This real-world study examined the prevalence of programmed death ligand-1 (PD-L1) expression and assessed the frequency of microsatellite instability-high (MSI-H) status and Epstein-Barr virus (EBV) ...positivity in Japanese patients with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. This multicenter (5 sites), retrospective, observational study (November 2018-March 2019) evaluated Japanese patients with advanced gastric and GEJ adenocarcinoma after surgical resection (Stage II/III at initial diagnosis) or unresectable advanced cancer (Stage IV). The primary objectives were prevalence of PD-L1 expression (combined positive score CPS ≥1), MSI status, and EBV positivity. Tumor specimens of 389/391 patients were analyzed (male, 67.1%; mean age, 67.6 ± 12.2 years); 241/389 (62%) were PD-L1 positive, 24/379 (6.3%) had MSI-H tumors, and 13/389 (3.3%) were EBV positive. PD-L1 expression was higher in tumor-infiltrating immune cells than in tumor cells for lower CPS cutoffs. Among patients with MSI-H tumors and EBV-positive tumors, 19/24 (79.2%) and 9/13 (69.2%), respectively, were PD-L1 positive. A greater proportion of patients with MSI-H tumors (83.3% 20/24) were PD-L1 positive than those with MSI-low/stable tumors (60.8% 216/355; p = .0297); similarly, an association was observed between history of H pylori infection and PD-L1 expression. A higher proportion of patients with MSI-H tumors demonstrated PD-L1 expression with a CPS ≥10 (66.7% 16/24) vs those with MSI-low/stable tumors (24.8% 88/355; p < .0001). The prevalence of PD-L1 positivity among Japanese patients was comparable to that in previous pembrolizumab clinical trials and studies in gastric cancer. Particularly, higher PD-L1 expression was observed in MSI-H tumors.
Cetuximab, a chimeric immunoglobulin G 1 (IgG1) anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), has shown efficacy in 10% of patients with metastatic colorectal cancer (CRC). ...Recent studies demonstrate antibody-dependent cell-mediated cytotoxicity (ADCC) is one of the modes of action for rituximab and trastuzumab. Fragment c (Fc) portion of IgG1 mAb has shown to induce ADCC. Fragment c gamma receptors (FcgammaR) play an important role in initiating ADCC. Studies have shown that two IgG FcgammaR polymorphisms (FCGR2A-H131R and FCGR3A-V158F) independently predict response to rituximab in patients with follicular lymphoma. We tested the hypothesis of whether these two polymorphisms are associated with clinical outcome in metastatic CRC patients treated with single-agent cetuximab.
Thirty-nine metastatic CRC patients were enrolled onto the ImClone0144 trial. Using an allele-specific polymerase chain reaction (PCR) -based method, gene polymorphisms of FCGA2A-H131R and FCGA3A-V158F were assessed from genomic DNA extracted from peripheral blood samples.
FCGR2A-H131R and FCGR3A-V158F polymorphisms were independently associated with progression-free survival (PFS; P = .037 and .055, respectively; log-rank test). Combined analysis of these two polymorphisms showed that patients with the favorable genotypes (FCGR2A, any histidine allele, and FCGR3A, any phenylalanine allele) showed a median PFS of 3.7 months (95% CI, 2.4 to 4.4 months), whereas patients with any two unfavorable genotypes (FCGR2A arginine/arginine or valine/valine) had a PFS of 1.1 months (95% CI, 1.0 to 1.4 months; P = .004; log-rank test).
Our preliminary data suggest that these two polymorphisms may be useful molecular markers to predict clinical outcome in metastatic CRC patients treated with cetuximab and that they may indicate a role of ADCC of cetuximab.
Background
Few studies have compared the outcomes of endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) in patients with early gastric cancer.
Methods
We studied 780 ...lesions for which endoscopic treatment was indicated according to the Japanese Gastric Cancer Association (JGCA) criteria or the extended National Cancer Center (NCC) criteria from April 1995 to December 2007. A total of 359 lesions were treated by endoscopic aspiration mucosectomy (EAM) between April 1995 and March 2003 (EAM group), and 421 lesions were treated by ESD between April 2003 and December 2007 (ESD group). Long-term outcomes (local recurrence rate, overall survival) were compared between the groups.
