Efficacy and safety of definitive chemoradiotherapy with or without induction immune checkpoint inhibitors in patients with stage III non-small cell lung cancer.

Background: In 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. Methods: 123 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. Results: The 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. Conclusions: Combined 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.

Effectiveness of S-1-Based Chemoradiotherapy in Patients 70 Years and Older With Esophageal Squamous Cell Carcinoma: A Randomized Clinical Trial.

Importance: Double-agent intravenous chemotherapy concurrent with radiotherapy is the standard of care for patients with inoperable esophageal cancer. However, patients tend to tolerate intravenous chemotherapy less well with age and comorbidities. It is essential to find a better treatment modality that improves survival outcomes without reducing the quality of life. Objective: To evaluate the effectiveness of simultaneous integrated boost radiotherapy (SIB-RT) with concurrent and consolidated oral S-1 chemotherapy for patients aged 70 years and older with inoperable esophageal squamous cell carcinoma (ESCC). Design, Setting, and Participants: This multicenter, phase III randomized clinical trial was conducted between March 2017 and April 2020 in 10 centers in China. Patients with inoperable, locally advanced, clinical stage II to IV ESCC were enrolled and randomized to receive SIB-RT concurrent with and followed by oral S-1 chemotherapy (CRTCT group) or SIB-RT alone (RT group). Data analysis was completed on March 22, 2022. Interventions: In both groups, the planning gross tumor volume was administered with radiation dose of 59.92 Gy and the planning target volume was administered with radiation dose of 50.4 Gy, in 28 fractions each. In the CRTCT group, concurrent S-1 was administered on radiotherapy days, and consolidated S-1 was administered at 4 to 8 weeks after SIB-RT. Main Outcomes and Measures: The primary end point was overall survival (OS) of the intent-to-treat population. Secondary end points were progression-free survival (PFS) and toxicity profile. Results: A total of 330 patients (median [IQR] age, 75.5 [72-79] years; 220 [66.7%] male patients) were included, with 146 patients randomized to the RT group and 184 randomized to the CRTCT group. A total of 107 patients (73.3%) in the RT group and 121 patients (67.9%) in the CRTCT group were clinically diagnosed with stage III to IV disease. At the time of analysis of the 330 patients in the intent-to treat-population (March 22, 2022), OS was improved in the CRTCT group compared with the RT group at 1 year (72.2% vs 62.3%) and 3 years (46.2% vs 33.9%; log-rank P = .02). PFS was similarly improved in the CRTCT group compared with the RT group at 1 year (60.8% vs 49.3%) and 3 years (37.3% vs 27.9%; log-rank P = .04). There was no significant difference in the incidence of treatment-related toxic effects higher than grade 3 between the 2 groups. Grade 5 toxic effects occurred in each group, including 1 patient who experienced myelosuppression and 4 patients with pneumonitis in the RT group and 3 patients with pneumonitis and 2 patients with fever in the CRTCT group. Conclusions and Relevance: These findings suggest that oral S-1 chemotherapy administered with SIB-RT should be considered as an alternative treatment option for patients aged 70 years and older with inoperable ESCC, since it improved survival outcomes without additional treatment-related toxic effects compared with SIB-RT alone. Trial Registration: ClinicalTrials.gov Identifier: NCT02979691.

Superiority of integrated cervicothoracic immobilization in the setup of lung cancer patients treated with supraclavicular station irradiation.

Objective: To 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. Methods: One 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. Results: The 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<0.001), and in Z direction than those in ICTID arms-down (p<0.001) and TAFID groups (p=0.034). For the rotational errors of the four groups in the directions of sagittal plane, transverse plane, and coronal plane, the ICTID arms-up group had the smallest setup errors in the sagittal plane than that of TAFID groups and similar rotation setup errors with those of the other three groups. Conclusion: For patients requiring radiation of primary lung lesion and positive supraclavicular lymph nodes, an integrated frame fixation device is preferred the ICTID arms-up methods provide the smallest set up error and satisfied repeatability of body position, compared with TAFID and HNSID.

