Nivolumab Rechallenge After Immune-related Adverse Events in Patients With Unresectable Advanced or Recurrent Esophageal Cancer.

BACKGROUND/AIM: Rechallenge with immune checkpoint inhibitors following immune-related adverse events (irAEs) during the treatment of certain cancers reportedly has good efficacy. However, the subsequent clinical course of esophageal cancer remains unclear. This study investigated the nature of irAEs and the efficacy of a nivolumab rechallenge for patients with esophageal cancer. PATIENTS AND METHODS: This study retrospectively analyzed 44 patients with unresectable advanced or recurrent esophageal cancer who were treated with nivolumab as a second-line or later regimen and developed irAEs between February 2020 and May 2022. The cohort was divided into continuation, rechallenge, and discontinuation groups based on nivolumab administration after the occurrence of irAEs. The proportion of each group was investigated according to the type of irAEs. The progression-free and overall survival periods were retrospectively analyzed for each group. RESULTS: Among patients with skin-related irAEs, 78.6% continued nivolumab administration, 14.3% rechallenged, and 7.1% discontinued nivolumab. Among patients with gastrointestinal disorders, 30.8% continued, 46.2% rechallenged, and 23.1% discontinued nivolumab. Among patients with interstitial pneumonia, none continued, 55.6% rechallenged, and 44.4% discontinued nivolumab. In those with endocrine disorders, 83.3% continued, none rechallenged, and 16.7% discontinued nivolumab. The median progression-free survival after irAE occurrence in the continuation, rechallenge, and discontinuation groups was 210, 333, and 72.5 days, respectively (p=0.022), while the median overall survival after irAE occurrence was 714, 848, and 223 days, respectively (p=0.008). CONCLUSION: Rechallenge with nivolumab may be considerably effective, depending on the type and severity of irAEs, and may improve the prognosis of patients with unresectable advanced or recurrent esophageal cancer.

[Indication and Perioperative Management for Esophagectomy in Elderly Patients of Esophageal Cancer].

Esophagectomy is a highly invasive surgery for elderly patients. The incidence of esophageal cancer is relatively high among the aging population in Japan. Therefore, it is crucial to determine the indications for esophagectomy and implement effective pre- and post-operative management strategies, considering the reduced physical function often observed in elderly patients. In our study, approximately 20% of patients with stageⅡ/Ⅲ esophageal cancer underwent esophagectomy. When we assessed thesepatients using the estimation of physiologic ability and surgical stress (E-PASS) scoring system, we found that the E-PASS score was significantly lower in the group that underwent surgery compared to those who received chemotherapy, radiation, or palliative treatment. Evaluating the risk of esophagectomy using tools such as E-PASS or others is crucial in establishing appropriate indications and ensuring patient safety. Regarding the perioperative period, our study revealed that the complication rate did not differ significantly between patients aged 74 years or younger and those aged 75 years or older. However, patients aged 75 years or older experienced significantly longer total and post-hospital stays. This prolonged postoperative stay in elderly patients can be attributed to a decline in activities of daily living (ADL) following esophagectomy, primarily due to their lower physical function. These results emphasize the importance of considering the potential decline in ADL resulting from lower physical function in elderly patients during perioperative management. Establishing multidisciplinary perioperative teams and rehabilitation programs can enhance the quality of life for patients after esophagectomy.

[A Case of Specific Pneumonia Diagnosed as Peritumoral Infiltration during Nivolumab Treatment for Esophageal Cancer].

The patient is a 54-year-old man who was diagnosed with advanced unresectable esophageal cancer. He underwent three courses of FP therapy and was followed up for observation after chemoradiotherapy and PR. Metastasis appeared in the upper lobe of the left lung and new lung metastasis was found in the lower lobe of the right lung despite FP therapy 2 years and 1 month after the start of treatment. Nedaplatin and docetaxel were administered as a second-line chemotherapy; however, the lung metastasis worsened. Consequently, nivolumab was introduced as a third-line chemotherapy. The metastases in the lower lobe of the right lung disappeared with pneumonia after 6 courses of nivolumab, which was diagnosed as a peritumoral infiltration(PTI). PTI is difficult to distinguish from drug-induced lung injury and should be diagnosed carefully because it is an imaging finding that reflects the desired antitumor effect.

[A Case of Locally Advanced Unresectable Esophageal Cancer Treated with Nivolumab and Ipilimumab Therapy Followed by Surgery].

