Single-Agent Versus Double-Agent Chemotherapy in Concurrent Chemoradiotherapy for Esophageal Squamous Cell Carcinoma: Prospective,Randomized, Multicenter Phase II Clinical Trial

Lessons Learned

• The efficacy of single‐agent chemotherapy was not significantly different from that of double‐agent chemotherapy in concurrent chemoradiotherapy for inoperable esophageal squamous cell carcinoma.
• Single‐agent concurrent chemoradiotherapy had lower gastrointestinal and hematologic toxicity.
• Overall survival and progression‐free survival were not significantly different between single‐ and double‐agent concurrent chemoradiotherapy.

BackgroundThis multicenter, randomized, phase II trial aimed to compare the efficacy and safety of single‐agent concurrent chemoradiotherapy using the oral fluoropyrimidine S‐1 with those of double‐agent concurrent chemoradiotherapy using S‐1 and cisplatin in patients with inoperable esophageal squamous cell carcinoma.MethodsPatients with inoperable esophageal squamous cell carcinoma (clinical stages I to III) were randomly allocated to the single‐agent group (S‐1) or the double‐agent group (S‐1/cisplatin). The concurrent intensity‐modulated radiation therapy plan was similar for both groups: planning target volume 1.8 Gy/f*30–33f and planning gross target volume of 2 Gy/f*30–33f. The primary outcome measure was the endoscopic complete response rate.ResultsOf the 105 patients randomized, 89 were assessable. The endoscopic complete response rate was 46.9% (23/49) in the single‐agent group and 52.5% (21/40) in double‐agent group. The median progression‐free survival within a median follow‐up of 23 months was 20 and 21 months, respectively. The median overall survival was 26 months and not reached, respectively. Grade 3 hematological toxicities occurred in 4.1% and 27.5% of the patients in the single‐ and the double‐agent group, respectively.ConclusionSingle‐agent chemotherapy in concurrent chemoradiotherapy for inoperable esophageal squamous cell carcinoma has good efficacy and safety, thus warranting a phase III trial.     

Concurrent Chemotherapy and Radiation Therapy for Locally Advanced Carcinoma of the Esophagus

A pilot study was undertaken to clarify the efficacy of concurrentchemoradiotherapy against locally advanced esophageal carcinoma.The 20 patients in this study had previously untreated esophagealcarcinoma with evidence of T4 disease and/or distant node metastases.Chemotherapy consisted of protracted infusion of 5-fluorouracilat a dose of 400 mg/m²/day on days 1–5 and 8–12,combined with a 2-h infusion of cisplatinum at 40 mg/m² on days1 and 8. Radiation treatment for the mediastinum was administered5 days per week for 3 wk at 2 Gy/day, along with chemotherapy.These schedules were repeated twice to give a total radiationdose of 60 Gy. For patients who responded, two additional coursesof chemotherapy were administered. Five of the 20 patients hadUICC stage III disease and 15 had stage IV. Seventeen (85%)of the 20 patients exhibited an objective response, including6 (30%) complete responses. Local control was excellent with10 (50%) complete responses. Toxic effects were severe. Majortoxicities were leukocytopenia of grade 3 or more in 45% ofthe patients and esophagitis, including four perforations. Therewere two treatment-related deaths. The median survival timewas 9 mo (range: 2 to 34+). Concurrent chemotherapy and radiotherapywas effective even for locally advanced esophageal carcinoma,but was associated with significant toxicity.     

A Phase II Study of Apatinib in Patients with Chemotherapy-Refractory Esophageal Squamous Cell Carcinoma (ESO-Shanghai 11)

Lessons Learned

• Apatinib has potential as an effective and safe second‐line or higher treatment for patients with chemotherapy‐refractory esophageal squamous cell carcinoma (ESCC).
• Clinical safety is of potential concern when administering apatinib to patients with uncontrolled esophageal lesions or severe invasion of trachea, bronchi, or major blood vessels.
• To the best of the authors'' knowledge, this is the first prospective phase II study to investigate apatinib for patients with chemotherapy‐refractory ESCC. Apatinib could provide an alternative option for ESCC after first‐line or higher therapy in carefully selected patients.

