Doublet chemotherapy, triplet chemotherapy, or doublet chemotherapy combined with radiotherapy as neoadjuvant treatment for locally advanced oesophageal cancer (JCOG1109 NExT): a randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Neoadjuvant therapy is the standard treatment for patients with locally advanced oesophageal squamous cell carcinoma (OSCC). However, the prognosis remains poor and more intensive neoadjuvant treatment might be needed to improve patient outcomes. We therefore aimed to compare the efficacy and safety of neoadjuvant doublet chemotherapy, triplet chemotherapy, and doublet chemotherapy plus radiotherapy in patients with previously untreated locally advanced OSCC. METHODS: In this randomised, open-label, phase 3 trial, patients aged 20-75 years with previously untreated locally advanced OSCC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were recruited from 44 centres across Japan. Patients were randomly assigned (1:1:1) centrally via a web-based system to receive neoadjuvant doublet chemotherapy (two courses of fluorouracil [800 mg/m2 per day intravenously on days 1-5] and cisplatin [80 mg/m2 per day on day 1] separated by an interval of 3 weeks [NeoCF]), triplet chemotherapy (three courses of fluorouracil [750 mg/m2 per day on days 1-5], cisplatin [70 mg/m2 per day on day 1], and docetaxel [70 mg/m2 per day on day 1] repeated every 3 weeks [NeoCF+D]), or doublet chemotherapy (two courses of fluorouracil [1000 mg/m2 per day on days 1-4] and cisplatin [75 mg/m2 per day on day 1] separated by an interval of 4 weeks) plus 41·4 Gy radiotherapy [NeoCF+RT]) followed by oesophagectomy with regional lymph node dissection. Randomisation was stratified by T stage and institution. Participants, investigators, and those assessing outcomes were not masked to group assignment. The primary endpoint was overall survival, analysed by intention to treat. Analysis of safety included all patients who received at least one course of chemotherapy, and analysis of surgical complications included those who also underwent surgery. This study is registered with the Japan Registry of Clinical Trials, jRCTs031180202, and the trial is complete. FINDINGS: A total of 601 patients (529 male individuals and 72 female individuals) were randomly assigned between Dec 5, 2012, and July 20, 2018, with 199 patients in the NeoCF group, 202 patients in the NeoCF+D group, and 200 patients in the NeoCF+RT group. Compared with the NeoCF group, during a median follow-up period of 50·7 months (IQR 23·8-70·7), the 3-year overall survival rate was significantly higher in the NeoCF+D group (72·1% [95% CI 65·4-77·8] vs 62·6% [55·5-68·9]; hazard ratio [HR] 0·68, 95% CI 0·50-0·92; p=0·006) but not in the NeoCF+RT group (68·3% [61·3-74·3]; HR 0·84, 0·63-1·12; p=0·12). Grade 3 or higher febrile neutropenia occurred in two (1%) of 193 patients in the NeoCF group, 32 (16%) of 196 patients in the NeoCF+D group, and nine (5%) of 191 patients in the NeoCF+RT group. Treatment-related adverse events leading to termination of neoadjuvant therapy were more common in the NeoCF+D group (18 [9%] of 202 participants) than in the NeoCF+RT group (12 [6%] of 200) and NeoCF group (eight [4%] of 199). There were three (2%) treatment-related deaths during neoadjuvant therapy in the NeoCF group, four (2%) deaths in the NeoCF+D group, and two (1%) deaths in the NeoCF+RT group. Grade 2 or higher postoperative pneumonia, anastomotic leak, and recurrent laryngeal nerve paralysis were reported in 19 (10%), 19 (10%), and 28 (15%) of 185 patients, respectively, in the NeoCF group; 18 (10%), 16 (9%), and 19 (10%) of 183 patients, respectively, in the NeoCF+D group; and 23 (13%), 23 (13%), and 17 (10%) of 178 patients, respectively, in the NeoCF+RT group. The in-hospital deaths following surgery included three deaths in the NeoCF group, two deaths in the NeoCF+D group, and one in the NeoCF+RT group. INTERPRETATION: Neoadjuvant triplet chemotherapy followed by oesophagectomy resulted in a statistically significant overall survival benefit compared with doublet chemotherapy and might be the new standard of care for locally advanced OSCC who are in good condition in Japan. Neoadjuvant doublet chemotherapy plus radiotherapy did not show significant improvement of survival compared with doublet chemotherapy. FUNDING: Japan Agency for Medical Research and Development and National Cancer Center Research and Development Fund.

Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma.

BACKGROUND: First-line chemotherapy for advanced esophageal squamous-cell carcinoma results in poor outcomes. The monoclonal antibody nivolumab has shown an overall survival benefit over chemotherapy in previously treated patients with advanced esophageal squamous-cell carcinoma. METHODS: In this open-label, phase 3 trial, we randomly assigned adults with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamous-cell carcinoma in a 1:1:1 ratio to receive nivolumab plus chemotherapy, nivolumab plus the monoclonal antibody ipilimumab, or chemotherapy. The primary end points were overall survival and progression-free survival, as determined by blinded independent central review. Hierarchical testing was performed first in patients with tumor-cell programmed death ligand 1 (PD-L1) expression of 1% or greater and then in the overall population (all randomly assigned patients). RESULTS: A total of 970 patients underwent randomization. At a 13-month minimum follow-up, overall survival was significantly longer with nivolumab plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (median, 15.4 vs. 9.1 months; hazard ratio, 0.54; 99.5% confidence interval [CI], 0.37 to 0.80; P<0.001) and in the overall population (median, 13.2 vs. 10.7 months; hazard ratio, 0.74; 99.1% CI, 0.58 to 0.96; P = 0.002). Overall survival was also significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (median, 13.7 vs. 9.1 months; hazard ratio, 0.64; 98.6% CI, 0.46 to 0.90; P = 0.001) and in the overall population (median, 12.7 vs. 10.7 months; hazard ratio, 0.78; 98.2% CI, 0.62 to 0.98; P = 0.01). Among patients with tumor-cell PD-L1 expression of 1% or greater, a significant progression-free survival benefit was also seen with nivolumab plus chemotherapy over chemotherapy alone (hazard ratio for disease progression or death, 0.65; 98.5% CI, 0.46 to 0.92; P = 0.002) but not with nivolumab plus ipilimumab as compared with chemotherapy. The incidence of treatment-related adverse events of grade 3 or 4 was 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, and 36% with chemotherapy alone. CONCLUSIONS: Both first-line treatment with nivolumab plus chemotherapy and first-line treatment with nivolumab plus ipilimumab resulted in significantly longer overall survival than chemotherapy alone in patients with advanced esophageal squamous-cell carcinoma, with no new safety signals identified. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 648 ClinicalTrials.gov number, NCT03143153.).

Identification of barriers to implementation of precision oncology in patients with rare cancers.

Established treatment options for rare cancers are limited by the small number of patients. The current comprehensive genomic profiling (CGP) testing might not fully exploit opportunities for precision oncology in patients with rare cancers. Therefore, we aimed to explore the factors associated with CGP testing utility in rare cancers and identify barriers to implementing precision oncology. Patients who underwent CGP testing at our institution between September 2019 and June 2021 were enrolled in this retrospective study. Based on their results, the patients received molecularly targeted drugs or immune checkpoint inhibitors. Univariate and multivariate analyses evaluated the association between patient characteristics and the proportion of patients receiving molecularly targeted drugs. Overall, 790 patients underwent CGP testing. Among them, 333 patients with rare cancers were identified, of whom 278 (83.5%) had actionable genomic alterations, 127 (38.1%) had druggable genomic alterations, and 25 (7.5%) received genomically matched therapy. The proportion of patients receiving molecularly targeted drugs was significantly higher among those with treatment options with evidence levels A-D (8.7%) than those without treatment options with evidence levels A-D (2.9%). A potential barrier to CGP testing utility in rare cancers is the limited number of molecularly targeted drugs with clinical evidence. We propose that CGP testing be performed in patients with rare cancers who have treatment options with evidence levels A-D to maximize CGP testing utility in real-world practice.

