Role of chemotherapy in patients with nasopharynx carcinoma treated with radiotherapy (MAC-NPC): an updated individual patient data network meta-analysis.

BACKGROUND: The meta-analysis of chemotherapy for nasopharynx carcinoma (MAC-NPC) collaborative group previously showed that the addition of adjuvant chemotherapy to concomitant chemoradiotherapy had the highest survival benefit of the studied treatment regimens in nasopharyngeal carcinoma. Due to the publication of new trials on induction chemotherapy, we updated the network meta-analysis. METHODS: For this individual patient data network meta-analysis, trials of radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma that completed accrual before Dec 31, 2016, were identified and updated individual patient data were obtained. Both general databases (eg, PubMed and Web of Science) and Chinese medical literature databases were searched. Overall survival was the primary endpoint. A frequentist network meta-analysis approach with a two-step random effect stratified by trial based on hazard ratio Peto estimator was used. Global Cochran Q statistic was used to assess homogeneity and consistency, and p score to rank treatments, with higher scores indicating higher benefit therapies. Treatments were grouped into the following categories: radiotherapy alone, induction chemotherapy followed by radiotherapy, induction chemotherapy without taxanes followed by chemoradiotherapy, induction chemotherapy with taxanes followed by chemoradiotherapy, chemoradiotherapy, chemoradiotherapy followed by adjuvant chemotherapy, and radiotherapy followed by adjuvant chemotherapy. This study is registered with PROSPERO, CRD42016042524. FINDINGS: The network comprised 28 trials and included 8214 patients (6133 [74·7%] were men, 2073 [25·2%] were women, and eight [0·1%] had missing data) enrolled between Jan 1, 1988, and Dec 31, 2016. Median follow-up was 7·6 years (IQR 6·2-13·3). There was no evidence of heterogeneity (p=0·18), and inconsistency was borderline (p=0·10). The three treatments with the highest benefit for overall survival were induction chemotherapy with taxanes followed by chemoradiotherapy (hazard ratio 0·75; 95% CI 0·59-0·96; p score 92%), induction chemotherapy without taxanes followed by chemoradiotherapy (0·81; 0·69-0·95; p score 87%), and chemoradiotherapy followed by adjuvant chemotherapy (0·88; 0·75-1·04; p score 72%), compared with concomitant chemoradiotherapy (p score 46%). INTERPRETATION: The inclusion of new trials modified the conclusion of the previous network meta-analysis. In this updated network meta-analysis, the addition of either induction chemotherapy or adjuvant chemotherapy to chemoradiotherapy improved overall survival over chemoradiotherapy alone in nasopharyngeal carcinoma. FUNDING: Institut National du Cancer and Ligue Nationale Contre le Cancer.

A Novel Tumor Staging System Incorporating Tumor Regression Grade (TRG) With Lymph Node Status (ypN-Category) Results in Better Prognostication Than ypTNM Stage Groups After Neoadjuvant Therapy for Esophageal Squamous Cell Carcinoma.

OBJECTIVE: This study aims at constructing a staging system incorporating tumor regression grade and ypN-category (TRG-N) in patients with neoadjuvant therapy before esophagectomy. It is hypothesized that this would prognosticate better than the current American Joint Committee on Cancer (AJCC) postneoadjuvant therapy (ypTNM) stage groups. BACKGROUND: Conventional pathological T-category is defined by the depth of invasion, and may lose prognostic relevance after neoadjuvant therapy. TRG defines treatment response by the degree of tumor regression, and when combined with ypN-category may be more prognostic than AJCC postneoadjuvant therapy (ypTNM) stage groups. METHODS: A training cohort of 210 patients with esophageal squamous cell carcinoma and who had had neoadjuvant therapy before esophagectomy were studied. A validation cohort comprised 107 patients from another hospital. Resected esophagi were assessed by ypT-category and TRG, the latter assigned according to the Becker 4-tier system. These categories were grouped with ypN-category into a TRG-N system. Patients' survival was compared between the current AJCC postneoadjuvant therapy (ypTNM) stage groups and this TRG-N system. RESULTS: In the training cohort, 5-year survival rates according to ypTNM stage I, II, IIIA, IIIB, and IVA were 53%, 39.4%, 47%, 18.3%, and 0%, respectively. For TRG-N stages I, II, III, and IV, the respective figures were 59.6%, 43.5%, 23.8%, and 15.6%. TRG-N stage showed better fit in survival than ypTNM stage groups, indicated by lower Akaike Information Criteria (AIC) and Bayesian Information Criterion values. Similar results were found in the validation cohort. Multivariate analysis showed that TRG-N stage ( P =0.02), age ( P =0.006), and sex ( P =0.005) were independent prognostic factors. CONCLUSION: TRG-N stage shows better prognostication than the AJCC postneoadjuvant therapy (ypTNM) stage groups.

