Preoperative chemoradiotherapy in older patients with rectal cancer guided by comprehensive geriatric assessment within a multidisciplinary team-a multicenter phase II trial.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as "fit" by comprehensive geriatric assessment (CGA). METHODS: A single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of "fit" (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22). RESULTS: One hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category. Sixty-eight fit patients with a median age of 74 years were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced non-hematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47). CONCLUSION: This phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA. TRIAL REGISTRATION: The registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).

Minimal residual disease profiling predicts pathological complete response in esophageal squamous cell carcinoma.

Accurate presurgical prediction of pathological complete response (pCR) can guide treatment decisions, potentially avoiding unnecessary surgeries and improving the quality of life for cancer patients. We developed a minimal residual disease (MRD) profiling approach with enhanced sensitivity and specificity for detecting minimal tumor DNA from cell-free DNA (cfDNA). The approach was validated in two independent esophageal squamous cell carcinoma (ESCC) cohorts. In a cohort undergoing neoadjuvant, surgical, and adjuvant therapy (NAT cohort), presurgical MRD status precisely predicted pCR. All MRD-negative cases (10/10) were confirmed as pCR by pathological evaluation on the resected tissues. In contrast, MRD-positive cases included all the 27 non-pCR cases and only one pCR case (10/10 vs 1/28, P < 0.0001, Fisher's exact test). In a definitive radiotherapy cohort (dRT cohort), post-dRT MRD status was closely correlated with patient prognosis. All MRD-negative patients (25/25) remained progression-free during the follow-up period, while 23 of the 26 MRD-positive patients experienced disease progression (25/25 vs 3/26, P < 0.0001, Fisher's exact test; progression-free survival, P < 0.0001, log-rank test). The MRD profiling approach effectively predicted the ESCC patients who would achieve pCR with surgery and those likely to remain progression-free without surgery. This suggests that the cancer cells in these MRD-negative patients have been effectively eliminated and they could be suitable candidates for a watch-and-wait strategy, potentially avoiding unnecessary surgery.

A deep neural network predictor to predict the sensitivity of neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

Neoadjuvant chemoradiotherapy (NCRT) is widely used for locally advanced rectal cancer (LARC). This study aimed to conduct an effective model to predict NCRT sensitivity and provide guidance for clinical treatment. Biomarkers for NCRT sensitivity were identified by applying transcriptome profiles using logistic regression and subsequently screened out by Spearman correlation analysis and four machine learning algorithms. A deep neural network (DNN) predictor was constructed by using in-house dataset and validated in two independent datasets. Additionally, a web-based program was developed. Wnt/ß-catenin signaling and linoleic acid metabolism (LA) pathways were associated with NCRT sensitivity and prognosis in LARC, antagonistically. A DNN predictor with an 18-gene signature was conducted within in-house datasets. In two validation cohorts, area under ROC curve (AUC) achieved 0.706 and 0.897. The DNN subtypes were significantly associated with NCRT sensitivity, survival status et al. Moreover, NK and cytotoxic T cells were observed contribution to NCRT sensitivity while regulatory T, myeloid-derived suppressor cells and dysfunction of CD4 T effector memory cells could impede NCRT response. A DNN predictor could predict NCRT sensitivity in LARC and stratify LARC patients with different clinical and immunity characteristic.

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.

Metastasis risk stratification and response prediction through dynamic viable circulating tumor cell counts for rectal cancer in a neoadjuvant setting.

PURPOSE: Distant metastasis (DM) and neoadjuvant treatment response prediction remain critical challenges in the management of locally advanced rectal cancer (LARC). The aim of this study was to investigate the clinical relevance of viable circulating tumor cells (CTCs) for DM or response in patients with LARC in a neoadjuvant setting. METHODS: The detection of viable CTCs at different stages of treatment was planned for consecutive patients from a prospective trial. The Kaplan-Meier method, Cox proportional hazards model, and logistic regression model were utilized to analyze factors associated with DM or pathological complete response (pCR) and clinical complete response (cCR). RESULTS: Between December 2016 and July 2018, peripheral blood samples from 83 patients were collected before any treatment (median follow-up time, 49.3 months). CTCs were present in 76 of 83 patients (91.6%) at baseline, and more than three CTCs detected in the blood sample was considered high risk. Only the CTC risk group was significantly associated with 3-year metastasis-free survival (MFS) (high risk vs. low risk, 57.1% (95% CI, 41.6-72.6) vs. 78.3% (95% CI, 65.8-90.8), p = 0.018, log-rank test). When all the important variables were entered into the Cox model, the CTC risk group remained the only significant independent factor for DM (hazard ratio (HR), 2.74; 95% CI, 1.17-6.45, p = 0.021). The pCR and continuous cCR rates were higher in patients with a decreased number of CTCs of more than one after radiotherapy (HR, 4.00; 95% CI, 1.09-14.71, P = 0.037). CONCLUSIONS: The dynamic detection of viable CTCs may strengthen pretreatment risk assessment and postradiotherapy decision making for LARC. This observation requires further validation in a prospective study.

