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Li Y.,Shanghai Proton and Heavy Ion Center | Hsi W.C.,Shanghai Proton and Heavy Ion Center
Physics in Medicine and Biology | Year: 2017

To analyze measurement deviations of patient-specific quality assurance (QA) using intensity-modulated spot-scanning particle beams, a commercial radiation dosimeter using 24 pinpoint ionization chambers was utilized. Before the clinical trial, validations of the radiation dosimeter and treatment planning system were conducted. During the clinical trial 165 measurements were performed on 36 enrolled patients. Two or three fields of particle beam were used for each patient. Measurements were typically performed with the dosimeter placed at special regions of dose distribution along depth and lateral profiles. In order to investigate the dosimeter accuracy, repeated measurements with uniform dose irradiations were also carried out. A two-step approach was proposed to analyze 24 sampling points over a 3D treatment volume. The mean value and the standard deviation of each measurement did not exceed 5% for all measurements performed on patients with various diseases. According to the defined intervention thresholds of mean deviation and the distance-to-agreement concept with a Gamma index analysis using criteria of 3.0% and 2 mm, a decision could be made regarding whether the dose distribution was acceptable for the patient. Based measurement results, deviation analysis was carried out. In this study, the dosimeter was used for dose verification and provided a safety guard to assure precise dose delivery of highly modulated particle therapy. Patient-specific QA will be investigated in future clinical operations. © 2017 Institute of Physics and Engineering in Medicine.


Meng J.,Shanghai JiaoTong University | Li P.,Shanghai JiaoTong University | Zhang Q.,Fudan University | Zhang Q.,Shanghai Proton and Heavy Ion Center | And 3 more authors.
Oncotarget | Year: 2014

A 31-gene signature derived by integrating four different microarray experiments, has been found to have a potential for predicting radiosensitivity of cancer cells, but it was seldom validated in clinical cancer samples. We proposed that the gene signature may serve as a predictive biomarker for estimating the overall survival of radiation-treated patients. The significance of gene signature was tested in two previously published datasets from Gene Expression Omnibus (GEO) and The Cancer Genome Altas (TCGA), respectively. In GEO data set, patients predicted to be radiosensitive(RS) had an improved overall survival when compared with radioresistant(RR) patients in either radiotherapy(RT)-treated or non radiotherapy(RT)-treated subgroups(p < 0.0001 in the RT-treated group). Multivariate Cox regression analysis showed that the gene signature is the strongest predictor(p=0.0093) in the RT-treated subgroup of patients. However, it does not remain significant (p=0.7668) in non radiotherapy-treated group when adjusting for age and Karnofsky performance score (KPS) as covariates. Similarly, in the TCGA data set, radiotherapy-treated glioblastoma multiforme(GBM) patients assigned to RS group had an improved overall survival compared with RR group(p < 0.0001). Geneset enrichment analysis(GSEA) analysis revealed that enrichment of epithelial mesenchymal transition(EMT) pathway was observed with radioresistant phenotype. These results suggest that the signature is a predictive biomarker for radiation-treated glioma patients' prognostic.


Kong L.,Fudan University | Lu J.J.,Shanghai Proton and Heavy Ion Center
Chinese Clinical Oncology | Year: 2016

Local or locoregional recurrence of nasopharyngeal carcinoma (NPC) after high-dose radiotherapy remains a significant clinical problem. This is especially important in regions of the world in which NPC is endemic, such as Southern China. In this review, we briefly present the evolution in the definitive treatment of NPC, but focus more so on the historical and contemporary treatment approaches and outcomes utilized in the recurrent setting. Specifically, we highlight the various treatment strategies (repeat surgery, brachytherapy, conventional re-irradiation, SRS/SBRT, and salvage IMRT), and their technical, physical and biological limitations. Special attention is given towards salvage IMRT, as this is becoming the standard of care for locally recurrent NPC. Further, it is the most commonly indicated modality, since it can be used to treat larger tumors and more extensive disease stages, which represent the majority of recurrent cases. Predictive and prognostic factors for the efficacy of repeat treatment are discussed as well. The toxicities brought about by repeat radiotherapy courses are also highlighted, with an emphasis on their impact on mortality and quality of life, which underscore the difficulty that this clinical entity presents. Lastly, the rationale for particle radiation therapy, which is potentially safer and more efficacious, for the treatment of locally recurrent NPC is presented. ©Chinese Clinical Oncology.


