Intra-patient and inter-patient comparisons of DNA damage response biomarkers in Nasopharynx Cancer (NPC): analysis of NCC0901 randomised controlled trial of induction chemotherapy in locally advanced NPC.

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. G0 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 %FLICA0Gy and %FLICA8Gy 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 %FLICAbackground-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.

Longitudinal post-radiotherapy plasma Epstein-Barr virus DNA trends inform on optimal risk stratification in endemic nasopharyngeal carcinoma.

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 HR1-264 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 DNA8-12w versus 0.654 (95 %CI: 0.542-0.765) for stage + EBV DNA0-2w. 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.

The impact of the COVID-19 pandemic on nasopharyngeal carcinoma patients - a national cancer centre experience.

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.

18F-FMISO PET-guided dose escalation with multifield optimization intensity-modulated proton therapy in nasopharyngeal carcinoma.

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 cm3 (range .9-11.9cm3 ). 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.

Phase II study of nimotuzumab (TheraCim-hR3) concurrent with cisplatin/radiotherapy in patients with locally advanced head and neck squamous cell carcinoma.

BACKGROUND: The efficacy of a combination of nimotuzumab, a humanized monoclonal antibody to the epidermal growth factor receptor, with chemoradiation in locally advanced head and neck squamous cell carcinoma (HNSCC) was evaluated in a phase II study. METHODS: Patients with stage III/IV HNSCC received 3-weekly cisplatin 100 mg/m2 for three cycles and weekly nimotuzumab 200 mg for 8 weeks concurrently with radiotherapy. Primary endpoint was best overall response (BOR) and secondary endpoint was progression-free survival (PFS). RESULTS: Thirty-seven patients were included; the majority were Chinese (76%), male (89%), and had stage IVA/IVB HNSCC (92%). BOR of complete and partial response was seen in 22/37 (59%) and 10/37 (27%) patients, respectively. Median PFS was 17.5 months (95% CI: 11.1-54.5) and 3-year PFS was 40.4% (95% CI: 24.3-55.9). The frequency and type of adverse events observed were similar to standard chemoradiation. CONCLUSION: The combination of nimotuzumab with cisplatin and radiotherapy was safe and achieved high response rates in HNSCC.

Association of Clinicopathologic and Molecular Tumor Features With Recurrence in Resected Early-Stage Epidermal Growth Factor Receptor-Positive Non-Small Cell Lung Cancer.

