Xiao Long Fu

Plasma Proteomic Analysis May Identify New Markers for Radiation-Induced Lung Toxicity in Patients With Non–Small-Cell Lung Cancer

PURPOSEnTo study whether radiation induces differential changes in plasma proteomics in patients with and without radiation-induced lung toxicity (RILT) of Grade >/=2 (RILT2).nnnMETHODS AND MATERIALSnA total of 57 patients with NSCLC received radiation therapy (RT) were eligible. Twenty patients, 6 with RILT2 with tumor stage matched to 14 without RILT2, were enrolled for this analysis. Platelet-poor plasma was obtained before RT, at 2, 4, 6 weeks during RT, and 1 and 3 months after RT. Plasma proteomes were compared using a multiplexed quantitative proteomics approach involving ExacTag labeling, reverse-phase high-performance liquid chromatography and nano-LC electrospray tandem mass spectrometry. Variance components models were used to identify the differential protein expression between patients with and without RILT2.nnnRESULTSnMore than 100 proteins were identified and quantified. After excluding proteins for which there were not at least 2 subjects with data for at least two time points, 76 proteins remained for this preliminary analysis. C4b-binding protein alpha chain, Complement C3, and Vitronectin had significantly higher expression levels in patients with RILT2 compared with patients without RILT2, based on both the data sets of RT start to 3 months post-RT (p < 0.01) and RT start to the end of RT (p < 0.01). The expression ratios of patients with RILT2 vs. without RILT2 were 1.60, 1.36, 1.46, and 1.66, 1.34, 1.46, for the above three proteins, respectively.nnnCONCLUSIONSnThis proteomic approach identified new plasma protein markers for future studies on RILT prediction.

Baseline Plasma Proteomic Analysis to Identify Biomarkers that Predict Radiation-Induced Lung Toxicity in Patients Receiving Radiation for Non-small Cell Lung Cancer

Purpose: To identify new plasma proteomic markers before radiotherapy start to predict later grade ≥2 radiation-induced lung toxicity (RILT2). Methods: Fifty-seven patients with non-small cell lung cancer received radiotherapy (RT) were eligible. Forty-eight patients with minimum follow-up of 1 year, nine with RILT2 with tumor stage matched to 39 without RILT2, were enrolled for this analysis. Platelet-poor plasma was obtained within 2 weeks before radiotherapy. The plasma proteomes were compared using a multiplexed quantitative proteomics approach involving ExacTag labeling, reverse-phase high-performance liquid chromatography, and nano liquid chromatography electrospray ionization tandem mass spectrometry. Z scores and Bonferroni-adjusted p values for the two-sample mean comparison were used to identify the differential protein expression between patients with and without RILT2. Results: More than 200 proteins were identified and quantified. After excluding proteins that were not detected in at least 40% of the 48 patient samples, C4b-binding protein alpha chain and vitronectin had significantly higher (p < 0.001 and p = 0.02) expression levels in patients with RILT2 compared with patients without RILT2. These two proteins were validated by Western blot. Ingenuity pathway analysis revealed that they both play important roles in the inflammatory response and are associated with the known pathways of radiation-induced lung damage. Conclusions: This proteomic approach demonstrates new plasma protein biomarkers before treatment for future studies on RILT2 prediction.

Safety and efficacy of nimotuzumab in combination with radiotherapy for patients with squamous cell carcinoma of the esophagus.