Efficacy and Safety of Concurrent Chemoradiotherapy Combined with Nimotuzumab in Elderly Patients with Esophageal Squamous Cell Carcinoma: A Prospective Real-world Pragmatic Study.

BACKGROUND: Concurrent or definitive chemoradiotherapy is the standard treatment of locally advanced esophageal squamous cell carcinoma (ESCC). Elderly patients could not tolerate the standard concurrent chemotherapy and were treated with radiotherapy because of weak physical status and multiple comorbidities. OBJECTIVE: The efficacy and safety profile of concurrent (chemo) radiotherapy combined with nimotuzumab in elderly patients with ESCC were investigated. METHODS: Eligible elderly (≥70 years) patients with locally advanced ESCC were enrolled in this prospective, real-world pragmatic study and received concurrent chemoradiotherapy or radiotherapy combined with nimotuzumab. The primary endpoint was overall survival (OS). Secondary endpoints were objective response rate, disease control rate, progression-free survival (PFS), and adverse drug reactions. RESULTS: Fifty-three elderly patients were enrolled. Thirty-two (60.4%) were treated with radiotherapy combined with nimotuzumab (RT+N), and 21 (39.6%) with concurrent chemoradiotherapy combined with nimotuzumab (CRT+N). The median age was 75.8 years. Fourteen (56.0%) patients achieved a partial response, and 11 (44.0%) patients achieved stable disease at 3 months. The median follow-up duration was 24.4 (95%CI, 21.6-26.7) months. Median OS (mOS) was 27.0 (95%CI, 14.8-48.4) months. Median PFS (mPFS) was 22.6 (95%CI, 12.4-not reached) months. Higher mPFS (not reached vs. 12.0 months; p=0.022) and mOS (48.4 vs. 15.3 months; p=0.009) were observed in the CRT+N group compared with the RT+N group. Most adverse reactions were grade 1-2 (46, 86.8%). CONCLUSIONS: Concurrent chemoradiotherapy or radiotherapy combined with nimotuzumab was safe and well-tolerated in elderly patients with locally advanced ESCC. ESCC patients treated with CRT+N could live longer.

Induction Immune Checkpoint Inhibitors and Chemotherapy Before Definitive Chemoradiation Therapy for Patients With Bulky Unresectable Stage III Non-Small Cell Lung Cancer.

PURPOSE: In the era of immunotherapy, the treatment for bulky, locally advanced non-small cell lung cancer (LA-NSCLC) remains challenging. This study explored the feasibility of induction immune checkpoint inhibitors (ICIs) plus chemotherapy before definitive chemoradiation therapy (CRT) for bulky LA-NSCLC. METHODS AND MATERIALS: Patients with bulky, unresectable stage III NSCLC (primary tumor ≥5 cm in greatest dimension or metastatic lymph nodes ≥2 cm in shortest diameter) receiving ICIs and chemotherapy before CRT from 2018 to 2022 were identified. Survival outcomes and toxic effects were analyzed. Radiation therapy plans on computed tomography images before and after 2 cycles of induction chemoimmunotherapy were simulated to evaluate dosimetric outcomes. RESULTS: Seventy-five patients were included. One- and 2-year overall-survival (OS) rates were 91.5% (95% CI, 85.2%-98.3%) and 75.1% (95% CI, 64.1%-88.0%), respectively. One- and 2-year progression-free-survival (PFS) rates were 85.8% (95% CI, 78.0%-94.4%) and 64.2% (95% CI, 52.5%-78.6%), respectively. Median OS was not reached (NR). Median PFS was 30.6 months (95% CI, 25.9 months to NR). Grade 2 and ≥3 pneumonitis occurred in 26.7% and 9.3% of patients, respectively. Grade ≥3 pneumonitis was significantly associated with poorer OS (P = .003) and PFS (P = .018). Treatment discontinuation was significantly associated with shorter OS (P = .023) and PFS (P = .047). Patients with consolidation ICIs exhibited numerically better OS than those without consolidation ICIs (2-year OS, 85.8% vs 64.2%; P = .170). The objective response rate was 76.1% for induction treatment and 86.7% for induction treatment plus CRT. The disease control rate after 2 cycles of induction therapy was significantly greater than after 4 (P = .046) or more cycles (P = .025). Simulated radiation plans indicated that all target volumes, mean lung dose, and volume of lung parenchyma receiving ≥5 Gy, ≥20 Gy, and ≥30 Gy significantly decreased after 2 cycles (all P < .005). CONCLUSIONS: Two cycles of induction ICIs plus chemotherapy before definitive CRT were feasible for bulky LA-NSCLC, with significant tumor reduction and normal lung protection. Further investigations on CRT combined with induction and consolidation ICIs are warranted.