In cases of unresectable, locally advanced esophageal cancer, conversion surgery may be considered if chemotherapy produces favorable results and surgical resection is indicated. The use of immune checkpoint inhibitors in chemotherapy for esophageal cancer has expanded, and has increased the number of cases in which conversion surgery becomes possible. The patient in the present report had received a diagnosis of Stage Ⅳa esophageal carcinoma, and a prior nephroureterectomy discouraged the administration of platinum-based agents. Nivolumab and ipilimumab were administered as induction chemotherapy. Despite the achievement of stable disease, the patient's esophageal stricture deteriorated, necessitating surgical intervention. The resected specimen revealed that fewer than 50% of malignant cells remained viable and residual cancer cells were noticeably absent, particularly in the enlarged lymph nodes. We herein present the details of this case and discuss the literature concerning surgery following immune checkpoint inhibitor therapy.

[A Case of Unresectable Thoracic Esophageal Cancer Responding Well to Multimodal Therapy Including 5-FU plus CDDP plus Pembrolizumab].

A 51-year-old male presented with swelling on the left side of his neck. A diagnosis of thoracic esophageal cancer(Lt type 5a, squamous cell carcinoma, T3N4[16LN]M1[skin, bone, retroperitoneum, lung], cStage Ⅳb)was made, and treatment with a combination of 5-FU plus CDDP and pembrolizumab was initiated. After the 1st round of chemotherapy, there was an increase in metastases in the left cervical lymph node and skin, along with the development of back pain because of an L3 lumbar spine metastasis. Palliative radiotherapy(Σ24 Gy/6 Fr)was administered for all lesions. Subsequently, pembrolizumab was administered for the persistent decline in white blood cell and neutrophil counts. After 6 courses of pembrolizumab, computed tomography(CT)revealed an absence of lesions. Positron emission tomography/CT demonstrated no significant accumulation, prompting a diagnosis of complete response(CR). The patient is currently under pembrolizumab therapy and continues to remain in a state of CR.

[A Case of Suspected Pure Red Cell Aplasia Due to Nivolumab Treatment for Unresectable Esophageal Cancer].

Immune checkpoint inhibitor(ICI)combination therapy is the first-line of treatment for unresectable or recurrent esophageal cancer. The frequency and mechanism of immune-related adverse events(irAEs)associated with ICI are still unclear and may require differentiation from other diseases. The present study examined a patient with unresectable, advanced esophageal cancer treated with cisplatin plus 5-fluorouracil(CF)plus nivolumab as the first-line treatment. CF therapy was discontinued after 1 course owing to adverse events. Nivolumab was continued, but progressive anemia stemming from pure red cell aplasia(PRCA), an irAE of nivolumab administration, was observed. Nivolumab was discontinued, but later, interstitial pneumonia also developed, and pulse steroid therapy was begun. After steroid tapering, both the PRCA and interstitial pneumonia improved. At present, about 6 months have elapsed since the last nivolumab administration without any PRCA recurrence or evidence of tumor progression.

Left thoracoscopic approach in the supine position for torsion of the residual esophagus after esophagectomy: a case report.

BACKGROUND: Anastomotic stenosis can occur after esophagectomy and gastric tube reconstruction. The effective surgical treatment for refractory anastomotic stenosis, which seems difficult to resolve with endoscopic treatment, has not been established. We report a case of refractory stenosis due to esophageal torsion in which reconstructive surgery was possible using a left thoracoscopic approach in the supine position. CASE PRESENTATION: A 72-year-old man who underwent thoracoscopic subtotal esophagectomy and retrosternal gastric tube reconstruction for esophageal cancer 6 months previously presented to us. Postoperative endoscopy revealed that the residual esophagus was twisted approximately 360°, just above the anastomotic site. Conservative endoscopic treatment failed to improve the condition due to severe passage obstruction, and reconstructive surgery was repeated. Surgery was performed in the supine position using a left thoracoscopic approach. The entire circumferences of the gastric tube and residual esophagus were dissected from the inferior mediastinum to the top of the sternum, with focus on preserving the right gastroepiploic vein and gastric-tube wall. Subsequently, laparoscopic surgery was performed to remove the gastric tube from the thoracoabdominal junction. After separating the esophagus on the oral side of the torsion from the left cervical wound, the abdomen was opened, the gastric tube was pulled out through the abdominal wound, and adhesions in the abdominal cavity were peeled off to raise the gastric tube cranially via the retrosternal route. An end-to-side anastomosis was performed using a circular stapler, and the esophageal torsion and previous anastomosis were resected. Oral intake was resumed on the 7th postoperative day, and the patient was discharged on the 38th day. CONCLUSIONS: After subtotal esophagectomy and retrosternal gastric tube reconstruction, the left thoracoscopic approach is one of the most minimally invasive approaches and is especially useful for preserving the right gastroepiploic artery and veins and for mobilizing the gastric tube wall.

