Publications by authors named "Narikazu Boku"

321 Publications

Impact of COVID-19 on gastric cancer treatment in Japanese high-volume centers: a JCOG stomach cancer study group survey.

Surg Today 2021 Jul 20. Epub 2021 Jul 20.

Division of Gastric Surgery, Shizuoka Cancer Center, Shizuoka, Japan.

Purposes: The spread of coronavirus disease 2019 (COVID-19) has affected socioeconomic and healthcare systems in many countries. Accordingly, many individuals may have canceled their annual health-check programs, including esophagogastroduodenoscopy, which would have resulted in lower numbers of newly diagnosed patients with gastric cancer in comparison to other times.

Methods: Questionnaires were distributed to 62 hospitals every week from May 2020 to August 2020 (total 744) through mailing lists of the Stomach Cancer Study Group of the Japan Clinical Oncology Group. The number of patients with gastric cancer and hospital systems during the COVID-19 pandemic were surveyed.

Results: In total, 74% (551 out of 744) of the questionnaires were answered and analyzed. In early May, approximately 50% of hospitals had to restrict surgical slots due to the COVID-19 pandemic. However, they gradually loosened the restrictions thereafter. The number of gastrectomies was < 80% that of the same period in the previous year, and hospitals in Tokyo were seriously affected by a 50% decrease in the number of gastrectomies.

Conclusions: The number of gastrectomies was lower than that in the previous year. Further multi-center follow-up studies are required to evaluate the long-term effects of COVID-19 on the clinical outcomes of patients with gastric cancer.
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http://dx.doi.org/10.1007/s00595-021-02329-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294226PMC
July 2021

CD11bCTLA4 myeloid cells are a key driver of tumor evasion in colorectal cancer.

J Immunother Cancer 2021 Jul;9(7)

Department of Immune Medicine, National Cancer Center Research Institute, Tokyo, Japan

Background: Tumor metastasis is the major cause of death of colorectal cancer (CRC), and metastatic CRC remains incurable in many cases despite great advances in genetic and molecular profiling, and clinical development of numerous drugs, including immune checkpoint inhibitors. Thus, more effective treatments are urgently needed for the patients in clinical settings.

Methods: We used mouse CRC metastasis models that murine Colon26 cells were subcutaneously and intravenously implanted and attempted to elucidate the tumor biological and immunological mechanisms underlying cancer metastasis. Then, we evaluated in vivo antitumor efficacy induced by agents targeting the identified molecular mechanisms using the mouse models. We validated the clinical relevancy of the findings using peripheral blood mononuclear cells obtained from stage IV metastatic CRC patients.

Results: CD11bCTLA4 myeloid cells were systemically expanded in the metastatic settings and facilitated tumor progression and metastasis directly via generating lipid droplets in tumor cells and indirectly via inducing immune exhaustion. These events were mediated by IL1B produced via the CTLA4 signaling from the increased myeloid cells. Blocking CTLA4 and IL1B with the specific mAbs significantly suppressed tumor progression and metastasis in the mouse models resistant to anti-PD1 therapy, and the therapeutic efficacy was optimized by blocking cyclooxygenases with aspirin.

Conclusions: The CD11bCTLA4 cells are a key driver of tumor evasion, and targeting the CTLA4-IL1B axis could be a promising strategy for treating metastatic CRC. The triple combination regimen with anti-CTLA4/IL1B mAbs and aspirin may be useful in clinical settings.
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http://dx.doi.org/10.1136/jitc-2021-002841DOI Listing
July 2021

A Phase I study of pevonedistat plus capecitabine plus oxaliplatin in patients with advanced gastric cancer refractory to platinum (NCCH-1811).

Future Sci OA 2021 Aug 28;7(7):FSO721. Epub 2021 May 28.

Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Based on synergistic anti-tumor effects between blockades of NEDD8 activating enzyme and a platinum in preclinical studies, this Phase I study is designed to investigate the safety and tolerability of pevonedistat in combination with capecitabine plus oxaliplatin as third-line or later treatment in patients with unresectable advanced/recurrent gastric cancer who were previously treated with fluoropyrimidines and platinum (cisplatin or oxaliplatin) as the first-line treatment and paclitaxel (including nab-paclitaxel) as the second-line treatment. The aim of this trial is to determine the recommended dose of pevonedistat and to see its pharmacokinetics in combination with capecitabine plus oxaliplatin in the dose-finding part and explore its efficacy and safety in the expansion part. jRCT2031190020 (jRCTs: the Japan Registry of Clinical Trials).
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http://dx.doi.org/10.2144/fsoa-2021-0023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256327PMC
August 2021

Real-world emetic risk of chemotherapy and the corresponding antiemetic therapy in Japan: A study based on a nationwide database.

Cancer Rep (Hoboken) 2021 Jun 27:e1482. Epub 2021 Jun 27.

Center for Cancer Control and Information Services, National Cancer Center, Chuo-ku, Japan.

Background: Chemotherapy-induced nausea and vomiting (CINV) is a major concern of patients with cancer, leading to suboptimal treatment.

Aim: This study assessed the emetic risk associated with intravenous and oral chemotherapy and the prophylactic antiemetic drugs by cancer type in a real-world setting.

Methods And Results: We used the health services utilisation data for patients with cancer diagnosed in 2016. Patients aged at least 20 years at the time of diagnosis and who started their first course of chemotherapy were included. The emetic risk of chemotherapy was determined according to the cancer type and was classified based on clinical practice guidelines. The prescription of antiemetic drugs was assessed. Overall, 172 133 patients were evaluated, of whom 121 103 (70.4%) received intravenous chemotherapy. High-emetic-risk chemotherapy (HEC) was prescribed in 46 458 (27.0%) patients. HEC was prescribed most for patients with oesophageal cancer (80.3%), followed by malignant lymphoma (60.2%) and breast cancer (53.8%). Moderate-emetic-risk chemotherapy (MEC) was prescribed in 60 528 (35.2%) patients and was mostly prescribed for small cell lung cancer (59.9%). Meanwhile, more than 50% of the chemotherapy prescribed for patients with gastric, colorectal, and pancreatic cancer was low-emetic-risk chemotherapy. HEC was accompanied by three-drug antiemetic prophylaxis in more than 90% of patients with small cell lung, non-small cell lung, breast, and oesophageal cancer, whereas only 13.5% of patients with malignant lymphoma were administered CHOP (cyclophosphamide, doxorubicin, vincristine sulphate, and prednisolone) with prophylaxis.

