Chemotherapy For Advanced Gastric Cancer Research Articles

First-line camrelizumab (a PD-1 inhibitor) plus apatinib (an VEGFR-2 inhibitor) and chemotherapy for advanced gastric cancer (SPACE): a phase 1 study

Patients with advanced gastric cancer typically face a grim prognosis. This phase 1a (dose escalation) and phase 1b (dose expansion) study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapy for advanced gastric or gastroesophageal junction adenocarcinoma. The primary endpoints included maximum tolerated dose (MTD) in phase 1a and objective response rate (ORR) across phase 1a and 1b. Phase 1a tested three dose regimens of camrelizumab, apatinib, oxaliplatin, and S-1. Dose regimen 1: camrelizumab 200 mg on day 1, apatinib 250 mg every other day, oxaliplatin 100 mg/m² on day 1, and S-1 40 mg twice a day on days 1–14. Dose regimen 2: same as dose regimen 1, but oxaliplatin 130 mg/m². Dose regimen 3: same as dose regimen 2, but apatinib 250 mg daily. Thirty-four patients were included (9 in phase 1a, 25 in phase 1b). No dose-limiting toxicities occurred so no MTD was identified. Dose 3 was set for the recommended phase 2 doses and administered in phase 1b. The confirmed ORR was 76.5% (95% CI 58.8–89.3). The median progression-free survival was 8.4 months (95% CI 5.9-not evaluable [NE]), and the median overall survival (OS) was not mature (11.6-NE). Ten patients underwent surgery after treatment and the multidisciplinary team evaluation. Among 24 patients without surgery, the median OS was 19.6 months (7.8-NE). Eighteen patients (52.9%) developed grade ≥ 3 treatment-emergent adverse events. Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer (ChiCTR2000034109).

A scoring system for selecting nivolumab or irinotecan in the later-line chemotherapy for advanced gastric cancer: A Japanese multicenter retrospective study.

266 Background: Although Nivolumab (NIVO) or Irinotecan (IRI) monotherapy is one of the later-line chemotherapies for the advanced gastric cancer (AGC) patients, there are no prospective data of their comparison, and no indicators for selection of them. Methods: Clinical data of AGC patients treated with NIVO or IRI as later-line were collected from 7 institutions between September 2015 and September 2018. Efficacy of the two treatment groups was compared in the entire cohort and in the propensity score matching cohort. Factors which affect the prognosis were explored by multivariate analyses and the scoring system was developed using Cox regression. Results: In the analysis of entire cohort (317 patients), the median OS was 4.8 months (95% CI: 3.6–5.8) in the NIVO group and 5.9 months (95% CI: 4.9–7.2) in the IRI group, and those were 4.8 months (95% CI: 3.6–5.7) and 6.0 months (95% CI: 4.5–7.2) in the analysis of the propensity score matching cohort (248 patients), respectively. There were no differences in OS. We developed a risk score involving 1-Neutrophil to Lymphocyte Ratio (NLR), 2-age, 3-ECOG performance status, 4-peritoneal metastasis, 5-gastrectomy, and 6-liver metastasis to assess potential effect modification. Based on the result, IRI was favored in the higher-risk group (≥4 points, with double weight to 2, 3, and 4) for both OS/PFS. In contrast, NIVO was better OS/PFS in the lower-risk group (<1 point). Conclusions: According to the real-world data from multicenter in Japan, NIVO and IRI generally showed equivalent outcomes. The scoring system we explored may be useful for selecting appropriate later-line chemotherapy, either NIVO or IRI.

Correlation of multiple endpoints in the first-line chemotherapy of advanced gastric cancer: Pooled analysis of individual patient data from Japanese Phase III trials.

Individual-level surrogates are important for management in patients treated for advanced gastric cancer (AGC). This study aimed to comprehensively investigate the correlation of multiple clinical endpoints in the first-line chemotherapy of AGC. Individual patient data (IPD) were collected from four Japanese Phase III trials comparing S-1-based first-line chemotherapies (SPIRITS, START, GC0301/TOP-002, and G-SOX trials). Patients without Response Evaluation Criteria in Solid Tumors (RECIST)-based radiological assessments were excluded. Spearman's rank correlation coefficient was tested for correlation among overall survival (OS), progression-free survival (PFS), and postprogression survival (PPS). OS, PFS, and PPS were compared between responders (best response: complete response or partial response) and nonresponders (best response: stable disease or progressive disease). The study included a total of 1492 patients. Eighty percent of the patients (n = 1190) received subsequent chemotherapies after the failure of each trial's treatment protocol. PFS moderately correlated with OS (Spearman correlation coefficient = 0.66, p < 0.005), whereas the correlation between PPS and OS was strong (Spearman correlation coefficient = 0.87, p < 0.005). Responders had significantly longer OS (median, 17.7 vs. 9.1 months, p < 0.005), PFS (median, 6.9 vs. 2.8 months, p < 0.005), and PPS (median, 10.5 vs. 6.0 months, p < 0.005) than nonresponders. Our results reacknowledged the mild surrogacy of PFS and importance of postprogression treatments in patients with AGC receiving first-line chemotherapy. Consistent longer survival outcomes in better RECIST categories suggested that tumor response might be a useful individual-level surrogate.