Health-related quality-of-life analysis from KEYNOTE-590: pembrolizumab plus chemotherapy versus chemotherapy for advanced esophageal cancer.

BACKGROUND: In the KEYNOTE-590 study, first-line pembrolizumab plus chemotherapy provided statistically significant improvement in overall survival, progression-free survival, and objective response rate compared with chemotherapy, with a manageable safety profile in patients with advanced esophageal cancer. Prespecified health-related quality-of-life (HRQoL) outcomes are reported. MATERIALS AND METHODS: Change from baseline to week 18 in the EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) global health status/QoL (GHS/QoL) and QLQ-Esophageal cancer module (OES18) dysphagia, pain, and reflux scales were evaluated. RESULTS: The HRQoL analysis included 730 patients who received treatment and completed ≥1 HRQoL assessment. Least squares mean (LSM) change from baseline to week 18 was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 reflux scales. The QLQ-OES18 dysphagia (LSM difference, -5.54; 95% CI, -10.93 to -0.16) and pain (LSM difference, -2.94; 95% CI, -5.86 to -0.02) scales favored pembrolizumab plus chemotherapy over placebo plus chemotherapy. Median time to confirmed deterioration (TTD) was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 dysphagia and reflux scales. Compared with chemotherapy, pembrolizumab plus chemotherapy prolonged median TTD, as seen on the QLQ-OES18 pain scale (HR, 0.69; 95% CI, 0.51 to 0.95). CONCLUSION: The use of pembrolizumab plus chemotherapy maintained HRQoL at week 18 relative to baseline and was comparable with placebo plus chemotherapy. These HRQoL results together with published reports of efficacy, support the use of pembrolizumab plus chemotherapy as first-line therapy for advanced/metastatic esophageal cancer. CLINICALTRIALS.GOV ID: NCT03189719.

Significance of Surgery for Resectable M1 Lymph Node Metastases Without Organ Metastasis in Esophageal Carcinoma in the Era of Neoadjuvant Treatment.

BACKGROUND: M1 esophageal carcinoma goes beyond localized disease and requires treatment with systemic therapy. M1 status is primarily divided into two categories: M1 lymph node metastasis and distant organ metastasis. Oligometastasis is defined as a state of limited metastatic disease, and surgery for oligometastasis of distant organs is reported to be beneficial in limited conditions. The aim of this study was to investigate resected cases of M1 lymph node metastases as the only metastatic site in stage IVB esophageal carcinoma. PATIENTS AND METHODS: This study was a single-center retrospective cohort study. Patients with esophageal carcinoma who underwent esophagectomy with curative intent between April 2017 and December 2021 were examined. Neoadjuvant chemotherapy was our standard therapy and administered in almost all cases. We hypothesized that four sites of metastatic M1LN (supraclavicular (no. 104), pretracheal (no. 106pre), posterior thoracic para-aortic (no. 112aoP), and abdominal para-aortic (no. 16a2lat) LNs) were potentially resectable M1LN (rM1LN) metastases with curative intent and compared the prognosis of patients with and without rM1LN metastasis. RESULTS: Six hundred eight-two patients were included in the study. Among these patients, 80 had rM1LN metastasis and received surgery for curative intent. Short-term safety outcomes were equivalent between patients with and without rM1LN metastases. After propensity score matching, there were no significant differences in overall survival between patients with and without rM1LN metastasis. Multivariate analyses revealed that the only independent prognostic factor was ypN status. CONCLUSION: The present study suggests the feasibility and favorable OS in the patients with resection of rM1LN metastasis.

Neoadjuvant Chemotherapy Improves Feasibility of Larynx Preservation and Prognosis in Resectable Locally Advanced Cervical Esophageal Cancer.