Conclusion: The risk of CINV differs with cancer type. HEC was less prescribed compared with MEC. Most patients received the recommended anti-emetic prophylaxis.
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http://dx.doi.org/10.1002/cnr2.1482DOI Listing
June 2021

Impact of follow-up on generalized pairwise comparisons for estimating the irinotecan benefit in advanced/metastatic gastric cancer.

Contemp Clin Trials 2021 Jun 15;105:106400. Epub 2021 Apr 15.

Université de Versailles-St Quentin, France; Institut Curie & INSERM U900, Biostatistics for Precision Medicine (STAMPM), Saint-Cloud, France; Université Paris Saclay, France. Electronic address:

Background And Objectives: The net treatment effect (∆) is a new method to assess the treatment benefit that combines multiple time-to-event, binary and continuous endpoints according to a pre-specified sequence. It represents the net probability for a random patient treated in the experimental arm to have a better overall outcome than a random patient from the control arm does. We aimed at characterizing the impact of follow-up on ∆ estimated from both time-to-event and binary toxicity endpoints, in randomized controlled trials (RCTs) of irinotecan-based regimen in advanced/metastatic gastric cancer (AGC).

Study Design: Three RCTs are reanalysed. The net treatment effect using from one to three outcomes (i.e. overall survival, time to progression and toxicity in this order) and the hazard ratio (HR) were estimated after various cut-off dates and compared to the values obtained after complete follow-up were reported.

Results: In all three RCTs (897 patients), the irinotecan-based regimen was superior to the non-irinotecan containing regimen in terms of HR and ∆. This superiority was lower when the net treatment effect also accounted for toxicity. The HR was slightly less influenced by an incomplete follow-up than ∆ was, but correction proposed by Péron to account for censored observations showed quite robust results.

Conclusions: The net treatment effect using Péron's correction can be used in case of interim analyses or high censoring rates. In addition to relative measures such as the hazard ratio, it provides a simple mean to evaluate the net treatment effect with and without toxicity outcomes.
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http://dx.doi.org/10.1016/j.cct.2021.106400DOI Listing
June 2021

Panitumumab-Associated Drug-Induced Immune Thrombocytopenia in a Patient with Colorectal Cancer.

Case Rep Oncol 2021 Jan-Apr;14(1):85-89. Epub 2021 Feb 25.

Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.

Severe thrombocytopenia is a rare adverse event of panitumumab. Here, we report the first patient with metastatic colorectal cancer who developed severe thrombocytopenia, diagnosed as panitumumab-associated drug-induced immune thrombocytopenia (DITP). A clinical diagnosis of DITP can be obtained by excluding other causes of thrombocytopenia and is confirmed by the recovery of thrombocytopenia after the discontinuation of the suspected drug. Treatment includes permanent discontinuation of the suspected drug. Re-exposure should be avoided. It should be kept in mind that panitumumab can induce DITP in the case of a new, sudden, unexpected, and isolated drop in platelet count after excluding other causes of thrombocytopenia.
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http://dx.doi.org/10.1159/000512821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983597PMC
February 2021

Efficacy of second-line treatment and prognostic factors in patients with advanced malignant peritoneal mesothelioma: a retrospective study.

BMC Cancer 2021 Mar 20;21(1):294. Epub 2021 Mar 20.

Department of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Background: Standard treatment for malignant peritoneal mesothelioma has not been established, and systemic chemotherapy is administered according to malignant pleural mesothelioma. We previously reported the efficacy of cisplatin plus pemetrexed as first-line chemotherapy; however, the efficacy of second-line chemotherapy remains unknown.

Methods: We retrospectively evaluated patients with malignant peritoneal mesothelioma who started first-line systemic chemotherapy with platinum plus pemetrexed between March 2007 and February 2019 at the National Cancer Center Hospital. Patients who received second-line chemotherapy after failure of platinum plus pemetrexed were identified. We evaluated the efficacy of first- and second-line chemotherapy, and explored the prognostic factors. Survival outcomes were estimated using the Kaplan-Meier method, and between-group differences were compared using the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards models.

Results: A total of 54 and 26 patients received platinum plus pemetrexed as first- and second-line chemotherapy, respectively (gemcitabine in 12 patients; taxane, six; nivolumab, three; and others, five). In all patients, the median overall survival and progression-free survival after first-line chemotherapy were 16.6 and 7.3 months, respectively. Among patients who received second-line chemotherapy, the median overall survival, progression-free survival, and second-line overall survival were 16.9, 3.2, and 9.9 months, respectively. Patients who received ≥6 cycles of platinum plus pemetrexed as first-line chemotherapy had longer overall survival after second-line chemotherapy than those who did not (hazard ratio, 0.23; 95% confidence interval: 0.06-0.82; p = 0.02).

Conclusions: Second-line chemotherapy may be an option for refractory malignant peritoneal mesothelioma, especially in patients who have completed 6 cycles of platinum plus pemetrexed as first-line chemotherapy.
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http://dx.doi.org/10.1186/s12885-021-08025-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980334PMC
March 2021

Nivolumab in previously treated advanced gastric cancer (ATTRACTION-2): 3-year update and outcome of treatment beyond progression with nivolumab.

Gastric Cancer 2021 Jul 20;24(4):946-958. Epub 2021 Mar 20.

Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.

Background: ATTRACTION-2 demonstrated that nivolumab improved overall survival (OS) vs placebo in patients with advanced gastric cancer treated with ≥ 2 chemotherapy regimens. However, its long-term efficacy and outcome of treatment beyond progression (TBP) with nivolumab have not been clarified.

Methods: The 3-year follow-up data were collected. A subset analysis was performed to explore the efficacy of TBP by assessing postprogression survival (PPS) after the first event of disease progression.

Results: Overall, 493 patients were randomized (2:1) to receive nivolumab (n = 330) or placebo (n = 163). With a median follow-up of 38.5 (range 36.1-47.5) months, OS of the nivolumab group was significantly longer compared to the placebo group (median 5.3 vs 4.1 months; 3-year survival rate, 5.6% vs 1.9%; hazard ratio [HR], 0.62 [95% confidence interval (CI) 0.50-0.75], P < 0.0001). The median OS of responders (n = 32) who achieved complete response or partial response was 26.7 months and the 3-year survival rate was 35.5% in the nivolumab group. Overall, 109 patients in the nivolumab group and 37 patients in the placebo group received TBP. PPS tended to be longer in the nivolumab group vs placebo group (median 5.8 vs 4.5 months; HR [95% CI], 0.69 [0.47-1.01], P = 0.057). In contrast, PPS was similar between both treatment groups in non-TBP patients (median 2.3 vs 2.2 months; HR 0.90, P = 0.42).