NPC-0501 trial on the value of changing chemoradiotherapy sequence, replacing 5-fluorouracil with capecitabine, and altering fractionation for patients with advanced nasopharyngeal carcinoma.

BACKGROUND: A current recommendation for the treatment of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy (RT) with concurrent cisplatin followed by adjuvant cisplatin and 5-fluorouracil (PF). This randomized NPC-0501 trial evaluated the therapeutic effect of changing to an induction-concurrent sequence or accelerated-fractionation sequence, and/or replacing 5-fluorouracil with capecitabine (X). METHODS: Patients with American Joint Committee on Cancer/International Union Against Cancer stage III to stage IVB NPC initially were randomly allocated to 1 of 6 treatment arms (6-arm full-randomization cohort). The protocol was amended in 2009 to permit centers to opt out of randomization regarding fractionation (3-arm chemotherapy cohort). RESULTS: A total of 803 patients were accrued (1 of whom was nonevaluable) from 2006 to 2012. Based on the overall comparisons, neither changing the chemotherapy sequence nor accelerated fractionation improved treatment outcome. However, secondary analyses demonstrated that when adjusted for RT parameters and other significant factors, the induction-concurrent sequence, especially the induction-PX regimen, achieved significant improvements in progression-free survival (PFS) and overall survival. Efficacy varied among different RT groups: although no impact was observed in the accelerated-fractionation group and the 3-arm chemotherapy cohort, a comparison of the induction-concurrent versus concurrent-adjuvant sequence in the conventional-fractionation group demonstrated a significant benefit in PFS (78% vs 62% at 5 years; P = .015) and a marginal benefit in overall survival (84% vs 72%; P = .042) after adjusting for multiple comparisons. Comparison of the induction-PX versus the adjuvant-PF regimen demonstrated better PFS (78% vs 62%; P = .027) without an increase in overall late toxicity. CONCLUSIONS: For patients irradiated using conventional fractionation, changing the chemotherapy sequence from a concurrent-adjuvant to an induction-concurrent sequence, particularly using induction cisplatin and capecitabine, potentially could improve efficacy without an adverse impact on late toxicity. However, further validation is needed for confirmation of these findings.

Neoadjuvant Chemoradiotherapy Using Cisplatin and 5-Fluorouracil (PF) Versus Carboplatin and Paclitaxel (CROSS Regimen) for Esophageal Squamous Cell Carcinoma (ESCC): A Propensity Score-matched Study.

OBJECTIVE: This study compared the efficacy of PF-based and CROSS-based neoadjuvant chemoradiotherapy for ESCC. BACKGROUND: PF-based regimen has been a standard regimen for ESCC, but it has been replaced by the CROSS regimen in the past few years, despite no prospective head-to-head comparative study has been performed. METHODS: This is a single center retrospective study. Records of all ESCC patients who have received neoadjuvant PF with 40 Gy radiotherapy in 20 daily fractions (PFRT Group) or CROSS with 41.4 Gy radiotherapy in 23 daily fractions (CROSS Group) during the period 2002 to 2019 were retrieved. Propensity score matching (1:1) was performed to minimize baseline differences. The primary and secondary endpoints were overall survival and clinicopathological response. Subgroup analysis ("CROSS Eligibility") was performed based on tumor length, cT-stage, cM-stage, age, and performance status. RESULTS: One hundred (out of 109) patients (CROSS group) and propensity score matched 100 (out of 210) patients (PFRT group) were included. Esophagectomy rates in CROSS and PFRT group were 69% and 76%, respectively (P = 0.268). R0 resection rates were 85.5% and 81.6% (P = 0.525) and the pathological complete remission rates were 24.6% and 35.5% (P = 0.154). By intention-to-treat, the median survival was 16.7 and 32.7 months (P = 0.083). For "CROSS Eligible subgroup," the median survival of the CROSS and PFRT group was 21.6 versus 44.9 months (P = 0.093). CONCLUSIONS: There is no statistically difference in survival or clinicopathological outcome between both groups, but the trend favors PFRT. Prospective head-to-head comparison and novel strategies to improve the outcomes in resectable ESCC are warranted.

High risk Epstein-Barr virus variants characterized by distinct polymorphisms in the EBER locus are strongly associated with nasopharyngeal carcinoma.