Importance: The recently published ADAURA study has posed a significant dilemma for clinicians in selecting patients for adjuvant osimertinib. Risk factors for recurrence in early-stage epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) also remain undefined. Objective: To determine clinicopathologic characteristics and recurrence patterns of resected early-stage EGFR-positive NSCLC, using wildtype EGFR as a comparator cohort, and identify features associated with recurrence. Design, Setting, and Participants: This is a cohort study including patients diagnosed with AJCC7 Stage IA to IIIA NSCLC between January 1, 2010, and June 30, 2018, who underwent curative surgical procedures at a specialist cancer center in Singapore. The cutoff for data analysis was October 15, 2020. Patient demographic characteristics, treatment history, and survival data were collated. In exploratory analysis, whole-exome sequencing was performed in a subset of 86 patients. Data were analyzed from September 3, 2020, to June 6, 2021. Exposures: Adjuvant treatment was administered per investigator's discretion. Main Outcomes and Measures: The main outcome was 2-year disease-free survival (DFS). Results: A total of 723 patients were included (389 patients with EGFR-positive NSCLC; 334 patients with wildtype EGFR NSCLC). There were 366 women (50.6%) and 357 men (49.4%), and the median (range) age was 64 (22-88) years. A total of 299 patients (41.4%) had stage IA NSCLC, 155 patients (21.4%) had stage IB NSCLC, 141 patients (19.5%) had stage II NSCLC, and 125 patients (17.3%) had stage IIIA NSCLC. Compared with patients with wildtype EGFR NSCLC, patients with EGFR-positive NSCLC were more likely to be women (106 women [31.7%] vs 251 women [64.5%]) and never smokers (121 never smokers [36.2%] vs 317 never smokers [81.5%]). At median (range) follow up of 46 (0-123) months, 299 patients (41.4%) had cancer recurrence. There was no statistically significant difference in 2-year DFS for EGFR-positive and wildtype EGFR NSCLC (70.2% [95% CI, 65.3%-74.5%] vs 67.6% [95% CI, 62.2%-72.4%]; P = .70), although patients with EGFR-positive NSCLC had significantly better 5-year overall survival (77.7% [95% CI, 72.4%-82.1%] vs 66.6% [95% CI, 60.5%-72.0%]; P = .004). Among patients with EGFR-positive NSCLC, 2-year DFS was 81.0% (95% CI, 74.0%-86.3%) for stage IA, 78.4% (95% CI, 68.2%-85.6%) for stage IB, 57.1% (95% CI, 43.7%-68.4%) for stage II, and 46.6% (95% CI, 34.7%-57.7%) for stage IIIA. Overall, 5-year DFS among patients with stage IB through IIIA was 37.2% (95% CI, 30.1%-44.3%). Sites of disease at recurrence were similar between EGFR-positive and wildtype EGFR NSCLC, with locoregional (64 patients [16.5%] vs 56 patients [16.8%]), lung (41 patients [10.5%] vs 40 patients [12.0%]), and intracranial (37 patients [9.5%] vs 22 patients [6.6%]) metastases being the most common. A risk estimation model incorporating genomic data and an individual patient nomogram using clinicopathologic features for stage I EGFR-positive NSCLC was developed to improve risk stratification. Conclusions and Relevance: This cohort study found that recurrence rates were high in early-stage EGFR-positive NSCLC including stage IA, yet 37.2% of patients with stage IB through IIIA were cured without adjuvant osimertinib. Further studies are needed to elucidate individualized surveillance and adjuvant treatment strategies for early-stage EGFR-positive NSCLC.

Baseline Plasma EGFR Circulating Tumour DNA Levels in a Pilot Cohort of EGFR-Mutant Limited-Stage Lung Adenocarcinoma Patients Undergoing Radical Lung Radiotherapy.

The use of circulating cell-free tumour DNA (ctDNA) is established in metastatic lung adenocarcinoma to detect and monitor sensitising EGFR mutations. In early-stage disease, there is very little data supporting its role as a potential biomarker. We report on a prospective cohort of 9 limited-stage EGFR mutant lung cancer patients who were treated with radical radiotherapy. We looked at baseline plasma EGFR ctDNA and noted the detection rates to be higher in locally advanced disease. At a median follow-up of 13.5 months, an association between a detectable pre-radiotherapy plasma EGFR ctDNA and early tumour relapse (155 days vs. NR, p = 0.004) was noted. One patient with persistent plasma EGFR ctDNA predated radiological progression. The role of ctDNA in early-stage lung cancer is developing. Plasma EGFR ctDNA could be a useful biomarker in lung cancer patients undergoing radical treatments for staging, prognostication, and follow-up. These preliminary findings should be explored in larger studies.

Phenotypic and functional alterations of Vgamma2Vdelta2 T cell subsets in patients with active nasopharyngeal carcinoma.