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.

Direct Observation of HONO Emissions from Real-World Residential Natural Gas Heating in China.

Atmospheric nitrous acid (HONO) is an important precursor of atmospheric hydroxyl radicals. Vehicle emissions and heterogeneous reactions have been identified as major sources of urban HONO. Here, we report on HONO emissions from residential natural gas (RNG) for water and space heating in urban areas based on in situ measurements. The observed HONO emission factors (EFs) of RNG heating vary between 6.03 and 608 mg·m-3 NG, which are highly dependent on the thermal load. The highest HONO EFs are observed at a high thermal load via the thermal NO homogeneous reaction. The average HONO EFs of RNG water heating in winter are 1.8 times higher than that in summer due to the increased thermal load caused by the lower inlet water temperatures in winter. The power-based HONO EFs of the traditional RNG heaters are 1085 times and 1.7 times higher than those of gasoline and diesel vehicles that meet the latest emission standards, respectively. It is estimated that the HONO emissions from RNG heaters in a typical Chinese city are gradually close to emissions from on-road vehicles when temperatures decline. These findings highlight that RNG heating is a non-negligible source of urban HONO emissions in China. With the continuous acceleration of coal-to-gas projects and the continuous tightening of NOx emission standards for vehicle exhaust, HONO emissions from RNG heaters will become more prominent in urban areas. Hence, it is urgently needed to upgrade traditional RNG heaters with efficient emission reduction technologies such as frequency-converted blowers, secondary condensers, and low-NOx combustors.

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.

The safety of an MRI simulation-guided boost after short-course preoperative radiotherapy for unresectable rectal cancer (SUNRISE): interim analysis of a randomized phase II trial.

PURPOSE: The safety of an MRI simulation-guided boost after short-course preoperative radiotherapy (SCPRT) for unresectable rectal cancer is assessed with a planned interim analysis. METHODS AND MATERIALS: Patients diagnosed with clinical stage T3-4 or regional lymph node-positive disease with positive mesorectal fascia or T4b disease evaluated by pelvic MRI were randomly assigned to the SCPRT-boost group (25 Gy in 5 fractions plus 4 Gy delivered to the gross tumor volume, followed by four cycles of chemotherapy) or preoperative chemoradiotherapy group (50 Gy in 25 fractions with concurrent chemotherapy). Then, patients received total mesorectal excision surgery after preoperative treatment. The primary endpoint was the R0 resection rate. The interim analysis was performed when 42 patients completed their assigned treatments. RESULTS: From October 2018 to November 2019, a total of 43 patients were enrolled, and 42 patients were included in the interim analysis. During preoperative therapy, grade 3 or above toxicities were observed in 10/21 (47.6%) patients in the experimental group, and 4/21 (19.0%) patients in the control group. A total of 17 (81.0%) and 13 (61.9%) patients in the experimental group and control group underwent surgery, respectively. Overall, 65.1% of the patients achieved R0 resection in the intention-to-treat analysis. Surgery-related adverse complications were observed in 2 patients (11.8%) in the experimental group and 1 patient (7.7%) in the control group. CONCLUSION: Our results show that the toxicity of an MRI simulation-guided boost after SCPRT for unresectable rectal cancer is acceptable. Thus, this clinical trial will be continued as planned.

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.

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.

Case report: Radiotherapy plus pneumococcal conjugate vaccine stimulates abscopal immune response in a patient with ALK+ NSCLC.

Most patients with anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer (NSCLC) could benefit from the treatment with selected tyrosine kinase inhibitors (TKIs) for a period of time, but almost inevitably progress due to drug resistance. It was reported that these patients were generally unresponsive to immune-based therapies. Here, we reported that stereotactic body radiotherapy (SBRT) combined with pneumococcal conjugate vaccine (PCV) produced excellent therapeutic outcomes in a patient after multiple lines of TKI treatment. The patient's metastasis lesion experienced regression after SBRT for lumbar spine. Unexpectedly, the patient also experienced an abscopal complete pathological response (CPR) just after combination use of SBRT and PCV. Biopsy analysis indicated that the primary lung lesion was map-like necrotic and infiltrated by tumor-infiltrating lymphocytes (TILs), and multifocal granulomas and early tertiary lymphoid structures (TLS) were formed. Our case reported that radiotherapy plus PCV could specifically stimulate immune response and remodel the tumor immune microenvironment in TKI-resistant NSCLC, which may provide a new perspective for future immunotherapy in this challenging clinical situation.

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.

Antiemetic prophylaxis for chemoradiotherapy-induced nausea and vomiting in locally advanced head and neck squamous cell carcinoma: a prospective phase II trial.

