Immune Checkpoint Inhibitor, Nivolumab, Combined with Chemotherapy Improved the Survival of Unresectable Advanced and Metastatic Esophageal Squamous Cell Carcinoma: A Real-World Experience.

Patients with advanced esophageal squamous cell carcinoma (SCC) have a poor prognosis when treated with standard chemotherapy. Programmed death ligand 1 (PD-L1) expression in esophageal cancer has been associated with poor survival and more advanced stage. Immune checkpoint inhibitors, such as PD-1 inhibitors, showed benefits in advanced esophageal cancer in clinical trials. We analyzed the prognosis of patients with unresectable esophageal SCC who received nivolumab with chemotherapy, dual immunotherapy (nivolumab and ipilimumab), or chemotherapy with or without radiotherapy. Patients who received nivolumab with chemotherapy had a better overall response rate (ORR) (72% vs. 66.67%, p = 0.038) and longer overall survival (OS) (median OS: 609 days vs. 392 days, p = 0.04) than those who received chemotherapy with or without radiotherapy. In patients receiving nivolumab with chemotherapy, the duration of the treatment response was similar regardless of the treatment line they received. According to clinical parameters, liver and distant lymph nodes metastasis showed a trend of negative and positive impacts, respectively, on treatment response in the whole cohort and in the immunotherapy-containing regimen cohort. Nivolumab add-on treatment showed less gastrointestinal and hematological adverse effects, compare with chemotherapy. Here, we showed that nivolumab combined with chemotherapy is a better choice for patients with unresectable esophageal SCC.

Impact of the interval between neoadjuvant concurrent chemoradiotherapy and esophagectomy in the modern era: a population-based propensity-score-matched retrospective cohort study in Asia.

BACKGROUND: Neoadjuvant concurrent chemoradiotherapy (nCCRT) is one of the standard-of-care options for locally advanced esophageal squamous cell carcinoma (LA-ESqCC). The optimal interval between nCCRT and esophagectomy is unknown. METHODS: We constructed a propensity-score-matched [1:1 for long (8-12 weeks) vs short (4-7 weeks) intervals] cohort of LA-ESqCC patients who were diagnosed from 2011 to 2015 and treated with nCCRT via the Taiwan Cancer Registry and related databases. We compared the hazard ratios (HRs) of death using a robust variance estimator. We also evaluated alternative covariables, outcomes, and interval definitions. RESULTS: Our study population included 80 patients for each group; groups were balanced with respect to the observed covariables. There was no significant difference for the HR of death [1.22; 95% confidence interval 0.78-1.91, P = 0.39] when the long interval group was compared to the short interval group. There were also no significant differences when alternative covariables, outcomes, or interval definitions were evaluated. CONCLUSIONS: In this population-based study in modern Asia, we found that for LA-ESqCC patients treated with nCCRT and esophagectomy, overall survival was similar for either long or short intervals between nCCRT and esophagectomy. Randomized controlled trials are needed to verify this finding.

High endothelin-converting enzyme-1 expression independently predicts poor survival of patients with esophageal squamous cell carcinoma.

Patients with esophageal squamous cell carcinoma have poor survival and high recurrence rate, thus an effective prognostic biomarker is needed. Endothelin-converting enzyme-1 is responsible for biosynthesis of endothelin-1, which promotes growth and invasion of human cancers. The role of endothelin-converting enzyme-1 in esophageal squamous cell carcinoma is still unknown. Therefore, this study investigated the significance of endothelin-converting enzyme-1 expression in esophageal squamous cell carcinoma clinically. We enrolled patients with esophageal squamous cell carcinoma who provided pretreated tumor tissues. Tumor endothelin-converting enzyme-1 expression was evaluated by immunohistochemistry and was defined as either low or high expression. Then we evaluated whether tumor endothelin-converting enzyme-1 expression had any association with clinicopathological findings or predicted survival of patients with esophageal squamous cell carcinoma. Overall, 54 of 99 patients with esophageal squamous cell carcinoma had high tumor endothelin-converting enzyme-1 expression, which was significantly associated with lymph node metastasis ( p = 0.04). In addition, tumor endothelin-converting enzyme-1 expression independently predicted survival of patients with esophageal squamous cell carcinoma, and the 5-year survival was poorer in patients with high tumor endothelin-converting enzyme-1 expression ( p = 0.016). Among patients with locally advanced and potentially resectable esophageal squamous cell carcinoma (stage II and III), 5-year survival was poorer with high tumor endothelin-converting enzyme-1 expression ( p = 0.003). High tumor endothelin-converting enzyme-1 expression also significantly predicted poorer survival of patients in this population. In patients with esophageal squamous cell carcinoma, high tumor endothelin-converting enzyme-1 expression might indicate high tumor invasive property. Therefore, tumor endothelin-converting enzyme-1 expression could be a good biomarker to identify patients with worse survival and higher risks of recurrence, who might benefit from the treatment by endothelin-converting enzyme-1 inhibitor.

