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Abstract Background This study aimed to evaluate the efficiency of hippocampal avoidance whole-brain radiotherapy with a simultaneous integrated boost (HA-WBRT-SIB) treating brain metastases (BM) and utility of the Hopkins Verbal Learning Test-Revised (HVLT-R) (Chinese version) in Chinese lung cancer patients. Methods Lung cancer patients with BM undergone HA-WBRT-SIB at our center were enrolled. Brain magnetic resonance imaging, The HVLT total learning score, and side effects were evaluated before radiotherapy and 1, 3, 6, and 12 months after radiotherapy. This study analyzed the overall survival rate, progression-free survival rate, and changes in HVLT-R immediate recall scores. Results Forty patients were enrolled between Jan 2016 and Jan 2020. The median follow-up time was 14.2 months. The median survival, progression-free survival, and intracranial progression-free survival of all patients were 14.8 months, 6.7 months and 14.8 months, respectively. Multivariate analysis indicated that male sex and newly diagnosed stage IV disease were associated with poor overall survival and progression-free survival, respectively. HVLT-R scores at baseline and 1, 3, and 6 months after radiotherapy were 21.94 ± 2.99, 20.88 ± 3.12, 20.03 ± 3.14, and 19.78 ± 2.98, respectively. The HVLT-R scores at 6 months after radiotherapy decreased by approximately 9.8% compared with those at baseline. No grade 3 toxicities occurred in the entire cohort. Conclusions HA-WBRT-SIB is of efficiency and cognitive-conserving in treating Chinese lung cancer BM. Trial registration This study was retrospectively registered on ClinicalTrials.gov in 24th Feb, 2024. The ClinicalTrials.gov ID is NCT06289023.

Purpose This prospective study in a real-world setting investigated the feasibility and safety of S-1 plus nimotuzumab (S-1-Nimo) based concurrent chemoradiotherapy (CCRT) in locally advanced esophageal squamous cell carcinoma (LA-ESCC) patients who failed to neoadjuvant chemotherapy or chemoimmunotherapy.Methods LA-ESCC patients who failed to converse to resectable disease after neoadjuvant chemotherapy or chemoimmunotherapy were enrolled to receive the 4-week S-1-Nimo regimen of radiotherapy (40 Gy in 20 fractions, 5 days per week), S-1 chemotherapy, and nimotuzumab. Then, after surgical assessments, patients evaluated as resectable disease received surgery; patients with unresectable disease continued to receive definitive radiotherapy (50–60 Gy in 25–30 fractions, 5 days per week) concurrently with S-1-Nimo. The primary endpoint was event-free survival (EFS).Results Sixty-four patients were enrolled and evaluated. The median follow-up time was 23.2 months. Median EFS was 9.6 (95% confidence interval [CI], 7.1–14.0) months, with an estimated 2-year EFS rate of 24.2%. The median overall survival (OS) and the estimated OS rate at 2 years were 13.4 (95% CI, 10.3–17.5) months and 31.2%, respectively. Twelve underwent surgery, with a surgical conversion rate of 18.8% and an R0 resection rate of 100.0%. Subgroup analysis identified the significantly prolonged EFS and OS in patients who experienced radical surgery (median EFS, not reached vs. 8.7 months; p = .0117. median OS, 24.9 vs. 10.6 months; p = .0205) as compared to those treated with CCRT. Of 64 patients, grade 3 adverse events mainly included radiation esophagitis (4.7%), anemia (1.6%), and thrombocytopenia (1.6%).Conclusion The study demonstrated the reasonable efficacy and promising safety of the S-1-Nimo-based CCRT in LA-ESCC patients with failure to neoadjuvant chemotherapy or chemoimmunotherapy.

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for locally advanced non-small-cell lung cancer (LA-NSCLC), whereas responses to anti-programmed cell death-1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) are heterogeneous. Though consolidation ICI following concurrent chemoradiotherapy (cCRT) improves survival of NSCLC, this regimen is challenging for patients with bulky tumors due to excessive target volumes and radiation-resistant hypoxia during upfront cCRT, leading to higher risk of pneumonitis and inferior local-regional control. Recent trials have demonstrated neoadjuvant ICI brought greater benefit to stage III than stage I-II NSCLC. Our previous study also supported the therapeutic advantage of 2-cycle induction ICI for patients with bulky unresectable stage III NSCLC. In the context of induction immunotherapy, radiotherapy is more likely to exert immune synergistic effects, reverse anti-PD-1 resistance, and activate abscopal immune responses. Prospective trials to determine the efficacy and safety of induction ICI for bulky LA-NSCLC are necessary.MethodsThis randomized, open-label, two-arm phase II study aims to explore whether 2 cycles of induction anti-PD-1 toripalimab plus chemotherapy can improve progression-free survival (PFS) in bulky LA-NSCLC. Bulky tumors are defined as primary lesion ≥5 cm in greatest dimension or metastatic lymph nodes ≥2 cm in shortest diameter. A total of 50 patients with bulky unresectable stage III NSCLC will be recruited and 1:1 randomized into the experimental arm: 2-cycle induction PD-1 inhibitor toripalimab plus chemotherapy followed by cCRT and consolidation toripalimab; or control arm: 2-cycle induction chemotherapy followed by cCRT and consolidation toripalimab. Patients are stratified by pathology (squamous versus non-squamous). The primary endpoint is PFS. Secondary endpoints are overall survival, overall response rate, disease control rate, duration of response, and incidence of adverse events. Exploratory analyses include PD-L1 expression and liquid biopsy-based biomarker testing, tumor microenvironment profiling at single-cell levels, and quality-of-life assessments.DiscussionThe InTRist study is the first randomized phase II trial to investigate the feasibility of induction anti-PD-1 toripalimab plus chemotherapy followed by cCRT and consolidation toripalimab in bulky LA-NSCLC, providing novel evidence for the synergistic strategy combining anti-PD-1 blockade with radiotherapy to prolong immunotherapy benefits, overcome resistance, and enhance abscopal immune response.Clinical trial registrationClinicalTrials.gov, identifier NCT05888402.

BackgroundIn the era of immunotherapy, the optimal combination of immune checkpoint inhibitors (ICIs) and chemoradiotherapy (CRT) for stage III non-small cell lung cancer (NSCLC) is not defined. The current study investigated the efficacy and safety of definitive CRT(dCRT) plus consolidation ICIs with or without induction ICIs in stage III NSCLC.Methods123 consecutive patients treated with dCRT followed by consolidation ICIs at our institution from 2018 to 2022 were retrospectively reviewed. Failure patterns, survival outcomes, and toxicity profiles were analyzed.ResultsThe 1- and 2- year PFS rates were 75.3% and 56.9%, respectively, and median PFS was 30.83 months from the start of treatment. In-field failure (18.7%) was the most common failure pattern. The most common adverse event (AE) was pneumonitis caused by ICIs or RT. The incidence of Grade 3-4 and Grade 5 pneumonitis was 5.7% and 1.6%, respectively. Further analysis showed that the induction plus consolidation ICIs group has significantly lower cumulative incidence of distant metastasis rates (HR: 0.30, 95%CI: 0.09-1.00, p=0.043) and higher incidence of pneumonitis (p=0.039) compared with patients in the consolidation ICIs group.ConclusionsCombined CRT and consolidation ICIs achieved encouraging efficacy and manageable toxicity in patients with stage III NSCLC in China. Induction plus consolidation ICIs might reduce distant metastasis and deserve further investigation.

Abstract Objectives Whether curative‐intent radiotherapy could be safely applied to lung cancer patients with interstitial lung diseases (ILD) remains unclear. We aim to evaluate radiation induced lung toxicities (RILTs) and the efficacy of intensity‐modulated radiotherapy (IMRT) in these patients. ILD is characterized by inflammation or fibrosis in the interstitial tissue of the lung. Materials and Methods Stage III non–small cell lung cancer (NSCLC) and ILD patients treated with curative‐intent IMRT between 2010 and 2019 were retrospectively reviewed. Pre‐radiation computed tomography (CT) was scored according to a thin‐section CT scoring system for idiopathic pulmonary fibrosis. Results A total of 85 of 1261 stage III NSCLC patients were found with ILD. Seventeen (20%) of them developed G3+ (greater than or equal to grade 3) RILTs. The incidence abruptly dropped to 11.1%, 3.8%, and 0% for patients with honeycombing score ≤1, V20 1 and V20 ≥20% were independently associated with higher risk of G3+ RILTs. The median overall survival (OS) and progression‐free survival (PFS) were 14.0 months and 7.4 months in the whole group, whereas 26.5 months and 10.6 months in the low‐risk group (patients with honeycombing score 1 and V20 ≥20% were associated with high incidence of RILTs. However, patients with low risk might benefit from IMRT with acceptable toxicities and durable OS.