Induction PD-1 inhibitor toripalimab plus chemotherapy followed by concurrent chemoradiotherapy and consolidation toripalimab for bulky locally advanced non-small-cell lung cancer: protocol for a randomized phase II trial (InTRist study).

Background: Immune 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. 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 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. 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. Clinical trial registration: ClinicalTrials.gov, identifier NCT05888402.

Effect of Adjuvant Radiation Dose on Survival in Patients with Esophageal Squamous Cell Carcinoma.

Background: For patients with esophageal squamous cell carcinoma (ESCC) treated with surgery alone, the incidence of local-regional recurrence remains unfavorable. Postoperative radiotherapy (PORT) has been associated with increased local-regional recurrence-free survival (LRFS), although its application is limited by concerns of PORT-related toxicities. Methods: Among 3591 patients with ESCC analyzed in this study, 2765 patients with T3-4N0 and T1-4N1-3 lesions and specific local-regional status information were analyzed in a subsequent analysis of adjuvant radiation dose (aRTD) effect. Application of the restricted cubic spline regression model revealed a non-linear relationship between aRTD and survival/radiotoxicity. Linear regression analysis (LRA) was performed to evaluate correlations between LRFS and overall survival (OS)/ disease-free survival (DFS). Results: For patients staged T1−2N0, T1−2N1−3, T3−4N0, and T3−4N1−3, 5-year OS in PORT and non-PORT groups were 77.38% vs. 72.91%, p = 0.919, 52.35% vs. 46.60%, p = 0.032, 73.41% vs. 61.19%, p = 0.005 and 38.30% vs. 25.97%, p < 0.001. With aRTD escalation, hazard ratios (HRs) of OS/DFS declined until aRTD exceeded 50Gy, then increased, whereas that of LRFS declined until aRTD exceeded 50 Gy, then remained steady. HR of treatment-related mortality was stable until aRTD exceeded 50 Gy, then increased. LRA revealed strong correlations between LRFS and OS/DFS (r = 0.984 and r = 0.952, respectively). An absolute 1% advancement in LRFS resulted in 0.32% and 0.34% improvements in OS and DFS. Conclusions: An aRTD of 50Gy was well-tolerated, with favorable survival resulting from PORT-related LRFS improvement in patients staged T3−4N0 or T1-4N1−3. Further stratification analyses based on tumor burden would help determine potential PORT-beneficiaries.

Applying post-neoadjuvant pathologic stage as prognostic tool in esophageal squamous cell carcinoma.

Background: It 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 methods: A 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). Results: The 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. Conclusions: The 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.

Progression-free survival as surrogate endpoint of overall survival in esophageal squamous cell carcinoma: a real-world data and literature-based analysis.

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.

Intensity modulated radiotherapy might be effective for locally advanced esophageal carcinosarcoma: A single center's experience and review of literature.

