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.

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.

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.

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.

Preoperative docetaxel, cisplatin, and 5-fluorouracil for resectable locally advanced esophageal and esophagogastric junctional adenocarcinoma.

BACKGROUND: Chemotherapy consisting of 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel is the standard perioperative treatment for resectable esophageal adenocarcinoma and esophagogastric junctional adenocarcinoma (EGJ-AC) in Western countries. Meanwhile, preoperative chemotherapy consisting of docetaxel, cisplatin, and 5-fluorouracil (DCF) has been developed for esophageal squamous cell carcinoma in Japan. However, there are few reports on the safety and efficacy of preoperative DCF for resectable EGJ-AC in the Japanese population. METHODS: Patients with histologically confirmed resectable EGJ-AC who received preoperative DCF (docetaxel 70 mg/m2 and cisplatin 70 mg/m2 on day 1 and continuous infusion of 5-fluorouracil 750 mg/m2/day on days 1-5 every 3 weeks with a maximum of three cycles) between January 2015 and April 2020 were retrospectively evaluated. We assessed the rates of completion of ≥ 2 courses of DCF and R0 resection, histopathological response, progression-free survival (PFS), overall survival (OS), and adverse events. RESULTS: Thirty-two patients were included. Median follow-up was 28.7 (range, 5.2-70.8) months and median age was 63 (range, 42-80) years. Twenty-one patients (66%) had a performance status of 0. The proportions of clinical stage IIA/IIB/III/IVA/IVB disease were 3%/0%/44%/44%/9%, respectively. The treatment completion rate was 84%. A histopathological response of grade 1a/1b/2/3 was obtained in 58%/26%/13%/3% of cases. Median PFS was 40.7 months (95% confidence interval 11.8-NA). Median OS was not reached (80.8% at 3 years). Grade ≥ 3 adverse events were observed in 63% of cases (neutropenia, 44%; febrile neutropenia, 13%). No treatment-related deaths occurred. CONCLUSIONS: Preoperative DCF for resectable EGJ-AC was well tolerated and has promising efficacy.

Butterfly needle tap and suction (BTS) technique: a treatment for recurrent chronic subdural hematoma after burr hole craniostomy.

BACKGROUND: In this study, we propose a butterfly needle tap and suction (BTS) technique for recurrent chronic subdural hematoma (CSDH) as an alternative to reoperation with burr hole craniostomy (BHC) and investigate its efficacy and safety. The procedure involves percutaneous puncture through the burr hole created during the previous surgery and subsequent hematoma evacuation using a butterfly needle. METHODS: This retrospective study included patients who underwent BTS for CSDH at Ogaki Municipal Hospital between January 2017 and December 2020. The follow-up CT scans were reviewed after several weeks. We evaluated the number of percutaneous punctures required to resolve CSDH during the BTS technique, the volume of the evacuated hematoma, and procedure-related complications. RESULTS: Twenty-six patients were enrolled in the study, 21 of whom achieved resolution of the hematoma using punctures with the BTS technique alone (mean, 2.2 ± 1.5). Five patients had a recurrence of hematoma after one or more punctures during the BTS technique, and they underwent reoperation with BHC according to the surgeon's decision or patient requests. Among the 55 punctures, 43.0 ± 16.0 ml of hematoma was evacuated per puncture. The evacuated hematoma volume was 41.9 ± 16.4 ml in the BTS-alone group and 49.4 ± 12.9 ml in the reoperation group, with no significant difference (p = 0.25). Three patients complained of a headache during the puncture procedure, and no other complications, including intracranial hemorrhage or infection, were reported therein. CONCLUSIONS: The BTS technique is an effective alternative to reoperation with BHC.

[Comparison of Current Perspectives of Perioperative Treatments for Esophageal Cancer between Japan and the Western Countries-Toward International Collaborative Studies].

There are 2 main histologic types of esophageal cancer: squamous cell carcinoma and adenocarcinoma. Squamous cell carcinoma is the most common histology type in the world, but in Europe and the United States, adenocarcinoma is the most common type. The standard treatments differ between Japan and the Europe and the United States, especially in the perioperative treatments. Standard treatment in Japan is preoperative chemotherapy based on the results of the JCOG1109 trial. While in Europe and the United States, the standard treatment is preoperative chemoradiotherapy based on the results of the CROSS trial and postoperative nivolumab according to the results of CheckMate 577 trial. In surgical treatment, 3- region lymph node dissection is the standard in Japan, whereas in Europe and the United States, where the lower esophagus, mainly adenocarcinoma, is often treated, 2-region lymph node dissection of the middle and lower mediastinum is the standard. Due to these differences in established treatments, the results of clinical trials in other countries cannot be extrapolated to standard treatment in Japan. Therefore, it is essential to understand the differences in standard treatment in East Asia, where esophageal squamous cell carcinoma frequently occurs, and other countries, and to deepen exchanges with experts in each country, so that international clinical trials can be designed and standard treatment can be established.