BackgroundThe aim of this study was to evaluate the efficacy and adverse effects of the oral vascular endothelial growth factor receptor 2 (VEGFR‐2) tyrosine kinase inhibitor apatinib in patients with chemotherapy‐refractory esophageal squamous cell carcinoma (ESCC).MethodsWe enrolled patients with chemotherapy‐refractory ESCC. All patients received continuous apatinib 500 mg once daily.ResultsBetween July 2017 and August 2018, 40 patients were recruited, of whom 5 (12.5%) had uncontrolled primary tumors. Additionally, three patients with partial response (PR) and 23 with stable disease (SD) were observed for overall response rate (ORR) of 7.5% and disease control rate (DCR) of 65.0%. Median progression‐free survival (PFS) was 3.8 months (95% confidence interval [CI], 2.2–5.4); median overall survival (OS) was 5.8 months (95% CI, 3.2–8.4). Common adverse effects were fatigue (15%), hypertension (12.5%), and palmar‐plantar erythrodysesthesia syndrome (10%). Two cases of death from massive bronchopulmonary hemorrhage were observed, and esophageal fistula occurred in another two patients. Notably, both patients with esophageal fistula and one patient with massive fatal bronchopulmonary hemorrhage were individuals with uncontrolled primary tumors (3/5, 60%). Fatal bronchopulmonary hemorrhage in a second patient was associated with major blood vessel invasion.ConclusionApatinib has potential as an effective and safe treatment for patients with chemotherapy‐refractory ESCC whose primary tumors are controlled and without severe invasion of trachea, bronchi, or major blood vessels.     

食管梭形细胞癌临床病理分析

目的分析食管梭形细胞癌的临床病理特点,探讨其组织来源。方法回顾性分析4例食管梭形细胞癌的临床病理资料及复习有关文献。结果 4例患者为男性,1例为女性,平均年龄57.2岁,病变位于食管中下段,大体呈息肉型、髓质型、蕈伞型及溃疡型。显微镜下可见鳞状细胞癌和肉瘤样成份,其中3例未找到两者相移行的区域。免疫组织化学检查发现肉瘤样区域细胞中有AE1/AE3、vimentin蛋白表达,息肉型者软骨肉瘤样区域仅有Vimentin和S-100蛋白表达,纤维肉瘤成份仅有vimentin蛋白表达。结论食管梭形细胞癌本质上是1种特殊类型的癌,包括肉瘤样癌和癌肉瘤。肉瘤样癌区域可能是癌细胞双向分化的结果,癌肉瘤的发生机制有待于进一步研究。     

Radiation Dose-escalated Chemoradiotherapy Using Simultaneous Integrated Boost Intensity-Modulated Radiotherapy for Locally Advanced Unresectable Thoracic Oesophageal Squamous Cell Carcinoma: A Single-institution Phase I Study

AimsAbout 80% of cases of locally advanced unresectable thoracic oesophageal squamous cell carcinoma recur within the irradiation fields after chemoradiotherapy. Radiation dose escalation using advanced radiotherapy techniques is expected to improve clinical outcomes by reducing local and regional recurrence. The current study aimed to determine the recommended escalated radiation dose for these patients.Materials and methodsPatients with locally advanced unresectable thoracic oesophageal squamous cell carcinoma with good performance status underwent chemoradiotherapy using simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) with elective nodal irradiation. SIB-IMRT was delivered in five fractions per week. The radiation dose to the unresectable gross tumour was escalated from 66 Gy to a planned maximum dose of 72 Gy in 3 Gy increments in a standard 3 + 3 design. The doses to the resectable component, superficial tumours and elective nodal regions were fixed as 60, 51 and 48 Gy, respectively. Cisplatin and 5-fluorouracil were concurrently administered. Dose-limiting toxicity (DLT) was defined as acute grade 3 oesophagitis, grade 2 pneumonitis, grade 2 cardiac toxicity and a failure to complete planned radiotherapy within 60 days. Locoregional control and overall survival were estimated using the Kaplan–Meier method. Nine patients were enrolled.ResultsDLTs occurred in one of six and two of three patients at doses of 66 and 69 Gy, respectively. All DLTs were grade 3 oesophagitis. The recommended dose was determined as 66 Gy delivered in 30 fractions based on the predefined criteria. With a median follow-up period of 23 months, the 1-year locoregional control and overall survival rates were 67 (95% confidence interval = 19–90) and 78% (95% confidence interval = 36–94), respectively.ConclusionThe recommended radiation dose in chemoradiotherapy using SIB-IMRT with elective nodal irradiation was 66 Gy delivered in 30 fractions.     

Phase II evaluation of cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the esophagus: a Japanese Esophageal Oncology Group Trial.

Thirty-nine patients with advanced measurable squamous cell carcinomas were treated with two or more courses of 70 mg cisplatin/m2 on day 1 and 700 mg infused 5-fluorouracil/m2 on days 1-5 every 21 days. The overall response rate was 35.9 (95% confidence limits, 24.8-55.1%). Responses were seen in primary sites in the esophagus of five patients, in the lung of seven, the liver of one and the mediastinal lymph nodes of one. The average response duration was 3.5 (range 1-12) mo for patients who achieved partial response. The average survival time after the first administration was 9.5 mo for patients who responded to the treatment whereas, for those who did not, it was 5.6 mo. The major form of toxicity was myelosuppression and there were six patients with grade 3 toxicity and one with grade 4. The present study was designed to evaluate the effectiveness of combined cisplatin and 5-fluorouracil for advanced squamous cell carcinoma, and the results showed that it had a reasonable effect and might possibly be used as a postoperative chemotherapy because of its mild side effects.     

