ABSTRACT
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.).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Esophageal Neoplasms/drug therapy , Immune Checkpoint Inhibitors/administration & dosage , Ipilimumab/administration & dosage , Nivolumab/administration & dosage , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , B7-H1 Antigen/antagonists & inhibitors , Carcinoma, Squamous Cell/mortality , Esophageal Neoplasms/mortality , Female , Humans , Immune Checkpoint Inhibitors/adverse effects , Ipilimumab/adverse effects , Male , Middle Aged , Nivolumab/adverse effects , Progression-Free Survival , Survival AnalysisABSTRACT
BACKGROUND: The standard treatment for advanced esophageal cancer with synchronous distant metastasis is systemic chemotherapy or immunotherapy. Conversion surgery is not established for esophageal cancer with synchronous distant metastasis. This study aimed to investigate the clinical impact of conversion surgery for esophageal cancer with synchronous distant metastasis after induction therapy. METHODS: This multi-institutional retrospective study enrolled 66 patients with advanced esophageal cancer, including synchronous distant metastasis, who underwent induction chemotherapy or chemoradiotherapy followed by conversion surgery between 2005 and 2021. Short- and long-term outcomes were investigated. RESULTS: Distant lymph node (LN) metastasis occurred in 51 patients (77%). Distant organ metastasis occurred in 15 (23%) patients. There were 41 patients with metastatic para-aortic LNs, and 10 patients with other metastatic LNs. Organs with distant metastasis included the lung in seven patients, liver in seven patients, and liver and lung in one patient. For 61 patients (92%), R0 resection was achieved. The postoperative complication rate was 47%. The in-hospital mortality rate was 1%, and the 3- and 5-year overall survival (OS) rates for all the patients were 32.4% and 24.4%, respectively. The OS rates were similar between the patients with distant LN metastasis and the patients with distant organ metastasis (3-year OS: 34.9% vs. 26.7%; P = 0.435). Multivariate analysis showed that pathologic nodal status is independently associated with a poor prognosis (hazard ratio, 2.43; P = 0.005). CONCLUSIONS: Conversion surgery after chemotherapy or chemoradiotherapy for esophageal cancer with synchronous distant metastasis is feasible and promising. It might be effective for improving the long-term prognosis for patients with controlled nodal status.
Subject(s)
Esophageal Neoplasms , Induction Chemotherapy , Humans , Retrospective Studies , Esophageal Neoplasms/pathology , Prognosis , Lymph Nodes/surgery , Lymph Nodes/pathology , Lymphatic Metastasis/pathology , Survival Rate , Neoplasm StagingABSTRACT
BACKGROUND: Multidisciplinary treatment combining chemotherapy, chemo radiation therapy (CRT), and surgery has been utilized for advanced esophageal cancer. However, preoperative treatment could cause postoperative inflammation and complications. We hypothesized that fibrosis surrounding tumor tissue caused by preoperative treatment could induce postoperative systemic inflammation and influence postoperative complications. METHODS: Surgical specimens from patients with thoracic esophageal cancer who underwent preoperative CRT (38 cases) or chemotherapy (77 cases) and those who received no preoperative treatment (49 cases) were evaluated to measure the fibrotic area adjacent to the tumor (10 mm from the tumor edge) by applying Azan staining. Pleural effusion and peripheral blood serum interleukin-6 levels were analyzed to evaluate local and systemic postoperative inflammation in 37 patients. RESULTS: The fibrotic areas around the tumors were significantly larger in patients who underwent preoperative CRT than in patients who underwent chemotherapy (p < 0.001) or who had received no preoperative therapy (p < 0.001). Infectious complications were higher in patients who underwent preoperative CRT than chemotherapy (p = 0.047) or surgery alone (p < 0.001). The patients with larger fibrotic areas had more infectious complications (p = 0.028). Multivariate analysis showed that both a large fibrotic area and preoperative CRT were correlated with infectious complications, but not significantly. Pleural effusion interleukin-6 was significantly higher in patients who underwent preoperative CRT than in patients who received no preoperative therapy (p = 0.013). CONCLUSIONS: A large fibrotic peritumoral esophageal tissue area after preoperative treatment could cause postoperative inflammatory response and infectious complications.
