Efficacy of Concurrent Chemoradiotherapy With S-1 vs Radiotherapy Alone for Older Patients With Esophageal Cancer: A Multicenter Randomized Phase 3 Clinical Trial.

IMPORTANCE: Most older patients with esophageal cancer cannot complete the standard concurrent chemoradiotherapy (CCRT). An effective and tolerable chemoradiotherapy regimen for older patients is needed. OBJECTIVE: To evaluate the efficacy and toxic effects of CCRT with S-1 vs radiotherapy (RT) alone in older patients with esophageal cancer. DESIGN, SETTING, AND PARTICIPANTS: A randomized, open-label, phase 3 clinical trial was conducted at 23 Chinese centers between June 1, 2016, and August 31, 2018. The study enrolled 298 patients aged 70 to 85 years. Eligible participants had histologically confirmed esophageal cancer, stage IB to IVB disease based on the 6th edition of the American Joint Committee on Cancer (stage IVB: only metastasis to the supraclavicular/celiac lymph nodes) and an Eastern Cooperative Oncology Group performance status of 0 to 1. Data analysis was performed from August 1, 2020, to March 10, 2021. INTERVENTIONS: Patients were stratified according to age (<80 vs ≥80 years) and tumor length (<5 vs ≥5 cm) and randomly assigned (1:1) to receive either CCRT with S-1 or RT alone. MAIN OUTCOMES AND MEASURES: The primary end point was the 2-year overall survival rate using intention-to-treat analysis. RESULTS: Of the 298 patients enrolled, 180 (60.4%) were men. The median age was 77 (interquartile range, 74-79) years in the CCRT group and 77 (interquartile range, 74-80) years in the RT alone group. A total of 151 patients (50.7%) had stage III or IV disease. The CCRT group had a significantly higher complete response rate than the RT group (41.6% vs 26.8%; P = .007). Surviving patients had a median follow-up of 33.9 months (interquartile range: 28.5-38.2 months), and the CCRT group had a significantly higher 2-year overall survival rate (53.2% vs 35.8%; hazard ratio, 0.63; 95% CI, 0.47-0.85; P = .002). There were no significant differences in the incidence of grade 3 or higher toxic effects between the CCRT and RT groups except that grade 3 or higher leukopenia occurred in more patients in the CCRT group (9.5% vs 2.7%; P = .01). Treatment-related deaths were observed in 3 patients (2.0%) in the CCRT group and 4 patients (2.7%) in the RT group. CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial, CCRT with S-1 was tolerable and provided significant benefits over RT alone in older patients with esophageal cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02813967.

A phase I dose escalation study of S-1 with concurrent radiotherapy in elderly patients with esophageal cancer.

BACKGROUND: Concurrent chemoradiotherapy (CRT) with 5-fluorouracil (5-FU) and cisplatin (CDDP) are often associated with significant incidence of toxic effects in elderly patients with esophageal cancer. This phase I trial was designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of S-1, an oral 5-FU derivative, when given with radiotherapy in elderly patients. METHODS: Patients who were age of 70 years or older with histologically confirmed esophageal cancer, and had an Eastern Cooperative Oncology Group (ECOG) score of 0-2 were eligible for this study. Radiotherapy was administered in 1.8 Gy fractions 5 times weekly to a total dose of 54 Gy. S-1 was administered on days 1-14 and 29-42 at the following dosages: 60, 70, and 80 mg/m(2)/day. TRIAL REGISTRATION: NCT01175447 (ClinicalTrials.gov). RESULTS: Twelve previously untreated patients were enrolled in this study. No grade 3 or 4 toxicity was observed in six patients treated at the 60 and 70 mg/m(2) dose levels. DLT was observed in four of six patients treated at the 80 mg/m(2) dose level. Two patients developed grade 3 esophagitis, one patient developed grade 3 esophagitis and pneumonitis, and one patient developed grade 3 thrombocytopaenia. Endoscopic complete response (CR) was observed in eight patients (66.7%). The median progression free survival (PFS) was 20 months and median overall survival was 29 months. CONCLUSIONS: The MTD of S-1 was 80 mg/m(2), and the recommended dose (RD) for phase II studies was 70 mg/m(2). This regimen was well tolerated and active in elderly patients with esophageal cancer, meriting further investigation in phase II studies.

A phase II study of Endostatin in combination with paclitaxel, carboplatin, and radiotherapy in patients with unresectable locally advanced non-small cell lung cancer.