ObjectiveTo investigate the superiority of the integrated cervicothoracic immobilization devices (ICTID) on the mobility of the supraclavicular station in lung cancer patients requiring both primary lung lesion and positive supraclavicular lymph nodes irradiation.MethodsOne hundred patients with lung cancer were prospectively enrolled in the study. The following four different fixation methods are used for CT simulation positioning: thoracoabdominal flat immobilization device fixation with arms lifting (TAFID group), head-neck-shoulder immobilization device fixation with arms on the body sides (HNSID group), ICTID fixation with arms on the body sides (ICTID arms-down group), and n ICTID fixation with arms lifting (ICTID arms-up group). Cone-beam computed tomography (CBCT) images are taken daily or weekly before treatment, to assess anatomical changes during the radiotherapy course.ResultsThe translation errors in X (left-right direction), Y (head-foot direction), and Z (abdomen-back direction) directions of the ICTID arms-up, TAFID, ICTID arms-down and HNSID groups were (0.15 ± 0.18) cm, (0.15 ± 0.16) cm, (0.16 ± 0.16) cm, and (0.15 ± 0.20) cm; (0.15 ± 0.15) cm, (0.21 ± 0.25) cm, (0.28 ± 0.23) cm, and (0.27 ± 0.21) cm; (0.13 ± 0.14) cm, (0.15 ± 0.14) cm, (0.17 ± 0.13) cm, and (0.16 ± 0.14) cm, respectively. Among them, the ICTID arms-up group had the minimal setup errors in X direction than those in ICTID arms-down (p=0.001) and HNSID groups (p=0.001), and in Y direction than those in TAFID (p

Background: Systematic inflammation is believed to play a crucial role in tumorigenesis and metastasis. This study aims at evaluating the prognostic value of time-series behavior of systematic inflammation-immune status before and after definitive chemoradiotherapy (dCRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC). Methods: The relationship between systematic inflammation-immune score (SIS, defined as pretreatment peripheral platelet count × neutrophil count/lymphocyte count) and the prognosis was tested in a retrospective study of 386 consecutive LA-NSCLC patients (Group A) with pretreatment SIS and 161 patients (Group B) with SIS before and one month after the dCRT. Results: SIS of 1400 × 109 was found to be an optimal cutoff point to stratify the patients into high (>1400 × 109) and low (≤1400 × 109) SIS groups. Univariate and multivariate analyses revealed that the SIS, whether before or after dCRT, was an independent predictor for overall survival (OS), progress-free survival (PFS), and distant metastasis-free survival (DMFS). High SIS (>1400 × 109) was shown to predict poor 3-year OS (P=0.006, hazard ratio [HR]=2.427), PFS (P=0.001, HR=2.442) and DMFS (P=0.015, HR=2.119). However, SIS was not related to local regional recurrence-free survival in either Group A (P=0.346) or Group B (P=0.486). Further, the area under the receiver operating characteristic curve of the SIS for OS was higher than the neutrophil count/lymphocyte count ratio, platelet count/lymphocyte count ratio, and other conventional clinic-pathological indices. Conclusions: The SIS is a stable and more sensitive survival predictor than other inflammation-based factors and conventional clinical indices, which may aid in more accurately stratifying patients for risk assessment and treatment decisions.

Abstract Background The low incidence of primary mediastinal seminomas has precluded the development of clinical trials on mediastinal seminomas. We investigated the clinicopathologic characteristics, prognosis of patients with primary mediastinal seminomas as well as the efficiency of nonsurgical treatments compared with treatments containing surgery. Methods We retrospectively collected data on the clinicopathologic characteristics, treatments, toxicities, and survival of 27 patients from a single center between 2000 and 2018. Patients were divided into two groups according to whether they received operation. Survivals were assessed using the Kaplan–Meier method. Univariate analysis was performed using the log-rank test. Results The median age was 28 (13–63) years. The most common symptoms were chest pain (29.6%), cough (25.9%), and dyspnea (22.2%). There were 13 and 14 patients in surgery and non-surgery group. Patients in the non-surgical group were more likely to be with poor performance scores (100% vs. 76.9%) and disease invaded to adjacent structures (100% vs. 76.9%) especially great vessels (100% vs. 46.2%).The median follow-up period was 32.23 (2.7–198.2) months. There was no significant difference of overall survival (5-year 100% vs. 100%), cancer-specific survival (5-year 100% vs. 100%), local regional survival (5-year 91.7% vs. 90.0%, p = 0.948), distant metastasis survival (5-year 90.9% vs. 100.0%, p = 0.340) and progression-free survival (82.5% vs. 90.0%, p = 0.245) between patients with and without surgery. Conclusions Primary mediastinal seminoma was with favorable prognosis, even though frequently invasion into adjacent structures brings difficulties to surgery administration. Chemoradiotherapy is an alternative treatment with both efficacy and safety.

Abstract Background This study aimed to establish a predictive nomogram integrating epidermal growth factor receptor (EGFR) mutation status for 3‐ and 5‐year overall survival (OS) in unresectable/inoperable stage III non‐small cell lung cancer (NSCLC) treated with definitive chemoradiotherapy. Methods A total of 533 stage III NSCLC patients receiving chemoradiotherapy from 2013 to 2017 in our institution were included and divided into training and testing sets (2:1). Significant factors impacting OS were identified in the training set and integrated into the nomogram based on Cox proportional hazards regression. The model was subject to bootstrap internal validation and external validation within the testing set and an independent cohort from a phase III trial. The accuracy and discriminative capacity of the model were examined by calibration plots, C‐indexes and risk stratifications. Results The final multivariate model incorporated sex, smoking history, histology (including EGFR mutation status), TNM stage, planning target volume, chemotherapy sequence and radiation pneumonitis grade. The bootstrapped C‐indexes in the training set were 0.688, 0.710 for the 3‐ and 5‐year OS. For external validation, C‐indexes for 3‐ and 5‐year OS were 0.717, 0.720 in the testing set and 0.744, 0.699 in the external testing cohort, respectively. The calibration plots presented satisfying accuracy. The derivative risk stratification strategy classified patients into distinct survival subgroups successfully and performed better than the traditional TNM staging. Conclusions The nomogram incorporating EGFR mutation status could facilitate survival prediction and risk stratification for individual stage III NSCLC, providing information for enhanced immunotherapy decision and future trial design.

BackgroundIt is still uncertain whether the newly released eighth American Joint Committee on Cancer (AJCC) post-neoadjuvant pathologic (yp) tumor-node-metastasis (TNM) stage for esophageal carcinoma can perform well regarding patient stratification. The current study aimed to assess the prognostication ability of the eighth AJCC ypTNM staging system and attempted to explore how to facilitate the staging system for more effective evaluation of prognosis.Materials and methodsA total of 486 patients treated with neoadjuvant radiotherapy/chemoradiotherapy (nRT/CRT) were enrolled. ypN stage was reclassified by recursive partitioning. Prognostic performance, monotonicity, homogeneity, and discriminatory of yp and modified yp (myp) staging systems were assessed by time-dependent receiver operating characteristic (ROC), linear trend log-rank test, likelihood ratio χ2 test, Harrell’s c statistic, and Akaike information criterion (AIC).ResultsThe ypT stage, ypN stage, and pathologic response were significant prognostic factors of overall survival. Survival was not discriminated well using the eighth AJCC ypN stage and ypTNM stage. Recursive partitioning reclassified mypN0-N2 as metastasis in 0, 1–2, and ≥3 regional lymph nodes. Applying the ypT stage, mypN stage, and pathologic response to construct the myp staging system, the myp stage performed better in time-dependent ROC, linear trend log-rank test, likelihood ratio χ2 test, Harrell’s c statistic, and AIC.ConclusionsThe eighth AJCC ypTNM staging system performed well in differentiating prognosis to some extent. By reclassifying the ypN stage and enrolling pathologic response as a staging element, the myp staging system holds significant potential for prognostic discrimination.

