Evaluation of pembrolizumab plus cisplatin and fluorouracil in radical treatment for patients with T4b esophageal squamous cell carcinoma.

BACKGROUND: Pembrolizumab plus cisplatin and 5-fluorouracil administered as first-line therapy for advanced esophageal cancer patients has shown a better objective response and survival than conventional chemotherapy with less severe hematological adverse events. The safety and efficacy of this regimen were evaluated in patients with T4b esophageal squamous cell carcinoma (ESCC). METHODS: Eight consecutive patients with T4b ESCC received this regimen according to KEYNOTE-590 as induction, and they were evaluated after 1-3 courses. The programmed death-ligand 1 (PD-L1) combined positive score (CPS) was also evaluated before chemotherapy. Efficacy for the primary lesion was evaluated by our original formula for the tumor reduction rate. RESULTS: The numbers of patients with partial response (PR), stable disease, and progressive disease (PD) were 5, 1, and 2, respectively. The tumor reduction rate ranged from 69 to 87% in PR patients, and all PR patients had relief from T4b. Two patients underwent conversion surgery with R0 resection. PD-L1 CPS was over 90 in 2 PR patients, but under 10 in 2 other PR patients. PD-L1 CPS was under 10 in PD patients. One patient had hyperprogression, resulting in an esophago-pulmonary fistula. Greater than grade 3 adverse events were bleeding gastric ulcer in one patient (12.5%), neutropenia without G-CSF in 3 patients (37.5%), and hypopotassemia in 1 patient (12.5%). No patient had febrile neutropenia. CONCLUSIONS: Marked tumor reduction was confirmed in 62.5% of patients with pembrolizumab plus cisplatin and 5-fluorouracil with less adverse events. This regimen could be administered as induction chemotherapy for patients with T4b ESCC.

The real-world data of immune-checkpoint inhibitor combination therapy for unresectable or metastatic esophageal cancer: a multi-institutional cohort study.

BACKGROUND: The real-world efficacy, feasibility, and prognostic factors of immune-checkpoint inhibitor combination therapy for unresectable or metastatic esophageal cancer are not fully established. METHODS: This multi-institutional retrospective cohort study evaluated 71 consecutive patients treated with immune-checkpoint inhibitor combination therapy for esophageal cancer between March 2021 and December 2022. We assessed tumor response, safety, and long-term survival. RESULTS: In patients with measurable lesions, the response rate was 58%, and the disease control rate for all enrolled patients was 80%. Five patients (7.0%) underwent successful conversion surgery. Grade 3 or higher immune-related adverse events occurred in 13% of patients, and one patient (1.4%) died due to cholangitis. Median progression-free survival was 9.7 (95% confidence interval: 6.5-not reached). C-reactive protein levels and performance status were identified as significant predictors of progression-free survival through Cox proportional hazards analysis. CONCLUSIONS: Immune-checkpoint inhibitor combination therapy for esophageal cancer demonstrated comparable tumor response, safety, and long-term survival to previous randomized clinical trials. Patients with good performance status and low C-reactive protein levels may be suitable candidates for this treatment.

Pembrolizumab plus cisplatin and fluorouracil as induction chemotherapy followed by definitive chemoradiotherapy for patients with cT4 and/or supraclavicular lymph node metastasis (M1Lym) of esophageal squamous cell carcinoma.

Definitive chemoradiotherapy (DCRT) is administered as standard treatment for patients with cT4 and/or M1Lym esophageal squamous cell carcinoma (ESCC); however, its long-term result is inadequate. Although several studies have reported that conversion surgery can improve the survival of these patients, none have identified significantly better long-term survival than that achieved by DCRT. Thus, enhancing DCRT seems important to improve the survival of these patients. A strategy of shrinking tumor volume before DCRT and providing consolidation chemotherapy for systemic control is expected to improve the survival of these patients. Pembrolizumab plus cisplatin and fluorouracil has demonstrated good local control and significant improvement in the survival of patients with advanced esophageal cancer. Based on these results, the following strategy is proposed: This protocol should be applied as induction for these patients; then, DCRT should be provided depending on the initial response; and finally, adjuvant chemotherapy with an immune checkpoint inhibitor should be given to all responders.

Endoscopic submucosal dissection for gastric tube cancer after esophagectomy.