BACKGROUND: Endostatin inhibits the pro-angiogenic action of basic fibroblast growth factor and vascular endothelial growth factor in different human cancers. This study assessed the efficacy of endostatin combined with concurrent chemoradiotherapy of non-small cell lung cancer (NSCLC). METHODS: Nineteen patients with unresectable stage III NSCLC, Eastern Cooperative Oncology Group (ECOG) performance status 0-l, and adequate organ function were treated with 60-66 Gy thoracic radiation therapy over 30-33 fractions concurrent with weekly 7.5 mg/m(2) endostatin for 14 days, 50 mg/m(2) paclitaxel, and 2 mg/mL/min carboplatin over 30 min. Patients were then treated with 7.5 mg/m(2) endostatin for 14 days, 150 mg/m(2) paclitaxel, and 5 mg/mL/min carboplatin every 3 weeks for 2 cycles as the consolidation treatment. The objective response rate was recorded according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and the toxicity was evaluated using the National Cancer Institute (NCI) Common Toxicity Criteria. RESULTS: Six patients were unable to complete the consolidation treatment (4 pulmonary toxicity, 1 tracheoesophageal fistulae, and 1 progressive disease). Seventeen patients were included for data analysis. Specifically, one (5.9%) patient had a complete response and 12 (70.6%) had a partial response, whereas two patients had stable disease and the other two had disease progression. The overall response rate was 76% (95% confidence interval [CI], 51%-97%). The median progression-free survival was 10 months (95% CI, 7.6-12.3 months), and the median overall survival was 14 months (95% CI, 10.7-17.2 months). Early 10 patients who completed the treatment regimen showed that four patients experienced grade III pulmonary toxicity a few months after chemoradiotherapy, leading to the early closure of the trial according to the study design. CONCLUSIONS: The result of concurrent endostatin treatment with chemoradiotherapy in locally advanced unresectable NSCLC did not meet the goal per study design with unacceptable toxicity. The real impact of endostatin as the first-line treatment combined with chemoradiotherapy on the survival of NSCLC patients remains to be determined. (NCT 01158144).

Post-treatment serum lactic dehydrogenase as a predictive indicator for distant metastasis and survival of patients with nasopharyngeal carcinoma.

PURPOSE: To examine the function of serum lactic dehydrogenase (SLDH) level after intensity-modulated radiotherapy (IMRT) as a predictive factor for and loco-regional relapse free survival (LRFS), distant metastasis-free survival (DMFS), disease free survival (DFS), and overall survival(OS) among patients with in-situ nasopharyngeal carcinoma (NPC). RESULTS: Compared with the normal pt-SLDH group, elevated pt-SLDH demonstrated significant lower DMFS (46 versus 66 months, hazard ratio (HR) 4.07, 95% CI 2.43-6.80, p < 0.001), DFS (46 versus 63 months, HR 2.78, 95% CI 1.70-4.53, p < 0.001), and OS (54 versus 66 months, HR 2.93, 95% CI 1.65-5.23, p < 0.001). Distant metastasis were observed in 32.8% (20/61) patients with elevated pt-SLDH, and 8% (54/678) in normal SLDH (odds ratio (OR) 6.13, 95% CI 3.35-11.18, p < 0.001). COX regression showed that pt-SLDH was an independent prognostic factors for OS (HR 2.91, 95% CI 1.57-5.41, p < 0.001), DMFS (HR 4.21, 95% CI 2.51-7.07, p < 0.001), LRFS (HR 2.53, 95% CI 1.22-5.24, p < 0.001), and DFS (HR 2.81, 95% CI 1.72-4.59, p < 0.001). MATERIALS AND METHODS: The records of 739 in-situ NPC patients admitted to Zhejiang Cancer Hospital between January 2007 and May 2012 were retrospectively reviewed. The relationships between post-treatment SLDH (pt-SLDH) and LRFS, DMFS, DFS, and OS were analyzed. CONCLUSIONS: Our finding indicated that elevated pt-SLDH could be a simple available prognostic indicator for distant metastasis and survival for in-situ NPC patients.

Radiotherapy induced Lewis lung cancer cell apoptosis via inactivating ß-catenin mediated by upregulated HOTAIR.

