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

[This corrects the article DOI: 10.3389/fonc.2023.1135879.].

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.

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.

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.

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.

Development and validation of a prediction model using molecular marker for long-term survival in unresectable stage III non-small cell lung cancer treated with chemoradiotherapy.

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.

A Nomogram for Predicting Brain Metastasis in IIIA-N2 Non-Small Cell Lung Cancer After Complete Resection: A Competing Risk Analysis.

BACKGROUND: Brain 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 MATERIALS: Between 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 <0.05. RESULTS: A total of 517 patients were enrolled in our retrospective study. The median follow-up time for surviving patients was 53.2 months (range, 0.50-123.17 months). The median age was 57 (range, 25-80) years. Of the 517 patients, 122 (23.6%) had squamous cell carcinoma, 391 (75.6%) received adjuvant chemotherapy, and 144 (27.3%) received post-operative radiotherapy. The 1-, 3-, and 5-year survival rates were 94.0, 72.9, and 66.0%, respectively. The 1-, 3-, and 5-year BM rates were 5.4, 15.7, and 22.2%, respectively. According to the univariate analysis, female, non-smokers, patients with non-squamous cell carcinoma, bronchial invasion, perineural invasion, and patients who received adjuvant chemotherapy were more likely to develop BM. In a multivariate analysis, non-squamous cell carcinoma (subdistribution hazard ratios, SHR: 3.968; 95% confidence interval, CI: 1.743-9.040; P = 0.0010), bronchial invasion (SHR: 2.039, 95% CI: 1.325-3.139; P = 0.0012), perineural invasion (SHR: 2.514, 95% CI: 1.058-5.976; P = 0.0370), and adjuvant chemotherapy (SHR: 2.821, 95% CI: 1.424-5.589; P = 0.0030) were independent risk factors for BM. A nomogram model was established based on the final multivariable analysis result. The area under the curve was 0.767 (95% CI, 0.758-0.777). CONCLUSIONS: For patients with IIIA-N2 NSCLC after complete resection, a nomogram was established based on clinicopathological factors and treatment patterns for predicting the BM. Based on this nomogram, patients with a high risk of BM who may benefit from PCI can be screened.

Definitive Simultaneous Integrated Boost Versus Conventional-Fractionated Intensity Modulated Radiotherapy for Patients With Advanced Esophageal Squamous Cell Carcinoma: A Propensity Score-Matched Analysis.

BACKGROUND: The 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). METHODS: The 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. RESULTS: After 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. CONCLUSIONS: SIB-IMRT appears to be equivalent to CF-IMRT in treatment efficacy and safety, and could become an alternative option for definitive radiotherapy of ESCC.

Postoperative Adjuvant Therapy Versus Surgery Alone for Stage IIB-III Esophageal Squamous Cell Carcinoma: A Phase III Randomized Controlled Trial.

BACKGROUND: Retrospective studies have shown that adjuvant treatment improves survival of patients with stage IIB-III esophageal squamous cell carcinoma, but there is no evidence from prospective trials so far. MATERIALS AND METHODS: Patients with pathological stage IIB-III esophageal squamous cell carcinoma were randomly assigned to receive surgery alone (SA), postoperative radiotherapy (PORT), or postoperative concurrent chemoradiotherapy (POCRT). PORT patients received 54 Gy in 27 fractions; the POCRT group received 50.4 Gy in 28 fractions, plus concurrent chemotherapy with paclitaxel (135-150 mg/m2 ) and cisplatin or nedaplatin (50-75 mg/m2 ) every 28 days. The primary endpoint was disease-free survival (DFS), and the secondary endpoint was overall survival (OS). RESULTS: A total of 172 patients were enrolled (SA, n = 54; PORT, n = 54; POCRT, n = 64). The 3-year DFS was significantly better in PORT/POCRT patients than in SA patients (53.8% vs. 36.7%; p = .020); the 3-year OS was also better in PORT/POCRT patients (63.9% vs. 48.0%; p = .025). The 3-year DFS for SA, PORT, and POCRT patients were 36.7%, 50.0%, 57.3%, respectively (p = .048). The 3-year OS for SA, PORT, and POCRT patients were 48.0%, 60.8%, 66.5%, respectively (p = .048). CONCLUSION: PORT/POCRT (especially POCRT) may significantly improve DFS and OS in stage IIB-III esophageal squamous cell carcinoma. IMPLICATIONS FOR PRACTICE: The results of this phase III study indicated that postoperative radiotherapy/postoperative concurrent chemoradiotherapy (PORT/POCRT) could significantly improve disease-free survival and overall survival in stage IIB-III esophageal squamous cell carcinoma compared with surgery alone with acceptable toxicities. In-field and out-of-field recurrences were comparable between the POCRT and PORT groups, which demonstrates the rationality and safety of the radiation field used in this study. The postoperative regimens in this trial might be accepted as standard treatment options for pathological stage IIB-III esophageal cancer. Larger sample size prospective randomized trials to identify the value are warranted.