BackgroundWe investigated nimotuzumab (h-R3), a humanized monoclonal antibody against epidermal growth factor receptor, when combined with irradiation or chemoradiation for squamous cell carcinoma (SCC) of the esophagus. The aim of this study was to evaluate its safety and efficacy.MethodsWe retrospectively analyzed 66 patients with esophageal SCC treated with a combination of h-R3 and radiation or chemoradiation between December 2008 and September 2011 at Fudan University Shanghai Cancer Center. Fifty-two of the 66 patients received h-R3 combined with chemoradiation and 14 received h-R3 plus radiation. The median total irradiation dose was 61xa0Gy given by conventional fractionation. The h-R3 weekly dosage was 100xa0mg (6/66), 200xa0mg (54/66), or 400xa0mg (6/66) given concurrently during the irradiation period.ResultsPatients tolerated the treatment well. Grade 3–4 adverse events and toxicities occurred in 50xa0% of the patients. h-R3-related toxicities manifested as Grade 1 skin rash in 1 case and Grade 2 infusion-related reaction in 2 cases. The median overall survival (OS) and progression-free survival (PFS) were 26.0xa0months and 16.7xa0months, respectively. OS, PFS and locoregional control (LC) at 2 years were 54, 37 and 80xa0%, respectively.Conclusionsh-R3 in combination with irradiation or chemoradiation was safe and tolerable, and yielded encouraging OS, PFS and LC.

Safety of dose escalation by simultaneous integrated boosting radiation dose within the primary tumor guided by 18FDG-PET/CT for esophageal cancer

PURPOSEnTo observe the safety of selective dose boost to the pre-treatment high (18)F-deoxyglucose (FDG) uptake areas of the esophageal GTV.nnnMETHODSnPatients with esophageal squamous cell carcinoma were treated with escalating radiation dose of 4 levels, with a simultaneous integrated boost (SIB) to the pre-treatment 50% SUVmax area of the primary tumor. Patients received 4 monthly cycles of cisplatin and fluorouracil. Dose-limiting toxicity (DLT) was defined as any Grade 3 or higher acute toxicities causing continuous interruption of radiation for over 1 week.nnnRESULTSnFrom April 2012 to February 2014, dose has been escalated up to LEVEL 4 (70Gy). All of the 25 patients finished the prescribed dose without DLT, and 10 of them developed Grade 3 acute esophagitis. One patient of LEVEL 2 died of esophageal hemorrhage within 1 month after completion of radiotherapy, which was not definitely correlated with treatment yet. Late toxicities remained under observation. With median follow up of 8.9months, one-year overall survival and local control was 69.2% and 77.4%, respectively.nnnCONCLUSIONSnDose escalation in esophageal cancer based on (18)FDG-PET/CT has been safely achieved up to 70Gy using the SIB technique. Acute toxicities were well tolerated, whereas late toxicities and long-term outcomes deserved further observation.

Simultaneous integrated boost intensity-modulated radiotherapy in esophageal carcinoma: early results of a phase II study.