BACKGROUND: The optimal strategy for cervical advanced esophageal cancer remains controversial in terms of oncologic outcome as well as vocal and swallowing function. Recently, in East Asian countries, neoadjuvant chemotherapy (NAC) has been a standard strategy for advanced esophageal cancer. METHODS: This study included 37 patients who underwent NAC, and 33 patients who underwent definitive chemoradiation therapy (dCRT) as larynx-preserving treatment for locally advanced cervical esophageal cancer from 2016 to 2021. This study retrospectively investigated outcomes, with comparison between NAC and dCRT for locally advanced cervical esophageal cancer. RESULTS: Larynx preservation was successful for all the patients with NAC and dCRT. After NAC, the rate of complete or partial response was 78.4%, and 30 patients underwent larynx-preserving surgery. On the other hand, after dCRT, the complete response rate was 71.9%, and 4 patients underwent larynx-preserving salvage surgery. Overall survival (OS) and progression free survival were similar between the two groups. However, for the patients with resectable cervical esophageal cancer (cT1/2/3), the 2-year OS rate was significantly higher with NAC (79.9%) than with dCRT (56.8%) (P = 0.022), and the multivariate analyses identified only NAC and cN0, one of the two as a significantly independent factor associated with a better OS (NAC: P = 0.041; cN0, 1: P = 0.036). CONCLUSION: The study showed that NAC as larynx-preserving surgery for resectable cervical esophageal cancer preserved function and had a better prognosis than dCRT. The authors suggest that NAC may be standard strategy for larynx preservation in patients with resectable cervical esophageal cancer.

Theoretical investigation of multi-spin excited states of anthracene radical-linked π-conjugated spin systems by computational chemistry.

Multi-spin excited states of chromophore radical-linked π-conjugated spin systems are investigated by molecular orbital calculations based on density functional theory (DFT). The investigated systems consist of an anthracene photosensitive unit leading to a triplet-excited-state (S = 1), π-conjugated linker to propagate spin exchange-coupling, and stable organic radical with a doublet-ground-state (S = 1/2). The intramolecular exchange coupling (JDQ), g value, and fine-structure interaction of their excited states depended on the π-conjugation network (π-topology), type of radical, and molecular structure of the π-linker (length and dihedral angle). The exchange interaction was dependent on the π-topology and the type of radical species. A decrease in the dihedral angle between the anthracene moiety and phenyl linker in the photo-excited state led to larger exchange coupling. With an increase in the π-linker length (r), the magnitude of the exchange coupling gradually decreased in the photoexcited states according to JDQ = JEx0 exp(-ßr), similar to the ground-state exchange. The g values of the quartet (Q) state depended only on the radical type (independent of the linker). Conversely, the fine-structure interaction of the Q state was independent of the radical type and depended on both the linker length and the dihedral angle.

Background signal suppression by opposite polarity subtraction for targeted DNP NMR spectroscopy on mixture samples.

A novel method for background signal suppression is introduced to improve the selectivity of dynamic nuclear polarization (DNP) NMR spectroscopy in the study of target molecules within complex mixtures. The method uses subtraction between positively and negatively enhanced DNP spectra, leading to an improved contrast factor, which is the ratio between the target and background signal intensities. The proposed approach was experimentally validated using a reverse-micelle system that confines the target molecules together with the polarizing agent, OX063 trityl. A substantial increase in the contrast factor was observed, and the contrast factor was optimized through careful selection of the DNP build-up time. A simulation study based on the experimental results provides insights into a strategy for choosing the appropriate DNP build-up time and the corresponding selectivity of the method. Further analysis revealed a broad applicability of the technique, encompassing studies from large biomolecules to surface-modified polymers, depending on the nuclear spin diffusion rate with a range of gyromagnetic ratios.

Development of perioperative immune checkpoint inhibitor therapy for locally advanced esophageal squamous cell carcinoma.

The standard preoperative treatment for resectable locally advanced esophageal squamous cell carcinoma (ESCC) is chemoradiotherapy in western countries (based on the CROSS trial) and triplet chemotherapy in Japan (based on the JCOG1109 trial). Postoperative nivolumab has recently been shown to improve disease-free survival in resectable locally advanced esophageal cancer after preoperative chemoradiotherapy in patients who had residual pathological disease, based on the CheckMate 577 trial. Furthermore, preoperative immune checkpoint inhibitor-containing treatments have also been developed. The JCOG1804E trial is presently evaluating the safety and efficacy of preoperative nivolumab-containing chemotherapy for resectable locally advanced ESCC. This review discusses the treatment of resectable locally advanced ESCC and future perspectives on perioperative immune checkpoint inhibitor-containing treatments.