Conclusions: Long-term efficacy of nivolumab was confirmed at the 3-year follow-up, and a survival benefit of TBP with nivolumab was suggested. Biomarkers for selecting patients suitable for TBP with nivolumab should be identified in the future.
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http://dx.doi.org/10.1007/s10120-021-01173-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205916PMC
July 2021

Trastuzumab deruxtecan for the treatment of HER2-positive advanced gastric cancer: a clinical perspective.

Gastric Cancer 2021 May 1;24(3):567-576. Epub 2021 Mar 1.

Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Human epidermal growth factor receptor 2 (HER2)-positive gastric cancer is a subtype for which new drugs and specific treatment strategies should be developed. Trastuzumab deruxtecan (T-DXd) is a novel HER2-targeted antibody-drug conjugate containing topoisomerase I inhibitor as a payload. In the randomized phase 2 study (DESTINY-Gastric01) for HER2-positive advanced gastric or gastroesophageal junction cancer (AGC), patients treated with T-DXd showed a significantly higher response rate compared with the chemotherapy of physician's choice, associated with remarkably prolonged progression-free and overall survival. T-DXd also exhibits anti-tumor activity to HER2-negative tumor cells close to HER2-positive cells (so-called bystander killing effect). T-DXd was effective even for HER2-low expressing breast and gastric cancer in several clinical studies. Taking advantage of these strong points and synergism with other cytotoxic, molecular-targeted and immunological agents, it is expected that T-DXd will bring further progression in treatment both for strongly and weakly HER2 positive AGC in various treatment settings including perioperative chemotherapy.
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http://dx.doi.org/10.1007/s10120-021-01164-xDOI Listing
May 2021

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

Mol Clin Oncol 2021 Feb 30;14(2):41. Epub 2020 Dec 30.

Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo 104-0045, Japan.

Cervical esophageal squamous cell carcinoma (CESCC) is rare, accounting for 5% of all esophageal carcinomas. Several diagnostic and predictive markers have been studied. However, to the best of our knowledge, no biomarker is known to determine patient management except the clinical stage. The present study aimed to evaluate whether human papilloma virus (HPV) infection, epidermal growth factor receptor (EGFR) and its pathway-related gene mutations, known to be sensitive biomarkers of oropharyngeal carcinomas, could be used as biomarkers for the prediction of the prognosis of patients with CESCC. The present retrospective study included patients with CESCC who received chemoradiotherapy or surgery. HPV infection and the genomic status of , , , and of each tumor sample from patients with CESCC were analyzed by hybridizations (ISH) and PCR methods, respectively. The present study included 33 patients with CESCC (male/female, 29/4; median age, 62 years; age range, 41-86 years; clinical stage I/II/III/IV, 2/6/10/15). The present study detected HPV in one patient (3.0%) by ISH and PCR. Concerning the investigation of and its pathway-related gene mutations, the present study detected 15.1% of , 6.0% of , 3.5% of , 3.0% of and 3.0% for mutations, with no significant relationship between any gene mutations and the clinical prognostic factors. The HPV-infected patient did not exhibit any gene mutations. The present study indicated that HPV infection, EGFR and its pathway-related gene mutations rarely exist in patients with CESCC. The relationship between these biomarkers and the prognosis in patients with CESCC is still unclear.
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http://dx.doi.org/10.3892/mco.2020.2205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788557PMC
February 2021

Prospective evaluation and refinement of an S-1 dosage formula based on renal function for clinical application.

Cancer Sci 2021 Feb 6;112(2):751-759. Epub 2021 Jan 6.

Department of Surgery, Keio University School of Medicine, Tokyo, Japan.

In patients with impaired renal function, S-1-related toxicities increase due to higher exposure of 5-fluorouracil (5-FU). Our previous pharmacokinetic study in 16 cancer patients with various renal functions developed an S-1 dosage formula based on individual creatinine clearance (CLcr) and body surface area (BSA). To evaluate and refine the formula, this prospective study was conducted. Thirty-three patients with various renal functions received S-1 for 4 weeks at doses determined by the nomogram derived from the previously developed formula. A series of blood samples were collected after the first dose to calculate the area under the concentration-time curve (AUC) of 5-FU. Thirty patients with BSA of 1.14-1.84 m and CLcr of 23.8-96.4 mL/min were assessable for pharmacokinetics. The observed daily AUC ranged from 712.6 to 2868.7 ng·h/mL, and 18 patients achieved the target AUC (1447.8 ± 545.4 ng·h/mL). Three patients experienced S-1-related grade 3 adverse events during the first course. In the population pharmacokinetic analysis from the combined data of 46 patients in this study and the previous study, sex was identified as a statistically significant covariate for 5-FU clearance. Hence, the refined formula includes sex as an additional factor: Recommended daily dose = target AUC × (14.5 + 8.23 × SEX [0 for female and 1 for male] + 0.301 × CLcr) × BSA. Revised nomograms for recommended daily doses derived from the refined formula can be used in clinical practice to achieve the target AUC ensuring efficacy and safety of S-1.
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http://dx.doi.org/10.1111/cas.14758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894007PMC
February 2021

Case report: potential treatment of metastatic amphicrine carcinoma of the rectum with FOLFOXIRI chemotherapy.

Oxf Med Case Reports 2020 Nov 24;2020(11):omaa097. Epub 2020 Nov 24.

Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan.

Amphicrine carcinoma (AmC) is a unique epithelial tumor displaying exocrine and endocrine features in the same cell. It shows an adenocarcinoma-like cellular form and has endocrine granules. There are few reports describing chemotherapy for AmC. Here, we describe a case with metastatic AmC from the rectum that was treated with FOLFOXIRI chemotherapy. A 64-year-old man was diagnosed with a submucosal lesion on the scar produced after an endoscopic mucosal resection, which had been performed for adenocarcinoma of the rectum 2 years before. The endoscopic submucosal dissection revealed AmC. The abdominoperineal resection including lymph nodes dissection was performed. Thereafter, computed tomography showed multiple liver metastases, and FOLFOXIRI was administered. The best overall response was partial response, and progression-free survival was 8.7 months. After 16.0 months since first-line chemotherapy the patient died. We can therefore conclude that FOLFOXIRI may be effective for AmC of the rectum.
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http://dx.doi.org/10.1093/omcr/omaa097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685017PMC
November 2020

Current status of immunotherapy for advanced gastric cancer.