Whether certain variants of Epstein-Barr virus (EBV) are linked to the pathogenesis of nasopharyngeal carcinoma (NPC), which shows a marked geographic restriction, remains an unresolved issue. We performed a case-control study comparing genomic sequences of EBV isolated from saliva samples of 142 population carriers with those from primary tumour biopsies derived from 62 patients with NPC of Hong Kong. Cluster analysis discovered five EBV subgroups 1A-C and 2A-B amongst the population carriers in contrast to the predominance of 1A and -B in the majority of NPC. Genome-wide association study (GWAS) identified a panel of NPC-associated single nucleotide polymorphisms (SNPs) and indels in the EBER locus. The most significant polymorphism, which can be found in 96.8% NPC cases and 40.1% population carriers of Hong Kong, is a four-base-deletion polymorphism downstream of EBER2 (EBER-del) from coordinates 7188-7191 (p = 1.91 × 10-7 ). In addition, the predicted secondary structure of EBER2 is altered with likely functional consequence in nearly all NPC cases. Using the SNPs and indels associated with NPC, genetic risk score is assigned for each EBV variant. EBV variants with high genetic risk score are found to be much more prevalent in Hong Kong Chinese than individuals of other geographic regions and in NPC than other EBV-associated cancers. We conclude that high risk EBV variants with polymorphisms in the EBER locus, designated as HKNPC-EBERvar, are strongly associated with NPC. Further investigation of the biological function and potential clinical application of these newly identified polymorphisms in NPC and other EBV-associated cancers is warranted.

Hyperfractionation compared to standard fractionation in intensity-modulated radiation therapy for patients with locally advanced recurrent nasopharyngeal carcinoma.

We prospectively studied the efficacy and safety of hyperfractionated intensity-modulated radiation therapy (HF-IMRT) and compared to a historical cohort treated with standard fractionation (SF-IMRT) in patients with locally advanced recurrent (rT3-T4, rN0-N1, M0) nasopharyngeal carcinoma (NPC). Ten patients were treated with induction chemotherapy followed by HF-IMRT (64.8 Gy/54 fr/5.5 weeks) concurrent with weekly cisplatin. They were compared to another ten patients treated with induction chemotherapy followed by SF-IMRT (60 Gy/30 fr/6 weeks) concurrent with weekly cisplatin. After a median follow-up duration of 44.6 months, we demonstrated that the median local failure-free survival (LFFS) showed a trend in favor of HF-IMRT (28.2 vs. 16.6 months, p = 0.164). Overall survival (OS) (34.8 vs. 35.5 months, p = 0.603) was not different between the two groups. Treatment-related hemorrhage was slightly less with HF-IMRT (30.0 vs. 0 %), reaching marginal significance (p = 0.060). Judging from our study results, HF-IMRT offered a marginally better LFFS and an apparently more favorable toxicity profile compared to SF-IMRT in locally advanced recurrent NPC.

Efficacy and safety of afatinib in Chinese patients with EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) previously responsive to first-generation tyrosine-kinase inhibitors (TKI) and chemotherapy: comparison with historical cohort using erlotinib.

BACKGROUND: Afaitnib has shown anti-tumor activity against metastatic EGFR-mutated NSCLC after prior failure to first generation EGFR-TKI and chemotherapy. We prospectively evaluated the efficacy and safety of afatinib in Chinese patients who previously failed first-generation TKI and chemotherapy under a compassionate use program (CUP) and compared to the erlotinib cohort. METHODS: Patients who suffered from metastatic EGFR-mutated NSCLC previously responsive to first-generation TKI and chemotherapy received afatinib until progression, loss of clinical benefits or intolerable toxicity. Treatment response, survival and safety were evaluated and compared to the erlotinib cohort. RESULTS: Twenty-five and 28 patients received afatinib and erlotinib respectively. More patients in the afatinib group had worse performance status (ECOG 2) than the erlotinib group (p = 0.008). After a median follow-up of 12.1 months, afatinib demonstrated comparable objective response rate (ORR) (20.0% vs. 7.1%, p = 0.17) but significantly higher disease control rate (DCR) (68.0% vs. 39.3%, p = 0.04) compared to erlotinib. Median progression-free survival (PFS) (4.1 months [95% CI, 2.7-5.5 months] vs. 3.3 months [95% CI, 2.2-4.3 months], p = 0.97) and overall survival (OS) were not different between the two groups (10.3 months [95% CI, 7.5-13.0 months] vs. 10.8 months [95% CI, 7.4-14.2 months], p = 0.51). Multivariate analyses revealed that age ≤ 70 years and time to progression (TTP) ≥ 18 months for the 1st TKI therapy were prognostic of PFS (p = 0.006 and p = 0.008 respectively). Afatinib caused less rash (60.0% vs. 67.9%, p = 0.04) but more diarrhea (60.0% vs. 10.7%, p = 0.002) compared to erlotinib. CONCLUSION: Afatinib produced encouraging clinical efficacy as 2nd TKI therapy with manageable safety profiles in our Chinese patients after failure to another TKI and systemic chemotherapy. This study was registered at ClinicalTrials.gov (NCT02625168) on 3rd December 2015.

Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis.

BACKGROUND: A previous individual patient data meta-analysis by the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC) collaborative group to assess the addition of chemotherapy to radiotherapy showed that it improves overall survival in nasopharyngeal carcinoma. This benefit was restricted to patients receiving concomitant chemotherapy and radiotherapy. The aim of this study was to update the meta-analysis, include recent trials, and to analyse separately the benefit of concomitant plus adjuvant chemotherapy. METHODS: We searched PubMed, Web of Science, Cochrane Controlled Trials meta-register, ClinicalTrials.gov, and meeting proceedings to identify published or unpublished randomised trials assessing radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma and obtained updated data for previously analysed studies. The primary endpoint of interest was overall survival. All trial results were combined and analysed using a fixed-effects model. The statistical analysis plan was pre-specified in a protocol. All data were analysed on an intention-to-treat basis. FINDINGS: We analysed data from 19 trials and 4806 patients. Median follow-up was 7·7 years (IQR 6·2-11·9). We found that the addition of chemotherapy to radiotherapy significantly improved overall survival (hazard ratio [HR] 0·79, 95% CI 0·73-0·86, p<0·0001; absolute benefit at 5 years 6·3%, 95% CI 3·5-9·1). The interaction between treatment effect (benefit of chemotherapy) on overall survival and the timing of chemotherapy was significant (p=0·01) in favour of concomitant plus adjuvant chemotherapy (HR 0·65, 0·56-0·76) and concomitant without adjuvant chemotherapy (0·80, 0·70-0·93) but not adjuvant chemotherapy alone (0·87, 0·68-1·12) or induction chemotherapy alone (0·96, 0·80-1·16). The benefit of the addition of chemotherapy was consistent for all endpoints analysed (all p<0·0001): progression-free survival (HR 0·75, 95% CI 0·69-0·81), locoregional control (0·73, 0·64-0·83), distant control (0·67, 0·59-0·75), and cancer mortality (0·76, 0·69-0·84). INTERPRETATION: Our results confirm that the addition of concomitant chemotherapy to radiotherapy significantly improves survival in patients with locoregionally advanced nasopharyngeal carcinoma. To our knowledge, this is the first analysis that examines the effect of concomitant chemotherapy with and without adjuvant chemotherapy as distinct groups. Further studies on the specific benefits of adjuvant chemotherapy after concomitant chemoradiotherapy are needed. FUNDING: French Ministry of Health (Programme d'actions intégrées de recherche VADS), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.

Preliminary results of trial NPC-0501 evaluating the therapeutic gain by changing from concurrent-adjuvant to induction-concurrent chemoradiotherapy, changing from fluorouracil to capecitabine, and changing from conventional to accelerated radiotherapy fractionation in patients with locoregionally advanced nasopharyngeal carcinoma.

BACKGROUND: A current recommendation for locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy with concurrent cisplatin plus adjuvant cisplatin and fluorouracil (PF). In this randomized trial, the authors evaluated the potential therapeutic benefit from changing to an induction-concurrent chemotherapy sequence, replacing fluorouracil with oral capecitabine, and/or using accelerated rather than conventional radiotherapy fractionation. METHODS: Patients with stage III through IVB, nonkeratinizing NPC were randomly allocated to 1 of 6 treatment arms. The protocol was amended in 2009 to permit confining randomization to the conventional fractionation arms. The primary endpoint was progression-free survival. Secondary endpoints included overall survival and safety. RESULTS: In total, 803 patients were accrued, and 706 patients were randomly allocated to all 6 treatment arms. Comparisons of induction PF versus adjuvant PF did not indicate a significant improvement. Unadjusted comparisons of induction cisplatin and capecitabine (PX) versus adjuvant PF indicated a favorable trend in progression-free survival for the conventional fractionation arm (P = .045); analyses that were adjusted for other significant factors and fractionation reflected a significant reduction in the hazards of disease progression (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.36-0.80) and death (HR, 0.42; 95% CI, 0.25-0.70). Unadjusted comparisons of induction sequences versus adjuvant sequences did not reach statistical significance, but adjusted comparisons indicated favorable improvements by induction sequence. Comparisons of induction PX versus induction PF revealed fewer toxicities (neutropenia and electrolyte disturbance), unadjusted comparisons of efficacy were statistically insignificant, but adjusted analyses indicated that induction PX had a lower hazard of death (HR, 0.57; 95% CI, 0.34-0.97). Changing the fractionation from conventional to accelerated did not achieve any benefit but incurred higher toxicities (acute mucositis and dehydration). CONCLUSIONS: Preliminary results indicate that the benefit of changing to an induction-concurrent sequence remains uncertain; replacing fluorouracil with oral capecitabine warrants further validation in view of its convenience, favorable toxicity profile, and favorable trends in efficacy; and accelerated fractionation is not recommended for patients with locoregionally advanced NPC who receive chemoradiotherapy.