Results
The median follow-up was 73 months in the EAM group and 65 months in the ESD group. Overall, the local recurrence rate was significantly lower in the ESD group (0.2 %, 1/421) than in the EAM group (4.2 %, 15/359) (
p
< 0.05). For lesions meeting the JGCA criteria, the local recurrence rate was 2.9 % in the EAM group and 0 % in the ESD group (
p
< 0.05). For lesions meeting the NCC criteria, the local recurrence rate was 12.5 % in the EAM group and 0.6 % in the ESD group (
p
< 0.05). There was no significant difference between the groups in overall survival.
Conclusions
On long-term follow-up, ESD was associated with a lower rate of local recurrence than EAM for lesions that met the JGCA or the NCC criteria. From the point of view of radical curability, ESD can be recommended for the management of lesions that meet either set of criteria.
Background
Nivolumab, an anti-programmed death-1 agent, showed survival benefits in Asian patients, including Japanese, with gastric/gastro-esophageal junction (G/GEJ) cancer. We report the analysis ...of the Japanese subpopulation from ATTRACTION-2 that evaluated nivolumab versus placebo in unresectable advanced or recurrent G/GEJ cancer after ≥ 2 chemotherapy regimens.
Methods
Data from the Japanese subpopulation in the randomized, double-blind, placebo-controlled, phase 3 trial were analyzed (data cutoff, February 25, 2017). Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and objective response rate (ORR).
Results
Among the overall study population of 493 patients, 226 (nivolumab 152; placebo 74) were enrolled from 28 sites in Japan. In the Japanese subset, median OS was longer with nivolumab versus placebo (5.4 months, 95% CI 4.6–7.4 versus 3.6 months, 95% CI 2.8–5.0). The risk of death was lower in the nivolumab versus placebo group (hazard ratio 0.58, 95% CI 0.42–0.78;
p
= 0.0002). Incidences of serious adverse events were 23% (35/152) and 25% (18/72) in the nivolumab and placebo groups, respectively. In the Japanese ITT population, 22% of nivolumab-treated and 28% of placebo-treated patients received prior ramucirumab treatment. Overall, clinical activity of nivolumab was observed regardless of prior ramucirumab use. In the nivolumab group, ORR and PFS were numerically higher in patients with prior ramucirumab use than in those without.
Conclusions
In the Japanese subpopulation, patients receiving nivolumab had longer OS, similar to the overall population, with a manageable safety profile. The interaction between nivolumab and ramucirumab will be clarified in ongoing clinical trials.
Nimotuzumab is a humanized anti‐epidermal growth factor receptor IgG1 monoclonal antibody. This phase I study assessed the tolerability, safety, efficacy, and pharmacokinetics of nimotuzumab in ...combination with chemoradiotherapy in Japanese patients with esophageal cancer. Patients with stage II, III, and IV esophageal cancer were enrolled. Patients were planned to receive nimotuzumab (level 1: 200 mg/wk for 25 weeks; or level 2: 400 mg/wk in the chemoradiation period, 400 mg biweekly in an additional chemotherapy period 8 weeks after the chemoradiation period and a maintenance therapy period after chemotherapy to 25 weeks) combined with cisplatin (75 mg/m2 on day 1) and fluorouracil (1000 mg/m2 on days 1‐4) in the chemoradiation and additional chemotherapy periods. Radiotherapy was given concurrently at 50.4 Gy. A total of 10 patients were enrolled in level 1. Dose‐limiting toxicities were observed in 2 patients (grade 3 infection and renal disorder). Maximum‐tolerated dose was estimated to be at least 200 mg/wk and the dose was not escalated to level 2. The most common grade ≥3 toxicities were lymphopenia (90%), leukopenia (60%), neutropenia (50%), and febrile neutropenia, decreased appetite, hyponatremia, and radiation esophagitis (30% each). Neither treatment‐related death nor grade ≥3 skin toxicity was observed in any patient. Complete response rate was 50%. Progression‐free survival was 13.9 months. One‐ and 3‐year survival rates were 75% and 37.5%, respectively. Immunogenicity was not reported in any patient. Nimotuzumab in combination with concurrent chemoradiotherapy was tolerable and effective for Japanese patients with esophageal cancer.