Jpn J Clin Oncol 2021 Jan;51(1):20-27

Division of Gastric Surgery, Shizuoka Cancer Center, Nagaizumi.

Recently, immune checkpoint inhibitors such as anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) monoclonal antibodies have improved the overall survival of various types of cancers including advanced gastric cancer (AGC). Until now, two ant-PD-1 inhibitors were approved for AGC in Japan: nivolumab as third- or later-line treatment for AGC and pembrolizumab for previously treated patients with microsatellite instability-high tumours. However, a limited number of patients achieved clinical benefit, highlighting the importance of the better selection of patients or additional treatment to overcome resistance to PD-1/PD-L1 blockade. This review focused on pivotal clinical trials, biomarkers and novel combination therapy of immune checkpoint inhibitors forAGC.
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http://dx.doi.org/10.1093/jjco/hyaa202DOI Listing
January 2021

Gastrectomy with or without neoadjuvant S-1 plus cisplatin for type 4 or large type 3 gastric cancer (JCOG0501): an open-label, phase 3, randomized controlled trial.

Gastric Cancer 2021 Mar 16;24(2):492-502. Epub 2020 Nov 16.

Department of Surgery, Yodogawa Christian Hospital, Osaka, Japan.

Background: Specific treatment strategies are sorely needed for scirrhous-type gastric cancer still, which has poor prognosis. Based on the promising results of our previous phase II study (JCOG0210), we initiated a phase III study to confirm the efficacy of neoadjuvant chemotherapy (NAC) in type 4 or large type 3 gastric cancer.

Methods: Patients aged 20-75 years without a macroscopic unresectable factor as confirmed via staging laparoscopy were randomly assigned to surgery followed by adjuvant chemotherapy with S-1 (Arm A) or NAC (S-1plus cisplatin) followed by D2 gastrectomy plus adjuvant chemotherapy with S-1 (Arm B). The primary endpoint was overall survival (OS).

Results: Between October 2005 and July 2013, 316 patients were enrolled, allocating 158 patients to each arm. In Arm B, in which NAC was completed in 88% of patients. Significant downstaging based on tumor depth, lymph node metastasis, and peritoneal cytology was observed using NAC. Excluding the initial 16 patients randomized before the first revision of the protocol, 149 and 151 patients in arms A and B, respectively, were included in the primary analysis. The 3-year OS rates were 62.4% [95% confidence interval (CI)  54.1-69.6] in Arm A and 60.9% (95% CI  52.7-68.2) in Arm B. The hazard ratio of Arm B against Arm A was 0.916 (95% CI  0.679-1.236).

Conclusions: For type 4 or large type 3 gastric cancer, NAC with S-1 plus cisplatin failed to demonstrate a survival benefit. D2 surgery followed by adjuvant chemotherapy remains the standard treatment.
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http://dx.doi.org/10.1007/s10120-020-01136-7DOI Listing
March 2021

Time-dependent discrepancies between physician-assessed and patient-reported oxaliplatin-induced peripheral neuropathy in patients with metastatic colorectal cancer who received mFOLFOX6 plus bevacizumab: a post hoc analysis (WJOG4407GSS2).

Support Care Cancer 2021 Jul 16;29(7):3715-3723. Epub 2020 Nov 16.

Division of Gastroenterology, University of Tsukuba, Tsukuba, Japan.

Purpose: Cumulative sensory neurotoxicity induced by oxaliplatin impairs patients' quality of life and treatment continuation. This study investigated the relationship between physician-assessed and patient-reported oxaliplatin-induced peripheral neuropathy (OIPN) during treatment of metastatic colorectal cancer (mCRC) over time.

Methods: A post hoc analysis was conducted for 191 patients with mCRC who received mFOLFOX6 plus bevacizumab in the WJOG4407G trial. Physician-assessed OIPN was graded by CTCAE every 2 weeks. Patient-reported OIPN was assessed with the FACT/GOG-Ntx (11 items, best score 44) at baseline and at 3, 6, and 9 months. Physician underestimation was defined as when the highest scores of the NTX1-4 sensory subscale/CTCAE grade were 2/0, 3/0-1, or 4/0-1, and overestimation as 0/2-3, 1/2-3, or 2/3.

Results: The median total dose (range) of oxaliplatin was 762 (85-5950) mg/m. Overall, the least squares mean of FACT/GOG-Ntx scores (standard error), estimated by a linear mixed model, were 36 (0.8), 34 (0.9), 29 (1.0), and 27 (1.1) for CTCAE grades 0, 1, 2, and 3, respectively. FACT/GOG-Ntx scores were weakly-to-moderately correlated with CTCAE grade (Spearman's r = - 0.24 [p = 0.0026], - 0.46 [p < 0.0001], and - 0.56 [p < 0.0001] at 3, 6, and 9 months, respectively). OIPN was underestimated in 85/159 (54%), 43/109 (39%), and 18/69 (26%) patients at 3, 6, and 9 months, respectively. In contrast, OIPN was overestimated in less than 5% of the patients at any time.

Conclusion: During early treatment, physician underestimation of OIPN in patients with mCRC is likely.
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http://dx.doi.org/10.1007/s00520-020-05891-2DOI Listing
July 2021

Phase III Trial of Avelumab Maintenance After First-Line Induction Chemotherapy Versus Continuation of Chemotherapy in Patients With Gastric Cancers: Results From JAVELIN Gastric 100.

J Clin Oncol 2021 Mar 16;39(9):966-977. Epub 2020 Nov 16.

Seoul National University Hospital, Seoul, Republic of Korea.

Purpose: The role of maintenance therapy for gastric (GC) or gastroesophageal junction cancer (GEJC) is unclear. We investigated avelumab (anti-programmed death ligand-1 [PD-L1]) maintenance after first-line induction chemotherapy for GC/GEJC.

Patients And Methods: JAVELIN Gastric 100 was a global, open-label, phase III trial. Eligible patients had untreated, unresectable, human epidermal growth factor receptor 2-negative, locally advanced or metastatic GC or GEJC. Patients without progressive disease after 12 weeks of first-line chemotherapy with oxaliplatin plus a fluoropyrimidine were randomly assigned 1:1 to avelumab 10 mg/kg every 2 weeks or continued chemotherapy, stratified by region (Asia non-Asia). The primary end point was overall survival (OS) after induction chemotherapy in all randomly assigned patients or the PD-L1-positive randomly assigned population (≥ 1% of tumor cells; 73-10 assay).