OBJECTIVE: HOTAIR, a long intervening non-coding Hox transcript antisense intergenic RNA, negatively regulates transcription on another chromosome and is reported to reprogram chromatin organization and promote tumor progression. Nevertheless, little is known about its roles in the development of radiation therapy of lung cancer. In this study, we established a xenografed model of Lewis lung carcinoma in C57BL/6 mice and investigated the possible involvement of HOTAIR in this radiotherapy. METHODS: C57BL/6 mice were subcutaneously transplanted with Lewis lung carcinoma cells and locally irradiated followed by measurement in tumor volume. Levels of HOTAIR and WIF-1 mRNA expression were determined by using Quantitative Real-Time PCR. Levels of WIF-1 and ß-catenin were determined by using western blot assay. Cell viability was evaluated by MTT assay. Cell apoptosis was examined by using TUNEL assay. RESULTS: In mice bearing Lewis lung carcinoma tumor, local radiotherapy suppressed tumor growth and it also reduced level of HOTAIR but increased WIF-1 expression. When HOTAIR was overexpressed, radio-sensitivity was reduced. In vitro experiments, irradiation inhibited HOTAIR transportation to the nucleus. However, it was reversed by over-expressed HOTAIR. Cells transfected with pcDNA-HOTAIR or siRNA-HOTAIR resulted in decline or increase in radiosensitivity, which was abrogated by co-tansfected with siRNA-ß-catenin. CONCLUSION: Radiotherapy induced Lewis lung cancer cell apoptosis via inactivating ß-catenin mediated by upregulated HOTAIR.

Concurrent radiotherapy with gefitinib in elderly patients with esophageal squamous cell carcinoma: Preliminary results of a phase II study.

The survival rate associated with esophageal cancer is very poor due to diagnosis at advanced stages of disease and insensitivity to chemotherapy. This study investigated the efficacy of gefitinib combination with radiation in 20 elderly patients with esophageal squamous cell carcinoma (ESCC) who were not eligible for platinum-based chemotherapy. Immunohistochemistry was performed to analyze epidermal growth factor receptor (EGFR) expression, and the amplified refractory mutation system was used to detect EGFR mutations. Treatment response was assessed by endoscopy and computed tomography. Treatment toxicity was evaluated using the National Cancer Institute's Common Toxicity Criteria. The data showed that among these 20 patients, 5 experienced a complete response (CR), 13 a partial response (PR), and 2 had stable disease. The overall response rate (CR + PR) was 90%, the median overall survival (OS) was 14.0 months (95% confidence interval [CI]: 10.0-17.9 months), and the median progression-free survival was 7.0 months (95% CI: 0-17.2 months). Patients with good Eastern Cooperative Oncology Group performance status, never smoking, and EGFR mutated tumors had the best OS (14.0, 14.0, and 17.0 months, respectively). Treatment-related grade 3/4 toxicity occurred in five patients. No case of grade 3/4 impaired liver function or hematological toxicity was observed. Concurrent radiotherapy with gefitinib is effective and tolerable in elderly ESCC patients.

Up-regulation of BRAF activated non-coding RNA is associated with radiation therapy for lung cancer.

Radiation therapy has become more effective in treating primary tumors, such as lung cancer. Recent evidence suggested that BRAF activated non-coding RNAs (BANCR) play a critical role in cellular processes and are found to be dysregulated in a variety of cancers. The clinical significance of BANCR in radiation therapy, and its molecular mechanisms controlling tumor growth are unclear. In the present study, C57BL/6 mice were inoculated Lewis lung cancer cells and exposed to radiation therapy, then BANCR expression was analyzed using qPCR. Chromatin immunoprecipitation and western blot were performed to calculate the enrichment of histone acetylation and HDAC3 protein levels in Lewis lung cancer cells, respectively. MTT assay was used to evaluate the effects of BANCR on Lewis lung cancer cell viability. Finally, we found that BANCR expression was significantly increased in C57BL/6 mice receiving radiation therapy (P<0.05) compared with control group. Additionally, knockdown of BANCR expression was associated with larger tumor size in C57BL/6 mice inoculated Lewis lung cancer cells. Histone deacetylation was observed to involve in the regulation of BANCR in Lewis lung cancer cells. Moreover, over expression HDAC3 reversed the effect of rays on BANCR expression. MTT assay showed that knockdown of BANCR expression promoted cell viability surviving from radiation. In conclusion, these findings indicated that radiation therapy was an effective treatment for lung cancer, and it may exert function through up-regulation BANCR expression.