[Box: see text].

Nivolumab in unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma.

Esophageal cancer (EC) is the eighth most common cancer worldwide. In view of biology and anatomical restrictions, multimodality treatment strategies have been developed for EC. However, the prognosis of patients with advanced EC remains especially poor. Immunotherapy, such as PD-1/PD-L1 and CTLA-4/B7 blockade, has emerged as a potent treatment for many types of cancer and has been approved in many countries. Based on the results of the ATTRACTION-3 trial, nivolumab, an anti-PD-1 monoclonal antibody, was approved by the US FDA for patients with platinum-resistant, unresectable, recurrent or metastatic esophageal squamous cell carcinoma. The CheckMate 648 trial demonstrated that the combination of nivolumab with platinum-based fluoropyrimidine chemotherapy and combination immunotherapy with nivolumab and ipilimumab, an anti-CTLA-4 monoclonal antibody, showed a survival benefit in patients with advanced esophageal squamous cell carcinoma compared with doublet chemotherapy. This review focuses on nivolumab-containing treatments for patients with advanced esophageal squamous cell carcinoma.

LEAP-014: first-line lenvatinib + pembrolizumab + chemotherapy in advanced/metastatic esophageal squamous cell carcinoma.

Treatment options for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) are improving. Current guidelines recommend first-line pembrolizumab plus chemotherapy for patients with unresectable or metastatic ESCC, which has led to improvements in survival outcomes. Antiangiogenic therapy combined with immune checkpoint inhibitors can act synergistically to convert the immunosuppressive tumor microenvironment to an immune supportive microenvironment, thus enhancing antitumor immune responses. In preclinical models, the antiangiogenic agent lenvatinib combined with an anti-PD-1 agent showed synergistic antitumor activity. We describe the design and rationale for the randomized, open-label, phase III LEAP-014 study of lenvatinib in combination with pembrolizumab plus chemotherapy in patients with advanced or metastatic ESCC. Overall survival and progression-free survival are the dual primary end points.Clinical Trial Registration: NCT04949256 (ClinicalTrials.gov).

[Box: see text].

Recent progress in chemoradiotherapy for oesophageal squamous cell carcinoma.

Oesophageal squamous cell carcinoma is a common malignancy worldwide. Definitive chemoradiotherapy is the standard treatment for patients with resectable stage oesophageal squamous cell carcinoma who cannot undergo surgery, as well as those with locally advanced unresectable oesophageal squamous cell carcinoma. However, it has several disadvantages such as poor survival, radiation-related toxicities and severe and lethal complications related to salvage treatment for residual or recurrent disease. Numerous clinical trials on chemoradiotherapy have been conducted to confirm the optimal combination of irradiation and chemotherapy. For advanced disease, multimodal treatment strategies including salvage surgery are essential. Palliative chemoradiotherapy is also crucial for dysphagia in locally advanced oesophageal squamous cell carcinoma with or without metastatic lesions. Recently, the synergistic mechanism of radiotherapy combined with immunotherapy has been reported. Early phase clinical trials suggest that a combination of immunotherapy and chemoradiotherapy can improve clinical outcomes with manageable side effects, but further investigations are needed. Here, we reviewed the existing clinical data and current development of chemoradiotherapy combined with immunotherapy in patients with oesophageal squamous cell carcinoma.

Rare malignant neoplasm of the esophagus: current status and future perspectives.