BACKGROUND: Recent improvements in the survival of patients after esophagectomy have led to an increasing occurrence of gastric tube cancer (GTC). Removal of the reconstructed gastric tube, however, can lead to high morbidity and mortality. OBJECTIVE: To assess the feasibility and effectiveness of endoscopic submucosal dissection (ESD) for GTC. DESIGN: Retrospective study. SETTING: National Cancer Center Hospital, Tokyo, Japan. PATIENTS: We investigated patients with GTC after esophagectomy undergoing ESD from 1998 to 2011. INTERVENTION ESD MAIN OUTCOME MEASUREMENTS: Patient characteristics, endoscopic findings, technical results, histopathology including curability and Helicobacter pylori gastritis, and long-term outcomes. RESULTS: There were 51 consecutive patients with 79 lesions including 38 lesions (48%) meeting the absolute indication, 31 (39%) satisfying the expanded indications, and 10 (13%) falling outside such indications. The median procedure time was 90 minutes. There were 73 en bloc resections (92%), 59 en bloc resections with tumor-free margins (R0 resections, 75%), and 51 curative resections (65%) based on the Japanese Gastric Cancer Association criteria. Fifty patients (98%) were assessed as H pylori gastritis positive. Adverse events included 3 perforations (3.8%) during ESD and 2 delayed perforations (2.5%) without any emergency surgery and 3 delayed bleeding (3.8%). Local recurrence was detected in 4 patients (7.8%), and metachronous GTCs were identified in 18 patients (35%). Five patients (10%) died of GTC including 3 metachronous lesions. The 5-year overall survival rate was 68.4%, and the disease-specific survival rate was 86.7% with 100% for curative and 72.7% for non-curative patients during a median follow-up period of 3.8 years (range, 0-12.1 years). LIMITATION: Single-center retrospective study. CONCLUSIONS: ESD for GTC was feasible and effective for curative patients; however, long-term outcomes for non-curative patients were less satisfactory.

Comparison of advanced adenocarcinomas of esophagogastric junction and distal stomach in Japanese patients.

BACKGROUND: There have been no reports on the incidence, characteristics, treatment outcomes, and prognosis of inoperably advanced or recurrent adenocarcinoma of the esophagogastric junction (AEGJ) in Japan. METHODS: We investigated the clinicopathological characteristics, treatment outcomes, and prognosis for 816 patients with esophagogastric junctional and gastric adenocarcinoma who received first-line chemotherapy between 2004 and 2009. RESULTS: Of 816 patients, 82 (10 %) had AEGJ. The patients with AEGJ had significantly more lung and lymph node metastasis, but less peritoneal metastasis, than those with gastric adenocarcinoma (GAC). The objective response rate to first-line chemotherapy was 23.3 % for patients with AEGJ and 22.6 % in patients with GAC (p = 0.90). The median survival was 13.0 months in AEGJ and 11.8 months in GAC (p = 0.445). In no patient was tumor site a significant prognostic factor (p = 0.472). In patients with AEGJ, ECOG PS ≥ 2, presence of liver metastasis, and absence of lung metastasis were significantly associated with poor prognosis. CONCLUSIONS: No significant differences were observed in treatment outcomes between advanced AEGJ and GAC. Therefore, the same chemotherapy regimen can be given as a treatment arm in future Japanese clinical trials to both patients with inoperably advanced or recurrent AEGJ and those with GAC.

Prognostic factors of second-line nivolumab monotherapy for unresectable or metastatic esophageal cancer: a multi-institutional cohort study for 184 cases.

BACKGROUND: The real-world efficacy, prognostic factors, and adverse events of second-line nivolumab monotherapy and subsequent third-line therapy for unresectable or metastatic esophageal cancer have not been fully evaluated. METHODS: This multi-institutional retrospective cohort study evaluated 184 consecutive patients treated with second-line nivolumab monotherapy for esophageal cancer between March 2021 and December 2022. We assessed tumor response, adverse events, long-term survival, and prognostic factors. RESULTS: Among 128 patients with measurable lesions, the response rate was 23% and the disease control rate for all enrolled patients was 45%. The incidence of grade 3 or higher adverse events was 14%, but no treatment-related deaths presented. Median progression-free survival was 5.1 months and overall survival was 14 months, respectively. C-reactive protein level and performance status were identified as significant prognostic factors of overall survival through Cox proportional hazards analysis. The group with two favorable prognostic factors showed better overall survival than the groups with either one or zero prognostic factors (median overall survival: 22, 15, and 4.4 months, respectively). Among 69 patients who received third-line taxane anticancer agents, the progression-free survival was 6.7 months. CONCLUSIONS: Our study demonstrated that the real-world outcomes of second-line nivolumab monotherapy were comparable to those of previous randomized clinical trials in terms of tumor response, safety, and long-term survival. Furthermore, a good performance status and low C-reactive protein levels may identify patients who are likely to benefit from therapy. Third-line chemotherapy after nivolumab treatment may have an enhanced effect; however, further prospective studies are required to confirm this finding.