Esophageal carcinosarcoma is a rare type of esophageal cancer; however, few studies have investigated the effects of radiotherapy in locally advanced patients. This study aimed to report experience of the safety and efficacy of intensity-modulated radiotherapy for locally advanced esophageal carcinosarcoma and review the literature. By searching the institutional database between January 2010 and December 2020, along with the literature review, 25 patients were eligible for the study. The clinical and radiologic information of all patients with esophageal carcinosarcoma who underwent radiotherapy were collected. Survival outcomes were calculated using Kaplan-Meier plots. In our series, 5 patients were in the curative/neoadjuvant radiotherapy group and 10 patients were in the adjuvant group. Most tumors were protruding (n = 10, 66.7%). All patients underwent intensity-modulated radiotherapy. In the curative/neoadjuvant radiotherapy group, 2 patients underwent concurrent chemoradiotherapy before surgery, and the other three received radiotherapy alone as the initial treatment. The median follow-up time was 43.1 months. All patients showed a partial response at the efficacy evaluation. The median time of overall survival and progression-free survival were 40.2 months (95% confidence interval [CI], 13.1-67.3 months) and 19.0 months (95% CI, 13.9 months-24.1 months) for the entire cohort, but were not reached for curative/neoadjuvant radiotherapy group. Overall survival (hazard ratio [HR] 0.81, 95% CI, 0.15-4.43; P = .805) and progression-free survival (HR 1.68, 95% CI, 0.35-8.19; P = .514) did not differ significantly between the 2 groups. When considering the literature review data in the final analysis, overall survival (HR 0.84, 95% CI, 0.25-2.81; P = .779) and progression-free survival (HR, 0.68; 95% CI, 0.26-1.76; P = .425) were also not different between the 2 groups. Treatment based on intensity-modulated radiotherapy with neoadjuvant or curative intent may be an option for patients with unresectable esophageal carcinosarcoma. Further research with a larger sample size is needed to validate the reliability.

A Single Center Analysis of Thymic Neuroendocrine Tumors.

PURPOSE: Thymic neuroendocrine tumors (TNETs) are a collection of slow-progressing neoplasms located in the anterior mediastinum. Relatively few previously published studies have focused on thymic carcinomas. This study investigated the basic clinical characteristics, treatment, and prognosis of TNETs. METHODS: Patients were enrolled in the study from January 2003 to December 2017 who had been diagnosed with TNETs through pathological screening and treated at our institution. Demographic data from each patient, the Masaoka stage, histology and size of the tumor, tumor invasion characteristics, and therapeutic strategies were gathered. The Kaplan-Meier method was used to assess patient survival. In addition, the log-rank test was used to carry out univariate analyses. RESULTS: Twenty-six patients were eligible for inclusion in the study. The median age of the patients was 46.5 (25-69) years. The tumor median maximum diameter was 7.9 cm (from 3 to 19 cm). Twenty-four patients were treated surgically. Nineteen patients completed radiation therapy, and sixteen patients underwent chemotherapy. A median follow-up time of 54.95 months was observed. The survival rate for three years was 75.0% and 70.6% for five years. The corresponding progression-free survival rates for three and five years were 55.7% and 37.7%, respectively. The local, regional recurrence-free survival (LRFS) rates were 87.2% and 81.7%, and the distant metastasis-free survival (DMFS) rates were 55.7% and 37.7%, at three and five years, respectively. Local recurrence (six patients) and bone metastasis (six patients) were observed as the most frequent failures. CONCLUSION: TNET was observed to be an aggressive but rare malignant lesion. While the predominant treatment was complete resection, chemotherapy and radiotherapy were also required due to the high recurrence rate.

Severe radiation-induced lymphopenia during postoperative radiotherapy or chemoradiotherapy has poor prognosis in patients with stage IIB-III after radical esophagectomy: A post hoc analysis of a randomized controlled trial.

Objective: To investigate whether radiation-induced lymphopenia (RIL) affects survival and identify the predictors of RIL in postoperative esophageal cancer. Materials and methods: Post 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. Results: Median 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<0.001). Baseline absolute lymphocyte count was comparable between G1-3 and G4 patients (2.0 ± 0.8 *109/L vs 1.7 ± 0.5 *109/L; p=0.101). The 3-year DFS was significantly lower in group G4 lymphopenia than that in group G1-3 (31.3% vs 57.6%, p=0.036). The 3-year OS was comparable between both groups (50.0% vs 66.5%, p=0.095). Logistic regression analysis revealed that exposed more thoracic marrow (TM V20 ≥75%; TVB V20 ≥71%), heart (V15 ≥40%) and PTV (volume ≥507 ml) were associated with G4 lymphopenia (p<0.05). Conclusions: G4 RIL had poor disease-free survival, which may be related to more dose exposure of thoracic marrow and heart due to larger PTV. Reasonably reducing the radiation field combined with concurrent chemotherapy, or radiation dose constraints for these normal tissues may be sufficient to decrease the incidence of G4 lymphopenia, but further prospective trials are needed to verify the results. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02279134.