INTRODUCTION: Human Vgamma2Vdelta2 T cells play important role in immunity to infection and cancer by monitoring self and foreign isoprenoid metabolites with their gammadelta T cell antigen receptors. Like CD4 and CD8 alphabeta T cells, adult peripheral Vgamma2Vdelta2 T cells represent a pool of heterogeneous cells with distinct functional capabilities. PURPOSE: The aim of this study was to characterize the phenotypes and functions of various Vgamma2Vdelta2 T cell subsets in patients with nasopharyngeal carcinoma (NPC). We sought to develop a better understanding of the role of these cells during the course of disease and to facilitate the development of immunotherapeutic strategies against NPC. RESULTS: Although similar total percentages of peripheral blood Vgamma2Vdelta2 T cells were found in both NPC patients and normal donors, Vgamma2Vdelta2 T cells from NPC patients showed decreased cytotoxicity against tumor cells whereas Vgamma2Vdelta2 T cells from normal donors showed potent cytotoxicity. To investigate further, we compared the phenotypic characteristics of Vgamma2Vdelta2 T cells from 96 patients with NPC and 54 healthy controls. The fraction of late effector memory Vgamma2Vdelta2 T cells (T(EM RA)) was significantly increased in NPC patients with corresponding decreases in the fraction of early memory Vgamma2Vdelta2 T cells (T(CM)) compared with those in healthy controls. Moreover, T(EM RA) and T(CM) Vgamma2Vdelta2 cells from NPC patients produced significantly less IFN-gamma and TNF-alpha, potentially contributing to their impaired cytotoxicity. Radiotherapy or concurrent chemo-radiotherapy further increased the T(EM RA) Vgamma2Vdelta2 T cell population but did not correct the impaired production of IFN-gamma and TNF-alpha observed for T(EM RA) Vgamma2Vdelta2 T cells. CONCLUSION: We have identified distinct alterations in the Vgamma2Vdelta2 T cell subsets of patients with NPC. Moreover, the overall cellular effector function of gammadelta T cells is compromised in these patients. Our data suggest that the contribution of Vgamma2Vdelta2 T cells to control NPC may depend on the activation state and differentiation of these cells.

Clinical and dosimetric predictors of physician and patient reported xerostomia following intensity modulated radiotherapy for nasopharyngeal cancer - A prospective cohort analysis.

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.

Comparison of radiomics tools for image analyses and clinical prediction in nasopharyngeal carcinoma.

OBJECTIVE: Radiomics pipelines have been developed to extract novel information from radiological images, which may help in phenotypic profiling of tumours that would correlate to prognosis. Here, we compared two publicly available pipelines for radiomics analyses on head and neck CT and MRI in nasopharynx cancer (NPC). METHODS AND MATERIALS: 100 biopsy-proven NPC cases stratified by T- and N-categories were enrolled in this study. Two radiomics pipeline, Moddicom (v. 0.51) and Pyradiomics (v. 2.1.2) were used to extract radiomics features of CT and MRI. Segmentation of primary gross tumour volume was performed using Velocity v. 4.0 by consensus agreement between three radiation oncologists. Intraclass correlation between common features of the two pipelines was analysed by Spearman's rank correlation. Unsupervised hierarchical clustering was used to determine association between radiomics features and clinical parameters. RESULTS: We observed a high proportion of correlated features in the CT data set, but not for MRI; 76.1% (51 of 67 common between Moddicom and Pyradiomics) of CT features and 28.6% (20 of 70 common) of MRI features were significantly correlated. Of these, 100% were shape-related for both CT and MRI, 100 and 23.5% were first-order-related, 61.9 and 19.0% were texture-related, respectively. This interpipeline heterogeneity affected the downstream clustering with known prognostic clinical parameters of cTN-status and GTVp. Nonetheless, shape features were the most reproducible predictors of clinical parameters among the different radiomics modules. CONCLUSION: Here, we highlighted significant heterogeneity between two publicly available radiomics pipelines that could affect the downstream association with prognostic clinical factors in NPC. ADVANCES IN KNOWLEDGE: The present study emphasized the broader importance of selecting stable radiomics features for disease phenotyping, and it is necessary prior to any investigation of multicentre imaging datasets to validate the stability of CT-related radiomics features for clinical prognostication.

Are heart doses associated with survival in patients with non-small cell lung cancer who received post-operative thoracic radiotherapy?: A national population-based study.