Subject(s)
Esophageal Neoplasms , Pleural Effusion , Humans , Interleukin-6/therapeutic use , Esophageal Neoplasms/surgery , Esophageal Neoplasms/pathology , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Inflammation , Retrospective Studies , Treatment OutcomeABSTRACT
PURPOSE: To investigate the indications for neoadjuvant chemotherapy (NAC) in esophageal cancer patients aged 75 years or older. METHODS: We analyzed data, retrospectively, from 155 patients over 75 years old, who underwent esophagectomy for esophageal cancer between 2010 and 2020. Forty-one patients underwent upfront surgery (US group) and 114 were treated with NAC followed by surgery (NAC group). We compared the patient backgrounds and perioperative outcomes including prognosis, between the two groups. RESULTS: The NAC group patients were significantly younger and had significantly more advanced clinical stage disease than the US group patients. The incidence of postoperative complications was similar in the two groups. Patients with a good pathological response to NAC had a significantly better prognosis than those with a poor response and those in the US group. Among patients with a performance status (PS) of 0, the 5-year OS rate was 56.5% in the NAC group and 38.1% in the US group (HR = 0.63, 95% CI 0.35-1.12). Among those with a PS of 1-2, the 5-year OS rates were 28.1% and 57.1%, respectively (HR = 1.69, 95% CI 0.99-2.89; P = 0.037 for interaction). CONCLUSIONS: NAC did not improve the postoperative prognosis of older esophageal cancer patients with a PS of 1 or higher.
Subject(s)
Esophageal Neoplasms , Neoadjuvant Therapy , Humans , Aged , Esophagectomy/adverse effects , Retrospective Studies , Esophageal Neoplasms/surgery , PrognosisABSTRACT
PURPOSE: As Japanese society ages, the number of surgeries performed in elderly patients with hiatal hernia (HH) is increasing. In this study, we examined the feasibility, safety, and potential effectiveness of the addition of anterior gastropexy to hiatoplasty with or without mesh repair and/or fundoplication in elderly Japanese HH patients. METHODS: We retrospectively evaluated 39 patients who underwent laparoscopic HH repair between 2010 and 2021. We divided them into 2 groups according to age: the "younger" group (< 75 years old, n = 21), and the "older" group (≥ 75 years old, n = 18). The patient characteristics, intraoperative data, and postoperative results were collected. RESULTS: The median ages were 68 and 82 years old in the younger and older groups, respectively, and the female ratio was similar between the groups (younger vs. older: 67% vs. 78%, p = 0.44). The older group had more type III/IV HH cases than the younger group (19% vs. 83%, p < 0.001). The operation time was longer in the older group than in the younger group, but there was no significant difference in blood loss, perioperative complications, or postoperative length of stay between the groups. The older group had significantly more cases of anterior gastropexy (0% vs. 78%, p < 0.001) and less fundoplication (100% vs. 67%, p = 0.004) than the younger group. There was no significant difference in HH recurrence between the groups (5% vs. 11%, p = 0.46). CONCLUSIONS: The addition of anterior gastropexy to other procedures is feasible, safe, and potentially effective in elderly Japanese patients with HH.
Subject(s)
Feasibility Studies , Fundoplication , Gastropexy , Hernia, Hiatal , Laparoscopy , Humans , Hernia, Hiatal/surgery , Aged , Aged, 80 and over , Female , Male , Retrospective Studies , Age Factors , Treatment Outcome , Gastropexy/methods , Laparoscopy/methods , Fundoplication/methods , Herniorrhaphy/methods , Operative Time , Asian People , Middle Aged , Japan , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Safety , East Asian PeopleABSTRACT
PURPOSE: Suprapancreatic lymph node dissection is one of the most challenging procedures performed in the treatment of gastric cancer. This study aimed to investigate whether the pancreas-left gastric artery angle (PLA) can be used to predict the difficulty of the procedure. METHODS: This was a single-center cross-sectional study. Before gastrectomy, the patients were classified according to the size of the PLA into the small PLA (s-PLA; < 30°) and large PLA (l-PLA; ≥ 30°) groups in a surgeon-blinded manner. After gastrectomy, a surgeon evaluated suprapancreatic lymph node dissection as hard, normal, or easy to perform. RESULTS: Seventy-three patients were enrolled in the study. Surgeons evaluated lymph node dissection as hard in 43.8 and 8.7% of patients in the s-PLA and l-PLA groups, respectively (p = 0.002). The time taken for suprapancreatic lymph node dissection was also significantly longer in the s-PLA group than in the l-PLA group (p = 0.040). In patients who underwent laparoscopic gastrectomy, the time for node dissection in the s-PLA group was also significantly longer than that in the s-PLA group (p = 0.021), while there was no difference in those who underwent robotic surgery (p = 0.815). CONCLUSION: PLA is useful for predicting the degree of difficulty of suprapancreatic lymph node dissection during gastrectomy for gastric cancer.