Esophageal cancer is common worldwide, including in Japan, and its major histological subtype is squamous cell carcinoma. However, there are some rare esophageal cancers, including neuroendocrine neoplasm, gastrointestinal stromal tumor, carcinosarcoma and malignant melanoma. The biological and clinical features of these cancers differ from those of esophageal squamous cell carcinoma. Therefore, different treatment strategies are needed for these cancers but are based on limited evidence. Neuroendocrine neoplasm is mainly divided into neuroendocrine tumor and neuroendocrine carcinoma by differentiation and the Ki-67 proliferation index or mitotic index. Epidemiologically, the majority of esophageal neuroendocrine neoplasms are neuroendocrine carcinoma. The treatment of neuroendocrine carcinoma is similar to that of small cell lung cancer, which has similar morphological and biological features. Gastrointestinal stromal tumor is known to be associated with alterations in the c-KIT and platelet-derived growth factor receptor genes and, if resectable, is treated in accordance with the modified Fletcher classification. Carcinosarcoma is generally resistant to both chemotherapy and radiotherapy and requires multimodal treatments such as surgery plus chemotherapy to achieve cure. Primary malignant melanoma is resistant to cytotoxic chemotherapy, but immune checkpoint inhibitors have recently demonstrated efficacy for malignant melanoma of the esophagus. This review focuses on the current status and future perspectives for rare cancer of the esophagus.

Protocol digest of a randomized controlled adaptive Phase II/III trial of neoadjuvant chemotherapy for Japanese patients with oesophagogastric junction adenocarcinoma: Japan Clinical Oncology Group Study JCOG2203 (NEO-JPEG).

Treatment strategies for oesophagogastric junction adenocarcinoma have not been standardized despite its poor prognosis due to differences in the incidence rates between Western countries and Asia. This randomized Phase II/III trial was initiated in June 2023 to determine which neoadjuvant chemotherapy regimen, docetaxel, oxaliplatin and S-1 or fluorouracil, oxaliplatin and docetaxel, is a more promising treatment in Phase II and confirm the superiority of neoadjuvant chemotherapy with docetaxel, oxaliplatin and S-1 or fluorouracil, oxaliplatin and docetaxel followed by surgery and postoperative chemotherapy over upfront surgery and postoperative chemotherapy in terms of overall survival in patients with Clinical Stage III or IVA oesophagogastric junction adenocarcinoma in Phase III. A total of 460 patients, including 150 patients in Phase II and 310 patients in Phase III, are planned to be enrolled from 85 hospitals in Japan over 5 years. This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031230182 (https://jrct.niph.go.jp/latest-detail/jRCTs031230182).

A phase III randomized controlled trial comparing local field with additional prophylactic irradiation in chemoradiotherapy for clinical-T1bN0M0 esophageal cancer: ARMADILLO trial (JCOG1904).

Chemoradiotherapy has been considered as one of the standard treatment options for clinical T1bN0M0 esophageal squamous cell carcinoma with organ preservation. However, 20% of patients develop locoregional recurrence after chemoradiotherapy, which requires salvage treatment including salvage surgery and endoscopic resection. Salvage surgery can cause complications and treatment-related death. Interestingly, chemoradiotherapy with elective nodal irradiation has been reported to reduce the locoregional recurrence of advanced esophageal squamous cell carcinoma. Hence, we are conducting a clinical trial to confirm whether modified chemoradiotherapy with elective nodal irradiation was superiority to that without elective nodal irradiation for the patients with cT1bN0M0 esophageal squamous cell carcinoma. The primary endpoint is major progression-free survival, defined as the time from randomization to the date of death or disease progression, excluding successful curative resection through salvage endoscopic resection. We plan to enroll 280 patients from 54 institutions over 4 years. This trial has been registered in the Japan Registry of Clinical Trials (jRCTs031200067).

Use of clinical variables for preoperative prediction of lymph node metastasis in endometrial cancer.