The aim of this retrospective national cohort study is to assess the association between various radiation heart dosimetric parameters (RHDPs), acute myocardial infarct (AMI) and overall survival (OS) outcomes in non-small cell lung cancer (NSCLC) patients treated with post-operative thoracic radiotherapy (PORT) using contemporary radiation techniques.We identified patients with stage I to III NSCLC treated with PORT at the 2 national cancer institutions from 2007 to 2014. We linked their electronic medical records to the national AMI and death registries. Univariable Cox regression was performed to assess the association between various RHDPs, AMI, and OS.We included 43 eligible patients with median follow-up of 36.6 months. Median age was 64 years. Majority of the patients had pathological stage III disease (72%). Median prescription dose was 60Gy. Median mean heart dose (MHD) was 9.4Gy. There were no AMI events. The 5-year OS was 34%. Univariable Cox regression showed that age was significantly associated with OS (hazard ratio, 1.06; 95% confidence interval, 1.01 to 1.10; P = .008). Radiation heart doses, including MHD, volume of heart receiving at least 5, 25, 30, 40, 50Gy and dose to 30% of heart volume, were not significantly associated with OS.There is insufficient evidence to conclude that RHDPs are associated with OS for patients with NSCLC treated with PORT in this study. Studies with larger sample size and longer term follow-up are needed to assess AMI outcome.

Induction concurrent chemoradiotherapy using Paclitaxel and Carboplatin combination followed by surgery in locoregionally advanced non-small cell lung cancer--Asian experience.

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.

Adoption of prophylactic cranial irradiation (PCI) for extensive stage small cell lung cancer (ES-SCLC): a population based outcome study.

BACKGROUND: The survival benefit of PCI in ES-SCLC reported by a European randomized trial (RCT) in 2007 was not replicated by a Japanese RCT published in 2017. This study aimed to evaluate the uptake of PCI before and after publication of the European RCT and its association with survival in ES-SCLC. METHODS: We identified eligible patients in the only two Singapore national cancer centres from 2003 to 2010. We linked their electronic medical records to the national death registry. We described the utilization of PCI in patients diagnosed from 2003 to 2006 (pre-adoption cohort) with patients diagnosed from 2007 to 2010 (post-adoption cohort). We performed univariable and multivariable Cox regression analysis to assess the association between PCI and survival. RESULTS: We identified 224 patients with ES-SCLC with no brain metastases. Among the 71 patients who had at least stable disease after first line chemotherapy, there was an increase in the use of PCI from the period 2007 to 2010 compared with 2003 to 2006 (32% versus 10%, P = 0.044). PCI was associated with improved OS (hazard ratio 0.22, 95% CI 0.10 to 0.47, P < 0.001) compared to no PCI in the multivariable analysis. CONCLUSION: There was an increase in the adoption of PCI for ES-SCLC since 2007. PCI was associated with improved survival in patients who did not have mandatory MRI brain imaging prior to PCI and had stable disease or better after first line chemotherapy, suggesting that the results of the European RCT are reproducible in the real-world practice.

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 (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.

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.

Differences between small-cell lung cancer and non-small-cell lung cancer among tobacco smokers.

It is known that smoking increases the risk for all histological subtypes of lung cancer. To date, the factors that determine why some patients develop small-cell lung cancer (SCLC) while others develop non-small-cell lung cancer (NSCLC) remain unknown. We compared the characteristics of 774 smokers with SCLC and NSCLC diagnosed during the period January 1999 till December 2002. Multivariate logistic regression was used to estimate the odds ratio (OR) with 95% CI. Testing of linear trend across categories of pack-years was also conducted. Six hundred and sixty-five NSCLC were compared to 109 SCLC. Among SCLC, there were significantly more females (20.2% versus 12.8%), current-smokers (81.7% versus 71.9%) as well as smokers who had smoked more than 40 pack-years (75.6% versus 50.3%). Comparing SCLC with NSCLC among the men only, having smoked more than 40 pack-years was associated with a significantly elevated odds ratio (OR) of 3.71 of developing SCLC (95% CI, 1.05-13.1; p=0.041). There was a decreasing trend in OR with increasing smoking cessation period. When comparing SCLC with adenocarcinoma, the women had a higher OR of 2.37 of developing SCLC (95% CI, 1.05-5.31; p=0.037) compared to the men. Our findings suggest that cumulative smoking exposure in terms of pack-years smoked is an important determining factor for the preferred development of SCLC among smokers.