In this phase I study, we assessed the tolerability, safety, efficacy, and PK of nimotuzumab (200 mg/wk; determined to be the maximum‐tolerated dose) in combination with chemoradiotherapy in Japanese patients with esophageal cancer. The most common grade ≥3 toxicities were lymphopenia (90%), leukopenia (60%), and neutropenia (50%). Nimotuzumab in combination with concurrent chemoradiotherapy was tolerable and effective for Japanese patients with esophageal cancer.
A previous phase 1 study suggested that definitive chemoradiation therapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) is tolerable and active in patients with advanced esophageal cancer ...(AEC). This phase 2 study was designed to confirm the efficacy and toxicity of DCF-R in AEC.
Patients with previously untreated thoracic AEC who had T4 tumors or M1 lymph node metastasis (M1 LYM), or both, received intravenous infusions of docetaxel (35 mg/m(2)) and cisplatin (40 mg/m(2)) on day 1 and a continuous intravenous infusion of 5-fluorouracil (400 mg/m(2)/day) on days 1 to 5, every 2 weeks, plus concurrent radiation. The total radiation dose was initially 61.2 Gy but was lowered to multiple-field irradiation with 50.4 Gy to decrease esophagitis and late toxicity. Consequently, the number of cycles of DCF administered during radiation therapy was reduced from 4 to 3. The primary endpoint was the clinical complete response (cCR) rate.
Characteristics of the 42 subjects were: median age, 62 years; performance status, 0 in 14, 1 in 25, 2 in 3; TNM classification, T4M0 in 20, non-T4M1LYM in 12, T4M1LYM in 10; total scheduled radiation dose: 61.2 Gy in 12, 50.4 Gy in 30. The cCR rate was 52.4% (95% confidence interval CI: 37.3%-67.5%) overall, 33.3% in the 61.2-Gy group, and 60.0% in the 50.4-Gy group. The median progression-free survival was 11.1 months, and the median survival was 29.0 months with a survival rate of 43.9% at 3 years. Grade 3 or higher major toxicity consisted of leukopenia (71.4%), neutropenia (57.2%), anemia (16.7%), febrile neutropenia (38.1%), anorexia (31.0%), and esophagitis (28.6%).
DCF-R frequently caused myelosuppression and esophagitis but was highly active and suggested to be a promising regimen in AEC. On the basis of efficacy and safety, a radiation dose of 50.4 Gy is recommended for further studies of DCF-R.
Background Most previous studies of endoscopic submucosal dissection (ESD) for superficial esophageal neoplasms were retrospective; prospective studies are scant. Objective To prospectively assess ...the efficacy and safety of ESD for superficial esophageal neoplasms. Design Phase II study. Setting University hospital. Patients Fifty-two patients (median age 68 years; 48 men) who had a histologic diagnosis of superficial esophageal cancer without metastasis on CT or high-grade intraepithelial neoplasia (HGIN) were enrolled from April 2009 through November 2011. Intervention ESD was used to treat 56 lesions. All procedures were done by 4 endoscopists who each had previously performed ESD in more than 100 patients with gastric tumors. Main Outcome Measurements The primary endpoint was the R0 resection rate, and secondary endpoints were the safety and the rate of accurately diagnosing tumor depth on endoscopic examination. Results The median treatment time was 69 minutes (24-168 minutes). The histopathologic diagnosis was squamous cell carcinoma in 49 lesions, HGIN in 5, and tubular adenocarcinoma in 2. The en bloc resection rate and R0 resection rate were 100% and 94.6%, respectively. The rates of adverse events during ESD and after ESD were 22.2% and 53.8%, respectively, but most events were mild. One patient (1.9%) had mediastinal emphysema without perforation. The rate of accurately diagnosing tumor depth on endoscopic examination was 76.8%. Limitations Single-center, nonrandomized study. Conclusion Our study showed that ESD was an effective and relatively safe treatment for superficial esophageal neoplasms. ESD may be a useful treatment option for superficial esophageal neoplasms in hospitals with endoscopists who are experts in performing ESD for gastric tumors. (Clinical trial registration number: UMIN000002047 .)
Background
The optimal dose of each drug used in the docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy remains to be clarified for the Japanese population. The purpose of this study was to determine ...a recommended dose for a combination neoadjuvant DOS chemotherapy for Japanese patients with locally advanced adenocarcinoma of the esophagogastric junction (AEG).