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BACKGROUND: Fogging and staining of a laparoscope lens negatively impact surgical visualization. We hypothesized that the disposable hot pack could not only warm but also clean laparoscopes. Hence, this study verified and developed the disposable hot pack with anti-fogging and cleaning function. MATERIAL AND METHODS: The laparoscope was inserted into a swine abdominal cavity for five minutes. Then, the laparoscopic tip was heated with 65 °C saline or the folded disposable hot pack with nonwoven fabric coated surfactant for ten seconds (n = 15). Also, a laparoscopic tip with dirt was wiped with the prototype or conventional gauze for 10 s (n = 10). The dirt, fogging, and temperature of the laparoscopic tip were respectively evaluated after the laparoscope was inserted into the abdominal cavity. RESULTS: The laparoscopic tip temperature five minutes after insertion into the abdominal cavity was similar (31.1 °C vs 31.2 °C, p = 0.748) and there was no fogging in both methods. The conventional gauze had significantly less temperature of the laparoscopic tip after cleaning and higher fogging occurrence than the prototype (29.5 °C vs 34.0 °C, p < 0.001, 30% vs 0%, p = 0.030, respectively), although there was no dirt left after both methods. CONCLUSION: The disposable hot pack has a strong potential as an anti-fogging and cleaning device for use during laparoscopic surgery.
Subject(s)
Laparoscopy , Lenses , Animals , Swine , Laparoscopy/methods , Laparoscopes , Temperature , Hot TemperatureABSTRACT
INTRODUCTION: Surgical site infection (SSI) poses a substantial postoperative challenge, affecting patient recovery and healthcare costs. While surgical wound irrigation is pivotal in SSI reduction, consensus on the optimal method remains elusive. We developed a novel device for surgical wound irrigation and conducted preclinical and clinical evaluations to evaluate its efficacy and safety. METHODS: Two preclinical experiments using swine were performed. In the washability test, two contaminated wound model were established, and the cleansing rate between the device and the conventional method were compared. In the contamination test, the irrigation procedure with a fluorescent solution assessed the surrounding contamination of drapes. Subsequently, a clinical trial involving patients undergoing abdominal surgery was conducted. RESULTS: The washability test demonstrated significantly higher cleansing rates with the device method (86.4% and 82.5%) compared to the conventional method (65.2% and 65.1%) in two contamination models. The contamination test revealed a smaller contaminated region with the device method than the conventional method. In the clinical trial involving 17 abdominal surgery cases, no superficial SSIs or adverse events related to device use were observed. CONCLUSIONS: Our newly developed device exhibits potential for achieving more effective and safe SSI control compared to conventional wound irrigation.
Subject(s)
Surgical Wound Infection , Therapeutic Irrigation , Therapeutic Irrigation/instrumentation , Therapeutic Irrigation/methods , Swine , Pilot Projects , Surgical Wound Infection/prevention & control , Humans , Animals , Female , Male , Middle Aged , Aged , Surgical Wound/therapy , Adult , Abdomen/surgeryABSTRACT
BACKGROUND: The association between recurrence timing and prognosis in patients with locally advanced resectable esophageal cancer undergoing neoadjuvant chemotherapy (NAC) followed by esophagectomy remains unclear. This study aimed to clarify this association using multicenter prospective clinical trial data. METHODS: Among 162 patients enrolled in a NAC phase II study comparing the efficacy of cisplatin and fluorouracil plus docetaxel with cisplatin and fluorouracil plus adriamycin, 64 patients with recurrence after R0 resection were included in this study. We evaluated the association between recurrence timing and overall survival after recurrence (OSr), along with clinicopathological factors associated with recurrence timing and OSr. RESULTS: Among 64 patients, 46 (71.9%) and 59 (92.2%) experienced recurrence within 1 and 2 years after surgery, respectively. Groups based on recurrence timing, including ≤ 6, 6-12, and > 12 months, had median OSr of 3.6, 13.9, and 13.4 months, respectively. The prognosis was significantly poorer for patients with recurrence ≤ 6 months after surgery than for other patients (P < 0.001). Multivariate analysis revealed pathological lymph node staging as an independent factor associated with early recurrence (odds ratio: 3.46, 95% confidence interval: 1.47-8.02, P = 0.0045). On the other hand, multivariate analysis for factors associated with OSr revealed pT (hazard ratio [HR]: 1.91, 95%CI 1.26-2.88, P = 0.0022), early recurrence (HR: 6.88, 95%CI 2.68-17.6, P < 0.001), and treatment after recurrence, with both local treatment (HR: 0.47, 95%CI 0.22-0.98, P = 0.043) and chemotherapy (HR: 0.25, 95%CI 0.11-0.58, P = 0.0011) as independent prognostic factors. CONCLUSION: Patients with advanced esophageal cancer experiencing recurrence within 6 months after esophagectomy following NAC have an extremely poor prognosis, suggesting that an advanced pN stage is associated with early recurrence.