Results: A total of 805 patients received induction; 499 were randomly assigned to avelumab (n = 249) or continued chemotherapy (n = 250). Median OS was 10.4 months (95% CI, 9.1 to 12.0 months) versus 10.9 months (95% CI, 9.6 to 12.4 months) and 24-month OS rate was 22.1% versus 15.5% with avelumab versus chemotherapy, respectively (hazard ratio [HR], 0.91; 95% CI, 0.74 to 1.11; = .1779). In the PD-L1-positive population (n = 54), the HR for OS was 1.13 (95% CI, 0.57 to 2.23; = .6352). In an exploratory analysis of the PD-L1-positive population, defined as combined positive score ≥ 1 (22C3 assay; n = 137), median OS was 14.9 months (95% CI, 8.7 to 17.3 months) with avelumab versus 11.6 months (95% CI, 8.4 to 12.6 months) with chemotherapy (unstratified HR, 0.72; 95% CI, 0.49 to 1.05). With avelumab and chemotherapy, treatment-related adverse events (TRAEs) occurred in 149 (61.3%) and 184 (77.3%) patients, including grade ≥ 3 TRAEs in 31 (12.8%) and 78 (32.8%) patients, respectively.

Conclusion: JAVELIN Gastric 100 did not demonstrate superior OS with avelumab maintenance versus continued chemotherapy in patients with advanced GC or GEJC overall or in a prespecified PD-L1-positive population.
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http://dx.doi.org/10.1200/JCO.20.00892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078426PMC
March 2021

Impact of preoperative chemotherapy as initial treatment for advanced gastric cancer with peritoneal metastasis limited to positive peritoneal lavage cytology (CY1) or localized peritoneal metastasis (P1a): a multi-institutional retrospective study.

Gastric Cancer 2021 May 11;24(3):701-709. Epub 2020 Nov 11.

Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Background: Gastric cancer (GC) patients with peritoneal metastasis are defined as stage IV in the Japanese classification of GC. For patients with peritoneal metastasis limited to positive peritoneal lavage cytology (CY1) and/or localized peritoneal metastasis (P1a), gastrectomy followed by S1 monotherapy is one of the most widely accepted therapeutic strategy in Japan. This study investigated the efficacy of preoperative chemotherapy as initial treatment in GC patients with CY1 and/or P1a.

Methods: We retrospectively reviewed GC patients diagnosed with CY1 and/or P1a at 34 institutions in Japan between 2008 and 2012. Selection criteria were: adenocarcinoma, no distant metastasis except CY1 or P1a, and no prior treatment. The subjects were divided into an Initial-Chemotherapy group and an Initial-Surgery group, according to the initial treatment.

Results: A total of 824 patients were collected and 713 eligible patients were identified for this study. As the initial treatment, 150 patients received chemotherapy (Initial-Cx), and 563 patients underwent surgery (Initial-Sx). Initial-Cx regimens were cisplatin plus S1/docetaxel plus cisplatin plus S1/others (n = 90/37/23). Both overall survival (OS) and progression-free survival (PFS) were similar between the Initial-Cx and Initial-Sx groups (median OS 24.8 and 24.0 months, HR 1.07, 95% CI 0.87-1.3; median PFS 14.9 and 13.9 months, HR 1.04, 95% CI 0.85-1.27). The 5-year OS rates were 22.3% in the Initial-Cx group and 21.5% in the Initial-Sx group.

Conclusions: Although, the preoperative chemotherapy did not show a survival benefit for GC patients with CY1 and/or P1a, initial-Cx showed favorable survival in patients who converted to P0 and CY0.
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http://dx.doi.org/10.1007/s10120-020-01137-6DOI Listing
May 2021

Nutritional and inflammatory measures predict survival of patients with stage IV colorectal cancer.

BMC Cancer 2020 Nov 11;20(1):1092. Epub 2020 Nov 11.

Department of Colorectal Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 1040045, Japan.

Background: This study aimed to evaluate the prognostic impact of nutritional and inflammatory measures (controlling nutritional status (CONUT) score, prognostic nutritional index (PNI), and modified Glasgow prognostic score (mGPS)) on overall survival (OS) in patients with stage IV colorectal cancer (CRC).

Methods: Subjects were 996 patients with stage IV CRC who were referred to the National Cancer Center Hospital between 2001 and 2015. We retrospectively investigated correlations between OS and CONUT score, PNI, and mGPS. Multivariate analyses were performed using Cox proportional hazards regression models.

Results: After adjusting for known factors (age, gender, BMI, ECOG performance status, location of primary tumor, CEA levels, histological type, M category, and prior surgical treatment), all three measures were found to be independent prognostic factors for OS in patients with stage (CONUT score, p < 0.001; PNI, p < 0.001; mGPS, p < 0.001). Significant differences in OS were found between low CONUT score (0/1) (n = 614; 61%) and intermediate CONUT score (2/3) (n = 276; 28%) (hazard ratio (HR) = 1.20, 95% confidence interval (CI): 1.02-1.42, p = 0.032), and intermediate CONUT score and high CONUT score (≥4) (n = 106; 11%) (HR = 1.30, 95% CI: 1.01-1.67, p = 0.045). Significant differences in OS were found between mGPS = 0 (n = 633; 64%) and mGPS = 1 (n = 234; 23%) (HR = 1.84, 95% CI: 1.54-2.19, p < 0.001), but not between mGPS = 1 and mGPS = 2 (n = 129; 13%) (HR = 1.12, 95% CI: 0.88-1.41, p = 0.349). Patients with low PNI (< 48.0) (n = 443; 44%) showed a significantly lower OS rate than those with high PNI (≥48.0) (n = 553; 56%) (HR = 1.39, 95% CI: 1.19-1.62, p < 0.001).

Conclusions: CONUT score, PNI, and mGPS were found to be independent prognostic factors for OS in patients with stage IV CRC, suggesting that nutritional and inflammatory status is a useful host-related prognostic indicator in stage IV CRC.
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http://dx.doi.org/10.1186/s12885-020-07560-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656744PMC
November 2020

Optimizing antiemetic treatment for chemotherapy-induced nausea and vomiting in Japan: Update summary of the 2015  Japan Society of Clinical Oncology Clinical Practice Guidelines for Antiemesis.

Int J Clin Oncol 2021 Jan 8;26(1):1-17. Epub 2020 Nov 8.

Department of Surgery, Surgical Oncology and Science, Sapporo Medical University Postgraduate School of Medicine, Sapporo, Hokkaido, Japan.