Effectiveness of taxanes following nivolumab in patients with advanced esophageal squamous cell carcinoma: a retrospective chart review of patients in ATTRACTION-3.

BACKGROUND: The phase III ATTRACTION-3 study showed that second-line nivolumab monotherapy for advanced esophageal squamous cell carcinoma prolonged overall survival (OS) but did not improve progression-free survival (PFS). Subsequent systemic therapy after discontinuing nivolumab may affect these outcomes. To test this possibility, we evaluated the outcomes of treatment with taxanes after nivolumab in ATTRACTION-3. METHODS: We reviewed the charts of Japanese patients who had discontinued second-line nivolumab in ATTRACTION-3 and started subsequent third-line taxanes between January 7, 2016, and November 12, 2018. The primary endpoint was objective response rate (ORR) to third-line taxanes. RESULTS: Of the 75 patients included in this study, 54 (72%), 18 (24%), and 3 (4%) patients received either paclitaxel, docetaxel, or combination therapy comprising docetaxel, cisplatin, and 5-fluorouracil, respectively. The ORR in the overall, paclitaxel, and docetaxel groups was 29.6%, 36.5%, and 12.5%, respectively; these numbers were comparable to those (20-44%) in patients receiving taxanes as first- and second-line therapy. The median OS in the overall, paclitaxel, and docetaxel groups was 9.9, 9.9, and 9.3 months, respectively, whereas the corresponding median PFS was 4.9, 4.7 and 6.5 months, respectively. Treatment-related adverse events were observed in 65 (87%) patients, of which grade 3-4 occurred in 37 (49%) patients. CONCLUSIONS: Favorable effectiveness and safety profile of taxanes following second-line nivolumab was observed in Japanese patients with advanced esophageal squamous cell carcinoma. When a patient with advanced esophageal squamous cell carcinoma receiving nivolumab becomes refractory or intolerant, subsequent taxane treatment may be a promising option.

Significance of lymphovascular invasion in esophageal squamous cell carcinoma undergoing neoadjuvant chemotherapy followed by esophagectomy.

BACKGROUND: Lymphovascular invasion (LVI) was previously reported to be an independent factor associated with survival in locally advanced esophageal squamous cell carcinoma (LAESCC) patients receiving neoadjuvant chemotherapy (NAC); however, the detailed clinicopathological significance of LVI remains unclear. This study evaluated the prognostic impact of LVI in patients with LAESCC after NAC with cisplatin and 5-fluorouracil (CF) or docetaxel, cisplatin and 5-fluorouracil (DCF) followed by surgery and in LAESCC patients with recurrence after NAC and surgery. METHODS: 438 patients with thoracic LAESCC who had undergone NAC followed by an esophagectomy with three-field lymphadenectomy were assessed using a propensity score matched analysis, and their long-term outcomes were retrospectively reviewed. RESULTS: In matched cohort, a multivariate analysis of relapse-free survival (RFS) in the NAC-CF group suggested that ypN (≥ 1, HR = 3.715, p = 0.004) and LVI (positive, HR = 3.366, p = 0.012) were independent factors associated with RFS; in the NAC-DCF group, ypN (≥ 1, HR = 4.829, p < 0.001) was the only independent factor associated with RFS. Comparisons of overall survival (OS) between the ypN + /LVI + group and other groups among patients with recurrence in each NAC regimen showed significant differences in both of NAC groups (p < 0.001, respectively). The ypN + /LVI + group had a significantly poor OS in both an oligometastatic recurrence (OMR) group (p < 0.001) and a non-OMR group (p < 0.001). CONCLUSIONS: The present study suggested that the independent factor associated with prognosis of patients with LAESCC after NAC and surgery may differ according to the NAC regimen, and the presence of both ypN and LVI was a prognostic factor for patients with recurrence, including those with OMR. These results might be helpful when deciding on an additional treatment strategy for LAESCC patients.

Safety and short-term efficacy of preoperative FOLFOX therapy in patients with resectable esophageal squamous cell carcinoma who are ineligible for cisplatin.