PurposeThe safety and efficacy of using simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) for patients with esophageal squamous cell carcinoma were evaluated in a single-institution phasexa0II setting.Methods and materialsBetween June 2007 and October 2009, 45xa0patients underwent concurrent chemoradiotherapy (nu2009=u200927) or radiotherapy alone (nu2009=u200918). Two planning target volumes (PTV) were defined for the SIB: PTVC and PTVG, with prescribed doses of 50.4xa0Gy to the PTVC (1.8xa0Gy/fraction) and 63xa0Gy to the PTVG (2.25xa0Gy/fraction), both given in 28xa0fractions.ResultsAt a median follow-up interval of 20.3xa0months, the 3-year overall survival (OS) and progression-free survival (PFS) rates were 42.2 and 40.7u2009%, respectively. The median overall survival time was 21xa0months; locoregional control rates were 83.3u2009% at 1xa0year and 67.5u2009% at 3xa0years. According to CTCAE (version 3.0) criteria, none of the patients developed gradexa04–5 toxicity. The most common gradexa02 and 3 radiation-related toxicity was radiation esophagitis, occurring in 64u2009% of all patients (but only 13u2009% as gradexa03). No patient developed grade >u20092 pulmonary complications.ConclusionSIB-IMRT is a feasible therapeutic approach for esophageal carcinoma patients and provides encouraging locoregional control with a low toxicity profile. Further investigations should focus on dose escalation and optimization of the combination with systemic therapies.ZusammenfassungZielDie Wirksamkeit und Effektivität einer intensitätsmodulierten Radiotherapie mit einem simultan integrierten Boost (SIB-IMRT) für Patienten mit Ösophaguskarzinom wurde in einer Single-Institution-Phase-II-Studie bewertet.Methoden und MaterialZwischen Juni 2007 und Oktober 2009 wurden 45xa0Patienten mit einer simultanen Radiochemotherapie (nu2009=u200927) oder einer alleinigen Strahlentherapie (nu2009=u200918) behandelt. Zwei Planungszielvolumen (PTV) wurden für die SIB definiert: PTVC und PTVG, mit vorgeschriebenen Dosen von 50,4xa0Gy für PTVC (1,8xa0Gy/Fraktion) und 63xa0Gy für PTVG (2,25xa0Gy/Fraktion), beide in 28xa0Fraktionen verabreicht.ErgebnisseBei einer mittleren Verlaufsbeobachtung von 20,3xa0Monaten lagen die 3-Jahres-Überlebensraten für das Gesamtüberleben (OS) und das progressionsfreie Überleben (PFS) bei jeweils 42,2 und 40,7u2009%. Das mediane OS betrug 21xa0Monate; lokoregionäre Kontrollraten waren 83,3u2009% nach 1xa0Jahr und 67,5u2009% nach 3xa0Jahren. Bei keinem Patienten entwickelten sich eine Toxizität von Gradxa04–5 gemäß der CTCAE-Kriterien (Version 3.0). Die häufigste strahlenbedingte Toxizität von Gradxa02 und 3 war bei 64u2009% aller Patienten eine Ösophagitis (aber nur 13u2009% mit Gradxa03). Bei keinem Patienten entwickelten sich pulmonale Komplikationen >u2009Gradxa02.SchlussfolgerungSIB-IMRT funktioniert grundsätzlich für Patienten mit Ösophaguskarzinom. Es bewirkt eine Förderung der lokoregionären Kontrolle mit akzeptabler Toxizität. Weitere Untersuchungen zur Dosissteigerung und Optimierung der Kombination sollten mit einer systemischen Therapie durchgeführt werden.

Patterns of local-regional failure in completely resected stage IIIA(N2) non-small cell lung cancer cases: implications for postoperative radiation therapy clinical target volume design.

PURPOSEnTo analyze patterns of local-regional failure (LRF) for completely resected stage IIIA(N2) non-small cell lung cancer (NSCLC) patients treated in our hospital and to propose a clinical target volume (CTV) for postoperative radiation therapy (PORT) in these patients.nnnMETHODS AND MATERIALSnFrom 2005 to 2011, consecutive patients with pT1-3N2 NSCLC who underwent complete resection in our hospital but who did not receive PORT were identified. The patterns of first LRF were assessed and evaluated as to whether these areas would be encompassed by our proposed PORT CTV.nnnRESULTSnWith a median follow-up of 24 months, 173 of 250 patients (69.2%) experienced disease recurrence. Of the 54 patients with LRF as the first event, 48 (89%) had recurrence within the proposed PORT CTV, and 6 (11%) had failures occurring both within and outside the proposed CTV (all of which occurred in patients with right-lung cancer). Ninety-three percent of failure sites (104 of 112) would have been contained within the proposed PORT CTV. For left-sided lung cancer, the most common lymph node station failure site was 4R, followed by 7, 4L, 6, 10L, and 5. For right-sided lung cancer, the most common site was station 2R, followed by 10R, 4R, and 7.nnnCONCLUSIONSnLRF following complete surgery was an important and potentially preventable pattern of failure in stage IIIA(N2) patients. Ipsilateral superior mediastinal recurrences dominated for right-sided tumors, whereas left-sided tumors frequently involved the bilateral superior mediastinum. Most of the LRF sites would have been covered by the proposed PORT CTV. A prospective investigation of patterns of failure after PORT (following our proposed CTV delineation guideline) is presently underway and will be reported in a separate analysis.

A prospective evaluation of staging and target volume definition of lymph nodes by 18FDG PET/CT in patients with squamous cell carcinoma of thoracic esophagus.