Background: The surrogacy of progression-free survival (PFS) for overall survival (OS) in esophageal squamous cell carcinoma (ESCC) remains unelucidated. This study aimed to determine the validity of PFS as a surrogate endpoint for OS in ESCC patients treated with definitive radiotherapy or definitive chemoradiotherapy (dRT/dCRT), as well as characterize the prognostic factors and survival of such patients. Methods: A total of 3662 patients from 10 cancer centers were enrolled. One-, 2-, and 3-year PFS (PFS12, PFS24, and PSF36, respectively) were used as time points for analysis. At each time point, ESCC-specific mortality and OS were characterized using competing risk and conditional survival models, while correlation between PFS and OS was evaluated by linear regression. Results: At PFS12, PFS24, and PFS36, a progressive decrease in 5-year ESCC-specific mortality (35.2%–13.4%) and increase in 5-year OS (46.6%–62.9%) were observed. Regardless, the OS of patients remained markedly lower than those of the age- and sex-matched Chinese general population. TNM stage remained a significant prognostic factor at PFS36. Strong correlation was found between 3-year PFS and 5-year OS, which was further externally validated. Conclusions: Three-year PFS may act as a potential surrogate endpoint for 5-year OS. TNM stage was considered a significant prognostic factor for OS, and may represent the optimal prognostic tool to guide clinical decision-making and post-treatment follow-up.

ObjectiveTo investigate whether radiation-induced lymphopenia (RIL) affects survival and identify the predictors of RIL in postoperative esophageal cancer.Materials and methodsPost hoc analysis was conducted on data from 116 patients with esophageal cancer from a randomized controlled trial comparing adjuvant therapy with surgery alone. Doses of 54 Gy in 27 fractions was delivered in the postoperative radiotherapy (PORT) group and 50.4 Gy in 28 fractions combined with chemotherapy was delivered in postoperative concurrent chemoradiotherapy (POCRT) group. Blood counts were obtained before, during, and at first follow-up after treatment. Lymphopenia was graded per version 4.03 of the Common Terminology Criteria for Adverse Events. Disease-free survival (DFS) and overall survival (OS) were analyzed using the Kaplan-Meier method, and compared between groups using the log-rank test. Receiver operating characteristic curves identified thresholds for preventing grade 4 (G4) lymphopenia.ResultsMedian follow-up duration was 56.0 months. During treatment, 16 patients (13.8%) had G4 lymphopenia. All cases of G4 lymphopenia occurred in group PORT (30.2% vs 0.0%, p

Abstract Purpose To investigate the interobserver variability (IOV) in target volume delineation of definitive radiotherapy for thoracic esophageal cancer (TEC) among cancer centers in China, and ultimately improve contouring consistency as much as possible to lay the foundation for multi-center prospective studies. Methods Sixteen cancer centers throughout China participated in this study. In Phase 1, three suitable cases with upper, middle, and lower TEC were chosen, and participants were asked to contour a group of gross tumor volume (GTV-T), nodal gross tumor volume (GTV-N) and clinical target volume (CTV) for each case based on their routine experience. In Phase 2, the same clinicians were instructed to follow a contouring protocol to re-contour another group of target volume. The variation of the target volume was analyzed and quantified using dice similarity coefficient (DSC). Results Sixteen clinicians provided routine volumes, whereas ten provided both routine and protocol volumes for each case. The IOV of routine GTV-N was the most striking in all cases, with the smallest DSC of 0.37 (95% CI 0.32–0.42), followed by CTV, whereas GTV-T showed high consistency. After following the protocol, the smallest DSC of GTV-N was improved to 0.64 (95% CI 0.45–0.83, P = 0.005) but the DSC of GTV-T and CTV remained constant in most cases. Conclusion Variability in target volume delineation was observed, but it could be significantly reduced and controlled using mandatory interventions.

Abstract Background To investigate the survival benefit of concurrent chemoradiotherapy (CCRT) for patients with locally advanced esophageal squamous cell carcinoma (ESCC) during the years of intensity‐modulated radiotherapy (IMRT). Methods Medical records of 1089 patients with ESCC who received IMRT from January 2005 to December 2017 were retrospectively reviewed. A total of 617 patients received CCRT, 472 patients received radiotherapy (RT) alone. Propensity score matching (PSM) method was used to eliminate baseline differences between the two groups. Survival and toxicity profile were evaluated afterward. Results After a median follow‐up time of 47.9 months (3.2–149.8 months), both overall survival (OS) and progression‐free survival (PFS) of the CCRT group were better than those of the RT alone group, either before or after PSM. After PSM, the 1‐, 3‐, and 5‐year OS of RT alone and CCRT groups were 59.0% versus 70.2%, 27.7% versus 40.5% and 20.3% versus 33.1%, respectively (p

Objective: This study aimed to determine the long-term survival of patients with cT4 esophageal cancer (EC) and whether neoadjuvant chemoradiotherapy/radiotherapy plus surgery (nCRT/RT + S) is superior to definitive CRT(dCRT)/RT in terms of survival in cT4 EC downstaged after nCRT/RT. Summary background data: Treatment options for cT4 EC include dCRT/RT and nCRT/RT + S, but it is not clear whether the latter provides survival benefit in patients downstaged after nCRT/RT. Methods: From 2002 to 2017, 726 patients with cT4 esophageal squamous cell carcinoma (ESCC) were retrospectively analyzed. Patients achieving clinical complete response (cCR) or partial response (PR) after 4-week RT (median dose, 40.7 Gy) and considered fit for surgery were offered esophagectomy. Of the 726 patients, 308 (42.4%) achieved cCR/PR, while 74 patients received subsequent surgery (nCRT/RT + S group), 234 patients received dCRT/RT. Results: Median follow-up was 58 months. The 3-year overall survival (OS) and progression-free survival (PFS) rates for all patients were 33.3% and 35.6%, respectively. The corresponding OS and PFS rates were 54.8% and 48.5% in the nCRT/RT + S group versus 30.0% and 22.1% in the dCRT/RT group (both p

PurposeWhilst survival benefits of thoracic radiotherapy (TRT) followed by immune checkpoint inhibitor (ICI) have been reported in patients with lung cancer, the potential high risk of treatment-related pneumonitis remains a concern. Asians may be more sensitive to lung toxicity than other races. This retrospective study intended to provide a comprehensive pneumonitis profile of TRT followed by ICI and investigate the risk factors from a Chinese cohort of lung cancer.Methods and MaterialsFrom January 2016 to July 2021, 196 patients with lung cancer who received TRT prior to ICI were retrospectively analyzed. Treatment-related pneumonitis, including checkpoint inhibitor pneumonitis (CIP), radiation pneumonitis (RP), and radiation recall pneumonitis (RRP), were recorded and graded through medical records and chest computed tomography. Characteristics predictive of pneumonitis were assessed using logistic regression models, and the receiver operating characteristic analyses were performed to identify optimal cut points for quantitative variables.ResultsWith a median follow-up of 18 months, a total of 108 patients (55.1%) developed treatment-related pneumonitis during ICI therapy, with an incidence of 25.5% for grade 2 or higher (G2+) and 4.1% for G3+. The overall rates of CIP, RP and RRP were 8.2% (n=16), 46.9% (n=92) and 7.1% (n=14), respectively. With a total mortality rate of 1.5%, vast majority of the patients recovered from pneumonitis or remained stable. No patients died of RRP. Half of the patients with G2+ RP who withheld ICI therapy restarted ICI safely after resolution of RP. The history of chronic pulmonary diseases (P=0.05), mean lung dose (MLD, P=0.038), percent volume of lung receiving ≥5 Gy (V5, P=0.012) and percent volume of lung receiving ≥20 Gy (V20, P=0.030) predicted the occurrence of RRP in univariate analyses. Interval between TRT and ICI less than 3 months was an independent predictor for G2+ treatment-related pneumonitis in a multivariate model (Odds ratio OR=2.787, P=0.004).ConclusionsTreatment-related pneumonitis, especially RRP, is acceptable and manageable in the setting of TRT followed by ICI in this Asian population. Dosimetric parameters MLD, V5 and V20 may improve the predictions of RRP in clinical practice.