[Treatment Strategies for Liver Oligometastases of Esophageal Cancer].

Benefits of local therapy for liver oligometastases of esophageal cancer has not been established. There are 2 cases of resection for liver oligometastases of esophageal cancer. Case 1: A 65-year-old male diagnosed with liver metastasis of esophageal cancer 12 months after initial treatment. A tumor located in segment 7 was resected after 6 months of chemotherapy. Case 2: A 71-year-old female diagnosed with liver metastasis of esophageal cancer 14 months after initial treatment. During 6 months of chemotherapy, tumor diameter increased but there were no new lesions. The tumor located in segment 8 was resected. In both cases, R0 resection was performed without intraoperative injury to the reconstructed esophagus. They had a recurrence free survival of more than 5 months. Resection of liver metastasis of esophageal cancer may be useful in combination with drug therapy in case it was diagnosed with liver oligometastases.

Development and Validation of a Disease-Specific Instrument to Measure Diet-Targeted Quality of Life for Postoperative Patients with Esophagogastric Cancer.

BACKGROUND: Patients who have undergone esophagectomy or gastrectomy have certain dietary limitations because of changes to the alimentary tract. This study attempted to develop a psychometric scale, named "Esophago-Gastric surgery and Quality of Dietary life (EGQ-D)," for assessment of impact of upper gastrointestinal surgery on diet-targeted quality of life. METHODS: Using qualitative methods, the study team interviewed both patients and surgeons involved in esophagogastric cancer surgery, and we prepared an item pool and a draft scale. To evaluate the scale's psychometric reliability and validity, a survey involving a large number of patients was conducted. Items for the final scale were selected by factor analysis and item response theory. Cronbach's alpha was used for assessment of reliability, and correlations with the short form (SF)-12, esophagus and stomach surgery symptom scale (ES(4)), and nutritional indicators were analyzed to assess the criterion-related validity. RESULTS: Through multifaceted discussion and the pilot study, a draft questionnaire comprising 14 items was prepared, and a total of 316 patients were enrolled. On the basis of factor analysis and item response theory, six items were excluded, and the remaining eight items demonstrated strong unidimensionality for the final scale. Cronbach's alpha was 0.895. There were significant associations with all the subscale scores for SF-12, ES(4), and nutritional indicators. CONCLUSIONS: The EGQ-D scale has good contents and psychometric validity and can be used to evaluate disease-specific instrument to measure diet-targeted quality of life for postoperative patients with esophagogastric cancer.

Development and validation of a symptom scale to evaluate postoperative patients with esophagogastric cancer.

BACKGROUND: Postgastrectomy or esophagectomy symptoms can be a significant burden for patients. However, no standard scale for evaluating these symptoms has been established. We recently developed a postoperative symptom-specific scale. STUDY DESIGN: After a draft scale was prepared based on a pilot study, psychometric methods were used to assess its reliability and validity. This study involved specialized and multifaceted discussions by a team consisting of gastrointestinal surgeons, gastroenterologists, psychologists, and epidemiologic researchers. The draft questionnaire included 40 questions and 3 domains. A factor analysis was carried out to refine the items and subscale design. To assess the reliability, Cronbach's alpha and score distributions were estimated. To assess the criterion-related validity, the correlations with the Short Form (SF)-12, Gastrointestinal Symptom Rating Scale (GSRS), endoscopic findings, and nutritional indicators were analyzed. RESULTS: A total of 344 patients were enrolled in this study. In an exploratory factor analysis (principal factor method), the eigenvalue attenuation data showed 4 domains. The final scale, named the Esophagus and Stomach Surgery Symptom Scale (ES(4)), included 23 items and 4 domains; 7 items for cervico-thoracic symptoms, 6 for abdominal hypersensitivity symptoms, 4 for abdominal distention symptoms, and 6 items for systemic symptoms. Cronbach's alphas for these domains were 0.82, 0.81, 0.79, and 0.74, respectively. The scale scores were normally distributed, and there were significant associations with the endoscopic findings, nutritional indicators, the summary score of the SF-12, and the GSRS. CONCLUSIONS: The ES(4) scale has high psychometric validity and can evaluate the profiles and severity of postoperative symptoms. This scale is applicable as an outcomes measure for various interventional studies on esophagogastric surgery aimed at alleviating postoperative symptoms.

[A case of pneumatosis cystoides intestinalis receiving chemotherapy for esophageal and tonsillar cancers].