FDG-PET/CT imaging for tumor staging and definition of tumor volumes in radiation treatment planning in non-small cell lung cancer.

18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) has the potential to improve the staging and radiation treatment (RT) planning of various tumor sites. However, from a clinical standpoint, questions remain with regard to what extent PET/CT changes the target volume and whether PET/CT reduces interobserver variability in target volume delineation. The present study analyzed the use of FDG-PET/CT images for staging and evaluated the impact of FDG-PET/CT on the radiotherapy volume delineation compared with CT in patients with non-small cell lung cancer (NSCLC) who were candidates for radiotherapy. Intraobserver variation in delineating tumor volumes was also observed. In total, 23 patients with stage I-III NSCLC were enrolled and treated with fractionated RT-based therapy with or without chemotherapy. FDG-PET/CT scans were acquired within two weeks prior to RT. PET and CT data sets were sent to the treatment planning system, Pinnacle, through compact discs. The CT and PET images were subsequently fused by means of a dedicated RT planning system. Gross tumor volume (GTV) was contoured by four radiation oncologists on CT (GTV-CT) and PET/CT images (GTV-PET/CT). The resulting volumes were analyzed and compared. For the first phase, two radiation oncologists outlined the contours together, achieving a final consensus. Based on PET/CT, changes in tumor-node-metastasis categories occurred in 8/23 cases (35%). Radiation targeting with fused FDG-PET and CT images resulted in alterations in radiation therapy planning in 12/20 patients (60%) in comparison with CT targeting. The most prominent changes in GTV were observed in cases with atelectasis. For the second phase, the variation in delineating tumor volumes was assessed by four observers. The mean ratio of largest to smallest CT-based GTV was 2.31 (range, 1.01-5.96). The addition of the PET results reduced the mean ratio to 1.46 (range, 1.02-2.27). PET/CT fusion images may have a potential impact on tumor staging and treatment planning. Implementing matched PET/CT results reduced observer variation in delineating tumor volumes significantly with respect to CT only.

Prognostic impact of postoperative radiation in patients undergoing radical esophagectomy for pathologic lymph node positive esophageal cancer.

PURPOSE: Though postoperative radiation for esophageal squamous cell carcinoma is offered in selected cases, there is conflicting evidence as to whether it improves overall survival (OS). A retrospective investigation was performed to analyze the prognostic impact of postoperative radiation therapy (PORT) in a large cohort of patients. METHODS: From 2001 to 2009, 725 patients underwent radical esophagectomy (R0) with or without PORT were eligible for retrospective analysis. Patients were grouped into surgery alone (n = 467) and surgery plus PORT (n = 258). Median irradiation doses were 50 Gy (range: 40-56 Gy). Radiation fields encompassed the bilateral supraclavicular fossa, mediastinum, subcarinal area, and the tumor bed for the upper/middle-third disease; the bilateral supraclavicular fossa, mediastinum, the tumor bed, subcarinal area, and lower thoracic paraesophageal area for the lower-third disease. Kaplan-Meier and Cox regression analysis were used to compare OS. RESULTS: After median follow-up of 53 months, the median OS was 29 months in the PORT group and 23 months in the surgery alone group. The addition of PORT improved OS at 3 years from 36.6 to 43.6% compared with surgery alone. The use of PORT was associated with significantly improved OS (p = 0.018). For American Joint Committee on Cancer (AJCC) stage III esophageal cancer (T1-2N2M0, T3N1-2M0, T4N1-3M0), there was significant improvement in OS (p = 0.002) in the PORT group, not only for lymph-node metastatic ratio (LNMR) ≥0.25 (p = 0.001), but also for LNMR <0.25 (p = 0.043). However, for stage IIB disease (T1-2N1M0) there was no significant differences. The addition of POCT didn't prolong the OS significantly (Surgery alone group, p = 0.079; PORT group, p = 0.111). CONCLUSIONS: This large retrospective analysis supports the use of PORT for pathologic lymph node positive stage III esophageal squamous cell carcinoma. Given the retrospective nature of this study, the results should be confirmed by appropriately powered randomized trials. Further development of adjuvant therapy in EC is warranted.

The value of endoscopic ultrasonography in defining longitudinal gross target volumes for esophageal squamous carcinoma.