Abstract Background Concurrent epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKI) with radiotherapy in patients with EGFR‐mutant unresectable stage III non‐small cell lung cancer (NSCLC) might improve survival. However, both treatments carry a potential risk of pneumonitis. Methods Between May 2012 and December 2017, patients with unresectable stage III NSCLC treated with concurrent radiotherapy and EGFR‐TKI were enrolled in this retrospective study. The baseline characteristics were evaluated to determine correlations with toxicity development. Results Among 45 eligible patients, 20 (44.4%) had an EGFR mutation and 44 (97.8%) received 50–66 Gy of radiotherapy. The median follow‐up was 62.7 months. The median progression free survival (PFS) and overall survival (OS) for patients with EGFR‐mutations were 27.9 (95% CI: 18.7–37.2) and 49.7 (95% CI: 27.7–71.8) months, and 13.8 (95% CI: 8.8–18.9) and 31.1 (95% CI: 9.8–52.4) months for EGFR wild‐type/unknown patients. A total of 17 patients (37.7%) developed radiation pneumonitis/pneumonitis (14 grade 2, 3 grade 3). In 16 patients, pneumonitis occurred within the radiation field and one patient had bilateral pneumonitis. The median time from the initial radiotherapy to pneumonitis was 74 days. Logistic regression analysis revealed a trend between the time of EGFR‐TKI and the development of G2+ pneumonitis. For late toxicity, only two patients had G2+ fibrosis. The daily dyspnea symptoms of patients with G2+ pneumonitis recovered significantly after the phase of pneumonitis (P = 0.007). Conclusions Combined EGFR‐TKI and radiotherapy showed favorable survival in EGFR‐mutant patients with inoperable stage III NSCLC, with a 6.7% incidence of grade 3 radiation pneumonitis/pneumonitis, despite a higher incidence of mild‐to‐moderate radiation pneumonitis. Key points Significant findings of the study We evaluated the outcomes and radiation pneumonitis after EGFR‐TKI during interval radiotherapy. EGFR‐TKI plus radiotherapy increased survival in patients with EGFR‐mutant inoperable stage III NSCLC. The mild‐to‐moderate radiation pneumonitis incidence increased but no grade 4–‐5 adverse events occurred. What this study adds The combination of EGFR‐TKI and radiotherapy might carry a risk of pneumonitis; however, there are limited data concerning dose constraints. Our results showed a slightly higher incidence of mild or moderate radiation pneumonitis by strict dose limitation.

Abstract Background Since the development of three-dimensional conformal radiotherapy and intensity-modulated radiotherapy (IMRT), no prospective study has investigated whether concurrent chemoradiotherapy (SIB-IMRT with 60 Gy) remains superior to radiotherapy (SIB-IMRT) alone for unresectable esophageal cancer (EC). Furthermore, the optimal therapeutic regimen for patients who cannot tolerate concurrent chemoradiotherapy is unclear. We recently completed a phase I/II radiation dose-escalation trial using simultaneous integrated boost (SIB), elective nodal irradiation, and concurrent chemotherapy for unresectable EC. We now intend to conduct a prospective, phase III, randomized study of SIB-IMRT with or without concurrent chemotherapy. We aim to find a safe, practical, and effective therapeutic regimen to replace the conventional segmentation (1.8–2.0 Gy) treatment mode (radiotherapy ± chemotherapy) for unresectable EC. Methods This two-arm, open, randomized, multicenter, phase III trial will recruit esophageal squamous cell carcinoma patients (stage IIA–IVB [UICC 2002]; IVB only with metastasis to the supraclavicular or celiac lymph nodes). In all, 164 patients will be randomized using a 1:1 allocation ratio, and stratified by study site and disease stage, especially the extent of lymph node metastasis. Patients in the SIB arm will receive definitive SIB radiotherapy (95% planning target volume/planning gross tumor volume, 50.4 Gy/59.92 Gy/28 f, equivalent dose in 2-Gy fractions = 60.62 Gy). Patients in the SIB + concurrent chemotherapy arm will receive definitive SIB radiotherapy with weekly paclitaxel and a platinum-based drug (5–6 weeks). Four cycles of consolidated chemoradiotherapy will also be recommended. The primary objective is to compare the 1-year, 2-year, and 3-year overall survival of the SIB + chemotherapy group and SIB groups. Secondary objectives include progression-free survival, local recurrence-free rate, completion rate, and adverse events. Detailed radiotherapy protocol and quality-assurance procedures have been incorporated into this trial. Discussion In unresectable, locally advanced EC, a safe and effective total radiotherapy dose and reasonable segmentation doses are required for the clinical application of SIB-IMRT + two-drug chemotherapy. Whether this protocol will replace the standard treatment regimen will be prospectively investigated. The effects of SIB-IMRT in patients with poor physical condition who cannot tolerate definitive chemoradiotherapy will also be investigated. Trial registration clinicaltrials.gov ( NCT03308552 , November 1, 2017).

Abstract Background Currently, adjuvant therapy is not recommended for patients with thoracic esophageal squamous cell cancer (TESCC) after radical surgery, and a proportion of these patients go on to develop locoregional recurrence (LRR) within 2 years. Besides, there is no evidence for salvage chemoradiation therapy (CRT) in patients with residual tumor after esophagectomy (R1/R2 resection). In addition, factors like different failure patterns and relationship with normal organs influence the decision for salvage strategy. Here, we aimed to design a modularized salvage CRT strategy for patients without a chance of salvage surgery according to different failure patterns (including R1/R2 resection), and further evaluated its efficacy and safety. Methods Our study was designed as a one arm, multicenter, prospective clinical trial. All enrolled patients were stratified in a stepwise manner based on the nature of surgery (R0 or R1/2), recurrent lesion diameter, involved regions, and time-to-recurrence, and were further assigned to undergo either elective nodal irradiation or involved field irradiation. Then, radiation technique and dose prescription were modified according to the distance from the recurrent lesion to the thoracic stomach or intestine. Ultimately, four treatment plans were established. Discussion This prospective study provided high-level evidence for clinical salvage management in patients with TESCC who developed LRR after radical surgery or those who underwent R1/R2 resection. Trial registration Prospectively Registered. ClinicalTrials.gov NCT03731442 , Registered November 6, 2018.

Abstract Background The objectives of this study were to determine the objective effective response rate, survival, and safety of radiotherapy combined with gefitinib in patients with locally advanced non-small cell lung cancer (NSCLC) who were unfit for surgery or concurrent chemoradiotherapy. Methods The patients with the locally advanced NSCLC who were unfit to receive surgery or concurrent chemoradiotherapy, received thoracic intensity-modulated radiotherapy (IMRT) combined with gefitinib 250 mg daily. Results 29 patients were enrolled between July 2014 and March 2017. 28 patients was in the analysis. Of the 28 patients, 21 (75.0%) experienced a partial response, 5 (17.9%) had stable disease, and 2 (7.1%) experienced progression of disease. The objective response rate was 75.0%, and the disease control rate was 92.9%. The median follow-up time was 51 months. The disease progression showed in 25 (89.3%) patients, including local progression in 19 (67.9%) and distant metastasis in 16 (57.1%). The median overall survival and progression-free survival time (PFS) were 26 and 11 months, respectively. The 3-, 4-, 5-year survival rates were 39.0, 30.1 and 30.1%, respectively. The 3-, 4-, 5-year PFS rates were 14.3, 9.5 and 9.5%. Two patients developed grade 3 acute adverse events. Seven patients developed grade 2 acute irradiation pneumonitis, and there was no grade 3 acute irradiation pneumonitis. Conclusions For patients with locally advanced NSCLC who are not eligible for surgery or concurrent chemoradiotherapy, IMRT combined with gefitinib can improve the objective effective rate and is generally well-tolerated.

