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Mechanisms of radiotherapy resistance and radiosensitization strategies for esophageal squamous cell carcinoma.

ABSTRACT: Esophageal squamous cell carcinoma (ESCC) is the sixth most common cause of cancer-related mortality worldwide, with more than half of them occurred in China. Radiotherapy (RT) has been widely used for treating ESCC. However, radiation-induced DNA damage response (DDR) can promote the release of cytokines and chemokines, and triggers inflammatory reactions and changes in the tumor microenvironment (TME), thereby inhibiting the immune function and causing the invasion and metastasis of ESCC. Radioresistance is the major cause of disease progression and mortality in cancer, and it is associated with heterogeneity. Therefore, a better understanding of the radioresistance mechanisms may generate more reversal strategies to improve the cure rates and survival periods of ESCC patients. We mainly summarized the possible mechanisms of radioresistance in order to reveal new targets for ESCC therapy. Then we summarized and compared the current strategies to reverse radioresistance.

SUBMITTER: An L

PROVIDER: S-EPMC10439611 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Mechanisms of radiotherapy resistance and radiosensitization strategies for esophageal squamous cell carcinoma.

An Lingbo L Li Mingyang M Jia Qingge Q

Molecular cancer 20230819 1

Esophageal squamous cell carcinoma (ESCC) is the sixth most common cause of cancer-related mortality worldwide, with more than half of them occurred in China. Radiotherapy (RT) has been widely used for treating ESCC. However, radiation-induced DNA damage response (DDR) can promote the release of cytokines and chemokines, and triggers inflammatory reactions and changes in the tumor microenvironment (TME), thereby inhibiting the immune function and causing the invasion and metastasis of ESCC. Radi ...[more]

PMID: 37598158

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Project description:BackgroundThe literature regarding esophageal fistula after definitive concurrent chemotherapy and intensity modulated radiotherapy (IMRT) for esophageal squamous cell carcinoma (ESCC) remains lacking. We aimed to investigate the risk factors of esophageal fistula among ESCC patients undergoing definitive concurrent chemoradiotherapy (CCRT) via IMRT technique.MethodsA total of 129 consecutive ESCC patients receiving definitive CCRT with IMRT between 2008 and 2018 were reviewed. The cumulative incidence of esophageal fistula and survival of patients were estimated by the Kaplan-Meier method and compared between groups by the log-rank test. The risk factors of esophageal fistula were determined with multivariate Cox proportional hazards regression analysis.ResultsMedian follow-up was 14.9 months (IQR, 7.0-28.8). Esophageal perforation was identified in 20 (15.5%) patients, resulting in esophago-pleural fistula in nine, esophago-tracheal fistula in seven, broncho-esophageal fistula in two, and aorto-esophageal fistula in two patients. The median interval from IMRT to the occurrence of esophageal fistula was 4.4 months (IQR, 3.3-10.1). Patients with esophageal fistula had an inferior median overall survival (10.0 vs. 17.2 months, p = 0.0096). T4 (HR, 3.776; 95% CI, 1.383-10.308; p = 0.010) and esophageal stenosis (HR, 2.601; 95% CI, 1.053-6.428; p = 0.038) at baseline were the independent risk factors for esophageal fistula. The cumulative incidence of esophageal fistula was higher in patients with T4 (p = 0.018) and pre-treatment esophageal stenosis (p = 0.045). There was a trend toward better survival after esophageal fistula among patients receiving repair or stenting for the fistula than those only undergoing conservative treatments (median survival, 5.9 vs. 0.9 months, p = 0.058).ConclusionsT4 and esophageal stenosis at baseline independently increased the risk of esophageal fistula in ESCC treated by definitive CCRT with IMRT. There existed a trend toward improved survival after the fistula among patients receiving repair or stenting for esophageal perforation.