Qi W.-X.,Shanghai Proton and Heavy Ion Center | Fu S.,Shanghai Proton and Heavy Ion Center | Fu S.,Fudan University | Zhang Q.,Shanghai Proton and Heavy Ion Center | And 2 more authors.
Radiotherapy and Oncology | Year: 2015

Purpose To perform a systematic review and meta-analysis to compare the clinical outcomes and toxicity of hepatocellular carcinoma (HCC) patients treated with charged particle therapy (CPT) with those of individuals receiving photon therapy. Methods We identified relevant clinical studies through searching databases. Primary outcomes of interest were overall survival (OS) at 1, 3, 5 years, progression-free survival (PFS), and locoregional control (LC) at longest follow-up. Results 73 cohorts from 70 non-comparative observational studies were included. Pooled OS was significantly higher at 1, 3, 5 years for CPT than for conventional radiotherapy (CRT) [relative risk (RR) 1·68, 95% CI 1·22-2·31; p < 0·001; RR 3.46, 95% CI: 1.72-3.51, p < 0.001; RR 25.9, 95% CI: 1.64-408.5, p = 0.02; respectively]. PFS and LC at longest follow-up was also significantly higher for CPT than for CRT (p = 0·013 and p < 0.001, respectively), while comparable efficacy was found between CPT and SBRT in terms of OS, PFS and LC at longest follow-up. Additionally, high-grade acute and late toxicity associated with CPT was lower than that of CRT and SBRT. Conclusion Survival rates for CPT are higher than those for CRT, but similar to SBRT in patients with HCC. Toxicity tends to be lower for CPT compared to photon radiotherapy. © 2014 Elsevier Ireland Ltd. All rights reserved.


Qi W.-X.,Shanghai Proton and Heavy Ion Center | Fu S.,Shanghai Proton and Heavy Ion Center | Fu S.,Fudan University | Zhang Q.,Shanghai Proton and Heavy Ion Center | And 2 more authors.
BMC Medicine | Year: 2014

Background: Anti-epidermal growth factor receptor (EGFR)-monoclonal antibodies (MoAbs) have been widely used in a variety of malignancies. Severe infections (≥grade 3) are potentially life-threatening adverse events with these drugs. However, the contribution of anti-EGFR MoAbs to infections is still unknown. We performed this meta-analysis to determine the overall incidence and risk of severe infections in cancer patients treated with these drugs. Methods: The databases of PubMed and abstracts presented at oncology conferences and published in the proceedings were searched for relevant studies from January 2000 to May 2014. Summary incidences, relative risks (RRs) and 95% confidence intervals (CIs) were calculated by using either random effects or fixed effect models according to the heterogeneity of included studies. Results: A total of 14,066 patients from 26 randomized controlled trials (RCTs) were included. The use of anti-EGFR-MoAbs significantly increased the risk of developing severe infections (RR 1.34, 95%CI: 1.10 to 1.62, P = 0.003) in cancer patients, but not for fatal infections (RR 1.62, 95%CI: 0.81 to 3.26, P = 0.18). Meta-regression indicated the infections might possibly occur early in the treatment with anti-EGFR MoAbs. On sub-group analysis, the risk of severe infections significantly varied with tumor type (P = 0.001). When stratified by specific anti-EGFR MoAbs, a significantly increased risk of infections with cetuximab was observed (P <0.001), but not for panitumumab (P = 0.98). Additionally, the use of anti-EGFR MoAbs significantly increased the risk of severe infections when used in conjunction with cisplatin (RR 1.48, 95%CI 1.22 to 1.79, P <0.001) or irinotecan (RR 1.53, 95%CI 1.12 to 2.10, P = 0.008). When stratified by specific infectious events, anti-EGFR-MoAbs significantly increased the risk of developing severe sepsis (RR 4.30, 95%CI: 1.80 to 10.27; P = 0.001). Conclusions: Anti-EGFR MoAbs treatment significantly increases the risk of developing severe infectious events in cancer patients. The risk may vary with tumor types. Clinicians should be aware of the risks of severe infections with the administration of these drugs in cancer patients.