Abstract Background There is no consensus on the therapeutic approach to ECOG 2 patients with locally advanced non-small-cell lung cancer (LA-NSCLC), despite the sizable percentage of these patients in clinical practice. This study focused on the efficacy, toxicity and the optimal chemotherapy regimen of CCRT in ECOG 2 patients in a phase III trial. Methods Patients capable of all self-care with bed rest for less than 50% of daytime were classified as ECOG 2 subgroup. A subgroup analysis was performed for ECOG 2 patients recruited in the phase III trial receiving concurrent EP (etoposide + cisplatin)/PC (paclitaxel + carboplatin) chemotherapy with intensity-modulated radiation therapy (IMRT) or three-dimensional conformal external beam radiation therapy (3D-CRT). Results A total of 71 ECOG 2 patients were enrolled into the study. Forty-six (64.8%) patients were treated with IMRT technique. The median overall survival (OS) and progression free survival (PFS) for ECOG 2 patients were 16.4 months and 9 months, respectively. No difference was observed in treatment compliance and toxicities between ECOG 2 patients and ECOG 0–1 patients. Within the ECOG 2 group (31 in the EP arm and 40 in the PC arm), median OS and 3-year OS were 15.7 months and 37.5% for the EP arm, and 16.8 months and 7.5% for the PC arm, respectively (p = 0.243). The incidence of grade ≥ 3 radiation pneumonitis was higher in the PC arm (17.5% vs. 0.0%, p = 0.014) with 5 radiation pneumonitis related deaths, while the incidence of grade 3 esophagitis was numerically higher in the EP arm (25.8% vs. 10.0%, p = 0.078). Conclusions CCRT provided ECOG 2 patients promising outcome with acceptable toxicities. EP might be superior to PC in terms of safety profile in the setting of CCRT for ECOG 2 patients. Prospective randomized studies based on IMRT technique are warranted to validate our findings. Trial registration ClinicalTrials.gov registration number: NCT01494558 . (Registered 19 December 2011).

Abstract Background Information on the optimal salvage regimen for recurrent esophageal cancer is scarce. We aimed to assess the patterns of locoregional failure, and evaluate the therapeutic efficacy of salvage therapy along with the prognostic factors in recurrent thoracic esophageal squamous cell carcinoma (TESCC) after radical esophagectomy. Methods A total of 193 TESCC patients who were diagnosed with recurrence after radical surgery and received salvage treatment at our hospital were retrospectively reviewed from 2004 to 2014. The patterns of the first failure were assessed. The post-recurrence survival rate was determined using the Kaplan-Meier method and analyzed using the log-rank test. Multivariate prognostic analysis was performed using the Cox proportional hazard model. Results The median time of failure was 7.0 months. Among the 193 patients, 163 exhibited isolated locoregional lymph node (LN) recurrence and 30 experienced locoregional LN relapse with hematogenous metastasis. Among the 193 patients, LN recurrence was noted at 302 sites; the most common sites included the supraclavicular (25.8%; 78/302) and mediastinal LNs (44.4%; 134/302), particularly stations 1 to 6 for the mediastinal LNs (36.4%; 110/302). The median overall survival (OS) was 13.1 months after recurrence. In those treated with salvage chemoradiotherapy, with radiotherapy, and without radiotherapy, the 1-year OS rates were 68.5, 55.0, and 28.6%; the 3-year OS rates were 35.4, 23.8, and 2.9%; and the 5-year OS rates were 31.8, 17.2, 2.9%, respectively (P

Abstract Background Preoperative chemoradiotherapy (CRT) followed by surgery is the most common approach for patients with resectable esophageal cancer. Nevertheless, considerable numbers of esophageal-cancer patients undergo surgery as the first treatment. The benefit of neoadjuvant therapy might only be for patients with a pathologic complete response, so stratified research is necessary. Postoperative treatments have important roles because of the poor survival rates of patients with stage-IIB/III disease treated with resection alone. Five-year survival of patients with stage-IIB/III thoracic esophageal squamous cell carcinoma (TESCC) after surgery is 20.0–28.4%, and locoregional lymph-node metastases are the main cause of failure. Several retrospective studies have shown that postoperative radiotherapy (PORT) and postoperative chemoradiotherapy (POCRT) after radical esophagectomy for esophageal carcinoma with positive lymph-node metastases and stage-III disease can decrease locoregional recurrence and increase overall survival (OS). Using intensity-modulated RT, PORT reduces locoregional recurrence further. However, the rate of distant metastases increases to 30.7%. Hence, chemotherapy may be vital for these patients. Therefore, a prospective randomized controlled trial (RCT) is needed to evaluate the value of PORT and concurrent POCRT in comparison with surgery alone (SA) for esophageal cancer. Method This will be a phase-II/III RCT. The patients with pathologic stage-IIB/III esophageal squamous cell carcinoma will receive concurrent POCRT or PORT after radical esophagectomy compared with those who have SA. A total of 120 patients in each group will be recruited. POCRT patients will be 50.4 Gy concurrent with paclitaxel (135–150 mg/m2) plus cisplatin or nedaplatin (50–75 mg/m2) treatment every 28 days. Two cycles will be required for concurrent chemotherapy. The prescription dose will be 54 Gy for PORT. The primary endpoint will be disease-free survival (DFS). The secondary endpoint will be OS. Other pre-specified outcome measures will be the proportion of patients who complete treatment, toxicity, and out-of-field regional recurrence rate between PORT and POCRT. Discussion This prospective RCT will provide high-level evidence for postoperative adjuvant treatment of pathologic stage-IIB/III esophageal squamous cell carcinoma. Trial registration clinicaltrials.gov (NCT02279134). Registered on October 26, 2014.

Background: EGFR tyrosine kinase inhibitor (TKI) is recommended as the first-line therapy for patients with EGFR-mutant metastatic non-small cell lung cancer (NSCLC). Yet, resistance often occurs in 1 year after therapy and most progressions occur at the initial sites of disease. Addition of local therapy to the first-line TKI therapy may delay the progression and provide survival benefit to the patients. Methods: From 2010 to 2017, metastatic NSCLC patients with EGFR activating mutations who received first-line TKI and relatively radical local therapy (RRLT) were reviewed. RRLT was defined as local curative therapy to the main site or any intensity of local therapy to all sites of disease. The Kaplan-Meier method and log-rank test were used for survival estimation and comparison. Results: A total of 45 patients were included in this retrospective study with a median follow-up of 48.0 months. The median progression-free survival (PFS) and overall survival (OS) was 17.0 months (95% confidence interval [CI]: 14.6-19.3) and 55.0 months (95% CI: 49.3-60.6), respectively. Univariate analysis indicated that age ⩽ 60 years ( P = .019), first-line TKI duration ⩾ 10 months ( P = .028), and accumulated TKI duration ⩾ 20 months ( P = .016) were significantly associated with favorable OS. Among the 36 patients who progressed during the follow-up, 55.8% of the progressions occurred at the new sites. RRLT combined with TKI did not show any severe toxicity to the patients. Conclusions: Combined application of RRLT and first-line TKI may improve the survival and alter the pattern of failure for metastatic NSCLC patients with EGFR activating mutations.