Project description:Purpose: The reported data of elderly ESCC are rather limited and there is a lack of information to guide treatment decisions for elderly patients with esophageal cancer. This study aims to identify the efficacy and factors for optimal treatment approaches for elderly esophageal squamous cell carcinoma (ESCC) treated with radiotherapy (RT) alone or concurrent chemoradiation (CCRT). Methods: This study included 184 I-III elderly ESCC patients aged ≥70 years treated by oral single agent CCRT (sCCRT) or double agents CCRT (dCCRT) or RT alone at a single institution in China. RT was delivered with Intensity Modulated Irradiation Therapy (IMRT) or Volumetric-Modulated Arc Therapy (VMAT). Sequential or simultaneous integrated boost (SIB) approach was applied for GTV dose escalation. Toxicities were evaluated by criteria of Radiation Therapy Oncology Group. Statistical analyses were performed on survival and failure patterns. Results: At a median follow-up time of 15.5 months, the 2- and 3-year estimated overall survival (OS) were 43.5% and 35.2%, respectively. T and N stage, GTV dose (cutoff value 56Gy), simultaneous integrated boost (SIB) technique and CCRT were significant predictors for the outcomes. sCCRT was significantly associated with higher OS, LRFS, and DFS when compared with RT alone and no difference was observed between sCCRT and dCCRT. 44% patients experienced treatment failure, among whom 65.4% developed local failure. 81.3% local failure occurred in GTV and 70.6% regional failures occurred out of radiation field. dCCRT was the only independent prediction factor for grade ≥ 2 neutropenia and gastrointestinal reactions compared with sCCRT and RT alone. No significant difference of toxicities was observed between sCCRT and RT alone. Conclusions: Our results demonstrated that CCRT in elderly patients had significant survival benefit compared to RT alone, especially using Single oral agent. sCCRT had less toxicities compared to dCCRT, and the toxicity was similar to RT alone. GTV dose ≥ 56 Gy and SIB technique were optimal approaches for radiotherapy.

Project description:Lessons learnedRadiotherapy plus anti-PD-1 antibody as first-line therapy is safe and feasible in locally advanced esophageal squamous cell carcinoma (ESCC). Tumor-infiltrating and peripheral lymphocytes were associated with patient survival. Further studies combining chemoradiotherapy with immunotherapy in locally advanced ESCC and exploration of predictive biomarkers are warranted.BackgroundWe conducted a phase Ib study of radiotherapy plus programmed cell death protein 1 (PD-1) monoclonal antibody camrelizumab as first-line treatment for locally advanced esophageal squamous cell carcinoma (ESCC).MethodsWe planned to enroll 20 patients with newly diagnosed locally advanced ESCC. Patients received 60 Gy radiation (2.0 Gy/fraction, 5 fractions/week), with camrelizumab (200 mg every 2 weeks) starting with radiotherapy and continuing for 32 weeks (i.e., for 16 cycles). The primary endpoints were safety and feasibility. Secondary endpoints were rates of radiologic and pathologic response, overall survival (OS), and progression-free survival (PFS). Study data were collected by the week during radiotherapy (RT), every month during the maintenance camrelizumab treatment, and every 3 months after treatment. Tumor microenvironment and peripheral blood were monitored at baseline and after 40 Gy radiation for association with efficacy.ResultsTwenty patients were enrolled and received treatment. One patient (patient 10) was excluded upon discovery of a second tumor in the bladder during treatment, leaving 19 patients for analysis. Toxicity was deemed tolerable. Fourteen (74%) patients had assessed objective response. At a median follow-up time of 31.0 months (95% confidence interval [CI], 27.0-35.1), median OS and PFS times were 16.7 months (95% CI, 5.9-27.9) and 11.7 months (95% CI, 0-30.3), respectively. OS and PFS rates at 24 months were 31.6% and 35.5%, respectively. Kaplan-Meier analysis revealed associations between the following factors and OS/PFS: tumor programmed cell death ligand 1 (PD-L1) expression, PD-1+ CD8+ , PD-1+ CD4+ T cells, and PD-L1+ CD4+ T cells; peripheral blood CD4+ , CD8+ , CD4+ regulatory T cells, and their subsets.ConclusionRadiotherapy plus camrelizumab had manageable toxicity and antitumor efficacy for locally advanced ESCC. Several biomarkers were associated with clinical benefit and deserve further study.

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Mechanisms of radiotherapy resistance and radiosensitization strategies for esophageal squamous cell carcinoma.

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Mechanisms of radiotherapy resistance and radiosensitization strategies for esophageal squamous cell carcinoma.

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