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BACKGROUND: Real-world clinical outcomes of and prognostic factors for nivolumab treatment for esophageal squamous-cell carcinoma (ESCC) remain unclear. This study aimed to evaluate real-world outcomes of nivolumab monotherapy in association with relevant clinical parameters in recurrent/unresectable advanced ESCC patients. METHODS: This population-based multicenter cohort study included a total of 282 patients from 15 institutions with recurrent/unresectable advanced ESCC who received nivolumab as a second-line or later therapy between 2014 and 2022. Data, including the best overall response, progression-free survival (PFS), and overall survival (OS), were retrospectively collected from these patients. RESULTS: Objective response and disease control rates were 17.0% and 47.9%, respectively. The clinical response to nivolumab treatment significantly correlated with development of overall immune-related adverse events (P < .0001), including rash (P < .0001), hypothyroidism (P = .03), and interstitial pneumonia (P = .004). Organ-specific best response rates were 20.6% in lymph nodes, 17.4% in lungs, 15.4% in pleural dissemination, and 13.6% in primary lesions. In terms of patient survival, the median OS and PFS was 10.9 and 2.4 months, respectively. Univariate analysis of OS revealed that performance status (PS; P < .0001), number of metastatic organs (P = .019), C-reactive protein-to-albumin ratio (CAR; P < .0001), neutrophil-lymphocyte ratio (P = .001), and PMI (P = .024) were significant. Multivariate analysis further identified CAR [hazard ratio (HR) = 1.61, 95% confidence interval (CI) 1.15-2.25, P = .0053)] in addition to PS (HR = 1.65, 95% CI 1.23-2.22, P = .0008) as independent prognostic parameters. CONCLUSIONS: CAR and PS before nivolumab treatment are useful in predicting long-term survival in recurrent/unresectable advanced ESCC patients with second-line or later nivolumab treatment. TRIAL REGISTRATION: UMIN000040462.
Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Neoplasm Recurrence, Local , Nivolumab , Humans , Nivolumab/therapeutic use , Male , Female , Middle Aged , Aged , Retrospective Studies , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/pathology , Esophageal Neoplasms/mortality , Neoplasm Recurrence, Local/drug therapy , Esophageal Squamous Cell Carcinoma/drug therapy , Esophageal Squamous Cell Carcinoma/mortality , Esophageal Squamous Cell Carcinoma/pathology , Antineoplastic Agents, Immunological/therapeutic use , Treatment Outcome , Aged, 80 and over , Adult , Prognosis , Progression-Free SurvivalABSTRACT
BACKGROUND: S-588410, a cancer peptide vaccine (CPV), comprises five HLA-A*24:02-restricted peptides from five cancer-testis antigens. In a phase 2 study, S-588410 was well-tolerated and exhibited antitumor efficacy in patients with urothelial cancer. Therefore, we aimed to evaluate the efficacy, immune response, and safety of S-588410 in patients with completely resected esophageal squamous cell carcinoma (ESCC). METHODS: This phase 3 study involved patients with HLA-A*24:02-positive and lymph node metastasis-positive ESCC who received neoadjuvant therapy followed by curative resection. After randomization, patients were administered S-588410 and placebo (both emulsified with Montanide™ ISA 51VG) subcutaneously. The primary endpoint was relapse-free survival (RFS). The secondary endpoints were overall survival (OS), cytotoxic T-lymphocyte (CTL) induction, and safety. Statistical significance was tested using the one-sided weighted log-rank test with the Fleming-Harrington class of weights. RESULTS: A total of 276 patients were randomized (N = 138/group). The median RFS was 84.3 and 84.1 weeks in the S-588410 and placebo groups, respectively (P = 0.8156), whereas the median OS was 236.3 weeks and not reached, respectively (P = 0.6533). CTL induction was observed in 132/134 (98.5%) patients who received S-588410 within 12 weeks. Injection site reactions (137/140 patients [97.9%]) were the most frequent treatment-emergent adverse events in the S-588410 group. Prolonged survival was observed in S-588410-treated patients with upper thoracic ESCC, grade 3 injection-site reactions, or high CTL intensity. CONCLUSIONS: S-588410 induced immune response and had acceptable safety but failed to reach the primary endpoint. A high CTL induction rate and intensity may be critical for prolonging survival during future CPV development.
