell responses. Additionally, they are frequently associated with dose-limiting immune-related toxicities. On the other hand, RT is a conventional strategy for NPC treatment, which has demonstrated high efficacy in local tumor control and has also been reported to exhibit immune modulatory effects. However, the abscopal effect of RT alone, i.e., the regression of distant metastases outside of the irradiation field, remains a rare phenomenon. Furthermore, RT treatment efficacy is also limited by radioresistance and radiation-related toxicities. Hence, the combination of RT and immunotherapy has the potential to improve treatment efficacy over either individual therapies alone. Here, we reviewed the clinical problem in locally advanced and recurrent/metastatic NPC, and discussed how combinatorial RT and immunotherapeutic strategies can be relevant to NPC treatment in each clinical scenario by examining the underlying mechanisms involved in the different strategies.

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 volume recurrence hazard ratio [HR], 1.01/mL increase [ P < .001], age recurrence 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 (Harrell's 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.

High-coverage whole-genome sequence studies have so far focused on a limited number of geographically restricted populations, or been targeted at specific diseases, such as cancer. Nevertheless, the availability of high-resolution genomic data has led to the development of new methodologies for inferring population history and refuelled the debate on the mutation rate in humans. Here we present the Estonian Biocentre Human Genome Diversity Panel (EGDP), a dataset of 483 high-coverage human genomes from 148 populations worldwide, including 379 new genomes from 125 populations, which we group into diversity and selection sets. We analyse this dataset to refine estimates of continent-wide patterns of heterozygosity, long- and short-distance gene flow, archaic admixture, and changes in effective population size through time as well as for signals of positive or balancing selection. We find a genetic signature in present-day Papuans that suggests that at least 2% of their genome originates from an early and largely extinct expansion of anatomically modern humans (AMHs) out of Africa. Together with evidence from the western Asian fossil record, and admixture between AMHs and Neanderthals predating the main Eurasian expansion, our results contribute to the mounting evidence for the presence of AMHs out of Africa earlier than 75,000 years ago., Competing Interests: The authors declare no competing financial interests.

Epidemiological trends during the past decade suggest that although incidence of nasopharyngeal carcinoma is gradually declining, even in endemic regions, mortality from the disease has fallen substantially. This finding is probably a result of a combination of lifestyle modification, population screening coupled with better imaging, advances in radiotherapy, and effective systemic agents. In particular, intensity-modulated radiotherapy has driven the improvement in tumour control and reduction in toxic effects in survivors. Clinical use of Epstein-Barr virus (EBV) as a surrogate biomarker in nasopharyngeal carcinoma continues to increase, with quantitative assessment of circulating EBV DNA used for population screening, prognostication, and disease surveillance. Randomised trials are investigating the role of EBV DNA in stratification of patients for treatment intensification and deintensification. Among the exciting developments in nasopharyngeal carcinoma, vascular endothelial growth factor inhibition and novel immunotherapies targeted at immune checkpoint and EBV-specific tumour antigens offer promising alternatives to patients with metastatic disease., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: It has been established that combined chemoradiotherapy treatment benefits selected patients with stage III Non Small Cell Lung Cancer (NSCLC). However, locoregional recurrence still poses a problem. The addition of surgery as the third modality may provide a possible solution. We report our experience of using the triple-modality approach in this group of patients., Materials and Methods: This is a retrospective review of 33 patients with stage III NSCLC treated between 1997 and 2005. Patients have good performance status and no significant weight loss. There were 26 males (79 %) with median age of 63 years (range, 43 to 74) and median follow-up of 49 months. Seventy-six percent had Stage IIIA disease. Chemotherapy consisted of paclitaxel at 175 mg/m2 over 3 hours followed by carboplatin at AUC of 5 over 1 hour. Thoracic radiotherapy was given concurrently with the second and third cycles of chemotherapy. All patients received 50 Gray in 25 fractions over 5 weeks., Results: The main toxicities were grade 3/4 neutropenia (30%), grade 3 infection (15 %) and grade 3 oesophagitis (9%). Twenty-five patients (76%) underwent surgery. Of the 8 who did not undergo surgery, 1 was deemed medically unfit after induction chemoradiotherapy and 4 had progressive disease; 3 declined surgery. Nineteen patients (58 %) had lobectomy and 6 had pneumonectomy. The median overall survival was 29.9 months and 12 patients are still in remission., Conclusion: The use of the triplemodality approach is feasible, with an acceptable tolerability and resectability rate in this group of patients.