OBJECTIVE: Endometrial cancer is the most common gynaecological cancer, and most patients are identified during early disease stages. Noninvasive evaluation of lymph node metastasis likely will improve the quality of clinical treatment, for example, by omitting unnecessary lymphadenectomy. METHODS: The study population comprised 611 patients with endometrial cancer who underwent lymphadenectomy at four types of institutions, comprising seven hospitals in total. We systematically assessed the association of 18 preoperative clinical variables with postoperative lymph node metastasis. We then constructed statistical models for preoperative lymph node metastasis prediction and assessed their performance with a previously proposed system, in which the score was determined by counting the number of high-risk variables among the four predefined ones. RESULTS: Of the preoperative 18 variables evaluated, 10 were significantly associated with postoperative lymph node metastasis. A logistic regression model achieved an area under the curve of 0.85 in predicting lymph node metastasis; this value is significantly higher than that from the previous system (area under the curve, 0.74). When we set the false-negative rate to ~1%, the new predictive model increased the rate of true negatives to 21%, compared with 6.8% from the previous one. We also provide a spreadsheet-based tool for further evaluation of its ability to predict lymph node metastasis in endometrial cancer. CONCLUSIONS: Our new lymph node metastasis prediction method, which was based solely on preoperative clinical variables, performed significantly better than the previous method. Although additional evaluation is necessary for its clinical use, our noninvasive system may help improve the clinical treatment of endometrial cancer, complementing minimally invasive sentinel lymph node biopsy.

Potential utility of pretreatment serum miRNAs for optimal treatment selection in advanced high-grade serous ovarian cancer.

OBJECTIVE: The primary treatment of patients with advanced ovarian cancer is selected from whether primary debulking surgery or neoadjuvant chemotherapy. We investigated whether pretreatment serum microRNA profiles are useful for selecting patients with advanced high-grade serous ovarian cancer who obtain better outcomes from undergoing primary debulking surgery or neoadjuvant chemotherapy. METHODS: Consecutive patients with clinical stage IIIB-IVB and serum microRNA data were selected. Patients who underwent primary debulking surgery or neoadjuvant chemotherapy were subjected to 1:1 propensity score matching before comparing their progression-free survival using Cox modelling. Progression-free probabilities for the selected microRNA profiles were calculated, and the estimated progression-free survival with the recommended primary treatment was determined and compared with the actual progression-free survival of the patients. RESULTS: Of the 108 patients with stage IIIB-IVB disease, the data of 24 who underwent primary debulking surgery or neoadjuvant chemotherapy were compared. Eleven and three microRNAs were independent predictors of progression-free survival in patients who underwent primary debulking surgery and neoadjuvant chemotherapy, respectively. Two microRNAs correlated significantly with complete resection of the tumours in primary debulking surgery. No differences were found between the actual and estimated progression-free survival in the primary debulking surgery and neoadjuvant chemotherapy groups (P > 0.05). The recommended and actual primary treatments were identical in 27 (56.3%) of the 48 patients. The median improved survival times between recommended and actual treatment were 11.7 and 32.6 months for patients with actual primary debulking surgery and neoadjuvant chemotherapy, respectively. CONCLUSIONS: Pretreatment microRNA profiles could be used to select subgroups of patients who benefited more from primary debulking surgery or neoadjuvant chemotherapy and might contribute to selecting the optimal primary treatment modality in advanced high-grade serous ovarian cancer patients.

Long-term outcomes after non-curative endoscopic resection for esophageal squamous cell carcinoma followed by additional chemoradiotherapy.

Endoscopic resection (ER) of esophageal squamous cell carcinoma (ESCC) is evaluated pathologically, and additional treatment is recommended for cases resulting in non-curative resection, defined as pMM with lymphovascular invasion (LVI), pSM, or positive vertical margin. This study aimed to assess long-term outcomes and risk factors for recurrence in patients with ESCC treated with non-curative ER followed by additional chemoradiotherapy (CRT). We retrospectively reviewed the clinical courses of patients who underwent non-curative ER followed by additional CRT for ESCCs between August 2007 and December 2017. Recurrence rates and risk factors for recurrence were analyzed. Among 97 patients with non-curative ER, 73 underwent additional CRT. With a median follow-up period of 71 months, recurrences were observed in 10 (14%) of 73 patients, with a median interval of 24.5 (1-59 months). The 3- and 5-year recurrence-free survival were 89 and 85%, respectively, and the 3- and 5-year overall survival rates were 96 and 91%, respectively. Multivariate analysis showed that lymphatic invasion was an independent risk factor for recurrence in patients with non-curative ESCC receiving additional CRT. Among the 10 patients with recurrence, 4, 3, 2, and 1 underwent surgery, chemotherapy, supportive care, and CRT, respectively. Notably, all four patients who underwent surgery survived, regardless of regional and/or distant lymph node metastasis. Lymphatic invasion is an independent risk factor for the recurrence of non-curative ESCCs. Careful follow-up is required for at least 5 years after ER with additional CRT.