Sonographic appearance of thyroid glands in patients treated with intensity-modulated radiotherapy or conventional radiotherapy for nasopharyngeal carcinoma.

BACKGROUND: This study aimed to investigate the sonographic appearances of the thyroid glands in nasopharyngeal carcinoma (NPC) patients whose cervical lymph nodes were treated with conventional radiotherapy (RT) or intensity-modulated radiotherapy (IMRT). The post-RT sonographic appearances of the thyroid glands in NPC patients were also correlated with the thyroid function. METHODS: One hundred and three NPC patients who had completed RT of cervical lymph nodes using the anterior cervical field, 30 NPC patients who had completed RT of cervical lymph nodes using IMRT, and 61 healthy subjects were included in the study. Thyroid glands were sonographically assessed for their size, echogenicity, vascularity, and internal architecture. Thyroid function tests were also performed on each subject. RESULTS: In comparison with the patients with abnormal thyroid function, the thyroid glands of the patients with normal thyroid function tended to be homogeneous and to have greater volume and echogenicity index (p < 0.05). Compared with those of the healthy subjects, the thyroid glands of patients previously treated with IMRT and those treated with the anterior cervical field showed significantly lower thyroid volume, lower incidence and number of nodules, and higher vascularity index (p < 0.05). CONCLUSIONS: The patient's history of previous RT should be taken into consideration in the sonographic examination of the thyroid gland post-RT. © 2014 Wiley Periodicals, Inc. J Clin Ultrasound 43:210-223, 2015.

International Recommendations on Postoperative Management for Potentially Resectable Locally Recurrent Nasopharyngeal Carcinoma.

PURPOSE: Locally recurrent nasopharyngeal carcinoma (NPC) presents substantial challenges in clinical management. While postoperative re-irradiation (re-RT) has been acknowledged as a potential treatment option, standardized guidelines and consensus regarding the use of re-RT in this context are lacking. This article provides a comprehensive review and summary of international recommendations on postoperative management for potentially resectable locally recurrent NPC, with a special focus on postoperative re-RT. METHODS AND MATERIALS: A thorough search was conducted to identify relevant studies on postoperative re-RT for locally recurrent NPC. Controversial issues, including resectability criteria, margin assessment, indications for postoperative re-RT, and the optimal dose and method of re-RT, were addressed through a Delphi consensus process. RESULTS: The consensus recommendations emphasize the need for a clearer and broader definition of resectability, highlighting the importance of achieving clear surgical margins, preferably through an en bloc approach with frozen section margin assessment. Furthermore, these guidelines suggest considering re-RT for patients with positive or close margins. Optimal postoperative re-RT doses typically range around 60Gy, and hyperfractionation has shown promise in reducing toxicity. CONCLUSION: These guidelines aim to assist clinicians in making evidence-based decisions and improving patient outcomes in the management of potentially resectable locally recurrent NPC. By addressing key areas of controversy and providing recommendations on resectability, margin assessment, and re-RT parameters, these guidelines serve as a valuable resource for the clinical experts involved in the treatment of locally recurrent NPC. SUMMARY: This article provides international recommendations on postoperative management for potentially resectable locally recurrent nasopharyngeal carcinoma (NPC), with a special focus on postoperative re-irradiation (re-RT). The consensus guidelines highlight the importance of achieving clear surgical margins, suggest considering re-RT for patients with positive or close margins, recommend an optimal re-RT dose of around 60Gy, and propose the use of hyperfractionation to reduce toxicity. The aim is to improve patient outcomes in the management of resectable locally recurrent NPC.