BACKGROUND: The standard preoperative treatment for resectable locally advanced esophageal squamous cell carcinoma (LAESCC) in Japan is docetaxel, cisplatin (CDDP), and 5-fluorouracil. However, patients with renal or cardiac dysfunction and elderly patients are ineligible for a CDDP-containing regimen because of toxicities. Oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) therapy has less renal toxicity than CDDP-containing regimens and does not require hydration. However, there are limited data on preoperative FOLFOX therapy in these patients. METHODS: This retrospective study analyzed patients with resectable LAESCC who were aged ≥ 75 years or had renal or cardiac dysfunction and received preoperative FOLFOX between 2019 and 2021. FOLFOX was administered every 2 weeks for 3 or 4 cycles and was followed by surgery. Adverse events associated with chemotherapy, the complete resection (R0) rate, relative dose intensity (RDI), and histopathological response were evaluated. RESULTS: Thirty-five patients were eligible. Median age was 77 (range 65-89) years; 68.6% were aged ≥ 75 years, 74.3% had renal dysfunction, and 17.1% had cardiac dysfunction. The RDI was 70.2% and 87.1% for bolus and continuous intravenous 5-fluorouracil, respectively and 85.2% for oxaliplatin. The most common grade ≥ 3 adverse events were neutropenia (60.0%) and leucopenia (28.6%). Two patients (5.7%) had febrile neutropenia and grade 3 pneumonia. Thirty-one patients underwent surgery. The R0 resection rate was 87.1%, and there was no histopathological evidence of residual tumor in 16.1%. There were no treatment-related deaths. CONCLUSIONS: Preoperative FOLFOX had a manageable safety profile and showed favorable short-term efficacy in patients with resectable LAESCC who were ineligible for CDDP-containing treatment.

Pembrolizumab for the treatment of advanced esophageal cancer.

The prognosis of patients with advanced esophageal cancer (EC) remains poor and there are limited effective therapeutic agents for EC. Pembrolizumab monotherapy exerts clinically meaningful benefits for advanced esophageal squamous cell carcinoma patients with a combined positive score of ≥10. Additionally, pembrolizumab plus doublet chemotherapy results in a significant survival benefit for patients with advanced EC as first-line treatment compared with chemotherapy alone. We provide an overview of immune checkpoint inhibitors and present important clinical data related to treatment for EC patients. In our opinion, pembrolizumab plus chemotherapy should be the standard first-line treatment for patients with advanced EC, regardless of histology and combined positive score. Biomarker studies to identify patient populations in which immune checkpoint inhibitors are expected to show efficacy are needed.

Current perspectives of the Japanese Esophageal Oncology Group on the development of immunotherapy for esophageal cancer.

Esophageal cancer is the seventh most common cancer worldwide and continues to have a poor prognosis. Starting with the development of immune checkpoint inhibitors for patients with metastatic melanoma, many clinical trials have been conducted to evaluate the efficacy and safety of immune checkpoint inhibitors against various malignancies. Although few effective drugs are available for patients with advanced esophageal cancer, two immune checkpoint inhibitors, nivolumab and pembrolizumab, have been approved as second-line treatments for advanced esophageal squamous cell carcinoma. Recently, immune checkpoint inhibitors have shown promising results as post-operative therapies and first-line treatments for advanced esophageal cancer. Nivolumab has been approved as a post-operative therapy based on the CheckMate-577 trial, and nivolumab, ipilimumab and pembrolizumab have been approved as first-line treatments based on the CheckMate-648 trial and the KEYNOTE-590 trial. In addition, many trials of immune checkpoint inhibitors plus pre-operative treatment or definitive chemoradiotherapy are ongoing. The Japan Esophageal Oncology Group was established in 1978 and has conducted numerous clinical trials, most of which have examined multimodality treatments. In the era of immunotherapy, Japan Esophageal Oncology Group is conducting a clinical trial studying multimodality treatment with an immune checkpoint inhibitor. JCOG1804E (FRONTiER) is a phase I trial to evaluate the safety and efficacy of nivolumab plus pre-operative chemotherapy followed by surgery. These results might improve the clinical outcomes of esophageal cancer patients.

Dysfunctional paraspinal muscles in adult spinal deformity patients lead to increased spinal loading.