A man in his 50, underwent chemotherapy for esophageal and tonsillar cancers. Diarrhea appeared on the 4th day and worsened daily. On the 12th day, free air was pointed out on abdominal X-ray and he consulted our department. At that time, there was no peritoneal irritation sign. Though CT showed pneumatosis and free air, there were neither perforation nor intestinal necrosis, therefore we diagnosed pneumatosis cystoides intestinalis (PCI). Conservative management was performed. He could ingest orally on the 14th day and was discharged on the 37th day. After that, chemotherapy was performed on several occasions for cancer, but there was no recurrence of PCI.

[Successful conservative therapy for mediastinitis caused by multiple esophageal perforations].

A 77-year-old man was admitted to our hospital on a diagnosis of acute mediastinits, 17 days after he had high fever. Computed tomography of the chest revealed an abscess cavity in the left upper mediastinum. Endoscopic examination showed multiple pin-hole perforations in the upper esophagus from 23 to 24cm distal from the incisors and drainage through the perforation. We diagnosed acute mediastinitis caused by multiple esophageal perforations of unknown etiology. We initiated conservative therapy. Oral intake was restarted on the 17th day because radiological examination showed the esophageal perforation had closed. The patient was discharged on the 36th day from admission. Although mediastinitis caused by esophageal perforation often demands surgical treatment, conservative nonoperative therapy was successful in this patient.

[Usefulness of induction chemotherapy followed by chemo-radiotherapy for patients with advanced cervical esophageal cancer].

To obtain a good prognosis and preserve laryngeal function is one of the most important issues for patients with advanced cervical esophageal cancer. It is reported that induction chemotherapy (ICT) followed by concurrent chemoradiotherapy (CRT) is useful. We treated 8 consecutive patients with advanced cervical esophageal cancer by ICT and following CRT between 2003 and 2006. The regimen of ICT was FAP therapy (fluorouracil 1,000 mg/day and cisplatin 20mg/day on days 1-5, and doxorubicin 50mg/day on day 1) every 4 weeks. After 2-4 courses of FAP therapy, low-dose FP-CRT (fluorouracil 200mg/24 hours/day and cisplatin 5mg/day with radiation of 60-66 Gy, 2 Gy/day) were given. Effect of ICT was PR in 5 cases, SD in 1 case, and PD in 2 cases. Furthermore, the effect of ICT+CRT was CR in 5 cases and PD in 3 cases. The one-year survival rate was 62. 5%. Grade 3 hematological toxicity related to ICT was observed in 1 patient (12.5%). Grade 3 anorexia and esophagitis related to CRT were observed in 3 patients (37.5%) and 2 patients (25.0%), respectively. Radiation pneumonitis as a late toxicity occurred in 1 patient (12.5%). The therapeutic effect of ICT and CRT was suggested to be useful for patients with advanced cervical esophageal cancer because it was performed safely with no serious adverse effect and the outcome of ICT predicted the effect of the subsequent CRT.

[Successfully treated case of hypopharyngeal and cervical esophageal squamous cell carcinoma with laryngeal preservation].

The patient suffering from getting something lodged was admitted to our hospital in October 2008. He was diagnosed as hypopharyngeal cancer (cT2N1M0, cStage III) and cervical esophageal cancer (cT2N1M0, cStage III). Firstly he was administered 5-FU, DXR and CDDP as induction chemotherapy. The response evaluation was PR according to RECIST criteria. After the induction chemotherapy, he was treated with chemoradiotherapy (64.8 Gy/54 fr, concurrent with weekly DOC 10 mg/m2). Since cervical lymph node metastases were still remaining with complete response of the primary sites, we performed a neck lymph node dissection as salvage surgery in July 2009. There has been no evidence of recurrence after the salvage surgery.

Endoscopic resection for T1a-MM and T1b-SM1 squamous cell carcinoma of the esophagus.

In Japan, the first paper on endoscopic resection (ER) for squamous cell carcinoma (SCC) of the esophagus confined to the mucosa was reported as endoscopic mucosal resection (EMR) in 1988. Since publication of that article, ER has been recommended as the standard treatment for squamous and mucosal cancer of the esophagus. T1a-EP and T1a-LPM esophageal cancer seldom involves lymph node metastasis. However, in cases of T1a-MM and T1b-SM1 esophageal cancer with lymph node metastasis (10% to 30%), the indication of ER is limited. The risk factors for lymph node metastasis in T1a-MM and T1b-SM1 esophageal cancer were cleared by clinical and pathological studies. Endoscopic findings such as type 0-I or type 0-III, size of 50 mm or more, and pathological findings such as lymphatic permeation, venous permeation, poorly differentiated SCC and INFb or INFc were suggestive of high risk for lymph node metastasis. In addition, histopathological findings of small cancer nests, defined as "budding" or "droplet infiltration," suggest frequent lymph node metastasis. In cases of T1a-MM and T1b-SM1 esophageal cancer with high risk of lymph node metastasis, adjuvant therapy including chemoradiotherapy and radical esophagectomy are recommended after ER. A recent advance in ER for esophageal cancer is the establishment of endoscopic submucosal dissection (ESD). It has allowed us to perform an en-block resection of a large mucosal lesion of the esophagus and detailed histopathological examination. However, ESD requires more difficult manipulation than EMR. The indication of EMR or ESD is sought.