PURPOSEnTo determine an optimal standardized uptake value (SUV) threshold for detecting lymph node (LN) metastases in esophageal cancer using (18)F-Fluorodeoxyglucose positron emission tomography/computer tomography (18FDG PET/CT) and to define the resulting nodal target volume, using histopathology as a gold standard.nnnMETHODSnSixteen patients with esophageal squamous cell carcinoma who underwent radical esophagectomy and three-field LN dissection after 18FDG PET/CT and CT scans were enrolled into this study. Locations of LN groups were recorded according to a uniform LN map. Diagnostic performance of different SUV thresholds was assessed by receiver operating characteristic analysis. The optimal cutoff SUV was determined by plotting the false-negative rate (FNR) and false-positive rate (FPR), the sum of both error rates (FNR+FPR), and accuracy against a hypothetical SUV threshold. For each patient, nodal gross tumor volumes (GTVNs) were generated with CT alone (GTVNCT), PET/CT (GTVNPET), and pathologic data (GTVNpath). GTVNCT or GTVNPET was compared with GTVNpath by means of a conformity index (CI), which is the intersection of the two GTVNs divided by the sum of them minus the intersection, e.g., CICT&path=GTVNCT&path/(GTVNCT+GTVNpath-GTVNCT&path).nnnRESULTSnLN metastases occurred in 21 LN groups among the 144 specimens taken from the 16 patients. The area under the receiver operating characteristic curve was 0.9017±0.0410. The plot of error rates showed a minimum of FNR+FPR for an SUV of 2.36, at which the sensitivity, specificity, and accuracy were 76.19%, 95.93%, and 93.06%, respectively, whereas those of CT were 33.33%, 94.31%, and 85.42% (p values: 0.0117, 0.7539, and 0.0266). Mean GTVNCT, GTVNPET, and GTVNpath were 1.52±2.38, 2.82±4.51, and 2.68±4.16 cm3, respectively. Mean CICT&path and CIPET&path were 0.31 and 0.65 (p value=0.0352).nnnCONCLUSIONSnDiagnostic superiority of PET/CT at an SUV threshold of 2.36 over CT has potential value in nodal target volume definition, but whether this can contribute to better treatment outcomes needs prospective analyses of recurrences in a larger cohort of patients.

Prognostic value of tumor-infiltrating lymphocytes for patients with completely resected stage IIIA(N2) non-small cell lung cancer

Background The patient prognosis after complete resection for pathologic stage IIIA(N2) non-small cell lung cancer (NSCLC) remains a significant concern. The clinical relevance of the host immune response to NSCLC has yet to be established. We aimed to investigate the prognostic value of tumor-infiltrating lymphocytes (TILs) in a uniform cohort of patients with completely resected stage IIIA(N2) NSCLC. Methods From 2005 to 2012, consecutive patients with pathologic stage IIIA(N2) NSCLC who underwent complete resection at our institution were reviewed. For each case, full-face hematoxylin and eosin-stained sections from surgical specimens were evaluated for the TIL density. A published, recommended TIL scoring scale was followed. The patients were stratified into the TIL− or TIL+ group based on pathologic evaluation. Results Data from 320 patients were included in the analysis. Based on a median follow-up duration of 30.8 months, a higher density of TILs was associated with an improved postoperative survival time (P = 0.06). Subgroup analyses indicated that this positive effect was the greatest for patients with squamous cell carcinoma (SCC; P = 0.03). Among those with SCC, the TIL+ patients experienced a significantly increased 3-year distant metastasis-free survival (DMFS) compared to the TIL− patients (60.6% versus 42.7%, P = 0.02). Multivariate analyses of the 93 patients with SCC tumors confirmed that TIL+ was an independent prognostic factor for an increased DMFS (HR = 0.39, 95%CI 0.17–0.87, P = 0.02) and a prolonged overall survival (OS; HR = 0.47, 95%CI 0.22–1.00, P = 0.05). Conclusions Our data suggest a potential role of TILs in predicting the survival of patients with completely resected stage IIIA(N2) NSCLC. The beneficial effects of TILs were more pronounced in the prediction of the DMFS and the OS in patients with SCC. This parameter should be considered for prospective inclusion in clinical trials.