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Despite the effectiveness of imatinib, most gastrointestinal stromal tumors (GISTs) develop resistance to the treatment, mainly due to the reactivation of KIT tyrosine kinase activity. Sunitinib, which inhibits the phosphorylation of KIT and vascular endothelial growth factor (VEGF) receptor, has been established as second-line therapy for GISTs. The recently-developed heat shock protein 90 (HSP90) inhibitor pimitespib (PIM; TAS-116) demonstrated clinical benefits in some clinical trials; however, the effects were limited. The aim of our study was therefore to clarify the effectiveness and mechanism of the combination of PIM with sunitinib for imatinib-resistant GISTs. We evaluated the efficacy and mechanism of the combination of PIM with sunitinib against imatinib-resistant GIST using imatinib-resistant GIST cell lines and murine xenograft models. In vitro analysis demonstrated that PIM and sunitinib combination therapy strongly inhibited growth and induced apoptosis in imatinib-resistant GIST cell lines by inhibiting KIT signaling and decreasing auto-phosphorylated KIT in the Golgi apparatus. In addition, PIM and sunitinib combination therapy enhanced antitumor responses in the murine xenograft models compared to individual therapies. Further analysis of the xenograft models showed that the combination therapy not only downregulated the KIT signaling pathway but also decreased the tumor microvessel density. Furthermore, we found that PIM suppressed VEGF expression in GIST cells by suppressing protein kinase D2 and hypoxia-inducible factor-1 alpha, which are both HSP90 client proteins. In conclusion, the combination of PIM and sunitinib is effective against imatinib-resistant GIST via the downregulation of KIT signaling and angiogenic signaling pathways.
Subject(s)
Antineoplastic Agents , Gastrointestinal Stromal Tumors , Humans , Animals , Mice , Imatinib Mesylate/pharmacology , Imatinib Mesylate/therapeutic use , Sunitinib/pharmacology , Sunitinib/therapeutic use , Gastrointestinal Stromal Tumors/pathology , Vascular Endothelial Growth Factor A , Piperazines/pharmacology , Pyrimidines , Drug Resistance, Neoplasm , Antineoplastic Agents/therapeutic use , Proto-Oncogene Proteins c-kit/metabolism , Protein Kinase Inhibitors/pharmacologyABSTRACT
BACKGROUND: The efficacy of neoadjuvant chemotherapy (NACT) correlates with patient survival in oesophageal squamous cell carcinoma (OSCC), but optimal evaluation of the treatment response based on PET-CT parameters has not been established. METHODS: We analysed 226 OSCC patients who underwent PET-CT before and after NACT followed by surgery. We assessed SUVmax, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) for the primary tumour and the number of PET-positive lymph nodes before and after NACT to predict patient survival. RESULTS: In a stepwise analysis, we defined 60%, 80%, and 80% as the optimal cut-off values for SUVmax, MTV, and TLG reduction, respectively, to distinguish responders and non-responders to NACT. In the ROC analysis, the TLG reduction rate was the best predictor of recurrence among PET-CT parameters. The TLG responders achieved significantly more favourable prognoses than non-responders (2-year progression-free survival [PFS] rate: 64.1% vs. 38.5%; P = 0.0001). TLG reduction rate (HR 2.58; 95% CI 1.16-5.73) and the number of PET-positive lymph nodes after NACT (HR 1.79; 95% CI 1.04-3.08) were significant independent prognostic factors. CONCLUSIONS: TLG reduction is the best predictor of prognosis. Preoperative PET-CT evaluation of both the primary tumour and lymph nodes could accurately stratify risk in OSCC patients.
Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Humans , Positron Emission Tomography Computed Tomography , Fluorodeoxyglucose F18 , Esophageal Squamous Cell Carcinoma/diagnostic imaging , Esophageal Squamous Cell Carcinoma/metabolism , Prognosis , Lymph Nodes/diagnostic imaging , Lymph Nodes/metabolism , Esophageal Neoplasms/diagnostic imaging , Esophageal Neoplasms/therapy , Esophageal Neoplasms/metabolism , Glycolysis , Risk Assessment , Retrospective Studies , Radiopharmaceuticals/metabolism , Tumor BurdenABSTRACT
BACKGROUND: We report the long-term results as primary endpoint in a multicentre randomized prospective Phase 2 trial which compared chemoradiotherapy (CRT) and triplet chemotherapy (CT) as the initial therapy for conversion surgery (CS) in T4b esophageal cancer (EC). METHODS: Patients with T4b EC were randomly assigned to the CRT group or CT group as initial treatment. CS was performed if resectable after initial or secondary treatment. The primary endpoint was 2-year overall survival, analysed by intention-to-treat. RESULTS: The median follow-up period was 43.8 months. The 2-year survival rate was higher in the CRT group (55.1%; 95% CI: 41.1-68.3%) compared to the CT group (34.7%; 95% CI: 22.8-48.9%), although the difference was not significant (P = 0.11). Local and regional lymph node recurrence in patients undergoing R0 resection was significantly higher in the CT group compared to the CRT group (local: 30% versus 8%, respectively, P = 0.03; regional: 37% versus 8%, respectively, P = 0.002). CONCLUSIONS: Upfront CT was not superior to upfront CRT as induction therapy for T4b EC in terms of 2-year survival and was significantly inferior to upfront CRT in terms of local and regional control. REGISTRATION: The Japan Registry of Clinical Trials (s051180164).
Subject(s)
Chemoradiotherapy , Esophageal Neoplasms , Humans , Prospective Studies , Chemoradiotherapy/methods , Esophageal Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoadjuvant Therapy , Neoplasm StagingABSTRACT
BACKGROUND: Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates in non-lymphoid tissues, which are associated with improved prognosis in some cancer types. This study aimed to investigate the clinical significance of TLSs in oesophageal cancer (EC). METHODS: In a series of 316 EC surgical specimens from two different institutes, we evaluated the density and maturity of peritumoral TLSs using haematoxylin/eosin, immunohistochemistry, and multiplex immunofluorescence staining. We analysed the association between TLSs and clinicopathological parameters. The clinical significance of TLSs was further evaluated in a different cohort of 34 patients with recurrent EC treated with anti-PD-1 antibody. RESULTS: Tumours with high TLS density predominantly consisted of matured TLSs. High TLS density was significantly associated with less advanced tumour stage, absence of lymphatic/vascular invasion, better serum nutrition parameters (neutrophils count, albumin, neutrophil-to-lymphocyte ratio, and prognostic nutritional index), and prolonged survival. This survival trend was more remarkable in cases with matured TLSs, which represented an increased population of CD138+ plasma cells. In the second EC cohort, TLS density predicted the clinical response to anti-PD-1 antibody and patient survival. CONCLUSION: The density and maturity of peritumoral TLSs are useful parameters for predicting long-term survival and response to anti-PD-1 antibody treatment in EC patients.
Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Tertiary Lymphoid Structures , Humans , Immune Checkpoint Inhibitors , Esophageal Squamous Cell Carcinoma/drug therapy , Tertiary Lymphoid Structures/metabolism , Prognosis , Esophageal Neoplasms/drug therapy , Tumor MicroenvironmentABSTRACT
OBJECTIVES: Tumor-infiltrating lymphocytes (TILs) have long been recognized as playing an important role in tumor immune microenvironment. Lately, the Immunoscore (IS) has been proposed as a new method of quantifying the number of TILs in association with patient survival in several cancer types. METHODS: In 300 preoperatively untreated esophageal cancer (EC) patients who underwent curative resection at two different institutes, immunohistochemical staining using CD3 and CD8 antibodies was performed to evaluate IS, as objectively scored by auto-counted TILs in the tumor core and invasive margin. In addition, in pre-neoadjuvant chemotherapy (pre-NAC) endoscopic biopsies of a different cohort of 146 EC patients who received NAC, CD3, and CD8 were immunostained to evaluate TIL density. RESULTS: In all cases, the IS-high (score 3-4) group tended to have better survival [5-year overall survival (OS) of the IS-high vs low group: 77.6 vs 65.8%, P = 0.0722] than the IS-low (score 1-2) group. This trend was more remarkable in cStage II-IV patients (70.2 vs 54.5%, P = 0.0208) and multivariate analysis of OS further identified IS (hazard ratio 2.07, P = 0.0043) to be an independent prognostic variable. In preNAC biopsies, NAC-responders had higher densities than non-responders of both CD3 + ( P = 0.0106) and CD8 + cells ( P = 0.0729) and, particularly CD3 + cell density was found to be an independent prognostic factor (hazard ratio 1.75, P = 0.0169). CONCLUSIONS: The IS signature in surgical specimens and TIL density in preNAC- biopsies could be predictive markers of clinical outcomes in EC patients.
Subject(s)
Esophageal Neoplasms , Lymphocytes, Tumor-Infiltrating , Humans , Treatment Outcome , Prognosis , Esophageal Neoplasms/surgery , Esophageal Neoplasms/pathology , Biopsy , Tumor MicroenvironmentABSTRACT
BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. Since clinical benefits are limited to a subset of patients, we aimed to identify peripheral blood biomarkers that predict the efficacy of the anti-programmed cell death protein 1 (PD-1) antibody (nivolumab) in patients with gastric cancer. METHODS: We collected peripheral blood samples from gastric cancer patients (n = 29) before and after treatment with nivolumab and investigated the relationship between the frequency of surface or intracellular markers among nivolumab-binding PD-1+CD8+ T cells and treatment responses using multicolor flow cytometry. The tumors, lymph nodes, and peripheral blood of gastric cancer patients who underwent gastrectomy following nivolumab treatment were collected, and nivolumab-binding PD-1+CD8+ T cells in these tissue samples were characterized. RESULTS: Patients with a high frequency of CD103 among PD-1+CD8+ T cells in peripheral blood 2 weeks after the start of treatment had significantly better progression-free survival than the low group (P = 0.032). This CD103+PD-1+CD8+ T cell population mainly consisted of central memory T cells, showing the high expression of Ki-67 and few cytotoxic granules. In contrast, effector memory T cells were more frequently observed among CD103+PD-1+CD8+ T cells in tumors, which implied a change in the differentiated status of central memory T cells in lymph nodes and peripheral blood to effector memory T cells in tumors during the treatment with ICIs. CONCLUSIONS: A high frequency of CD103 among PD-1+CD8+ T cells 2 weeks after nivolumab treatment in patients with advanced gastric cancer may be a useful biomarker for predicting the efficacy of anti-PD-1 therapy.
Subject(s)
Stomach Neoplasms , Humans , Stomach Neoplasms/pathology , Nivolumab/therapeutic use , Nivolumab/pharmacology , CD8-Positive T-Lymphocytes , Biomarkers/metabolism , Progression-Free SurvivalABSTRACT
BACKGROUND: Although intramural metastasis (IM) in esophageal cancer is considered a poor prognostic factor, there are only limited reports detailing its clinicopathologic characteristics and prognostic impact. PATIENTS AND METHODS: We retrospectively included patients with esophageal squamous cell carcinoma (ESCC) with esophagectomy at our institution between 2010 and 2016. We compared patients with intramural metastases (IMs) (IM group) versus those without IMs (non-IM group) to clarify the clinical significance of intramural metastasis in ESCC. RESULTS: A total of 23 (3.9%) out of all 597 patients were identified to have IM. The IMs were located on the cranial side in 13 (56.5%) and caudal side in 10 (43.5%) of the primary tumor, with two multiple cases. The IM group, compared with the non-IM group, was associated with higher percentage of cN-positive (91.3 versus 67.9%, P = 0.02), pN-positive (82.6 versus 55.9%, P = 0.04), and pM(lym)-positive (30.4 versus 12.5%, P = 0.02) cases. Five-year recurrence-free survival (RFS) was significantly worse in the IM group than the non-IM group (14.9 versus 55.0 %, P < 0.001). Multivariable analysis of recurrence-free survival identified pT (HR 1.74, 95% CI 1.36-2.23, P < 0.001), pN (HR 2.11, 95% CI 1.60-2.78, P < 0.001), histological classification (HR 1.68, 95% CI 1.21-2.35, P = 0.002), and pM(LYM) (HR 1.64, 95% CI 1.64-2.95, P < 0.001), along with presence of IM (HR 2.24, 95% CI 1.37-3.64, P < 0.001) to be independent prognostic factors. Lymphatic (65.2 versus 24.9%, P < 0.001) and hepatic (26.1 versus 6.8%, P = 0.005) recurrences were significantly more common in the IM group than in the non-IM group. CONCLUSIONS: IM was shown to be associated with dismal survival after surgery. A treatment strategy emphasizing more intensive systemic control should be considered for patients with ESCC with IM.