Radical radiotherapy in stage I non-small cell lung cancer (NSCLC)--Singapore National Cancer Centre experience.

INTRODUCTION: The aim of this study was to assess the outcome of radical treatment for stage I non-small cell lung cancer (NSCLC) with external beam radiation therapy. MATERIALS AND METHODS: A retrospective series of 23 patients with stage I NSCLC treated radically with radiotherapy from September 1997 to December 2004 at the National Cancer Centre, Singapore. Eighteen patients had 3D conformal radiotherapy and 5 patients had 2D planning. The median radiation dose delivered was 55 Gy (range, 50 to 67.5 in 20 to 33 fractions). The estimated median BED(10) was 63.9 Gy (range, 57.6 to 70.1). Complete response (CR) rates, overall survival and cause-specific survival rates were analysed for evaluation of treatment results. Local regional failure was defined as disease in the ipsilateral lung and entire mediastinum. Recurrence at the contralateral lung and other distal organs was defined as distant metastases. Survival data were calculated using the Kaplan-Meier method and tested for significance with log-rank statistics. RESULTS: A total of 23 patients (16 males, 7 females) with a median age of 73 years (range, 45 to 88) were analysed. Six (26%) had stage IA and 17 (74%) had stage IB disease. Eleven patients refused surgery and 12 patients were medically inoperable. The median follow-up was 18.9 months (range, 6.2 to 117.4). The overall survival at 2 years and 3 years was 54.7% and 24.3% respectively. The overall cause-specific survival was 57.4% at 2 years and 25.6% at 3 years. Radiological CR was obtained in 6/23 patients (26%) and the median survival was 24.8 months as compared to 20 months in patients who attained partial response (PR) or unknown response (P = 0.24). The median survival for 12 patients who received a BED(10) of > or =63.9Gy was not reached as compared to 20 months in 11 patients with BED(10) of <63.9 Gy (P = 0.03). Sixteen patients died, 14 due to disease recurrence or progression and 2 of unrelated causes. Seven patients (29.2%) remained alive. The longest surviving patient had a follow-up time of 117.4 months. Four of these 7 patients were disease-free and 3 were alive with disease (2 with bone metastases and 1 with recurrence in the primary site). CONCLUSION: Our data are consistent with the reported literature for stage I NSCLC treated with radical radiotherapy. Patients who received a higher dose of radiation have a better outcome. The 3-year cause-specific survival of 25.6% is less than ideal and further investigations into dose escalation with modern radiotherapy techniques and perhaps the addition of chemotherapy or new targeted agents to radiation are warranted to improve the outcome.

Survival of small-cell lung cancer and its determinants of outcome in Singapore.

INTRODUCTION: The survival and epidemiology of small-cell lung cancer (SCLC) in Singapore has not been described. We aim to present the characteristics as well as determine the survival outcome and important prognostic factors for SCLC patients. MATERIALS AND METHODS: A retrospective analysis of SCLC patients diagnosed from 1999 to 2002 was conducted at the Outram campus, Singapore. Clinical characteristics and treatment data were obtained from case records and survival data were checked with the registry of births and deaths on 30 May 2005. RESULTS: One hundred and eleven patients were analysed. There were 38 (34.2%) limited-disease (LD) patients and 73 (65.8%) extensive-disease (ED) patients. The majority were current or former smokers (94.7% among LD and 94.5% among ED). More patients with LD had good performance status (92% versus 63%, P = 0.0003) and were treated with combined chemotherapy and radiotherapy (82% versus 48%, P = 0.012). The median survival time of LD patients treated with curative chemoradiotherapy was 14.2 months (95% CI, 10.96 to 17.44). Those given prophylactic cranial irradiation had a median survival time of 16.9 months (95% CI, 11.83 to 21.97). For ED patients, the median survival time was 8.17 months (95%CI, 5.44 to 10.89). None of the factors analysed were significant prognostic factors for LD patients while performance status and type of treatment given were significant among ED patients. CONCLUSIONS: We found that the characteristics and survival of SCLC patients in Singapore are fairly similar to that of other countries.