Discrepancy of financial burden among elderly visiting a private general hospital in Phnom Penh, Cambodia: A three-year cross-sectional study.

Objectives: This study aims to clarify the financial burden of health on the elderly. Out-of-pocket payment (OOPP) in a major private general hospital in Phnom Penh was considered an indicator of financial burden. Study design: This study is a three-year cross-sectional study. Methods: To investigate the characteristics of patients who visited the Sunrise Japan Hospital (SJH), their data were obtained from the electronic reception database. Results: A total of 119,938 patients who visited SJH from January 2017 to September 2019 were included. The median age (25th, 75th centiles) was 52 years (36, 66) and 38.31% of patients were aged over 60 years. The OOPP median (25th, 75th centiles was 73.78 USD (32, 161.89). The median OOPP was the lowest in the 20s and highest in the 90s. The OOPP of an emergency patient was the highest in the consultation classifications. Conclusions: The need to raise public awareness regarding the financial burden on the elderly is becoming increasingly urgent. It is vital to establish a social system to prevent the medical catastrophes.

[Salvage surgery in esophageal cancer treatment -- its review in this decade and promises for the next decade].

Since admirable therapeutic results from definitive chemoradiotherapy(CRT)have been reported, it has been a curative option for all clinical stages of esophageal squamous cell carcinoma(ESCC)that could preserve the esophagus. From 2001 to 2009, we treated 981 new patients with ESCC in our institute. The rate of patients who chose definitive CRT as curative modality remained at about 70% in stage I and 20% in stage II - III . The number of salvage surgeries have not increased dramatically. In this decade, we had 97 cases of salvage surgery with right thoracotomy. Pathologically, no residual(R0) resection was performed in 80(82%)cases. The earlier the clinical stage, the better the overall survival. Seven patients(7%) died of severe complications, including bronchial necrosis and airway fistula. To avoid lethal complications, we established a retrosternal gastric pull-up without prophylactic neck lymph node dissection as a standard procedure of salvage surgery in 2006. Compared to other therapeutic treatments before and after 2006, this procedure could reduce fatal complications. However, overall survival remained at the same level. Salvage surgery is a complement to definitive CRT. It is necessary, therefore, to consider definitive CRT and salvage surgery comprehensively so as to increase positive therapeutic results with this multimodal strategy in patients with ESCC.

[Salvage esophagectomy after definitive chemoradiotherapy].

Salvage surgery is the sole curative-intent treatment option for patients with esophageal cancer after definitive chemoradiotherapy. The most significant factor associated with long-term survival appears to be RO resection. Patients who undergo salvage esophagectomy have high morbidity and mortality rates. Extended three-field lymphadenectomy should be limited in salvage surgery. Ischemic tracheobronchial lesions are serious complications of salvage esophagectomy. The right posterior bronchial artery should be preserved, and neck dissection should be avoided to preserve the blood supply from the inferior thyroidal artery to the trachea. The anastomotic leak rate is also significantly increased after salvage esophagectomy. Irradiation of the esophagus and stomach may affect the blood supply, which may then contribute to leakage. Gastric conduit necrosis in the posterior mediastinum can cause mortal mediastinitis, necessitating surgical modifications to reduce the impact of leaks into the thoracic cavity. The reconstruction route was changed to the anterior mediastinum with cervical anastomosis. Long-term or late cardiopulmonary toxicity cannot be ignored in patients who undergo salvage esophagectomy. A high morbidity rate is acceptable in view of the potential for long-term survival after salvage esophagectomy. Patients should be carefully selected for salvage esophagectomy after high-dose chemoradiotherapy at referral centers that specialize in esophageal cancer treatment.

Relationship between cervical esophageal squamous cell carcinoma and human papilloma virus infection and gene mutations.