[History and Perspective of Chemotherapy in Advanced Esophageal Cancer].

Advanced esophageal carcinoma is one of the diseases with a poor prognosis. CF(cisplatin plus 5-FU)therapy and taxanes( paclitaxel or docetaxel)were considered standard treatments for first- and second-line treatment of advanced esophageal carcinoma based on the results of phase Ⅱ trials, although no randomized controlled trials were conducted. Subsequently, anti-epidermal growth factor receptor(EGFR)inhibitors, which had shown efficacy in head and neck cancer and colorectal cancer, were developed but failed to prolong survival both first- and second-line treatment. Immune checkpoint inhibitors have shown efficacy as single agents or in combination with chemotherapy in a variety of cancers, including esophageal cancer, where the KEYNOTE-181 trial and the ATTRACTION-3 trial demonstrated that single-agent pembrolizumab and nivolumab extended survival versus chemotherapy, respectively. In addition, the KEYNOTE-590 trial and the CheckMate 648 trial showed that pembrolizumab plus CF therapy was superior to CF, and nivolumab plus CF therapy and nivolumab plus ipilimumab were superior to CF in advanced esophageal carcinoma. These combinations have become the standard of care for the first-line treatment of advanced esophageal cancer. Immune checkpoint inhibitors had prolonged survival, but the results are still unsatisfactory, and CF therapy combined with immune checkpoint inhibitors and novel agents is being investigated. This article reviews the history of chemotherapy in advanced or recurrent esophageal cancer and discusses future prospects.

Second-line tislelizumab versus chemotherapy in Japanese patients with advanced or metastatic esophageal squamous cell carcinoma: subgroup analysis from RATIONALE-302.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has a poor prognosis, with limited second-line systemic therapy options, and represents an increasing disease burden in Japan. In the phase 3 RATIONALE-302 study, the anti-programmed cell death protein 1 antibody, tislelizumab, significantly improved overall survival (OS) versus chemotherapy as second-line treatment for advanced/metastatic ESCC. Here, we report the Japanese patient subgroup results. METHODS: Patients with advanced/metastatic ESCC, with disease progression during/after first-line systemic therapy were randomized 1:1 to open-label tislelizumab 200 mg every 3 weeks or investigator's choice of chemotherapy (paclitaxel/docetaxel). Efficacy and safety were assessed in all randomized Japanese patients. RESULTS: The Japanese subgroup comprised 50 patients (n = 25 per arm). Tislelizumab improved OS versus chemotherapy (median: 9.8 vs. 7.6 months; HR 0.59; 95% CI 0.31, 1.12). Among patients with programmed death-ligand 1 score ≥ 10%, median OS was 12.5 months with tislelizumab (n = 10) versus 2.9 months with chemotherapy (n = 6) (HR 0.31; 95% CI 0.09, 1.03). Tislelizumab improved progression-free survival versus chemotherapy (median: 3.6 vs. 1.7 months, respectively; HR 0.50; 95% CI 0.27, 0.95). Objective response rate was greater with tislelizumab (32.0%) versus chemotherapy (20.0%), and responses were more durable (median duration of response: 8.8 vs. 2.6 months, respectively). Fewer patients experienced ≥ grade 3 treatment-related adverse events with tislelizumab (24.0%) versus chemotherapy (47.8%). Tislelizumab demonstrated an improvement in health-related quality of life versus chemotherapy. CONCLUSIONS: As second-line therapy for advanced/metastatic ESCC, tislelizumab improved OS versus chemotherapy, with a favorable safety profile, in the Japanese patient subgroup, consistent with the overall population. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov: NCT03430843.