BackgroundBrain metastasis (BM) is one of the most common failure patterns of pIIIA-N2 non-small cell lung cancer (NSCLC) after complete resection. Prophylactic cranial irradiation (PCI) can improve intracranial control but not overall survival. Thus, it is particularly important to identify the risk factors that are associated with BM and subsequently provide instructions for selecting patients who will optimally benefit from PCI.Methods and MaterialsBetween 2011 and 2014, patients with pIIIA-N2 NSCLC who underwent complete resection in our institution were reviewed and enrolled in the study. Clinical characteristics, pathological parameters, treatment mode, BM time, and overall survival were analyzed. A nomogram was built based on the corresponding parameters by Fine and Gray’s competing risk analysis to predict the 1-, 3-, and 5-year probabilities of BM. Receiver operating characteristic curves and calibration curves were chosen for validation. A statistically significant difference was set as P

Background: A reliable model is needed to estimate the risk of postoperative recurrence and the benefits of postoperative radiotherapy (PORT) in patients with thoracic esophageal squamous cell cancer (TESCC). Methods: The study retrospectively reviewed 3652 TESCC patients in stage IB-IVA after radical esophagectomy, with or without PORT. In one institution as the training cohort ( n = 1620), independent risk factors associated with locoregional recurrence (LRR), identified by the competing-risks regression, were used to establish a predicting nomogram, which was validated in an external cohort ( n = 1048). Area under curve (AUC) values of receiver operating characteristic curves were calculated to evaluate discrimination. Risk stratification was conducted using a decision tree analysis based on the cumulative point score of the LRR nomogram. After balancing the baseline of characteristics between treatment groups by inverse probability of treatment weighting, the effect of PORT was evaluated in each risk group. Results: Sex, age, tumor location, tumor grade, and N category were identified as independent risk factors for LRR and added into the nomogram. The AUC values were 0.638 and 0.706 in the training and validation cohorts, respectively. Three risk groups were established. For patients in the intermediate- and high-risk groups, PORT significantly improved the 5-year overall survival by 10.2% and 9.4%, respectively ( p

BackgroundThe aim of this study was to compare the effects of simultaneous integrated boost–intensity modulated radiotherapy (SIB-IMRT) and conventional fractionated-IMRT (CF-IMRT) for patients with esophageal squamous cell carcinoma (ESCC).MethodsThe data of 1173 patients treated with either CF-IMRT or SIB-IMRT for a curative intent from 2005 to 2016 were retrospectively reviewed. Propensity score matching (PSM) was used to create a well-balanced cohort of 687 patients at 1:2 ratio (237 patients in SIB-IMRT group and 450 patients in CF-IMRT group). Overall survival (OS), progression-free survival (PFS), recurrence pattern, and toxicity profiles were evaluated and compared between the two groups after PSM.ResultsAfter a median follow-up time of 42.3 months (range, 3.0-153.2 months) for surviving patients, survival results were comparable in the two groups. After PSM, the 1-year, 2-year and 4-year OS rates in the SIB-IMRT and CF-IMRT groups were 70.0% vs. 66.4%, 41.9% vs. 41.7% and 30.2% vs. 27.6%, respectively (p = 0.87). The 1-year, 2-year and 4-year PFS rates were 48.4% vs. 49.1%, 31.2% vs. 29.4%, and 26.1% vs. 17.9%, respectively (p = 0.64). Locoregional recurrence (p = 0.32) and distant metastasis (p = 0.54) rates were also comparable between two groups. The toxicity profile was similar in the two groups. Multivariate analyses in the matched samples showed that female, concurrent chemotherapy and earlier clinical stage were independently associated with longer OS and PFS.ConclusionsSIB-IMRT appears to be equivalent to CF-IMRT in treatment efficacy and safety, and could become an alternative option for definitive radiotherapy of ESCC.

Background Whether postoperative radiotherapy is beneficial in the treatment of esophageal squamous cell carcinoma with one or two regional lymph node (LN) metastases (pN1) after esophagectomy is uncertain. This study aimed to explore the effect of postoperative radiotherapy (PORT) on survival. Methods Propensity score‐matching (PSM) analysis was conducted to balance the two arms (surgery only [S] or surgery plus postoperative radiotherapy [PORT]). The survival rate was calculated by the Kaplan‐Meier method and analyzed using the log‐rank test. Results A total of 992 cases confirmed positive for one or two regional LN metastases were eligible. After PSM, 622 patients were reviewed. Each group consisted of 311 cases. The median follow‐up was 80.7 months. For the overall cohort, the one‐, three‐ and five‐year overall survival (OS) were 90.6%, 51.9% and 38.2%, respectively. Disease‐free survival (DFS) was 76.0%, 41.4% and 32.1%, respectively. The five‐year OS and DFS were 45.0% and 39.8% for PORT, which was significantly higher than the S group (31.3% and 24.2%, both P

Abstract Background Consistent results are lacking as regards the comparative effectiveness of simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) versus conventional intensity-modulated radiotherapy in patients with locally advanced non-small-cell lung cancer (LA-NSCLC). Therefore, we conducted a retrospective analysis to demonstrate the role of SIB-IMRT for patients. Methods Patients who had histologically confirmed NSCLC, stage III disease and received thoracic IMRT between 2014 and 2016 were retrospectively reviewed. The survival, toxicities and dose to organs at risk (OAR) were compared among patients irradiated with different techniques. The SIB-IMRT plans were designed to deliver 45–59.4Gy (median: 50.4Gy) to PTV while simultaneously delivering 50-70Gy (median: 59.92Gy) to PGTV. As for conventional IMRT plans, a total dose of 50-70Gy (median: 60Gy) was delivered to PTV. Results 426 patients with stage III NSCLC were eligible for analysis, including 128 with SIB-IMRT and 298 with conventional IMRT. The SIB-IMRT group had more stage IIIB disease (69.5% vs. 53%, P = 0.002), larger planning treatment volumes (median: 504 ml vs. 402 ml, P

Abstract Background There were few reports of postoperative radiotherapy (PORT) in stage pIII-N2 Non-small-cell Lung Cancer (NSCLC) patients receiving pneumonectomy followed by adjuvant chemotherapy. This study aims to evaluate safety and efficacy of PORT among these patients. Methods Between Jan. 2004 and Dec. 2015, stage pIII-N2 NSCLC patients receiving pneumonectomy and adjuvant chemotherapy with or without PORT in our institution were retrospectively reviewed. Results Totally 119 patients were included, 32 patients receiving adjuvant chemotherapy and PORT (PORT group) and 87 receiving adjuvant chemotherapy alone (Control group). There were more patients with non-R0 resection in PORT group than Control group (25% vs. 8%, p = 0.031). In PORT group, ≥Grade 2 radiation-induced pneumonitis was 2/32. No severe radiation-related heart injury was observed. There was no PORT-related death. Of all patients, median follow-up time was 25 months. Median overall survival time (mOS) and median disease-free survival time (mDFS) were 46 months and 15 months, respectively. The PORT group had significantly better OS (not reached vs. 34 months, p = 0.003), DFS (19 months vs. 13 months, p = 0.024), local recurrence free survival (LRFS, p = 0.012), and distant metastasis free survival (DMFS, p = 0.047) than the Control group. As for failure pattern, PORT significantly reduced local regional failure rate (39.1% vs. 15.6%, p = 0.016). In subgroup analysis, patients with R0 resection (n = 104), OS and LRFS in PORT group were significantly longer, and PORT tended to increase DFS and DMFS. Conclusion For patients with stage pIII-N2 NSCLC after pneumonectomy and adjuvant chemotherapy, PORT can improve OS, DFS, LRFS and DMFS with tolerable toxicity.

Background The role of thoracic radiation therapy (TRT) after chemotherapy (CHT) in extensive‐stage small cell lung cancer (ES‐SCLC) has not been well defined. We investigated whether intensity‐modulated radiotherapy (IMRT) improves outcomes in ES‐SCLC after CHT compared to CHT alone. Methods A total of 292 patients who reached a complete response (CR), partial response (PR), or stable disease (SD) after CHT were assigned into groups: CHT + TRT and CHT alone. Propensity score matching was used to balance patient groups (n = 72 each). Results The five‐year overall survival (OS: 12.3% vs. 3.6%; P 6 cycles of CHT (P = 0.042), CR + PR after CHT (P

Abstract Background The importance of definitive radiotherapy for elderly patients with esophageal and esophagogastric-junction cancer is pronounced. However, little is known in terms of the best way to combine radiotherapy with other treatment options. This study aims to compare the efficiency of SIB radiotherapy alone with SIB radiotherapy concurrent and consolidated with S-1 for elderly patients. Comprehensive geriatric assessment is also incorporated in the procedure of treatment. Methods/design The study is a two arm, open, randomized multicenter Phase III trial with patients over 70 years old with stage IIA-IVB (UICC 2002, IVB only with metastasis to supraclavicular or celiac lymph nodes) squamous cell carcinoma or adenocarcinoma of esophagus or gastroesophageal junction. A total of 300 patients will be randomized using a 1:1 allocation ratio stratified by disease stage and study site. Patients allocated to the SIB arm will receive definitive SIB radiotherapy (95%PTV/PGTV 50.4Gy/59.92Gy/28f) while those randomized to SIB + S-1 arm will receive definitive SIB radiotherapy concurrent and consolidated with S-1. The primary endpoint of the trial is 1-year overall survival. Secondary objectives include progression-free survival, recurrence-free survival (local-regional and distant), disease failure pattern, toxicity profile as well as quality of life. Besides, detailed radiotherapy protocol and quality assurance procedure have been incorporated into this trial. Discussion The proportion of elderly patients in esophageal cancer is now growing, but there is a lack of evidence in term of treatment standard for this group of patients, which is what we aim to obtain through this prospective phase III study. Trial registration clinicaltrials.gov NCT02979691. Registered November 22, 2016.