Survival benefit of surgery in patients with clinical T4 esophageal cancer who achieved complete or partial response after neoadjuvant chemoradiotherapy or radiotherapy.

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 < 0.0001). After adjusting the confounding variables with inverse probability of treatment weighting, the adjusted 3-year OS rates were 50.4% in the nCRT/RT + S group versus 50.8% in the dCRT/RT group (p = 0.15). However, the adjusted 3-year PFS rates were significantly different between the two groups (49.0% and versus 38.3%, p = 0.004). Postoperative complications occurred in 18 (24.3%) patients. Conclusion: The long-term survival of cT4 ESCC was improved after the use of three-dimensional CRT. In cT4, EC responded to nCRT/RT, surgery improves PFS but not OS.

Comprehensive Pneumonitis Profile of Thoracic Radiotherapy Followed by Immune Checkpoint Inhibitor and Risk Factors for Radiation Recall Pneumonitis in Lung Cancer.

Purpose: Whilst 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 Materials: From 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. Results: With 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). Conclusions: Treatment-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.

Comparison of setup errors of immobilization devices for thoracic radiotherapy.

Performance of thoracic radiotherapy may be assisted by the use of thoracoabdominal flat immobilization devices (TAFIDs) and integrated cervicothoracic immobilization devices (ICTIDs). This study was performed to compare setup errors of TAFIDs and ICTIDs. Forty-four patients with lung cancer were retrospectively reviewed; 22 patients were immobilized with a TAFID and 22 with an ICTID. In total, 343 cone-beam computed tomography images of these patients were collected for radiotherapy setup. The 3-dimensional setup errors and the displacement of the acromioclavicular joint against the supraclavicular region were calculated. An independent-samples t-test and rank-sum test were used for statistical analyses. The translational setup errors of the TAFID group vs ICTID group in the left-right (LR), superior-inferior (SI), and anterior-posterior (AP) directions were 0.14 ± 0.17 vs 0.14 ± 0.16 cm (p = 0.364), 0.23 ± 0.26 vs 0.15 ± 0.15 cm (p = 0.000), and 0.16 ± 0.15 vs 0.12 ± 0.14 cm (p = 0.049), respectively. The relative displacement of the acromioclavicular joint against the supraclavicular joint in the LR, SI, and AP directions were 0.10 ± 0.12 vs 0.09 ± 0.10 cm (p = 0.176), 0.13 ± 0.13 vs 0.11 ± 0.12 cm (p = 0.083), and 0.17 ± 0.16 vs 0.12 ± 0.11 cm (p = 0.001), respectively. The overall displacement of the supraclavicular region was 0.28 ± 0.19 vs 0.23 ± 0.15 cm (p < 0.001). The recommended planning target volume margins in the LR, SI, and AP directions were 0.46 vs 0.74 cm, 0.51 vs 0.47 cm, and 0.49 vs 0.41 cm, respectively. For patients with lung cancer, using an ICTID can reduce setup errors in the SI direction and displacements of the acromioclavicular joint and supraclavicular region compared with a TAFID. Therefore, an ICTID is preferred for patients with lung cancer with supraclavicular target volume.

Factors affecting the completion of concurrent chemotherapy and impact of non-completion on survival in locally advanced esophageal squamous cell carcinoma.