Thyroid V40 Predicts Primary Hypothyroidism After Intensity Modulated Radiation Therapy for Nasopharyngeal Carcinoma.

PURPOSE: To investigate the various clinical and thyroid dosimetric parameters that could predict the risk of primary hypothyroidism (HT) after intensity modulated radiation therapy (IMRT) for nasopharyngeal carcinoma (NPC) and to determine useful thyroid dose constraints to guide radiation therapy planning. METHODS AND MATERIALS: From September 2009 to August 2012, 102 clinically euthyroid NPC patients were included in this study. All patients were treated with IMRT and randomized to induction chemotherapy followed by concurrent chemo-IMRT or concurrent chemo-IMRT alone. Thyroid function was evaluated by measuring thyroid-stimulating hormone and free thyroxine at each annual follow-up visit. Various clinical and dosimetric parameters (eg, V40 [percentage of thyroid volume receiving >40 Gy]) were obtained. Univariate and multivariate logistic regression analyses were performed to identify predictors of HT. RESULTS: Median follow-up was 48.8 months. Among the 102 patients, 44 (43.1%) developed HT within 2 years after radiation therapy. The median time to HT was 36.7 months (range, 24.9-49.0 months). The 1-year and 2-year cumulative incidence rates of HT were 33% and 44.5%, respectively. Univariate analysis revealed that younger age, early T stage, minimum dose to the thyroid gland, V40, and V45 were associated with HT. On multivariate analysis, younger age (P=.017), early T stage (P=.005), and V40 (P=.009) remained statistically significant. Patients with V40 > 85% had significantly higher cumulative incidence rates of HT than patients with V40 ≤ 85% (P=.007). CONCLUSIONS: Thyroid V40 is predictive of primary HT after IMRT for NPC, and V40 ≤ 85% can be a useful dose constraint to adopt during IMRT planning without compromising tumor coverage.

Improved Survival of Advanced Lung Cancer in Singapore Over the Past Decade.

INTRODUCTION: We reviewed changes in clinical characteristics, treatment and survival of lung cancer patients in Singapore over the past decade. MATERIALS AND METHODS: We reviewed all primary lung cancer cases from January 2004 to December 2013. Basic demographic, clinical and treatment data were extracted from the database. Overall survival (OS) was calculated using Kaplan-Meier method; survival curves were compared using log-rank test. Linear regression trend lines were estimated using least squares approach, and Cox regression analyses were performed to identify prognostic factors. RESULTS: Among 6006 lung cancer patients, the median age was 68 years old, 65% were males, 88% were Chinese, 92% had non-small-cell lung cancer and 76% had advanced stage IIIB/IV. There were proportionally more adenocarcinomas diagnosed over the years, while that of squamous cell carcinoma (SCC) and small-cell-lung cancer (SCLC) have remained stable. The median OS of all patients increased from 9.2 months in 2004 to 11.5 months in 2013. This survival improvement was statistically significant among patients with stage IIIB/IV (6.7 to 8.7 months; P = 0.005) and adenocarcinoma (12.7 to 15.4 months; P = 0.041). There was no improvement in median OS for SCC or SCLC. The use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI) (hazard ratio [HR] 0.68; 95% CI, 0.63 to 0.73) and pemetrexed (HR, 0.69; 95% CI, 0.63 to 0.76) were significantly associated with improved OS. CONCLUSION: Survival of patients with advanced stage IIIB/IV lung adenocarcinoma has improved over the past decade, and is potentially associated with the use of EGFR TKI and pemetrexed.