Abstract Background To investigate the safety and tolerability of simultaneous integrated boost (SIB) technique concurrent with elective nodal irradiation (ENI) and dual-drug chemotherapy for patients with unresectable esophageal cancer. Methods In phase I, the prophylactic PTV received a stable dose of 50.40Gy/1.80Gy/28f while the boost area was planned with 3 consecutive dose levels: the first dose level was 60.76Gy/2.17Gy/28f, and then escalated approximately every 2 Gy. ENI was incorporated in Clinical Target Volume (CTV), and paclitaxel and nedaplatin were given concurrently for at least 5 weeks. In phase II, enrolled patients were treated with Maximum Tolerated Dose (MTD) obtained in phase I and the compliance rate, survival results and toxicities were evaluated. Results From December 2014 to April 2017, 53 patients were enrolled. In phase I, 2 out of 6 patients developed Dose-Limiting Toxicity (DLT) at dose level 1. Due to excessive treatment-related toxicities, the escalation process was suspended and de-escalated to 59.92Gy /2.14Gy /28 f. Three patients were treated at this dose level, all of whom completed at least 5 weeks of chemotherapy and none of whom reached a DLT, determining the newly added dose level to be the MTD. In phase II, 44 patients were treated with MTD, 31 of them (70.0%) completed at least 5 weeks of chemotherapy. The most common Grade 3 or 4 toxicities in phase II included leukopenia (21%) and esophagitis (15%). With a median follow-up time of 16.9 months, 1-y OS, DFS and local failure-free survival were 76.9, 63.6 and 78.8% respectively. Conclusion The SIB technique was feasible and safe at the MTD (95% PGTV/PTV 59.92/50.40Gy/28f) concurrent with ENI and dual-drug chemotherapy for patients with unresectable esophageal cancer. Trial registration clinicaltrials.gov NCT02429622. Retrospectively registered on April 24, 2015.

ObjectiveCirculating tumor cells (CTCs) can predict the efficacy of anti-cancer treatments and indicate prognosis. Here we investigate the significance of CTCs in relation to the prediction of treatment efficacy and prognosis in patients with small cell lung cancer (SCLC) who have received prophylactic cranial irradiation (PCI).MethodsCTCs were detected in 20 patients with SCLC before and after PCI using the oHSV1-hTERT-GFP method. The primary endpoints were progression-free survival (PFS) and overall survival (OS).ResultsEleven patients had limited-stage SCLC, and nine had extensive-stage SCLC. All patients completed chemo-radiotherapy and received PCI. The median baseline CTC count before PCI was 12. After PCI, the median CTC count was 4. The median follow-up time for all enrolled patients was 39.2 months. The median PFS and OS were significantly reduced in patients with ≥4 CTCs after PCI compared to those with

ObjectiveThe association between the prognosis of thymoma and MG remains controversial. Differences in clinical characteristics and treatments between patients with and without MG may affect the findings of those studies. We designed this propensity score matching trial to investigate whether MG is an independent prognostic predictor in thymoma.MethodsPatients with pathologically diagnosed thymoma and MG were enrolled in the MG group. Moreover, the propensity score matching method was used to select patients who were diagnosed with thymoma without MG from the database of two participating centers. Matched factors included sex, age, Masaoka stage, pathological subtypes, and treatments. Matched patients were enrolled in the non-MG group. Chi-squared test was used to compare the characteristics of the two groups. Overall survival, local-regional relapse-free survival, distant metastasis-free survival, progression-free survival, and cancer-specific survival were calculated from the diagnosis of thymoma using the Kaplan–Meier method.ResultsBetween April 1992 and October 2018, 235 patients each were enrolled in the MG and non-MG groups (1:1 ratio). The median ages of patients in the MG and non-MG groups were 46 years old. The World Health Organization pathological subtypes were well balanced between the two groups (B2 + B3: MG vs. non-MG group, 63.0 vs. 63.4%, p = 0.924). Most patients in both groups had Masaoka stages I–III (MG vs. non-MG group, 90.2 vs. 91.5%, p = 0.631). R0 resections were performed in 86.8 and 90.2% of the MG and non-MG groups, respectively (p = 0.247). The median follow-up time of the two groups was 70.00 months (MG vs. non-MG group, 73.63 months vs. 68.00 months). Five-year overall survivals were 92.5 and 90.3%, 8-year overall survivals were 84.2 and 84.2%, and 10-year overall survivals were 80.2 and 81.4% (p = 0.632) in the MG and non-MG groups, respectively. No differences were found in the progression-free survival, distant metastasis-free survival, and local-regional relapse-free survival between the two groups.ConclusionMG is not an independent or direct prognostic factor of thymoma, although it might be helpful in diagnosis thymoma at an early stage, leading indirectly to better prognosis.

Introduction: Intensive treatments can often not be administered to elderly patients with esophageal squamous cell carcinoma (ESCC), leading to a poorer prognosis. This multi-center phase II trial aimed to determine the toxicity profile and efficiency of S-1–based simultaneous integrated boost radiotherapy (SIB-RT) followed by consolidation chemotherapy with S-1 in elderly ESCC patients and to evaluate the usefulness of comprehensive geriatric assessment (CGA).Patients and Methods: We prospectively enrolled 46 elderly patients (age ≥ 70 years) with histopathologically proven ESCC. The patients underwent pretreatment CGA followed by SIB-RT (dose, 59.92 Gy/50.4 Gy) in 28 daily fractions administered using intensity-modulated radiotherapy or volumetric-modulated arc therapy. S-1 was orally administered (40–60 mg/m2) concurrently with radiotherapy and 4–8 weeks later, for up to four 3-week cycles at the same dose.Results: The median survival time was 22.6 months. The 1- and 2-year overall survival rates were 80.4 and 47.8%, respectively. The overall response rate was 78.3% (36/46). The incidence of grade 3–4 toxicities was 28% (13/46). The most common grade 3–4 toxicities were radiation esophagitis (5/46, 10.9%), nausea (4/46, 8.7%), anorexia (3/46, 6.5%), and radiation pneumonitis (3/46, 6.5%). There were no grade 5 toxicities. CGA identified that 48.8% of patients were at risk for depression and 65.5% had malnutrition.Conclusion: Concurrent S-1 treatment with SIB-RT followed by 4 cycles of S-1 monotherapy yielded satisfactory tumor response rates and manageable toxicities in selected elderly patients with ESCC. Pretreatment CGA uncovered numerous health problems and allowed the provision of appropriate supportive care.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT02979691.

Radiation pneumonitis (RP) is one of the major side effects of thoracic radiotherapy. The aim of this study is to build a dose distribution based prediction model, and investigate the correlation of RP incidence and high-order features of dose distribution. A convolution 3D (C3D) neural network was used to construct the prediction model. The C3D network was pre-trained for action recognition. The dose distribution was used as input of the prediction model. With the C3D network, the convolution operation was performed in 3D space. The guided gradient-weighted class activation map (grad-CAM) was utilized to locate the regions of dose distribution which were strongly correlated with grade≥2 and grade

OBJECTIVES: This study aimed to: (1) assess the prognostic significance of serum tumor markers in locally advanced squamous cell carcinoma in lung (LA-SCCL); (2) generate a nomogram to predict the overall survival (OS) and (3) identify a prognostic stratification to assist the therapeutic decision-making. METHODS: LA-SCCL patients receiving definitive radiotherapy and baseline tumor marker measurement were eligible for this retrospective study. Cox proportional hazards regression was used to determine independent factors associated with various survival indexes and a nomogram was created to estimate the 5-year OS probability for individual patient. The identified prognostic factors were recruited into a recursive partitioning analysis (RPA) for OS to stratify patients with distinct outcome. RESULTS: A total of 224 patients were eligible for analysis. Increased cytokeratin-19 fragment (CYFRA 21-1) was independently associated with inferior OS, progression free survival (PFS) and a borderline decreased local-regional progression free survival (LRPFS). Elevated carcino-embryonic antigen (CEA) served as an unfavorable determinant for OS and increased neuron-specific enolase (NSE) was predictive of poor distant metastasis free survival (DMFS). A nomogram integrating KPS, TNM stage, CEA and CYFRA 21-1 was created, resulting in a c-index of 0.62. RPA identified 4 prognostic classifications, with median OS of 27.6, 19.9, 17.3 and 10.9 months for low, intermediate, high and very-high risk groups, respectively. CONCLUSIONS: Baseline tumor marker panel including CYFRA 21-1, CEA and NSE can be prognostic of outcome for LA-SCCL receiving definitive radiotherapy. The RPA identified four prognostic subgroups, which could assist personalized therapy and clinical trial design in LA-SCCL.