Rh-Endostatin Plus Irinotecan/Cisplatin as Second-Line Therapy for Advanced Esophageal Squamous Cell Carcinoma: An Open-Label,Phase II Study

BackgroundThis open-label, phase II study aimed to investigate the efficacy and safety of recombinant human endostatin (Rh-endostatin) plus irinotecan/cisplatin as second-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC).MethodsEligible patients received 15mg/m² Rh-endostatin as a continuous intravenous pump infusion (7 continuous days), 60mg/m² irinotecan (days 1 and 8), and 60mg/m² cisplatin (day 1) every 3 weeks. The primary endpoint was progression-free survival (PFS).ResultsA total of 50 patients were assessable for efficacy and safety analysis. The median follow-up was 10.97 months (95%CI: 7.03-19.42) as the data cutoff. Median PFS was 4.01 months (95% CI: 3.19-5.49), and median overall survival (OS) was 12.32 months (95% CI: 8.21-17.45); 13 (26%; 95% CI: 15.87-39.55) of 50 patients had an objective response, and 31 (62%; 95% CI: 48.15-74.14) had disease control. Grade 3 or greater treatment-related adverse events (AEs) occurred in 12 (24.0%) patients, and no deaths were reported. The common grade 3 or greater AEs were leucopenia (18.0%) and neutropenia (16.0%). Five (10%) patients discontinued treatment because of AEs.ConclusionRh-endostatin plus irinotecan/cisplatin showed promising anti-tumor activity in advanced ESCC patients with a good safety profile in the second-line setting, which warrants further study in this population. (ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT03797625","term_id":"NCT03797625"}}NCT03797625).     

Accelerated Hyperfractionated Radiation Therapy and Concurrent 5-Fluorouracil/Cisplatin Chemotherapy for Locoregional Squamous Cell Carcinoma of the Thoracic Esophagus: A Phase II Study

Purpose: To improve the poor prognosis of patients with locoregional esophageal squamous cell cancer, we used concurrent accelerated hyperfractionated radiation therapy (ACC HFX RT) and chemotherapy (CHT).

Material and Methods: Between January 1988 and June 1993, 28 patients were treated with ACC HFX RT with 1.5 Gy twice daily, to a total dose of 54 Gy concurrently with 5-fluorouracil (5-FU) (300 mg/m², days 1–5) and cisplatin (CDDP) (10 mg/m², days 1–5), both given during weeks 1 and 4 of the ACC HFX RT course. Following the ACC HFX RT/CHT, two additional courses of 5-FU (500 mg/m², days 1–5) and CDDP (20 mg/m², days 1–5) were both given during weeks 7 and 10. The median age and Eastern Cooperative Oncology Group performance status were 62 and 1, respectively. The American Joint Committee on Cancer (AJCC) stage was I in 12 patients, II in 10, and III in 6.

Results: The median survival time was 26 months, and the 5-year survival rate was 29%. The rates at 5 years for freedom from relapse, locoregional recurrence, and distant metastasis were 29%, 61%, and 45%, respectively. Univariate analysis revealed that performance status, stage, weight loss, tumor length, and tumor location influenced survival, while age and sex did not. The most frequent acute high-grade (3 or 4) toxicities were esophagitis and leukopenia, seen in 50% and 39% of patients, respectively. Late high-grade toxicity was infrequent. There were no treatment-related deaths.

Conclusion: The results of this study compare favorably with those of previous studies, albeit of relatively high incidence of acute high-grade toxicity. Further studies are warranted to compare its efficacy with other approaches.     

A phase II study of vindesine in the treatment of esophageal carcinoma. Japanese Esophageal Oncology Group

A phase II study of Vindesine for esophageal carcinoma was carried out cooperatively by 10 Japanese institutions. Fifty patients were enrolled in the study over a year and ten months. Four patients could not be evaluated because less than 4 weeks had elapsed since their preceding therapy. There were one complete remission and five partial remissions among the 46 remaining patients, a response rate of 13.0%. The patient experiencing the complete remission is still alive more than 24 months after treatment. The main side effects were depilation, anorexia, stomatitis and leukopenia. Thrombocytopenia and elevations of blood urea nitrogen and creatinine were not marked. There was no mortality connected with the administration of Vindesine. It was concluded that Vindesine is useful in the treatment of esophageal carcinoma as a single agent.     