[Successful management of the recurrent esophageal cancer following esophagectomy at a different time with combined local treatment of chemoradiotherapy and hepatic arterial infusion chemotherapy].

A 63-year-old man who underwent radical resection for esophageal cancer (cStage III)was diagnosed with metastasis of the paraaortic lymph node 5 months after the surgery. He was treated with concomitant chemoradiotherapy (CRT)with low-dose FP(5-FU, CDDP)and 60 Gy of irradiation. The effect of CRT was a complete response. Seven months later, there was a metastasis to the liver(S4). He received systemic chemotherapy(5-FU, ADR, CDDP: FAP), but it was not effective, so hepatic arterial infusion chemotherapy(FAP)was performed. Hepatic artery infusion therapy( 5-FU 1,000 mg/3.5 h x ADR 10 mg/1 h x CDDP 10 mg/1 h)was given for 1 day at an interval of 2 weeks for 18 months. Since ADR reached the maximum dose, hepatic artery infusion of 5-FU(1,000 mg/3.5 h)and CDDP(10 mg/ 1 h)was continued for 14 months at an interval of 4 weeks. The recurrent lesion disappeared completely 9 months after beginning hepatic artery infusion therapy. The patient is alive 69 months after surgery without any evidence of recurrence. Most cases with recurrent esophageal cancer have multiple metastases, and the treatment is mainly systemic therapy. However, in a patient with recurrent tumors at different times, it is possible to achieve a complete response and long-time survival by local treatment with fewer side effects as in this case. Combined local treatments could be the second treatment option after failed systemic chemotherapy for recurrent tumors in patients with esophageal cancer. Further investigations are necessary.

[A case of advanced esophageal cancer with large liver metastasis successfully treated with FAP therapy].

A 70-year-old man with dysphagia was diagnosed as advanced esophageal cancer by a primary doctor, and he was admitted to our hospital for treatment in February, 2004. The pretreatment diagnosis was basaloid squamous carcinoma, Mt area, T4 (aorta) , N2 (No. 107) , M1 (liver), Stage IVb performed systemic chemotherapy by FAP (5-fluorouracil ( 5-FU)+doxorubicin (DXR)+cisplatin (CDDP) ) from March, 2004. After 4 courses, the local tumor almost entirely disappeared, and the liver metastasis was obviously reduced. We continued chemotherapy afterwards. As of March 31, 2007, he had local lesion CR and metastatic lesion PR. It is very important to perform FAP repeatedly, for local and metastatic lesion of esophageal cancer while maintaining the patient's general condition and avoiding adverse events.

[Superficial small cell carcinoma of esophagus treated by endoscopic mucosal resection combined with chemoradiotherapy--a case report].

The patient was a 70-year-old woman who was admitted to our hospital for positive fecal occult blood. Upper gastrointestinal endoscopy revealed a superficial plateau-type (0- I sep) submucosal cancer on the right wall of the esophagus 28 cm from the incisor. Biopsy revealed small cell carcinoma. CT scan detected neither lymph node metastasis, nor distant organ metastasis. Endoscopic mucosal resection (EMR) was performed. Post-EMR chemoradiotherapies were conducted. The patient has lived with no evidence of cancer recurrence for 40 months. This was the first case of esophageal small cell carcinoma treated by EMR combined with chemoradiotherapy.

[A case of recurrent esophageal cancer treated by local injection of OK-432 for 8 months and the patient survived for 2 years and 3 months].

It is sometimes difficult to decide a treatment strategy for postoperative recurrence of esophageal cancer. Such recurrent esophageal cancer cases often present with extremely poor prognosis. We report a case of an 85-year-old man with a massive recurrent tumor of mediastinum 3 years after esophagectomy for squamous cell carcinoma (T3N2M0, Stage III) of the intrathoracic esophagus. The operative procedures were transhiatal esophagectomy and gastric reconstruction via posterior mediastinal route. Endoscopic local injection of OK-432 and balloon dilation was given to this patient after mediastinal recurrence. This patient lived for two years and three months after recurrence without severe side effects. Local injection of OK-432 is effective as a palliative therapy for recurrent case.