Cervical esophageal squamous cell carcinoma (CESCC) is rare, accounting for 5% of all esophageal carcinomas. Several diagnostic and predictive markers have been studied. However, to the best of our knowledge, no biomarker is known to determine patient management except the clinical stage. The present study aimed to evaluate whether human papilloma virus (HPV) infection, epidermal growth factor receptor (EGFR) and its pathway-related gene mutations, known to be sensitive biomarkers of oropharyngeal carcinomas, could be used as biomarkers for the prediction of the prognosis of patients with CESCC. The present retrospective study included patients with CESCC who received chemoradiotherapy or surgery. HPV infection and the genomic status of EGFR, KRAS, BRAF, NRAS and PIK3CA of each tumor sample from patients with CESCC were analyzed by in situ hybridizations (ISH) and PCR methods, respectively. The present study included 33 patients with CESCC (male/female, 29/4; median age, 62 years; age range, 41-86 years; clinical stage I/II/III/IV, 2/6/10/15). The present study detected HPV in one patient (3.0%) by ISH and PCR. Concerning the investigation of EGFR and its pathway-related gene mutations, the present study detected 15.1% of EGFR, 6.0% of NRAS, 3.5% of BRAF, 3.0% of KRAS and 3.0% for PIK3CA mutations, with no significant relationship between any gene mutations and the clinical prognostic factors. The HPV-infected patient did not exhibit any gene mutations. The present study indicated that HPV infection, EGFR and its pathway-related gene mutations rarely exist in patients with CESCC. The relationship between these biomarkers and the prognosis in patients with CESCC is still unclear.

[Salvage surgery after definitive chemoradiation for esophageal carcinoma].

Definitive chemoradiation has become an effective modality for the treatment of advanced esophageal carcinoma, although local residual lesions or recurrence are detected in more than 50% of patients. For those patients, resection is the only salvage therapy. More than 40% of patients who undergo complete resection survive. After chemoradiation for esophageal carcinoma, severe adhesions may develop between the primary lesion and surrounding vital organs, leading to difficulty in R0 resection. Systemic function including the lungs, heart, and bone marrow could be also severely impaired. This may result in many severe complications after salvage surgery, such as airway necrosis or mediastinitis. To reduce complications, we restrict lymph node dissection, conserve the right bronchial artery, and reconstruct with a gastric tube through the poststernal course. It is also important to modify the method in each case. The more patients select chemoradiation for curative therapy of esophageal carcinoma, the more salvage surgery is needed. Surgeons should consider the indications and techniques for esophageal surgery to increase cure rates and decrease morbidity.

Clinical Outcomes of Resectable Esophageal Cancer with Supraclavicular Lymph Node Metastases Treated with Curative Intent.

BACKGROUND: In the seventh edition of the Union for International Cancer Control (UICC) TNM classification, supraclavicular lymph node (SCLN) in regard to thoracic esophageal cancer (EC) is regarded as a distant organ, therefore, if resectable, SCLN metastasis is considered a candidate for systemic chemotherapy. The purpose of this study was to clarify the survival outcome in patients with resectable thoracic EC with SCLN metastases (M1LYM) treated with curative intent. PATIENTS AND METHODS: Clinical outcomes in patients with resectable thoracic EC with SCLN metastases (M1LYM) treated by esophagectomy or definitive chemoradiotherapy (dCRT) were retrospectively analyzed. RESULTS: A total of 102 patients were divided in three groups: Surgery with perioperative therapy, n=45; surgery alone, n=19; and dCRT, n=38. Overall, median progression-free survival and median survival time were 9.3 and 26.7 months, respectively. The median survival time was 27.5 months in the group treated with surgery with perioperative treatment, 50.6 months in those treated with surgery alone, and 22 months in the dCRT group. No significant survival difference was seen among the three groups. CONCLUSION: Over 30% of patients with resectable M1LYM treated with curative intent achieved long-term survival.

A retrospective study on nonmalignant airway erosion after right transthoracic subtotal esophagectomy: incidence, diagnosis, therapy, and risk factors.