Patients with cancer should appropriately receive antiemetic therapies against chemotherapy-induced nausea and vomiting (CINV). Antiemetic guidelines play an important role in managing CINV. Accordingly, the first Japanese antiemetic guideline published in 2010 by the Japan Society of Clinical Oncology (JSCO) has considerably aided Japanese medical staff in providing antiemetic therapies across chemotherapy clinics. With the yearly advancements in antiemetic therapies, the Japanese antiemetic guidelines require revisions according to published evidence regarding antiemetic management worldwide. A revised version of the first antiemetic guideline that considered several upcoming evidences had been published online in 2014 (version 1.2), in which several updated descriptions were included. The 2015 JSCO clinical practice guideline for antiemesis (version 2.0) (in Japanese) has addressed clinical antiemetic concerns and includes four major revisions regarding (1) changes in emetogenic risk categorization for anti-cancer agents, (2) olanzapine usage as an antiemetic drug, (3) the steroid-sparing method, and (4) adverse drug reactions of antiemetic agents. We herein present an English update summary for the 2015 JSCO clinical practice guideline for antiemesis (version 2.0).
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http://dx.doi.org/10.1007/s10147-020-01818-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788035PMC
January 2021

A nonrandomized, single-arm confirmatory trial of expanded endoscopic submucosal dissection indication for undifferentiated early gastric cancer: Japan Clinical Oncology Group study (JCOG1009/1010).

Gastric Cancer 2021 Mar 8;24(2):479-491. Epub 2020 Nov 8.

Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: While endoscopic submucosal dissection (ESD) is recognized as a minimally invasive standard treatment for differentiated early gastric cancers (EGCs), it has not been indicated for undifferentiated EGC (UD-EGC) because of a relatively high risk of lymph node metastasis (LNM). However, patients with surgically resected mucosal (cT1a) UD-EGC ≤ 2 cm in size with no lymphovascular invasion or ulceration are reported to be at a very low risk of LNM. This multicenter, single-arm, confirmatory trial was conducted to evaluate the efficacy and safety of ESD for UD-EGC.

Methods: The key eligibility criteria were endoscopically diagnosed cT1a/N0/M0, single primary lesion, size ≤ 2 cm, no ulceration and histologically proven components of undifferentiated adenocarcinoma on biopsy. Based on the histological findings after ESD, additional gastrectomy was indicated if the criteria for curative resection were not satisfied. The subjects of the primary analysis were patients with UD-EGC as the dominant component. The primary endpoint was 5-year overall survival (OS) of patients with UD-EGC.

Results: Three hundred 46 patients were enrolled from 49 institutions. The proportion of en bloc resection was 99%. No ESD-related Grade 4 adverse events were noted. Delayed bleeding and intraoperative and delayed perforation occurred in 25 (7.3%), 13 (3.8%), and 6 (1.7%) patients, respectively. Among the 275 patients who were the subjects of the primary analysis, curative resection was achieved in 195 patients (71%), and 5-year OS was 99.3% (95% CI: 97.1-99.8).

Conclusions: ESD can be a curative and less invasive treatment for UD-EGC for patients meeting the eligibility criteria of this study.
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http://dx.doi.org/10.1007/s10120-020-01134-9DOI Listing
March 2021

Phase II study of lenvatinib for metastatic colorectal cancer refractory to standard chemotherapy: the LEMON study (NCCH1503).

ESMO Open 2020 08;5(4)

Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan

Background: Lenvatinib inhibits tyrosine kinases, including vascular endothelial growth factor (VEGF) receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor alpha, RET proto-oncogene and KIT proto-oncogene, receptor tyrosine kinase. We assessed the efficacy and safety of lenvatinib in patients with metastatic colorectal cancer after failure of standard chemotherapies.

Patients And Methods: This was an open-label, single centre, single-arm, phase 2 study. Eligible patients had unresectable metastatic colorectal adenocarcinoma, refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, trifluridine/tipiracil, anti-VEGF therapy and anti-epidermal growth factor receptor therapy (for tumours with wild-type ). Patients were treated with oral lenvatinib at 24 mg one time a day in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was centrally assessed disease control rate. Secondary endpoints included safety, response rate, progression-free survival and overall survival. The planned sample size was 30 patients to expect a disease control rate of 60% with a threshold disease control rate of 35%, one-sided alpha of 5% and power of 80% RESULTS: Between 24 October 2016 and 23 January 2018, 30 patients were enrolled; 11 (37%) and 19 (63%) had received 3 or ≥4 lines of prior chemotherapy for metastatic disease, respectively. The median number of lenvatinib cycles was 4 (range 1-13). The centrally assessed disease control rate was 70.0% (21/30, 90% CI 53.5% to 83.4%, one-sided p=0.0001); 2 patients had a partial response and 19 had a stable disease. Median progression-free survival was 3.6 months (95% CI 2.6 to 3.7). Median overall survival was 7.4 months (95% CI 6.4 to 10.8). The most common grade ≥3 adverse events were hypertension (53%), thrombocytopenia (10%), increased alanine aminotransferase and anorexia (7% each).

Conclusions: Lenvatinib showed promising clinical activity and was tolerated in patients with metastatic colorectal cancer after failure of standard chemotherapies.

Trial Registration Number: UMIN-CTR, UMIN000023446 and JAMCCT-CTR, JMA-IIA00261.
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http://dx.doi.org/10.1136/esmoopen-2020-000776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440718PMC
August 2020

Study protocol for a multi-institutional randomized phase III study comparing combined everolimus plus lanreotide therapy and everolimus monotherapy in patients with unresectable or recurrent gastroenteropancreatic neuroendocrine tumors; Japan Clinical Oncology Group Study JCOG1901 (STARTER-NET study).

Pancreatology 2020 Sep 25;20(6):1183-1188. Epub 2020 Jul 25.

Department of Medical Oncology, Kyorin University, Tokyo, Japan.