Essential data variables for a minimum dataset for head and neck cancer trials and clinical research: HNCIG consensus recommendations and database.

The Head and Neck Cancer International Group (HNCIG) has undertaken an international modified Delphi process to reach consensus on the essential data variables to be included in a minimum database for HNC research. Endorsed by 19 research organisations representing 34 countries, these recommendations provide the framework to facilitate and harmonise data collection and sharing for HNC research. These variables have also been incorporated into a ready to use downloadable HNCIG minimum database, available from the HNCIG website.

Measurement invariance of the Functional Assessment of Cancer Therapy-Colorectal quality-of-life instrument among modes of administration.

OBJECTIVES: To test for the measurement invariance of the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) in patients with colorectal neoplasms between two modes of administration (self- and interviewer administrations). It is important to establish the measurement invariance of the FACT-C across different modes of administration to ascertain whether it is valid to pool FACT-C data collected by different modes or to assess each group separately. METHODS: A cross-sectional sample of 391 Chinese patients with colorectal neoplasms was recruited from specialist outpatient clinics between September 2009 and July 2010. Confirmatory factor analysis (CFA) was used to test the original five-factor model of the FACT-C on data collected by self- and interviewer administrations in single-group analysis. Multiple-group CFA was then used to compare the factor structure between the two modes of administration using chi-square tests and other goodness-of-fit statistics. RESULTS: The hypothesized five-factor model of FACT-C demonstrated good fit in each group. Configural invariance and metric invariance were fully supported in multiple-group CFA. Some item intercepts and their corresponding error variances were not identical between administration groups, suggesting evidence of partial strict factorial invariance. CONCLUSIONS: Our results confirmed that the five-factor structure of FACT-C was invariant in Chinese patients using both self- and interviewer administrations. It is appropriate to pool or compare data in the emotional well-being and colorectal cancer subscale scores collected by both administrations. Measurement invariance in three items, one from each of the other subscales, may be contaminated by response bias between modes of administration.

Quantifying variability of intrafractional target motion in stereotactic body radiotherapy for lung cancers.

In lung stereotactic body radiotherapy (SBRT), variability of intrafractional target motion can negate the potential benefits of four-dimensional (4D) treatment planning that aims to account for the dosimetric impacts of organ motion. This study used tumor motion data obtained from CyberKnife SBRT treatments to quantify the reproducibility of probability motion function (pmf) of 37 lung tumors. The reproducibility of pmf was analyzed with and without subtracting the intrafractional baseline drift from the original motion data. Statistics of intrafractional tumor motion including baseline drift, target motion amplitude and period, were also calculated. The target motion amplitude significantly correlates with variations (1SD) of motion amplitude and baseline drift. Significant correlation between treatment time and variations (1 SD) of motion amplitude was observed in anterior-posterior (AP) motion, but not in craniocaudal (CC) and left-right (LR) motion. The magnitude of AP and LR baseline drifts significantly depend on the treatment time, while the CC baseline drift does not. The reproducibility of pmf as a function of time can be well described by a two-exponential function with a fast and slow component. The reproducibility of pmf is over 60% for the CC motion and over 50% for the AP and LR motions when baseline variations were subtracted from the original motion data. It decreases to just over 30% for the CC motion and about 20% for the AP and LR motion, otherwise. 4D planning has obvious limitations due to variability of intrafractional target motion. To account for potential risks of overdosing critical organs, it is important to simulate the dosimetric impacts of intra- and interfractional baseline drift using population statistics obtained from SBRT treatments.

Evaluation of dose prediction error and optimization convergence error in four-dimensional inverse planning of robotic stereotactic lung radiotherapy.

Inverse optimization of robotic stereotactic lung radiotherapy is typically performed using relatively simple dose calculation algorithm on a single instance of breathing geometry. Variations of patient geometry and tissue density during respiration could reduce the dose accuracy of these 3D optimized plans. To quantify the potential benefits of direct four-dimensional (4D) optimization in robotic lung radiosurgery, 4D optimizations using 1) ray-tracing algorithm with equivalent path-length heterogeneity correction (4EPL(opt)), and 2) Monte Carlo (MC) algorithm (4MC(opt)), were performed in 25 patients. The 4EPL(opt) plans were recalculated using MC algorithm (4MC(recal)) to quantify the dose prediction errors (DPEs). Optimization convergence errors (OCEs) were evaluated by comparing the 4MC(recal) and 4MC(opt) dose results. The results were analyzed by dose-volume histogram indices for selected organs. Statistical equivalence tests were performed to determine the clinical significance of the DPEs and OCEs, compared with a 3% tolerance. Statistical equivalence tests indicated that the DPE and the OCE are significant predominately in GTV D98%. The DPEs in V20 of lung, and D2% of cord, trachea, and esophagus are within 1.2%, while the OCEs are within 10.4% in lung V20 and within 3.5% in trachea D2%. The marked DPE and OCE suggest that 4D MC optimization is important to improve the dosimetric accuracy in robotic-based stereotactic body radiotherapy, despite the longer computation time.