BACKGROUND AND PURPOSE: To investigate the differences between endoscopic ultrasonography (EUS)-based longitudinal gross target volumes (GTV) (GTV(EUS)) and computed tomography (CT)-based longitudinal GTV (GTV(CT)) in diagnosing esophageal squamous carcinoma. METHODS: Thirty-six patients underwent EUS to define the superior and inferior extents of the tumor by using hemoclips. CT-planning scan was performed with the patient in the supine position during the treatment. GTV(CT) and GTV(EUS) were contoured respectively. The respective lengths (L(CT) and L(EUS)) and spatial locations of longitudinal GTV(CT) and longitudinal GTV(EUS) were compared. RESULTS: The mean LCT was 7.8 ± 3.2 cm and the mean L(EUS) was 7.4 ± 2.7 cm. No statistical difference was found between L(CT) and L(EUS) (P > 0.05) with a correlation coefficient of 0.61 (P<0.05). The mean conformal index was 0.79 ± 0.18 with spatial variations found in 71% (24/34) of the patients. CONCLUSIONS: EUS can provide additional information to CT in defining longitudinal GTV in thoracic esophageal squamous cell carcinoma, especially superficial and submucosal carcinomas, which may contribute to the development of better individual treatment regimens.

Concomitant chemoradiotherapy using pemetrexed and carboplatin for unresectable stage III non-small cell lung cancer (NSCLC): preliminary results of a phase II study.

BACKGROUND: Concomitant chemoradiotherapy is the standard treatment of unresectable stage III non-small cell lung cancer (NSCLC). However, the optimal chemotherapy regimen is still controversial. We have conducted a phase II clinical trial in a Chinese population to evaluate concomitant treatment using pemetrexed/carboplatin chemotherapy and thoracic radiotherapy followed by pemetrexed/carboplatin consolidation chemotherapy in these patients. The purpose of this study is to evaluate the feasibility and activity, and also assess its impact on progression-free survival (PFS). PATIENTS AND METHODS: A total of 21 patients were enrolled between January 2008 and October 2009. Patients received concomitant pemetrexed 500 mg/m(2), carboplatin area under the curve (AUC) 5 chemotherapy on day 1 repeated every 3 weeks for 2 cycles and thoracic radiotherapy, followed by pemetrexed/carboplatin for 3 cycles as consolidation therapy. Objective response rate according to the RECIST criteria was recorded and toxicity was evaluated using the NCI Common Toxicity Criteria. The Kaplan-Meier method was used to evaluate patient survival. Univariate analysis of patient characteristics and tumor responses was conducted using the Chi-square and Fisher's exact test. RESULTS: Five (23.8%) and 13 patients (61.9%) had a complete or partial response, respectively, while 2 patient's disease remained stable and 1 patient had progression of the disease. The overall response rate (85.7%, 95% confidence interval (CI): 61-97%) exceeded the goal per study design. The median PFS was 12.0 months (95% CI: 10.6-13.4 months). The statistical analysis of predictive factors of efficacy revealed that the response rate and PFS seemed to a trend favoring adenocarcinoma histology. Main toxicity (grade 3 or greater, %): neutropenia 6 (28.5%); thrombocytopenia 4 (19%); anaemia 5 (23.8%); nausea/vomiting 1 (4.8%); anorexia 1 (4.8%), dysphagia 2 (9.5%), radiation pneumonitis 1 (4.8%) and fatigue 2 (9.5%). CONCLUSION: This data suggests that concomitant treatment with pemetrexed/carboplatin at full systemic doses and thoracic radiotherapy was well tolerated, with promising activity in a Chinese population with unresectable stage III NSCLC. Better outcomes were observed in patients with adenocarcinoma in this study. Although the data presented herewith appears promising, this study is relatively small, and more data from randomized trials are needed to further validate this regimen.

[Diagnosis and treatment of basaloid squamous cell carcinoma of the esophagus].

OBJECTIVE: To investigate the histopathological features of basaloid squamous cell carcinoma of the esophagus, and to explore the ways of its diagnosis, differential diagnosis and treatment. METHODS: The clinical data and pathological features of 23 cases of esophageal basaloid squamous cell carcinoma were reviewed and analyzed retrospectively. RESULTS: The tumors were mainly located at the middle third segment of the esophagus. The 1-,2- and 3-year survival rates were 60.9%, 21.7% and 0, respectively. CONCLUSION: The basaloid squamous cell carcinoma of the esophagus is highly malignant with poor prognosis. Radical resection combined with radiotherapy and chemotherapy is required.