PURPOSE: Decreased spinal extensor muscle strength in adult spinal deformity (ASD) patients is well-known but poorly understood; thus, this study aimed to investigate the biomechanical and histopathological properties of paraspinal muscles from ASD patients and predict the effect of altered biomechanical properties on spine loading. METHODS: 68 muscle biopsies were collected from nine ASD patients at L4-L5 (bilateral multifidus and longissimus sampled). The biopsies were tested for muscle fiber and fiber bundle biomechanical properties and histopathology. The small sample size (due to COVID-19) precluded formal statistical analysis, but the properties were compared to literature data. Changes in spinal loading due to the measured properties were predicted by a lumbar spine musculoskeletal model. RESULTS: Single fiber passive elastic moduli were similar to literature values, but in contrast, the fiber bundle moduli exhibited a wide range beyond literature values, with 22% of 171 fiber bundles exhibiting very high elastic moduli, up to 20 times greater. Active contractile specific force was consistently less than literature, with notably 24% of samples exhibiting no contractile ability. Histological analysis of 28 biopsies revealed frequent fibro-fatty replacement with a range of muscle fiber abnormalities. Biomechanical modelling predicted that high muscle stiffness could increase the compressive loads in the spine by over 500%, particularly in flexed postures. DISCUSSION: The histopathological observations suggest diverse mechanisms of potential functional impairment. The large variations observed in muscle biomechanical properties can have a dramatic influence on spinal forces. These early findings highlight the potential key role of the paraspinal muscle in ASD.

Time course of symptomatic improvement after open-door laminoplasty for cervical spondylotic myelopathy.

BACKGROUND: Postoperative outcomes following cervical spondylotic myelopathy (CSM) are excellent overall, but there are few prospective studies using patient-reported outcome measures that have explored how long improvement can be expected after surgery. The aim of this prospective study was to investigate from when and until when symptoms improve after open-door laminoplasty in patients with CSM and the factors that affect surgical outcomes. METHODS: The subjects were 115 CSM patients who underwent laminoplasty. The Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ) was used for longitudinal evaluation, and surveys on cervical spine function, upper extremity function, lower extremity function, bladder function, and quality of life were conducted before surgery and at 3, 6, 12, 18, and 24 months after surgery. The patients were classified into 'effective' and 'ineffective' groups based on the points obtained for each domain, and the factors affecting the outcome of surgery were examined by multivariate analysis. RESULTS: JOACMEQ scores improved significantly at 3 months postoperatively compared to preoperatively for all four domains except cervical spine function, but there was no significant improvement after 3 months postoperatively. Multivariate analysis showed that the preoperative score (cervical spine function and upper extremity function) and the points obtained at 3 months postoperatively (upper and lower extremity function, bladder function, and quality of life) were the factors associated with membership of the effective group at 24 months postoperatively. CONCLUSIONS: Although upper and lower extremity function, bladder function, and quality of life domains improved in the relatively early postoperative period, improvement after 3 months postoperatively was limited. The results suggest that the preoperative score and the superiority of the improvement obtained up to 3 months after surgery may be indicators of postoperative outcomes, and this may provide new insights into the selection of surgical indications and patient explanations.

Novel pathological staging for patients with locally advanced esophageal squamous cell carcinoma undergoing neoadjuvant chemotherapy followed by surgery.

BACKGROUND: The aim of the present study was to clarify an appropriate staging system for patients with locally advanced esophageal squamous cell carcinoma (LAESCC) after neoadjuvant chemotherapy (NAC) prior to surgery. METHODS: A total of 388 patients with clinical stage II or III LAESCC who had undergone NAC followed by an esophagectomy with three-field lymphadenectomy were retrospectively reviewed. RESULTS: The relapse-free survival (RFS) curves plotted using ypN grading and ypTNM staging both monotonically decreased as the classification number increased, and the groups were more clearly separated than when the Japanese Classification (JC) was applied. A multivariate analysis of relapse free survival (RFS) suggested that ypN (HR = 2.911, P < 0.001), lymphovascular invasion (LVI) (HR = 2.608, P < 0.001) were independent factors associated with OS. The LVI+/ypN+ group had a significantly poorer outcome than the other groups (P < 0.001). The 5-year RFS rates for patients with ypStage IIIA or higher among the LVI-negative cases and ypStage II or higher among the LVI-positive cases were around 0.6 or under. The novel pathological staging which was based on the present results was proposed and RFS curves of each novel stage suggested the suitability of these staging for our cohort. CONCLUSIONS: The present results suggest that a novel pathological staging system using the ypTNM classification, in which the supraclavicular lymph node was regarded as a regional lymph node and the presence of LVI was included as a category, was appropriate for patients with LAESCC after NAC prior to surgery.

Short-term outcomes of induction chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF) in locally advanced nasopharyngeal carcinoma.