Abstract Background Heath-related quality of life (HRQoL) among survivors with unresectable locally-advanced non-small cell lung cancer (LA-NSCLC) treated with radiotherapy and chemotherapy still is not clear. The current study were performed to determine HRQoL for long-term survivors with unresectable LA-NSCLC and to identify risk factors for poor HRQoL. Methods Among patients with LA-NSCLC receiving radiotherapy and chemotherapy between January 2006 and December 2010, 82 long-term survivors beyond 5 years were identified in this cross-sectional study. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 and the lung cancer-specific questionnaire QLQ-LC13 were employed to gather information on HRQoL. HRQoL scores were compared between different subgroups to analyze factors related to HRQoL. Results Fifty-five out of 82 (67%) long-term survivors completed the HRQoL survey. They reported a mild reduction in global health status and physical and emotional functioning. Fatigue, dyspnea, coughing, and financial difficulties ranked the highest scores in the symptom scales. Analysis of risk factors for HRQoL showed age, exercise, smoking status, and treatment regimen were associated with global health status and functional scores, while age, gender, radiation pneumonitis, weight loss, and exercise were associated with symptom scores. Conclusions This study provides the first description of the HRQoL of long-term LA-NSCLC survivors receiving radiotherapy and chemotherapy who may experience a relatively high HRQoL. Factors related to poorer HRQoL are potential targets for intervention.

Purpose: To investigate whether a deep learning-assisted contour (DLAC) could provide greater accuracy, inter-observer consistency, and efficiency compared with a manual contour (MC) of the clinical target volume (CTV) for non-small cell lung cancer (NSCLC) receiving postoperative radiotherapy (PORT).Materials and Methods: A deep dilated residual network was used to achieve the effective automatic contour of the CTV. Eleven junior physicians contoured CTVs on 19 patients by using both MC and DLAC methods independently. Compared with the ground truth, the accuracy of the contour was evaluated by using the Dice coefficient and mean distance to agreement (MDTA). The coefficient of variation (CV) and standard distance deviation (SDD) were rendered to measure the inter-observer variability or consistency. The time consumed for each of the two contouring methods was also compared.Results: A total of 418 CTV sets were generated. DLAC improved contour accuracy when compared with MC and was associated with a larger Dice coefficient (mean ± SD: 0.75 ± 0.06 vs. 0.72 ± 0.07, p < 0.001) and smaller MDTA (mean ± SD: 2.97 ± 0.91 mm vs. 3.07 ± 0.98 mm, p < 0.001). The DLAC was also associated with decreased inter-observer variability, with a smaller CV (mean ± SD: 0.129 ± 0.040 vs. 0.183 ± 0.043, p < 0.001) and SDD (mean ± SD: 0.47 ± 0.22 mm vs. 0.72 ± 0.41 mm, p < 0.001). In addition, a value of 35% of time saving was provided by the DLAC (median: 14.81 min vs. 9.59 min, p < 0.001).Conclusions: Compared with MC, the DLAC is a promising strategy to obtain superior accuracy, consistency, and efficiency for the PORT-CTV in NSCLC.

Radiation pneumonitis (RP) is one of the major toxicities of thoracic radiation therapy. RP incidence has been proven to be closely associated with the dosimetric factors and normal tissue control possibility (NTCP) factors. However, because these factors only utilize limited information of the dose distribution, the prediction abilities of these factors are modest. We adopted the dosiomics method for RP prediction. The dosiomics method first extracts spatial features of the dose distribution within ipsilateral, contralateral, and total lungs, and then uses these extracted features to construct prediction model via univariate and multivariate logistic regression (LR). The dosiomics method is validated using 70 non-small cell lung cancer (NSCLC) patients treated with volumetric modulated arc therapy (VMAT) radiotherapy. Dosimetric and NTCP factors based prediction models are also constructed to compare with the dosiomics features based prediction model. For the dosimetric, NTCP and dosiomics factors/features, the most significant single factors/features are the mean dose, parallel/serial (PS) NTCP and gray level co-occurrence matrix (GLCM) contrast of ipsilateral lung, respectively. And the area under curve (AUC) of univariate LR is 0.665, 0.710 and 0.709, respectively. The second significant factors are V5 of contralateral lung, equivalent uniform dose (EUD) derived from PS NTCP of contralateral lung and the low gray level run emphasis of gray level run length matrix (GLRLM) of total lungs. The AUC of multivariate LR is improved to 0.676, 0.744, and 0.782, respectively. The results demonstrate that the univariate LR of dosiomics features has approximate predictive ability with NTCP factors, and the multivariate LR outperforms both the dosimetric and NTCP factors. In conclusion, the spatial features of dose distribution extracted by the dosiomics method effectively improves the prediction ability.

Following publication of the original article [1], the authors reported that an error in the Methods/Design, Study design and objectives section (third sentence).

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for locally advanced non-small-cell lung cancer (LANSCLC), whereas responses to anti-programmed cell death-1 (PD-1) or antiprogrammed death-ligand 1 (PD-L1) are heterogeneous. Though consolidation ICI following concurrent chemoradiotherapy (cCRT) improves survival of NSCLC, this regimen is challenging for patients with bulky tumors due to excessive target volumes and radiation-resistant hypoxia during upfront cCRT, leading to higher risk of pneumonitis and inferior local-regional control. Recent trials have demonstrated neoadjuvant ICI brought greater benefit to stage III than stage III NSCLC. Our previous study also supported the therapeutic advantage of 2-cycle induction ICI for patients with bulky unresectable stage III NSCLC. In the context of induction immunotherapy, radiotherapy is more likely to exert immune synergistic effects, reverse anti-PD-1 resistance, and activate abscopal immune responses. Prospective trials to determine the efficacy and safety of induction ICI for bulky LA-NSCLC are necessary. Methods: This randomized, open-label, two-arm phase II study aims to explore whether 2 cycles of induction anti-PD-1 toripalimab plus chemotherapy can improve progression-free survival (PFS) in bulky LA-NSCLC. Bulky tumors are defined as primary lesion ≥5 cm in greatest dimension or metastatic lymph nodes ≥2 cm in shortest diameter. A total of 50 patients with bulky unresectable stage III NSCLC will be recruited and 1:1 randomized into the experimental arm: 2-cycle induction PD-1 inhibitor toripalimab plus chemotherapy followed by cCRT and consolidation toripalimab; or control arm: 2-cycle induction chemotherapy followed by cCRT and consolidation toripalimab. Patients are stratified by pathology (squamous versus nonsquamous). The primary endpoint is PFS. Secondary endpoints are overall survival, overall response rate, disease control rate, duration of response, and incidence of adverse events. Exploratory analyses include PD-L1 expression and liquid biopsy-based biomarker testing, tumor microenvironment profiling at single-cell levels, and quality-of-life assessments. Discussion: The InTRist study is the first randomized phase II trial to investigate the feasibility of induction anti-PD-1 toripalimab plus chemotherapy followed by cCRT and consolidation toripalimab in bulky LA-NSCLC, providing novel evidence for the synergistic strategy combining anti-PD-1 blockade with radiotherapy to prolong immunotherapy benefits, overcome resistance, and enhance abscopal immune response. [ABSTRACT FROM AUTHOR]