Subject(s)
Carcinoma, Squamous Cell , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Humans , Esophageal Squamous Cell Carcinoma/surgery , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Neoplasms/pathology , Prognosis , Carcinoma, Squamous Cell/pathology , Retrospective Studies , Clinical Relevance , Esophagectomy , Neoplasm StagingABSTRACT
BACKGROUND: Preoperative risk assessment is important in older patients because they often have comorbidities and impaired organ function. We performed preoperative comprehensive geriatric assessment (CGA) for older patients with esophageal cancer. PATIENTS AND METHODS: A total of 217 patients over 75 years old who underwent esophagectomy for thoracic esophageal cancer were analyzed. The CGA was performed preoperatively and included the Mini-Mental State Examination (MMSE), Geriatric Depression Score (GDS), vitality index, Barthel index, and instrumental activities of daily living (IADL). We defined the robust group as patients with normal function on every instrument, and the pre-frail and frail groups as those with functional impairment on one instrument or two or more instruments, respectively. We assessed how the CGA correlated with postoperative complications and prognosis. RESULTS: Of the 217 patients, 86 (39.6%) were in the robust group, 68 (31.3%) in the pre-frail group, and 63 (29.0%) in the frail group. Postoperative pneumonia (P = 0.026) and anastomotic leakage (P = 0.032) were significantly more common in the frail group. The frail group had a significantly longer postoperative hospitalization period (P = 0.016) and significantly lower rate of discharge to home (P = 0.016). Overall survival (OS) was significantly worse in the frail group (5-year overall survival rate, frail group versus others, 37.8% versus 52.0%, P = 0.046), but it was not significant on multivariate analysis. CONCLUSIONS: The preoperative CGA in older patients with esophageal cancer was associated with risk of postoperative complications.
Subject(s)
Esophageal Neoplasms , Geriatric Assessment , Humans , Aged , Activities of Daily Living , Esophageal Neoplasms/surgery , Risk Assessment , Postoperative Complications , Frail ElderlyABSTRACT
BACKGROUND: Three-course neoadjuvant chemotherapy (NAC) followed by surgery has become a standard of care for locally advanced esophageal cancer (EC). However, some patients occasionally experience a poor tumor response to the third course and have a poor clinical outcome. METHODS: An exploratory analysis of data from the authors' recent multicenter randomized phase 2 trial compared patients with locally advanced EC who received two courses (n = 78) and those who received three courses (n = 68) of NAC. The association between tumor response and clinico-pathologic factors, including survival, was evaluated to identify risk factors in the three-course group. RESULTS: Of 68 patients who received three courses of NAC, 28 (41.2%) had a tumor reduction rate lower than 10% during the third course. This rate was associated with unfavorable overall survival (OS) and progression-free survival (PFS) compared with a tumor reduction rate of 10% or higher (2-year OS rate: 63.5% vs. 89.3%, P = 0.007; 2-year PFS rate: 52.6% vs. 79.7%, P = 0.020). The independent prognostic factors for OS were tumor reduction rate lower than 10% during the third course (hazard ratio [HR], 2.735; 95% confidence interval [CI] 1.041-7.188; P = 0.041) and age of 65 years or older (HR, 9.557, 95% CI 1.240-73.63; P = 0.030). Receiver operating characteristic curve and multivariable logistic regression analyses identified a tumor reduction rate lower than 50% after the first two courses as an independent predictor of a tumor reduction rate lower than 10% during the third course of NAC (HR, 4.315; 95% CI 1.329-14.02; P = 0.015). CONCLUSION: Continuing NAC through a third course may worsen survival for patients who do not experience a response to the first two courses in locally advanced EC.