Qi W.-X.,Fudan University | Qi W.-X.,Shanghai Proton and Heavy Ion Center | Fu S.,Fudan University | Fu S.,Shanghai Proton and Heavy Ion Center | And 3 more authors.
Clinical Drug Investigation | Year: 2014

Background and Objective: Congestive heart failure (CHF) risk with bevacizumab in breast cancer has been previously investigated in a meta-analysis, but its incidence and the risk of CHF in other tumor types remain unclear. Thus, we performed this meta-analysis to gather current data and evaluate the risk of CHF with bevacizumab in cancer patients, with a focus on different subgroups.Methods: The databases of PubMed and abstracts presented at the American Society of Clinical Oncology up to 31 December 2013 were searched for relevant articles. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR), and 95 % confidence intervals (CIs) by using either random-effects or fixed-effect models according to the heterogeneity of included studies.Results: A total of 16,962 patients from 19 RCTs were included. The use of bevacizumab significantly increased the risk of developing high-grade CHF in cancer patients (RR 1.98, 95 % CI 1.30–3.02, p = 0.002), but not for all-grade CHF (RR 1.14, 95 % CI 0.87–1.49, p = 0.33). Risk might vary with bevacizumab dose and tumor types. RRs for patients receiving bevacizumab at 5 and 2.5 mg/kg/week were 2.25 (95 % CI 1.43–3.56) and 1.00 (95 % CI 0.33–3.05), respectively. High risks were observed in patients with breast cancer (RR 2.43, 95 % CI 1.48–3.98), renal cell cancer (RR 3.66, 95 % CI 0.41–33.01), and glioblastoma (RR 4.90, 95 % CI 0.24–102.39). Additionally, bevacizumab in combination with taxanes significantly increased the risk of high-grade CHF (RR 2.15, 95 % CI 1.09–4.25, p = 0.027).Conclusions: Bevacizumab treatment significantly increases the risk of developing high-grade CHF in cancer patients. The risk may vary with bevacizumab dose and tumor types. Clinicians should be aware of the risks of CHF with the administration of this drug in cancer patients. © 2014, Springer International Publishing Switzerland.


Lin S.,Fujian Medical University | Lin S.,Fujian Provincial Key Laboratory of Translational Cancer Medicine | Pan J.,Fujian Medical University | Pan J.,Fujian Provincial Key Laboratory of Translational Cancer Medicine | And 9 more authors.
Radiotherapy and Oncology | Year: 2014

Background and purpose To establish the minimally required margins in different directions measured from GTV in the definitive treatment of nasopharyngeal carcinoma (NPC) using IMRT based on the 5-year results. Methods and materials Between November 2003 and May 2007, 414 patients with non-metastatic NPC were treated with IMRT according to our institutional protocol. Treatment outcomes at 5 years were analyzed. Distances from GTV-T to CTV2 (i.e., CTV 59.4 Gy) in 6 directions (anterior, posterior, superior, inferior, and bilateral) were measured and analyzed. Results The 5-year estimated overall survival (OS), disease free survival (DFS), local control (LC) were 80%, 77% and 95%, respectively. For the margins measured from GTV-T to CTV2, margins used with T4 disease were significantly and uniformly smaller than the whole group in all the 6 directions (P = 0.000, 0.000, 0.000, 0.000 and 0.046, respectively). However, no increase of local recurrence was associated to this limited margins used. Conclusions Our 5-years' experience showed a very high LC rate. The strategy we used for CTV delineation was safe and reliable. Determined CTV through GTV expansion to a minimally required margin, using GTV + margin (used in our T4 patients) + the whole nasopharyngeal mucosa, especially for the patients with early T disease, might be feasible. © 2013 Elsevier Ireland Ltd. All rights reserved.


Qi W.-X.,Shanghai Proton and Heavy Ion Center | Fu S.,Shanghai Proton and Heavy Ion Center | Fu S.,Fudan University | Zhang Q.,Shanghai Proton and Heavy Ion Center | And 2 more authors.
Current Medical Research and Opinion | Year: 2015