BACKGROUND: To investigate whether completion of concurrent chemotherapy (CCT) improves overall survival (OS) of patients with locally advanced esophageal squamous cell carcinoma (ESCC), and to identify predictors of non-completion of CCT. METHODS: Data of ESCC patients treated with definitive concurrent chemoradiotherapy from January 2012 to December 2017 were retrospectively analyzed. CCT completion was defined as receiving recommended cycles with at most 25% dose reduction. Propensity score matching (PSM) analysis was applied to adjust unbalanced covariates between groups. Multivariate logistic regression model was used to identify factors affecting CCT completion. RESULTS: Of the 487 patients in the study, 194 patients (39.8%) had completed CCT. The majority (90.7%) had stage III-IV disease. Three-year OS rate was significantly higher in the completion group than non-completion group (35.4% vs. 30.3%; p = 0.025). Multivariate Cox analysis showed CCT completion was independently associated with longer OS (p = 0.005). The independent risk factors for CCT non-completion were weekly CCT regimen [odds ratio (OR) = 4.35, 95% CI 2.26-8.37; p < 0.001], clinical target volume (CTV)-elective nodal irradiation (ENI) (OR = 3.86, 95% CI 2.41-6.18; p < 0.001), planning target volume (PTV)/50 cm3 (OR = 1.09, 95% CI 1.02-1.16; p = 0.017), age (OR = 1.04, 95% CI 1.01-1.07, p = 0.011), and tumor in middle/lower esophagus (OR = 1.59, 95% CI 1.05-2.43, p = 0.030). CONCLUSION: CCT completion can provide superior OS for ESCC patients treated with definitive CCRT. Weekly CCT regimen, CTV-ENI, PTV, older age, and tumor location are independent predictors of non-completion of CCT.

Treatment outcomes of patients with stage III non-small cell lung cancer and interstitial lung diseases receiving intensity-modulated radiation therapy: A single-center experience of 85 cases.

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 <20%, or both, respectively. Multivariate analysis showed that honeycombing score >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%). In the univariate analysis for overall survival, G3+ RILTs were evaluated as risk factors (p = 0.026) and low-risk group as the only protective factor (p = 0.063). In the multivariate analysis, G3+ RILTs were the only independent risk factor for OS. CONCLUSION: 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.

Local Therapy Combined With First-Line EGFR Tyrosine Kinase Inhibitor Achieves Favorable Survival in Patients With EGFR-Mutant Metastatic Non-Small Cell Lung Cancer.

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.

Adenoid Cystic Carcinoma of Lobar Bronchial Origin: 20-Year Experience at a Single Institution.

BACKGROUND: Pulmonary adenoid cystic carcinoma (ACC) is a rare type of lung malignancy. The prevalence of ACC of lobar bronchial origin is lower than that of other lung malignancies, and studies investigating it are lacking. This study aimed to evaluate survival of patients with ACC of the lobar bronchus after surgical resection and to explore its prognostic factors. METHODS: Between January 2000 and December 2019, 35 patients at the National Cancer Center/Cancer Hospital with a diagnosis of ACC of the lobar bronchus were included in the retrospective analysis. RESULTS: During a median follow-up period of 61 months (range, 10-194 months), the analysis showed a 5-year overall survival (OS) rate of 81.4%, a 5-year locoregional recurrence-free survival rate of 84.0%, and 5-year disease-free survival rate of 60.1%. The univariate analysis exclusively identified the surgical margin as a predictor of OS, and survival was significantly longer for the patients with negative surgical margins than for those with positive surgical margins (R0 vs. R1: 94.4% vs. 66.0%; p = 0.014). Adjuvant radiotherapy was administered to most of the patients with positive surgical margins, which might have contributed to prolonged OS (R0 vs. R1+RT: 94.4% vs. 66.7%, p = 0.173; R0 vs. R1+no RT: 94.4% vs. 62.5%, p = 0.007). CONCLUSIONS: For ACC of lobar bronchial origin, complete resection is the radical treatment, and the OS rate was significantly higher for the R0 patients than for the R1 patients. Adjuvant radiotherapy for patients with R1 may prolong survival.

Chemoradiotherapy is an alternative choice for patients with primary mediastinal seminoma.

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.