Methods
Patients with cT3 or more advanced AEG without distant metastasis were eligible for this study. The planned dosages of docetaxel (mg/m
2
, day 1), oxaliplatin (mg/m
2
, day 1), and S-1 (mg/day, days 1–14) were: 50/100/80–120 at level 1, and 60/100/80–120 at level 2, respectively. The treatment cycle was repeated every 3 weeks, and patients were assessed for response to the treatment after 2 and 3 cycles. This study was registered in the UMIN Clinical Trial Registry (UMIN 000022210).
Results
We enrolled 12 patients with locally advanced AEG in this study. At dose level 1, one of the six patients experienced dose-limiting toxicity (DLT) of grade 3 diarrhea and grade 3 febrile neutropenia. Two of the next six patients also experienced DLT of need for more than 2-week delay of the start of the second cycle due to adverse events at dose level 2. Based on these results, level 2 was considered the recommended dose for this regimen.
Conclusion
Recommended doses of docetaxel (mg/m
2
), oxaliplatin (mg/m
2
), and S-1 (mg/day) were 60/100/80–120. This chemotherapy scheme showed good preliminary efficacy with acceptable toxicity warranting a further phase II trial to investigate the efficacy of this regimen.
Background
The prognosis of patients with gastric cancer with bulky node metastasis, linitis plastica (type 4), or large ulcero-invasive-type tumors (type 3) remains poor. We conducted a phase II ...study to evaluate the safety and efficacy of neoadjuvant chemotherapy with docetaxel, cisplatin, and S-1 (DCS) for establishing a new treatment modality that improves prognosis.
Methods
Patients received up to four 28-day cycles of DCS therapy (docetaxel at 40 mg/m
2
, cisplatin at 60 mg/m
2
on day 1, and S-1 at 40 mg/m
2
twice daily for 2 weeks) followed by gastrectomy with D2 nodal dissection. S-1 chemotherapy was administered for 1 year after surgical resection. The primary endpoint was the percentage of complete resections of the primary tumor with clear margins (R0 resection). The planned sample size was 40; this was calculated based on an expected R0 rate of 85% and a threshold R0 rate of 65%, with a one-sided alpha of 5% and a power of 90%.
Results
Between 2010 and 2017, 40 patients were enrolled. The R0 resection rate was 90%. The most common grade 3 or 4 adverse events during DCS therapy were leukocytopenia (27.5%), neutropenia (55.0%), and hyponatremia (22.5%). The most common grade 3 or 4 surgical morbidity was pancreatic fistula (12.5%); mortality was 0%. The pathological response rate was 57.5% with a grade 3 histological response rate of 8%.
Conclusions
Neoadjuvant chemotherapy with DCS was feasible and showed a sufficient R0 resection rate. A future study with a sufficient follow-up period should confirm survival outcomes.
Purpose
A triplet regimen of docetaxel, cisplatin, and S-1(DCS) is highly effective against metastatic gastric cancer. We performed this study to clarify the safety and efficacy of surgical resection ...in patients with initially unresectable gastric cancer, after down-staging or disease control was achieved by DCS chemotherapy.
Methods
The subjects of this retrospective study were 31 consecutive patients with initially unresectable gastric cancer, who underwent surgical resection between October, 2006 and December, 2012, after down-staging or disease control was achieved by DCS chemotherapy. We evaluated the clinicopathological factors and clinical outcomes and assessed radiographic response based on the RECIST criteria, not by central review.
Result
Before DCS chemotherapy, 18 patients had extra-regional lymph node metastasis, 5 had liver metastasis, 8 had macroscopic peritoneal metastasis, and 8 had pancreatic head invasion. Twenty-three (74.2%) of the 31 patients underwent R0 resection. Postoperative morbidity and mortality rates were 16.1 and 0%. During chemotherapy, grade 3/4 toxicities included neutropenia (54.8%), leukopenia (32.3%), and anemia (16.1%). Median progression-free survival and median overall survival (OS) were 42.1 and 56.1 months, respectively. These results were similar for all patients, except those with locally advanced disease alone. In the multivariate analysis for OS, ypN remained an independent negative prognostic factor (
p
= 0.018).
Conclusion
Surgical resection after DCS chemotherapy for initially unresectable gastric cancer was safe and provided a reasonable R0 resection rate and good mid-term survival.
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