Phase II Study of Co-Administration of Uracil and Tegafur (UFT) in Hepatocellular Carcinoma

A Phase II study of co-administration of uracil and tegafur(UFT) was performed in 32 patients with unresectable hepatocellularcarcinoma. A dose of 400 mg/m²/day of UFT was administered orally,three times a day, for more than 4 weeks. Of 26 patients evaluablefor response, one (3.8%) showed a partial response of 9 months'duration. There were no complete responders. A dose-limitingtoxicity was gastrointestinal tract disturbance. Six patients(18.8%) had to discontinue UFT treatment because of gastrointestinaltoxicity. The clinical advantage of tegafur in the treatmentof hepatocellular carcinoma was not enhanced by co-administrationof uracil.     

食管鳞状细胞癌淋巴结转移对预后影响的分析

目的：探讨胸段食管鳞状细胞癌淋巴结转移数对预后的影响。方法：对1146例胸段食管鳞状细胞癌单纯手术切除的临床病理资料,应用Kaplan-Meier生存曲线和Spearmam相关进行研究,结果：1）0、1、≥个转移淋巴结间的生存率差异显著（P＜0．001）。2）Ⅱb期和Ⅲ期间的生存率无差异（P＞0．05）;1和≥2个转移淋巴结的T3N1M0期间的生存率差异显著（P＞0．001）;3基于0、1和≥2个转移淋巴结的分期,该分期中的Ⅱa期、Ⅱb期、Ⅲa期和Ⅲb期之间的生存率差异显著（P＜0．001）。结论：淋巴结转移数和基于淋巴结转移数的分期能够反映食管癌切除术预后的变化,但还需更大样本量和多中心的进一步研究。     

西妥昔单抗联合同步放化疗用于局部晚期全喉鳞癌术后的疗效

目的探究西妥昔单抗联合同步放化疗用于局部晚期全喉鳞癌术后的治疗效果。方法选取局部晚期全喉鳞癌患者共86例,随机分为实验组(n=43)与对照组(n=43)。患者均接受全喉切除术,术后4周伤口愈合后,实验组给予西妥昔单抗联合同步放化疗治疗,对照组给予单纯同步放化疗。2组患者均治疗6周。治疗结束后,比较2组患者的卡氏(Karnofsky,KPS)评分、治疗期间死亡率、毒副作用发生率等。依据患者纳入本研究的时间,依次对患者进行60个月的随访,统计随访期间的死亡人数及对应的死亡时间及复发率,采用Kaplan-Meier法和对数秩检验(log-rank test)进行生存分析。结果与对照组相比,实验组患者的KPS评分显著提高(P<0.05)、复发率显著降低(P<0.05)。而2组治疗期间死亡率差异无统计学意义(P>0.05)。对照组与观察组患者血液学反应、消化系统反应、肝肾功能损害与总不良反应的发生率均无明显差异(P>0.05)。生存分析结果表明,相比于对照组,实验组患者的5年总生存率与生存时间均显著提高,差异具有统计学意义(χ^2=6.129,P=0.013)。结论相比于单纯同步放化疗,联合西妥昔单抗可提高治疗效果,并提高患者生存率,在临床上具有推广使用价值。     

Association of p53 Protein Expression with Responses and Survival of Patients with Locally Advanced Esophageal Carcinoma Treated with Chemoradiotherapy

Immunohistochemical analysis was performed to determine theclinical role of p53 mutations in patients with locally advancedesophageal carcinomas treated with concurrent chemoradiotherapy.The subjects of this study were 20 patients with previouslyuntreated esophageal carcinomas with evidence of T4 diseaseand/or distant node metastases. Treatment comprised protracted5-fluorouracil and 2-h cisplatinum infusions along with radiationtreatment with a total radiation dose of 60 Gy. Tumor specimensfrom 18 of the 20 patients were analyzed immunohistochemically.Mutant p53 protein expression in the biopsy materials from theprimary tumors was analyzed by immunohistochemical stainingusing a polyclonal antibody, RSP53. Expression of p53 was detectedimmunohistochemically in 10 (56%) of the 18 esophageal tumors,the cancer cell nuclei of which were diffusely stained. Therewere no significant differences between the patient backgroundsof the p53-"positive" and "negative" groups. Four (40%) of the10 patients with p53 expression achieved overall complete remissions(CRs) and 7 (70%) of these 10 achieved CRs of their primarytumors. In contrast, none of the 8 p53-negative patients achievedoverall CRs and two (25%) achieved CRs of their primary tumors.The CR rates overall and of primary tumors tended to be higherin the p53-positive than negative group, but the differenceswere not significant. The survival rate for the 10 patientswith p53 expression was better than that for the 8 negativeones (P > 0.01): their median survival times were 12 and4.5 months, respectively. Expression of p53 protein may be anindicator of a favorable prognosis in patients with locallyadvanced esophageal carcinomas treated with concurrent chemoradiotherapy.