Purpose: Currently, the anti-epidermal-growth-factor-receptor (EGFR) agents have shown encouraging treatment benefits in patients with various types of solid tumors including non-small-cell lung cancer (NSCLC). Despite these advances, radiological complete response to these therapies is rare. We meta-Analyze the incidence of complete response (CR) in advanced NSCLC patients treated with anti-EGFR agents and controls in randomized controlled trials (RCTs).Methods: PubMed, Web of Science, Embase and Cochrane library databases were reviewed for phase III RCTs with EGFR-targeted agents vs. non-EGFR-targeted agents in patients with advanced NSCLC. We calculated the odds ratio of CR in patients assigned to anti-EGFR agents compared to controls.Results: A total of 11,568 patients from 17 RCTs were included for analysis. The incidence of CR in patients treated with anti-EGFR agents was 1.1% (95% CI, 0.7-1.7%) compared to 0.6% (95% CI, 0.4-0.9%) in control arms. Comparing the different types of anti-EGFR agents, the incidence of CR was 1.9% for gefitinib (95% CI: 1.4-2.6%), 1.4% for cetuximab (95% CI: 0.8-2.7%) and 0.9% for erlotinib (95% CI: 0.6-1.5%), respectively. The use of anti-EGFR agents significantly increased the odds ratio of obtaining a CR (OR 2.12, 95% CI: 1.28-3.49, p = 0.003) compared to controls. This was found to be higher in treatment arms involving more than 50% of: female patients, patients who had never smoked tobacco, patients of Asian descent or patients with adenocarcinoma or EGFR mutation. No significant differences in ORs were observed in any prespecified sub-groups.Conclusion: Although a CR is rare in advanced NSCLC patients receiving anti-EGFR agents, these drugs significantly increase the OR of a CR compared to controls, especially for patients with EGFR mutations. Further studies are needed to investigate whether the increase of CR with anti-EGFR therapy would be translated into survival benefits. © 2015 Informa UK Ltd.


Qi W.-X.,Fudan University | Qi W.-X.,Shanghai Proton and Heavy Ion Center | Shen F.,Fudan University | Shen F.,Shanghai Proton and Heavy Ion Center | And 3 more authors.
Tumor Biology | Year: 2014

Gastrointestinal (GI) perforation is a serious adverse event associated with aflibercept, a novel vascular endothelial growth factor (VEGF)-targeted agent currently approved as second-line treatment for previously treated metastatic colorectal cancer, but the incidence and risk of GI perforation associated with aflibercept has not been well determined. We thus conducted this meta-analysis to investigate the overall incidence and risk of developing GI perforation associated with aflibercept. Databases from PubMed, Web of Science, and abstracts presented at American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) meeting up to January, 2014 were searched to identify relevant studies. Eligible studies included prospective phase II and III trials evaluating aflibercept in cancer patients with adequate data on GI perforation. Statistical analyses were conducted to calculate the summary incidence, odds ratio, and 95 % confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of included studies. A total of 4,101 patients with a variety of solid tumors from eight clinical trials were included in our analysis. The incidence of GI perforation associated with aflibercept was 1.9 % (95 %CI, 1.0–3.8 %), with a mortality of 10.8 % (95%CI, 4.1–25.5 %). In addition, patients treated with aflibercept had a significantly increased risk of developing all-grade (OR 3.76; 95%CI, 1.94–7.25; p < 0.001) and high-grade GI (OR 4.14; 95 %CI; 2.12–8.06; p < 0.001) perforation compared with patients treated with control medication. No evidence of publication bias was observed. The use of aflibercept is associated with a significantly increased risk of GI perforation compared to controls. © 2014, International Society of Oncology and BioMarkers (ISOBM).


Purpose: Adequate evaluation of the results from multi-institutional trials involving light ion beam treatments requires consideration of the planning margins applied to both targets and organs at risk. A major uncertainty that affects the size of these margins is the conversion of x ray computed tomography numbers (XCTNs) to relative linear stopping powers (RLSPs). Various facilities engaged in multi-institutional clinical trials involving proton beams have been applying significantly different margins in their patient planning. This study was performed to determine the variance in the conversion functions used at proton facilities in the U.S.A. wishing to participate in National Cancer Institute sponsored clinical trials. Methods: A simplified method of determining the conversion function was developed using a standard phantom containing only water and aluminum. The new method was based on the premise that all scanners have their XCTNs for air and water calibrated daily to constant values but that the XCTNs for high density/high atomic number materials are variable with different scanning conditions. The standard phantom was taken to 10 different proton facilities and scanned with the local protocols resulting in 14 derived conversion functions which were compared to the conversion functions used at the local facilities. Results: For tissues within ±300 XCTN of water, all facility functions produced converted RLSP values within ±6% of the values produced by the standard function and within 8% of the values from any other facility's function. For XCTNs corresponding to lung tissue, converted RLSP values differed by as great as ±8% from the standard and up to 16% from the values of other facilities. For XCTNs corresponding to low-density immobilization foam, the maximum to minimum values differed by as much as 40%. Conclusions: The new method greatly simplifies determination of the conversion function, reduces ambiguity, and in the future could promote standardization between facilities. Although it was not possible from these experiments to determine which conversion function is most appropriate, the variation between facilities suggests that the margins used in some facilities to account for the uncertainty in converting XCTNs to RLSPs may be too small. © 2014 American Association of Physicists in Medicine.

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