Everolimus is recognized as one of the standard drugs for the treatment of unresectable or recurrent gastroenteropancreatic neuroendocrine tumors (NET). However, recent evidence has suggested that addition of somatostatin analogs to everolimus may yield better survival outcomes as compared to everolimus alone. In April 2020, we have initiated a randomized phase III trial in Japan, to confirm the superiority of combined everolimus plus lanreotide therapy over everolimus monotherapy in patients with unresectable or recurrent gastroenteropancreatic NETs with poor prognostic factors (Ki-67 labeling index: LI 5%-20% or Ki-67 LI < 5% with diffuse liver metastases). We plan to enroll a total of 250 patients from 76 institutions over an accrual period of 5 years. The primary endpoint is progression-free survival. The key secondary endpoint is overall survival, with response rate, disease control rate, and proportion of patients with adverse events as the other secondary endpoints. This trial is registered with the Japan Registry of Clinical Trials as jRCT1031200023 [https://jrct.niph.go.jp/en-latest-detail/jRCT1031200023].
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http://dx.doi.org/10.1016/j.pan.2020.07.010DOI Listing
September 2020

S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin as first-line therapy in patients with advanced gastric cancer (SOLAR): a randomised, open-label, phase 3 trial.

Lancet Oncol 2020 08 16;21(8):1045-1056. Epub 2020 Jul 16.

Division of Gastrointestinal Medical Oncology, National Cancer Centre Hospital, Tokyo, Japan. Electronic address:

Background: S-1 plus leucovorin and oxaliplatin showed promising efficacy for treatment of advanced gastric cancer in a randomised phase 2 study. We aimed to evaluate the efficacy and safety of oral TAS-118 (S-1 plus leucovorin) and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer.

Methods: We did a randomised, open-label, phase 3 trial in 62 centres across Japan and South Korea. Patients aged 20 years or older, with a histologically confirmed advanced gastric cancer with negative or unknown HER2 status, with Eastern Cooperative Oncology Group performance status of 0 or 1, measurable or evaluable metastatic lesions, and no previous treatment were randomly assigned (1:1) via an interactive web response system using the minimisation method, stratified by performance status, presence of a measurable lesion, and country, to receive TAS-118 (S-1 40-60 mg and leucovorin 25 mg orally twice daily for 7 days) plus oxaliplatin (85 mg/m intravenously on day 1) every 2 weeks, or S-1 (40-60 mg orally twice daily) for 21 days plus cisplatin (60 mg/m intravenously on day 1 or 8) every 5 weeks. The primary endpoint was overall survival in patients who had advanced gastric cancer with measurable or evaluable metastatic lesions and who received the study drug. Safety was assessed in all patients who received the study drug. This study was registered at ClinicalTrials.gov, NCT02322593.

Findings: Between Jan 28, 2015, and Dec 5, 2016, 711 patients were randomised to TAS-118 plus oxaliplatin (n=356) or S-1 plus cisplatin (n=355). 11 untreated patients and 19 ineligible patients were excluded from the primary analysis (TAS-118 plus oxaliplatin group n=347, S-1 plus cisplatin group n=334) following recommendation from the independent data monitoring committee. After median follow-up of 26·0 months (IQR 22·0-32·8), median overall survival was 16·0 months (95% CI 13·8-18·3) in the TAS-118 plus oxaliplatin group and 15·1 months (95% CI 13·6-16·4) in the S-1 plus cisplatin group (hazard ratio 0·83, 95% CI 0·69-0·99; p=0·039). The most common grade 3 or higher adverse events in the 352 patients in the TAS-118 plus oxaliplatin group and the 348 patients in the S-1 plus cisplatin group were anaemia (56 [16%] vs 64 [18%]), neutropenia (54 [15%] vs 88 [25%]), decreased appetite (53 [15%] vs 46 [13%]), diarrhoea (33 [9%] vs 15 [4%]), and peripheral sensory neuropathy (30 [9%] vs one [<1%]). Serious adverse events were observed in 155 (44%) of 352 patients in the TAS-118 plus oxaliplatin group and 159 (46%) of 348 patients in the S-1 plus cisplatin group. Two treatment-related deaths occurred in the TAS-118 plus oxaliplatin group (pulmonary tuberculosis and viral pneumonia).

Interpretation: TAS-118 plus oxaliplatin showed a clinically meaningful improvement in efficacy compared with S-1 plus cisplatin, and could be considered a new first-line treatment option for advanced gastric cancer in Asian patients.

Funding: Taiho Pharmaceutical and Yakult Honsha.
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http://dx.doi.org/10.1016/S1470-2045(20)30315-6DOI Listing
August 2020

Randomized controlled Phase III trial to evaluate omentum preserving gastrectomy for patients with advanced gastric cancer (JCOG1711, ROAD-GC).

Jpn J Clin Oncol 2020 Oct;50(11):1321-1324

Department of Gastric Surgery, Shizuoka Cancer Center, Shizuoka, Japan.

Gastrectomy with omentectomy and D2 lymph node dissection is the current standard procedure for locally advanced gastric cancer. However, some retrospective studies have reported that omentectomy increased post-operative abdominal complications but provided no survival advantage over omentum preservation. Therefore, we plan a randomized controlled phase III trial to confirm the non-inferiority of omentum preservation compared with omentectomy in patients with cT3 (SS) or cT4a (SE) gastric cancer. A total of 1050 patients will be enrolled from 62 institutions over a period of 6.5 years. The primary end point is relapse-free survival, and the secondary end points are overall survival, blood loss, operation time and adverse events. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000036253.
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http://dx.doi.org/10.1093/jjco/hyaa113DOI Listing
October 2020

Posttherapy topographical nodal status, ypN-site, predicts survival of patients who received neoadjuvant chemotherapy followed by curative surgical resection for non-type 4 locally advanced gastric cancer: supplementary analysis of JCOG1004-A.

Gastric Cancer 2021 Jan 22;24(1):197-204. Epub 2020 Jun 22.

Yodogawa Christian Hospital, Osaka, Japan.

Background: Perioperative treatment is an accepted standard approach for treating locally advanced gastric cancer (LAGC). Histopathological tumor regression with < 10% residual tumor is a globally accepted prognosticator in LAGC patients who received neoadjuvant chemotherapy (NAC) and curative surgery. However, despite a response of the primary tumor, a significant percentage of patients dies from recurrence and identification of those at risk for relapse remains challenging. We re-estimated the value of histopathological tumor regression as a prognosticator alongside other factors, especially posttherapy topographical nodal status, ypN-site.

Patients And Methods: Individual patient data including clinicopathological variables were used from the four JCOG trials investigating NAC (JCOG0001, JCOG0002, JCOG0210, JCOG0405) for analyzing prognosticators in patients with curative surgery excluding those with type 4 AGC by univariable and multivariable Cox regression analyses.