Dosimetric evaluation of four-dimensional dose distributions of CyberKnife and volumetric-modulated arc radiotherapy in stereotactic body lung radiotherapy.

Advanced image-guided stereotatic body lung radiotherapy techniques using volumetric-modulated arc radiotherapy (VMAT) with four-dimensional cone-beam computed tomography (4D CBCT) and CyberKnife with real-time target tracking have been clinically implemented by different authors. However, dosimetric comparisons between these techniques are lacking. In this study, 4D CT scans of 14 patients were used to create VMAT and CyberKnife treatment plans using 4D dose calculations. The GTV and the organs at risk (OARs) were defined on the end-exhale images for CyberKnife planning and were then deformed to the midventilation images (MidV) for VMAT optimization. Direct 4D Monte Carlo dose optimizations were performed for CyberKnife (4D(CK)). Four-dimensional dose calculations were also applied to VMAT plans to generate the 4D dose distributions (4D(VMAT)) on the exhale images for direct comparisons with the 4D(CK) plans. 4D(CK) and 4D(VMAT) showed comparable target conformity (1.31 ± 0.13 vs. 1.39 ± 0.24, p = 0.05). GTV mean doses were significantly higher with 4D(CK). Statistical differences of dose volume metrics were not observed in the majority of OARs studied, except for esophagus, with 4D(VMAT) yielding marginally higher D1% than 4D(CK). The normal tissue volumes receiving 80%, 50%, and 30% of the prescription dose (V80%, V50%, and V30%) were higher with 4D(VMAT), whereas 4D(CK) yielded slightly higher V10% in posterior lesions than 4D(VMAT). VMAT resulted in much less monitor units and therefore greater delivery efficiency than CyberKnife. In general, it was possible to produce dosimetrically acceptable plans with both techniques. The selection of treatment modality should consider the dosimetric results as well as the patient's tolerance of the treatment process specific to the SBRT technique.

Sonographic appearance of submandibular glands in patients treated with external beam radiotherapy for nasopharyngeal carcinoma.

PURPOSE: The purpose of this study was to investigate the sonographic (US) appearances of submandibular glands in patients with nasopharyngeal carcinoma after external beam radiotherapy (RT) and compare them with those of healthy subjects. METHODS: A total of 81 nasopharyngeal carcinoma patients treated with RT and 66 healthy subjects were recruited and underwent submandibular gland US. Bilateral submandibular glands were assessed for their size, echogenicity, echogenicity margin sharpness, and echotexture. RESULTS: The mean ± SD transverse dimension of submandibular glands in patients treated with RT (2.5 ± 0.4 cm) was significantly smaller than that of healthy subjects (3.3 ± 0.4 cm) (p < 0.05). Submandibular glands in patients treated with RT tended to be heterogeneous (72%) with hypoechoic areas (46%) and ill-defined margins (89%). However, there were no statistically significant differences in echogenicity and conspicuity of intraglandular ducts of submandibular glands between patients and healthy subjects. CONCLUSIONS: RT-induced changes of the submandibular glands were demonstrated on US.

Tissue tropism of swine influenza viruses and reassortants in ex vivo cultures of the human respiratory tract and conjunctiva.