Safety of image-guided radiotherapy in definitive radiotherapy for localized prostate cancer: a population-based analysis.

OBJECTIVES: Image-guided radiotherapy (IGRT) is a recommended advanced radiation technique that is associated with fewer acute and chronic toxicities. However, one Phase III trial showed worse overall survival in the IGRT arm. The purpose of this observational study is to evaluate the impact of IGRT on overall survival. METHODS: We used the Taiwan Cancer Registry Database to enroll cT1-4N0M0 prostate cancer patients who received definitive radiotherapy between 2011 and 2015. We used inverse probability treatment weighting (IPW) to construct balanced IGRT and non-IGRT groups. We compared the overall survival of those in the IGRT and non-IGRT groups. Supplementary analyses (SA) were performed with alternative covariates in propensity score (PS) models and PS approaches. The incidence rates of prostate cancer mortality (IPCM), other cancer mortality (IOCM), and cardiovascular mortality (ICVM) were also evaluated. RESULTS: There were 360 patients in the IGRT arm and 476 patients in the non-IGRT arm. The median follow-up time was 50 months. The 5-year overall survival was 88% in the IGRT arm and 86% in the non-IGRT arm (adjusted hazard ratio [HR] of death = 0.93; 95% CI, 0.61-1.45; p = 0.77). The SA also showed no significant differences in the overall survival between those in the IGRT and non-IGRT arms. Both groups did not significantly differ in terms of IPCM, IOCM, and ICVM. CONCLUSIONS: The overall survival of localized prostate cancer patients who underwent IGRT was not inferior to those who did not. ADVANCES IN KNOWLEDGE: We demonstrated that the overall survival for prostate cancer patients with IGRT was not worse than those who did not undergo IGRT; this important outcome comparison has not been previously examined in the general population.

Effectiveness of image-guided radiotherapy for locally advanced esophageal squamous cell carcinoma patients treated with definitive concurrent chemoradiotherapy.

BACKGROUND: Image-guided radiotherapy (IGRT) is an advanced radiotherapy technique to improve the accuracy of treatment delivery. However, a recent randomized controlled trial (RCT) for prostate cancer patients treated with radiotherapy either via IGRT or routine care (no daily IGRT) reported a statistically significant worse overall survival for those treated with IGRT. This raised the concern regarding the effectiveness of IGRT for definitive concurrent chemoradiotherapy (dCCRT) for locally advanced esophageal squamous cell carcinoma (LA-ESqCC). METHODS: Eligible LA-ESqCC patients diagnosed between 2011 and 2015 were identified via the Taiwan Cancer Registry. We estimated propensity scores to construct a 1:1 propensity-score-matched groups and balance observable potential confounders. The hazard ratio (HR) of death as well as other outcomes was compared between IGRT and non-IGRT matched groups during the entire follow-up period. The impact of additional covariables was considered in the sensitivity analysis. RESULTS: Our study population included 590 patients in the primary analysis. The HR for death when IGRT was compared with non-IGRT was 0.92 (95% confidence interval 0.77-1.10, P = 0.35). There were also no significant differences for other outcomes or sensitivity analyses. CONCLUSIONS: In this updated nonrandomized study using real world data, we found that the overall survival of LA-ESqCC patients treated with dCCRT was not statistically different between those treated with IGRT versus those without IGRT, although the hazard ratio was less than unity, ie, in favor of IGRT. The results should be interpreted with caution given the nonrandomized design and RCTs are needed to clarify our findings. KEY POINTS: Significant findings of the study: The OS of LA-ESqCC patients treated with dCCRT was not statistically different between those treated with IGRT versus those without IGRT, although the hazard ratio was less than unity, ie, in favor of IGRT. WHAT THIS STUDY ADDS: In this updated nonrandomized study using real world data with additional potential confounders, our study provided a reasonable tentative evidence of lack of RCT as suggested in the literature.

Comparative effectiveness of simultaneous integrated boost vs sequential intensity-modulated radiotherapy for oropharyngeal or hypopharyngeal cancer patients: A population-based propensity score-matched analysis.