BACKGROUND: This study investigated the incidence, diagnosis, treatment, and risk factors for nonmalignant airway erosion after subtotal esophagectomy for thoracic esophageal carcinoma. METHODS: Clinical data from all patients with thoracic esophageal carcinoma who underwent right transthoracic subtotal esophagectomy from 2000 to 2012 at our institution were retrospectively reviewed, and the clinical course and outcome of those who developed airway erosion were investigated in detail. Risk factors for airway erosion were calculated by multivariate analysis. RESULTS: Of 1,091 patients enrolled, 15 patients (1.4%) developed nonmalignant airway erosion, which occurred at postoperative day (POD) 7 to 92 (median, 24). Anastomotic leakage or gastric-tube necrosis was detected prior to airway erosion in 14 cases (93.3%). Endoscopic and surgical therapy was administrated to 3 patients. Airway erosion was cured in 9 patients (60.0%). Five patients died from airway erosion directly (mortality, 33.3%). Alimentary leakage or necrosis (p<0.001), preoperative radiotherapy (p=0.004), and reconstruction through the posterior mediastinal route (p=0.051) were independent risk factors for airway erosion development. CONCLUSIONS: Airway erosion is a fatal complication after subtotal esophagectomy. Preoperative radiotherapy dramatically increases the risk of developing airway erosion and reduces the probability of spontaneous healing. Aggressive treatment of alimentary leakage or necrosis and reconstruction through the anterior route help to decrease the risk of airway erosion, especially in high-risk patients.

Prognostic analysis of salvage esophagectomy after definitive chemoradiotherapy for esophageal squamous cell carcinoma: the importance of lymphadenectomy.

OBJECTIVES: The objective of this study was to review the prognostic factors for increased survival after salvage esophagectomy after definitive chemoradiotherapy for esophageal squamous carcinoma and determine the importance of lymphadenectomy from a prognostic view. METHODS: Clinical data for all patients from January 1999 to December 2012 who underwent salvage esophagectomy for residual tumor or tumor recurrence after definitive chemoradiotherapy were retrospectively collected. Survival was determined and prognostic factors were analyzed with univariate and multivariate analyses. RESULTS: Survival after 1, 3, and 5 years postoperatively was 74.4%, 39.8%, and 29.5%, respectively. The independent predictive factors for increased postoperative survival were tumor recurrence rather than residual tumor as the indication for salvage surgery (P < .001; odds ratio [OR], 0.292); complete tumor resection (P < .001; OR, 4.520); N category (P = .089; OR, 1.304); M category (P = .081; OR, 2.215), and total mediastinal dissection with 15 or more dissected mediastinal lymph nodes (P = .034; OR, 0.546). CONCLUSIONS: Salvage indications of recurrence, earlier disease, and complete tumor resection are related to longer survival. The total area of mediastinal dissection with a sufficient number of dissected mediastinal lymph nodes improves survival. Additional neck dissection does not add benefit. The optimal procedure for lymph node dissection in salvage esophagectomy should be established in future studies.

Diagnosis and surgical outcomes for primary malignant melanoma of the esophagus: a single-center experience.

BACKGROUND: We summarize the experience of diagnosis and surgical therapy for primary malignant melanoma of the esophagus (PMME). METHODS: Clinical data of 13 patients diagnosed as having PMME treated by surgery as their primary therapy from 2000 to 2012 were retrospectively analyzed, and survival information was collected through follow-up. RESULTS: The average age (±standard deviation) of participants in this study was 66.4±7.6 years, and 84.6% were male. Overall, 61.5% of tumors were located in the lower thoracic esophagus. The accuracies of clinical T stage, N stage, and TNM stage were 53.9%, 46.2%, and 38.5%, respectively, compared with pathological staging (kappa=0.252, p=0.023). Surgical mortality and morbidity were 7.7% and 53.9%, respectively. The incidence of lymph node metastasis for patients with tumor invading within the mucosa was 0, but increased to 42.9% (3 of 7) with tumor invading to the submucosal layer. Primary malignant melanoma of the esophagus in the mid third of the thoracic esophagus had a greater chance to metastasize to perigastric lymph nodes (2 of 5) than to middle mediastinal lymph nodes (1 of 5). For PMME located at the lower third of the thoracic esophagus, upper mediastinal lymph node metastasis was more likely to occur (2 of 4) with tumor invasion penetrating the proper muscle layer. Recurrence occurred within 1 year in all patients with tumor later than Stage Ib. The most common recurrent organ was the liver. The overall 1-year and 5-year postoperative survival rates were 54.0% and 35.9%, respectively, and lymph node metastasis was the independent predictive factor for postoperative survival (p=0.013; odds ratio, 15.05). CONCLUSIONS: Despite the similarity in lymph node metastatic patterns to squamous cell carcinoma, PMME is more inclined to distant metastasis. Clinical staging was inconsistent with pathological staging for PMME based on endoscopy and computed tomography. Surgical therapy was the optimal treatment for PMME at an earlier stage. Early diagnosis and aggressive lymph node dissection were beneficial for accurate staging, potentially reducing recurrence and thus improving survival.