There is an unmet need for improving survival outcomes of locally advanced nasopharyngeal carcinoma, for example, T4/ N3 stage disease. To this end, we administered induction chemotherapy (IC) with TPF (docetaxel, cisplatin, and fluorouracil) because this stage of disease is associated with a high risk of recurrence and is difficult to control with standard treatments, such as chemoradiotherapy (CRT) alone or CRT followed by adjuvant chemotherapy. The aim of this retrospective single-center study was to clarify the short-term outcomes of locally far-advanced nasopharyngeal carcinoma patients treated with IC-TPF, followed by CRT with cisplatin. Data from 11 patients were extracted from our database, indicating that the overall response rate to IC-TPF, clinical complete response rate after CRT, 1-year progression-free survival, and 1-year overall survival were 73%, 91%, 68%, and 89%, respectively. Hematological toxicity was the most common adverse event reported during IC-TPF with 64% of patients suffering grade 3 or 4 neutropenia, 55% grade 3 or 4 leucopenia and 9% febrile neutropenia. Despite the small number of patients, these data are important because there is a limited number of studies investigating IC-TPF followed by CRT in Japanese patients. This pilot study provides some indication of the short-term effectiveness and toxicity of this therapeutic approach, which may be superior to standard treatments. Long-term follow-up is warranted to assess the effectiveness of IC-TPF in terms of clinical outcome and late-phase toxicity.

Second-line chemotherapy after early disease progression during first-line chemotherapy containing bevacizumab for patients with metastatic colorectal cancer.

BACKGROUND: The ML18174 study, which showed benefits of bevacizumab (BEV) continuation beyond progression (BBP) for metastatic colorectal cancer (mCRC), excluded patients with first-line progression-free survival (PFS) shorter than 3 months. The present study was conducted to evaluate the efficacy of second-line chemotherapy after early disease progression during first-line chemotherapy containing bevacizumab. METHODS: The subjects of this study were mCRC patients who experienced disease progression < 100 days from commencement of first-line chemotherapy containing BEV initiated between Apr 2007 and Dec 2016. Second-line chemotherapy regimens were classified into two groups with and without BEV/other anti-angiogenic agents (BBP and non-BBP) and efficacy and safety were compared using univariate and multivariate analysis. RESULTS: Sixty-one patients were identified as subjects of this study. Baseline characteristics were numerically different between BBP (n = 37) and non-BBP (n = 25) groups, such as performance status (0-1/> 2/unknown: 89/8/3 and 56/40/4%), RAS status (wild/mutant/unknown: 32/54/16 and 76/16/8%). Response rate was 8.6% in BBP group and 9.1% in non-BBP group (p = 1.00). Median PFS was 3.9 months in BBP group and 2.8 months in non-BBP group (HR [95%CI]: 0.79 [0.46-1.34], p = 0.373, adjusted HR: 0.87 [0.41-1.82], p = 0.707). Median overall survival was 8.5 months in BBP group and 5.4 months in non-BBP group (HR 0.66 [0.38-1.12], p = 0.125, adjusted HR 0.53 [0.27-1.07], p = 0.078). CONCLUSION: In mCRC patients who experienced early progression in first-line chemotherapy, second-line chemotherapy showed poor clinical outcomes regardless use of anti-angiogenic agents.

Retrospective observational study of salvage line ramucirumab monotherapy for patients with advanced gastric cancer.

BACKGROUND: Ramucirumab monotherapy as a second-line treatment for advanced gastric cancer (AGC) prolongs survival compared to the best supportive care. However, in clinical practice, ramucirumab monotherapy is sometimes used as third- or later-line treatment for AGC refractory to fluoropyrimidine and taxanes. This study evaluated the efficacy and safety of salvage-line ramucirumab monotherapy for treating AGC. METHODS: The subjects of this retrospective study were advanced gastric or gastro-esophageal junction adenocarcinoma patients who received ramucirumab monotherapy after failure of 2 or more prior regimens containing fluoropyrimidine and taxanes but not ramucirumab. RESULTS: From June 2015 to April 2017, 51 patients were enrolled. The median progression-free survival (PFS) and overall survival (OS) were 1.8 (95% confidence interval [CI] = 1.6-2.2) and 5.1 (95% CI = 4.0-6.8) months, respectively. The objective response and disease control rates were 2 and 17%, respectively. Grade 3 adverse events (AEs; e.g., anemia, fatigue, hypertension, proteinuria, intestinal bleeding) occurred in seven (13%) patients, but no grade 4 AEs and treatment-related deaths were observed. A neutrophil-lymphocyte ratio (NLR) of < 2.5 and previous gastrectomy were associated with better PFS. CONCLUSIONS: Salvage-line ramucirumab monotherapy has acceptable toxicity and comparable efficacy to second-line treatment; therefore, we consider physicians might choose this therapy as a salvage-line treatment option for AGC refractory to the standard therapies.