There were 2 common radiotherapy dose fractionation strategies in head-and-neck cancer patients (such as oropharyngeal cancer [OPC] or hypopharyngeal cancer [HPC]) treated with radiotherapy: intensity-modulated radiotherapy using simultaneous integrated boost (IMRT-SIB) and sequential IMRT (IMRT-SEQ). There is a lack of high-level clinical evidence to compare IMRT-SIB vs IMRT-SEQ specifically for OPC or HPC patients. The present study investigated the survival outcomes of OPC or HPC patients receiving definite concurrent chemoradiotherapy (CCRT) with either IMRT-SIB or IMRT-SEQ via a population-based propensity score (PS)-based analysis.The localized stage OPC or HPC patients diagnosed between 2011 and 2015 were identified based on the Health and Welfare Data Science Center database in Taiwan. These patients received definitive CCRT with either IMRT-SIB or IMRT-SEQ. We constructed a PS-matched cohort (1:1 for IMRT-SIB vs IMRT-SEQ) to balance observable potential confounders. We compared the hazard ratio (HR) of death between IMRT-SIB and IMRT-SEQ during the entire follow-up period. We also evaluated other disease outcome or subgroups.Our study population constituted 200 patients with well balance in observed covariables. The HR of death when IMRT-SIB was compared to IMRT-SEQ was 1.23 (95% confidence interval 0.84-1.80, P = .29). The results were similar for other disease outcome or subgroups.We found the survival outcome might be comparable for those treated with IMRT-SIB vs those treated with IMRT-SEQ.

Human papillomavirus infection on initiating synchronous esophageal neoplasia in patients with head and neck cancer.

OBJECTIVES/HYPOTHESIS: Human papillomavirus (HPV) is a risk factor for head and neck squamous cell carcinoma (HNSCC) as well as esophageal squamous cell carcinoma (ESCC). We aimed to investigate whether HPV infection underlies the field cancerization phenomenon over upper aerodigestive tract to develop synchronous multiple cancers. STUDY DESIGN: A case control study. METHODS: The presence and subtype of HPV-DNA sequence in cancers were examined by polymerase chain reaction and sequencing in a prospective cohort with 100 HNSCCs, 50 of which had synchronous ESCCs. The clinicopathologic characteristics were further analyzed according to the presence of HPV. RESULTS: Twelve patients were HPV-positive, of which 11 were positive for HPV-16. The prevalence of HPV infection were not different between the synchronous and HNSCC alone groups (P = 0.357). Testing for HPV in paired HNSCC and ESCC tissues from the same patient revealed that none were concomitantly HPV-positive. Multivariate logistic regression showed drinking alcohol (odds ratio [OR], 18.75; P = 0.030), alcohol flushing (OR, 2.53; P = 0.041), and body mass index (OR, 0.77; P = 0.001) but not HPV infection were independent risk factors for synchronous phenotype. The patients with synchronous ESCCs had significantly poorer survival than those with HNSCC alone (5-year overall survival: 30% vs. 70%; log-rank P < 0.001). However, patients with HPV-positive HNSCC tend to have favorable outcome than those with HPV-negative HNSCC. CONCLUSIONS: HPV infection plays little role in field cancerization phenomenon to initiate synchronous SCC. The synchronous HNSCC and ESCC from the same patients had no clonal relationship. Routine endoscopic examination of the esophagus should be recommended for patients with risk factors identified. LEVELS OF EVIDENCE: NA. Laryngoscope, 126:1097-1102, 2016.

The impact of human papillomavirus infection on the survival and treatment response of patients with esophageal cancers.

OBJECTIVE: This study aimed to investigate the impact of human papillomavirus (HPV) infection on the prognosis and treatment response of esophageal squamous cell carcinoma (ESCC). METHODS: We examined the presence and subtypes of HPV in the tumors by polymerase chain reaction and sequencing in 150 ESCC patients. Their clinicopathological characteristics, treatment response and survival were further analyzed according to the presence of HPV infection. RESULTS: Of 150 ESCC tumor samples, 27 (18.0%) were HPV-positive, of which 22 (81.5%) had HPV-16 infection. The risk of developing multifocal ESCC was not significantly different in the HPV-positive and HPV-negative groups (29.6% vs 28.5%, P = 0.90). In subgroup analysis, patients with HPV-16-positive advanced ESCC had a significantly better survival than those with HPV-negative ESCC (3-year survival: 55% vs 21%, log-rank P = 0.03). Cox proportional hazards model showed that the presence of HPV-16 was associated with a significant reduction in the mortality rate (hazard ratio 0.41, 95% CI 0.18-0.96). Patients with HPV-16 infection had better response to chemoradiotherapy (CRT) than those without HPV-16 infection (P = 0.026). CONCLUSIONS: In patients with advanced ESCC, HPV-16-positive patients had a significantly favorable survival, especially those who received CRT. Larger scale studies are needed to determine the causal relationship.