BACKGROUND: There is sparse research reporting effective interventions for preventing nausea and emesis caused by concurrent chemoradiotherapy (CCRT) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). METHODS: Treatment-naïve LA-HNSCC patients received intensity-modulated radiotherapy with concomitant cisplatin 100 mg/m2 (33 mg/m2/days [d]1-3) every 3 weeks for two cycles. All patients were given oral aprepitant 125 mg once on d1, then 80 mg once on d2-5; ondansetron 8 mg once on d1; and dexamethasone 12 mg once on d1, then 8 mg on d2-5. The primary endpoint was complete response (CR). Pursuant to δ = 0.2 and α = 0.05, the expected CR rate was 80%. RESULTS: A total of 43 patients with LA-HNSCC were enrolled. The median age was 53 years, and 86.0% were male. All patients received radiotherapy and 86.0% of patients completed both cycles as planned. The overall CR rate was 86.0% (95% confidence interval [CI]: 72.1-94.7). The CR rates for cycles 1 and 2 were 88.4% (95% CI: 74.9-96.1) and 89.2% (95% CI: 74.6-97.0). The complete protection rate in the overall phase was 72.1% (95% CI: 56.3-84.7). The emesis-free and nausea-free responses in the overall phase were 88.4% (95% CI: 74.9-96.1) and 60.5% (95% CI: 44.4-75.0), respectively. The adverse events related to antiemetics were constipation (65.1%) and hiccups (16.3%), but both were grade 1-2. There was no grade 4 or 5 treatment-related toxicity with antiemetic usage. CONCLUSION: The addition of aprepitant into ondansetron and dexamethasone provided effective protection from nausea and emesis in patients with LA-HNSCC receiving radiotherapy and concomitant high-dose cisplatin chemotherapy.

Preoperative Concurrent Chemoradiotherapy Versus Neoadjuvant Chemotherapy for Locally Advanced Gastric Cancer: Phase II Randomized Study.

Objective: We evaluated and compared the efficacy and safety of neoadjuvant chemoradiotherapy (NACRT) versus neoadjuvant chemotherapy (NACT) for locally advanced gastric cancer (LAGC) in a single-center randomized phase II trial. Methods: Patients with LAGC were enrolled and received either NACT or NACRT, followed by gastrectomy and adjuvant chemotherapy. The primary endpoint was an R0 resection rate. Results: We enrolled 75 patients: 75.7% (NACT, 28/37 patients) and 76.3% (NACRT, 29/38 patients) underwent surgery; R0 resection rates were 73.0% (27/37) and 73.7% (28/38), respectively. The NACRT group had significantly better major pathological response than the NACT group (37.9% vs 17.9%, p = 0.019). Between-group postoperative complications were not significantly different. The median follow-up was 59.6 months; 5-year overall survival (OS) rate was 50.1% (NACT) and 61.9% (NACRT); neither group reached the median OS; median progression-free survival was 37.3 and 63.4 months, respectively. Conclusions: S-1-based NACRT did not improve the R0 resection rate, although it presented better tumor regression with similar safety to NACT. Trial registration: ClinicalTrial.gov NCT02301481.

Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR).

PURPOSE: To ascertain if preoperative short-term radiotherapy followed by chemotherapy is not inferior to a standard schedule of long-term chemoradiotherapy in patients with locally advanced rectal cancer. MATERIALS AND METHODS: Patients with distal or middle-third, clinical primary tumor stage 3-4 and/or regional lymph node-positive rectal cancer were randomly assigned (1:1) to short-term radiotherapy (25 Gy in five fractions over 1 week) followed by four cycles of chemotherapy (total neoadjuvant therapy [TNT]) or chemoradiotherapy (50 Gy in 25 fractions over 5 weeks, concurrently with capecitabine [chemoradiotherapy; CRT]). Total mesorectal excision was undertaken 6-8 weeks after preoperative treatment, with two additional cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) in the TNT group and six cycles of CAPOX in the CRT group. The primary end point was 3-year disease-free survival (DFS). RESULTS: Between August 2015 and August 2018, a total of 599 patients were randomly assigned to receive TNT (n = 302) or CRT (n = 297). At a median follow-up of 35.0 months, 3-year DFS was 64.5% and 62.3% in TNT and CRT groups, respectively (hazard ratio, 0.883; one-sided 95% CI, not applicable to 1.11; P < .001 for noninferiority). There was no significant difference in metastasis-free survival or locoregional recurrence, but the TNT group had better 3-year overall survival than the CRT group (86.5% v 75.1%; P = .033). Treatment effects on DFS and overall survival were similar regardless of prognostic factors. The prevalence of acute grade III-V toxicities during preoperative treatment was 26.5% in the TNT group versus 12.6% in the CRT group (P < .001). CONCLUSION: Short-term radiotherapy with preoperative chemotherapy followed by surgery was efficacious with acceptable toxicity and could be used as an alternative to CRT for locally advanced rectal cancer.