Results: Among 85 patients, 5-year overall survival (OS) was 46.0% [95% confidence interval (CI) 35.0-56.4] with a median follow-up of 3.2 years. On univariable analysis, histopathological tumor regression with ≥ 10% residual tumor and ypN-site 2-3 were negatively associated with OS [≥ 10% residual tumor: hazard ratio (HR) 2.60; 95% CI 1.22-5.54; P = 0.014; ypN2-3: HR 3.59; 95% CI 1.60-8.06; P = 0.002). On multivariable analysis, only ypN-site 2-3 was predictive of OS (HR 3.67; 95% CI 1.55-8.69; P = 0.003), whereas histopathological tumor regression with ≥ 10% residual tumor was not (HR 2.24; 95% CI 0.98-5.10; P = 0.055).

Conclusions: ypN-site may have greater impact on OS than histopathological tumor regression in patients who received NAC plus surgery for non-type 4 LAGC.
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http://dx.doi.org/10.1007/s10120-020-01098-wDOI Listing
January 2021

Palliation of dysphagia in metastatic oesogastric cancers: An international multidisciplinary position.

Eur J Cancer 2020 08 17;135:103-112. Epub 2020 Jun 17.

Department of Radiation Oncology, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France; Univ Paris Sud, Université Paris-Saclay, F-94270, Le Kremlin-Bicêtre, France.

Malignant dysphagia is the most common symptom in advanced oesogastric cancers patients. Relief of dysphagia allows quality of life improvement, nutritional replenishment and potentially improves prognosis. Chemotherapy alone is effective and should be prioritised in patients with metastatic disease a good performance status, and its impact on dysphagia should be determined before further interventions are planned. Regarding local treatments, the insertion of a covered self-expandable metallic stent is the most commonly used alternative, as it allows for the rapid relief of severe dysphagia. Although several randomised trials have highlighted the role of oesophageal brachytherapy, this technique is often not easily accessible. Contemporary trials are ongoing to better define the role of external radiation therapy. While awaiting these results, external radiation therapy can be considered as a second-best option for patients with a life-expectancy > 3 months. It is important to offer nutritional support and to integrate quality of life measures in the palliative management of dysphagia. This multidisciplinary international position paper aims to propose a decision-making process and highlight randomised trials for the management of malignant dysphagia in metastatic oesogastric cancer patients.
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http://dx.doi.org/10.1016/j.ejca.2020.04.032DOI Listing
August 2020

Randomised phase II study of panitumumab plus irinotecan versus cetuximab plus irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to fluoropyrimidine, irinotecan and oxaliplatin (WJOG 6510G).

Eur J Cancer 2020 08 8;135:11-21. Epub 2020 Jun 8.

Cancer Chemotherapy Center, Osaka Medical College, Osaka, Japan.

Background: Cetuximab has been shown to be clinically active when given in combination with irinotecan in patients with irinotecan-refractory metastatic colorectal cancer (mCRC). However, it has remained unclear whether panitumumab is effective when combined with irinotecan. We compared efficacies of both regimens in this randomised phase II study.

Patients And Methods: Patients with wild-type KRAS exon 2 mCRC previously treated with fluorouracil-, oxaliplatin- and irinotecan-based chemotherapies were randomised (1:1) to either panitumumab plus irinotecan (panitumumab arm) or cetuximab plus irinotecan (cetuximab arm). The primary end-point was progression-free survival (PFS). The planned sample size was 120, expecting a hazard ratio (HR) of 1.0 with non-inferiority margin of 1.3 (one-sided alpha error 0.2 and power 0.7). Major secondary end-points were overall survival (OS), response rate and safety.

Results: From December 2011 to September 2014, 121 patients were enrolled, and 61 and 59 patients were randomised to the panitumumab and cetuximab arms, respectively (1 patient excluded). Most patients (97%) had received prior chemotherapies containing bevacizumab. The median PFS was 5.42 months in the panitumumab arm and 4.27 months in the cetuximab arm (HR = 0.64, 95% confidence interval [CI] = 0.44-0.94, P < 0.001 for non-inferiority, P = 0.058 for superiority), and median OS was 14.85 and 11.53 months (HR = 0.66, 95% CI = 0.44-1.00, P = 0.050 for superiority), respectively. The incidence of grade 3 or 4 hypomagnesaemia was higher in the panitumumab arm than that in the cetuximab arm (17% vs. 7%).

Conclusion: Panitumumab may be non-inferior to cetuximab in combination with irinotecan in survival of patients with irinotecan-refractory mCRC.
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http://dx.doi.org/10.1016/j.ejca.2020.04.014DOI Listing
August 2020

Long-term outcomes of patients with recurrent squamous cell carcinoma of the esophagus undergoing salvage endoscopic resection after definitive chemoradiotherapy.

Surg Endosc 2021 04 30;35(4):1766-1776. Epub 2020 Apr 30.

Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo, Japan.

Background: Salvage endoscopic resection (ER) has been reported to be effective for patients with local failure of esophageal squamous cell carcinoma (ESCC) after definitive chemoradiotherapy (dCRT). This study aimed to evaluate the long-term outcomes of salvage ER for patients with local failure of ESCC and to identify risk factors associated with disease recurrence after salvage ER.

Methods: This study included 45 patients undergoing salvage ER after dCRT during 2000 to 2017. After ER, all patients were required to undergo surveillance esophagogastroduodenoscopy (EGD) once or twice every year, and a computed tomography (CT) examination was repeated every 3 to 6 months. We assessed short-term outcomes and long-term outcomes.

Results: Of the 45 patients in this study, the baseline clinical T stage before dCRT was T1 in 80%, 66% of the patients did not have nodal metastasis. The median time from CRT to the detection of local failure was 11 months (range 2-130 months). The en-bloc resection rate was 46%, and the R0 resection rate was 38%, respectively. Stricture occurred after salvage ER for one case, while adverse events such as bleeding or perforation and ER-related death did not occur. After a median observation period of 57 months, recurrence free survival at 3 years was 58%, overall survival was 72%, and disease specific survival was 81%. In multivariate analysis, clinical N stage before CRT was the only independent risk factor of recurrence after salvage ER (p = 0.04).

Conclusions: Salvage ER might be effective local treatment in patients with local failure after dCRT. For the patients with clinical N stage, frequent surveillance should be performed.
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http://dx.doi.org/10.1007/s00464-020-07571-yDOI Listing
April 2021

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

BMC Cancer 2020 Apr 21;20(1):338. Epub 2020 Apr 21.

Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi, Sunto-gun, Shizuoka, 411-8777, Japan.

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.
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http://dx.doi.org/10.1186/s12885-020-06865-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175590PMC
April 2020
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