Effect of Postoperative Radiotherapy for Patients With pIIIA-N2 Non-Small Cell Lung Cancer After Complete Resection and Adjuvant Chemotherapy: The Phase 3 PORT-C Randomized Clinical Trial.

IMPORTANCE: The role of postoperative radiotherapy (PORT) has not been well defined in resected pIIIA-N2 non-small cell lung cancer (NSCLC). OBJECTIVE: To evaluate the effect of PORT using modern techniques on survival and safety in patients with pIIIA-N2 NSCLC after complete resection and adjuvant chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: The PORT-C randomized clinical trial was conducted in 394 patients with pIIIA-N2 NSCLC treated with complete resection and 4 cycles of platinum-based chemotherapy between January 2009 and December 2017. Data were analyzed between March 2019 and December 2020. INTERVENTIONS: Patients were randomized equally into the PORT arm (n = 202) or the observation arm (n = 192). The total dose of PORT was 50 Gy. MAIN OUTCOMES AND MEASURES: The primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS), locoregional recurrence-free survival (LRFS), distant metastasis-free survival, and toxic effects. RESULTS: In total, 394 patients were enrolled and 364 were eligible, with a median (range) age of 55 (25-70) years. There were 202 (55.5%) male and 162 (44.5%) female patients. The median follow-up was 46.0 (95% CI, 41.9-51.4) months, and 230 DFS events were reported. There were 184 patients in the PORT arm and 180 patients in the observation arm. The 3-year DFS rates were 40.5% with PORT vs 32.7% with observation (median, 22.1 vs 18.6 months), and the difference in DFS was not statistically significant without adjustment (hazard ratio [HR], 0.84; 95% CI, 0.65-1.09; P = .20), though it was significant with preplanned yet exploratory analysis (stratified analysis by the number of detected lymph nodes and positive lymph nodes, HR, 0.75; log-rank P = .04). The 3-year OS rates were 78.3% vs 82.8% (HR, 1.02; P = .93), and LRFS was 66.5% vs 59.7% (HR, 0.71; 95% CI, 0.51-0.97; P = .03), respectively. For 310 per-protocol patients (140 with PORT and 170 with observation), PORT significantly improved DFS (42.8% vs 30.6%; HR, 0.75; 95% CI, 0.57-1.00; P = .05) but not OS (HR, 0.83; 95% CI, 0.53-1.30; P = .41). The 3-year local recurrence only rates were 9.5% and 18.3% in the 2 arms, respectively (Fine-Gray HR, 0.55; Gray test P = .04). No radiotherapy-related grade 4 or 5 adverse event was observed. CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial of patients with pIIIA-N2 NSCLC after complete resection and adjuvant chemotherapy, PORT did not improve DFS. Further studies exploring patients who might best benefit from PORT are needed. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00880971.

Comparison of Two Major Staging Systems in Predicting Survival and Recommendation of Postoperative Radiotherapy Based on the 11th Japanese Classification for Esophageal Carcinoma After Curative Resection: A Propensity Score-Matched Analysis.

OBJECTIVE: The aim of this study was to compare the prognostic predictive power of the 11th Japan Esophageal Society (JES) staging system with the 8th edition of the American Joint Committee on Cancer (AJCC) staging system in patients with thoracic esophageal squamous cell carcinoma (TESCC), and to estimate the survival benefits of postoperative radiotherapy (PORT) based on a substage of the JES staging system. METHODS: Area under the curve (AUC) values of the receiver operating characteristic curve were calculated to evaluate prognostic efficacy. Propensity score matching (PSM) analysis was conducted to balance the two groups (surgery only [S group] or surgery plus PORT [S+RT group]) across substages of the 11th JES staging system according to independent prognostic factors for overall survival (OS) identified using Cox proportional hazards regression. RESULTS: A total of 2960 patients were eligible. The 5-year OS AUC for the 8th AJCC staging system was significantly higher than that for the 11th JES staging system (0.701 vs. 0.675, p < 0.001). Before PSM, PORT significantly improved 5-year OS rates for patients in stage III and IVA by 9.1% (p < 0.001) and 21.1% (p < 0.001), respectively. After PSM, the 5-year OS rates in stage II, III, and IVA of the S+RT group were significantly higher than those in the S group (70.9%, 39.7%, and 35.1% vs. 57.8%, 27.2%, and 10.3%, respectively; p < 0.001). CONCLUSION: The 11th JES staging system was less capable of predicting prognosis than the 8th AJCC staging system and patients in stage III of the JES staging system were highly recommended to undergo PORT.