The 2009 pandemic influenza H1N1 (H1N1pdm) virus was generated by reassortment of swine influenza viruses of different lineages. This was the first influenza pandemic to emerge in over 4 decades and the first to occur after the realization that influenza pandemics arise from influenza viruses of animals. In order to understand the biological determinants of pandemic emergence, it is relevant to compare the tropism of different lineages of swine influenza viruses and reassortants derived from them with that of 2009 pandemic H1N1 (H1N1pdm) and seasonal influenza H1N1 viruses in ex vivo cultures of the human nasopharynx, bronchus, alveoli, and conjunctiva. We hypothesized that virus which can transmit efficiently between humans replicated well in the human upper airways. As previously reported, H1N1pdm and seasonal H1N1 viruses replicated efficiently in the nasopharyngeal, bronchial, and alveolar epithelium. In contrast, representative viruses from the classical swine (CS) (H1N1) lineage could not infect human respiratory epithelium; Eurasian avian-like swine (EA) (H1N1) viruses only infected alveolar epithelium and North American triple-reassortant (TRIG) viruses only infected the bronchial epithelium albeit inefficiently. Interestingly, a naturally occurring triple-reassortant swine virus, A/SW/HK/915/04 (H1N2), with a matrix gene segment of EA swine derivation (i.e., differing from H1N1pdm only in lacking a neuraminidase [NA] gene of EA derivation) readily infected and replicated in human nasopharyngeal and bronchial epithelia but not in the lung. A recombinant sw915 with the NA from H1N1pdm retained its tropism for the bronchus and acquired additional replication competence for alveolar epithelium. In contrast to H1N1pdm, none of the swine viruses tested nor seasonal H1N1 had tropism in human conjunctiva. Recombinant viruses generated by swapping the surface proteins (hemagglutinin and NA) of H1N1pdm and seasonal H1N1 virus demonstrated that these two gene segments together are key determinants of conjunctival tropism. Overall, these findings suggest that ex vivo cultures of the human respiratory tract provide a useful biological model for assessing the human health risk of swine influenza viruses.

Investigation of four-dimensional (4D) Monte Carlo dose calculation in real-time tumor tracking stereotatic body radiotherapy for lung cancers.

PURPOSE: To investigate the dosimetric variations and radiobiological impacts as a consequence of delivering treatment plans of 3D nature in 4D manner based on the 4D Monte Carlo treatment planning framework implemented on Cyberknife. METHODS: Dose distributions were optimized on reference 3D images at end of exhale phase of a 4DCT dataset for 25 lung cancer patients treated with 60 Gy∕3Fx or 48 Gy∕4Fx. Deformable image registrations between individual 3DCT images to the reference 3DCT image in the 4DCT study were performed to interpolate doses calculated on multiple anatomical geometries back on to the reference geometry to compose a 4D dose distribution that included the tracking beam motion and organ deformation. The 3D and 4D dose distributions that were initially calculated with the equivalent path-length (EPL) algorithm (3D(EPL) dose and 4D(EPL) dose) were recalculated with the Monte Carlo algorithm (3D(MC) dose and 4D(MC) dose). Dosimetric variations of V(60Gy∕48Gy) and D(99) of GTV, mean doses to the lung and the heart and maximum dose (D(1)) of the spinal cord as a consequence of tracking beam motion in deforming anatomy, dose calculation algorithm, and both were quantified by the relative change from 4D(MC) to 3D(MC) doses, from 4D(MC) to 4D(EPL) doses, and from 4D(MC) to 3D(EPL) doses, respectively. RESULTS: Comparing 4D(MC) to 3D(EPL) plans, V(60Gy ∕ 48Gy) and D(99) of GTV decreased considerably by 13 ± 22% (mean ± 1SD) and 9.2 ± 5.5 Gy but changes of normal tissue doses were not more than 0.5 Gy on average. The generalized equivalent uniform dose (gEUD) and tumor control probability (TCP) were reduced by 14.3 ± 8.8 Gy and 7.5 ± 5.2%, and normal tissue complication probability (NTCP) for myelopathy and pericarditis were close to zero and NTCP for radiation pneumonitis was reduced by 2.5% ± 4.1%. Comparing 4D(MC) to 4D(EPL) plans found decreased V(60Gy∕48Gy) and D(99) by 12.3% ± 21.6% and 7.3 ± 5.3 Gy, the normal tissues doses by 0.5 Gy on average, gEUD and TCP by 13.0 ± 8.6 Gy and 7.1% ± 5.1%. Comparing 4D(MC) to 3D(MC) doses, V(60Gy∕48Gy) and D(99) of GTV was reduced by 5.2% ± 8.8% and 2.6 ± 3.3 Gy, and normal tissues hardly changed from 4D(MC) to 3D(MC) doses. The corresponding decreases of gEUD and TCP were 2.8 ± 4.0 Gy and 1.6 ± 2.4%. CONCLUSIONS: The large discrepancy between original 3D(EPL) plan and benchmarking 4D(MC) plan is predominately due to dose calculation algorithms as the tracking beam motion and organ deformation hardly influenced doses of normal tissues and moderately decreased V(60Gy∕48Gy) and D(99) of GTV. It is worth to make a thoughtful weight of the benefits of full 4D(MC) dose calculation and consider 3D(MC) dose calculation as a compromise of 4D(MC) dose calculation considering the multifold computation time.