Potential values of metabolic tumor volume and heterogeneity measured with 18F-FDG PET/CT pretreatment to evaluate local control for esophageal squamous cell carcinoma treated with nonsurgical therapy

ObjectivesThe aim of the study was to evaluate the predictive value of fluorine-18 fluorodeoxyglucose (18F-FDG) PET/computed tomography (CT) pretreatment on local control (LC) and survival after radical radiotherapy or chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma (SCC) and to discuss its potential value for establishing optimal radiation treatment plans. MethodsFifty-eight patients with pathologically proven esophageal SCC who underwent 18F-FDG PET/CT pretreatment in our center were retrospectively reviewed. We examined the correlation between the PET parameters of primary tumors and LC and overall survival. The coefficient of variation was used to estimate the 18F-FDG uptake in heterogeneity. ResultsThe mean duration of follow-up for surviving patients was 38 months, and 36 patients died because of tumor recurrence or other diseases. The rates of 3-year overall survival and LC were 40.4 and 50.4%, respectively. Multivariate analysis of LC revealed that metabolic tumor volume (MTV) greater than 16.08u2009ml was the only predictor of outcome, with a lower 3-year LC (P=0.017, hazard ratio: 1.608, 95% confidence interval: 1.090–2.371). The coefficient of variations of their primary lesion were higher compared with those of patients who had smaller MTVs. ConclusionIn this study, MTV assessed by PET/CT might be an adverse factor for predicting LC in esophageal SCC. For those with higher MTVs, higher intratumor heterogeneity suggests that irradiation may need to be boosted in stable high-uptake regions to improve LC. These results need to be prospectively validated in larger cohorts.

The emerging outcome of postoperative radiotherapy for stage IIIA(N2) non-small cell lung cancer patients: Based on the three-dimensional conformal radiotherapy technique and institutional standard clinical target volume

BackgroundThe aim of this study was to evaluate the clinical efficacy of postoperative radiotherapy (PORT), administered using three-dimensional conformal radiotherapy (3D-CRT) and our institutional standard clinical target volume (CTV) delineation, for completely resected stage IIIA(N2) non-small cell lung cancer (NSCLC).MethodsFrom 2005 to 2012, consecutive patients with pT1-3N2 NSCLC who were treated with PORT employing our institutional CTV delineation after complete surgery or who underwent complete resection in our hospital but without PORT were identified. We excluded patients who had received neoadjuvant chemotherapy or radiation therapy (RT). Kaplan-Meier estimates for locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were performed. In the OS estimation, patients who received epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) during follow-up were censored at the time of TKI initiation.ResultsData from 70 patients in the PORT group and 287 in the non-PORT group were analysed. All 70 cases received 3D-CRT following our institutional CTV guideline, with a median total dose of 50.4xa0Gy at 1.8xa0Gy/fraction. At a median follow-up of 34.3xa0months for the PORT group and 31.2xa0months for the non-PORT group, PORT significantly improved local control (5-yr LRFS 91.9% for PORT vs 66.4% for non-PORT, Pu2009<u20090.001) and OS (5-yr OS 57.5% for PORT vs 35.1% for non-PORT, Pu2009=u20090.003), whereas no differences in DMFS were noted (Pu2009=u20090.18). In multivariable analyses, PORT was independently associated with an improved LRFS (HR 0.2, Pu2009=u20090.001) and OS (HR 0.4, Pu2009=u20090.001). All patients completed the planned RT dose without interruption of RT due to treatment-related complications.ConclusionsOur data suggested that PORT administered using the 3D-CRT technique following our institutional CTV delineation guideline resulted in a promising outcome with favourable survival for completely resected IIIA(N2) NSCLC, after controlling for subsequent EGFR-TKI confounding in the OS analysis. Prospective trials are needed to further corroborate these results.