Safety and Efficacy of Neoadjuvant Chemotherapy for Advanced Gastric Cancer in Elderly Patients.

Elderly patients with pathological stage II/III gastric cancer struggle to complete adjuvant chemotherapy. Neoadjuvant chemotherapy (NAC) for treating locally advanced gastric cancer (LAGC) has drawn attention; however, its indication for elderly patients who are vulnerable to chemotherapy is unclear. This study aimed to investigate the feasibility and efficacy of NAC for elderly patients with gastric cancer. In this study, patients aged ≥75 years who underwent curative gastrectomy for LAGC or adenocarcinoma of the esophagogastric junction between April 2013 and November 2021 were included. Vulnerable patients, with poor Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 2-3 were also included. The patients were classified into NAC+ (n=20) and NAC - (n=45) groups. The clinicopathological data of the patients were retrospectively investigated. The NAC+ group showed a higher R0 resection rate than the NAC- group (100% vs. 89.1%, p=0.3) and pathological downstaging was achieved in 12 (60%) cases, including five (25%) pathological complete responses. The incidence of adverse events during postoperative chemotherapy was 35%, and the rate of postoperative complications greater than Clavien-Dindo Grade II was comparable between the two groups (35% vs. 46.7%, p=0.43). The NAC+ group showed a higher three-year overall survival rate (75% vs. 36%, p=0.015). NAC was feasible and effective for elderly patients including vulnerable patients with LAGC or adenocarcinoma of the esophagogastric junction. It can be considered as treatment option, with a high down staging rate and better survival.

Pembrolizumab alone or in combination with chemotherapy versus chemotherapy for advanced gastric cancer: A cost-effectiveness analysis.

The KEYNOTE-062 trial demonstrated the efficacy and safety of pembrolizumab for advanced gastric cancer (GC). The current study evaluated the cost-effectiveness of pembrolizumab alone or in combination with chemotherapy versus chemotherapy for advanced GC from the perspective of the United States and China. And the results will provide evidence and data support for more drug selection-related decisions and research in the future. A partitioned survival approach with three states was created for treatment of advanced GC. The survival data were derived from KEYNOTE-062 trial and the individual patient data were generated by a specific algorithm. We fitted 21 survival functions to each treatment arm and selected the most suitable distribution type for each one. Direct costs and utility values were collected from the published, available database. Cost, quality-adjusted life-years (QALYs), and incremental cost-utility ratios (ICURs) were considered as the primary measure outcomes. One-way and probabilistic sensitivity analyses were performed to assess the reliability of the analyses. In the base-case analysis of combined positive score (CPS) ≥1 patients, the ICUR of pembrolizumab plus chemotherapy versus chemotherapy in American and Chinese setting is $345,209/QALY and $186,802.6/QALY, respectively. And the ICUR of pembrolizumab versus chemotherapy is $473,650/QALY and $377,753/QALY in the context of the US and China, respectively. For CPS≥10 patients, the ICUR of pembrolizumab plus chemotherapy versus chemotherapy in American and Chinese setting is $483,742/QALY and $262,965/QALY, respectively. And that of pembrolizumab versus chemotherapy is $96,550/QALY and $67,896/QALY in the context of the US and China. Compared with chemotherapy, either pembrolizumab plus chemotherapy or pembrolizumab monotherapy is not regarded as a cost-effective strategy for patients with CPS≥1, advanced gastric cancer in the current American and Chinese setting. But pembrolizumab monotherapy for CPS≥10 patients would become a cost-effective option in the American setting.

Evaluation of the relevance of the growth modulation index (GMI) from the FFCD 0307 randomized phase III trial comparing the sequence of two chemotherapeutic regimens

Precision medicine trials disrupted the paradigm of randomized controlled trials in large populations. Patient selection may be based on molecular alterations rather than on primary tumor location. In small patient populations, the growth modulation index (GMI) has been developed to evaluate treatment efficacy by using each patient as its own control. The FFCD 0307 randomized phase III trial compared two sequences of chemotherapy in advanced gastric cancer, which represents a unique opportunity to evaluate the relevance of the GMI. In the FFCD 0307 trial, patients with advanced gastric cancer were randomized between two chemotherapy sequences [ECX followed by FOLFIRI at disease progression (arm A) versus FOLFIRI followed by ECX (arm B)]. GMI was defined as the ratio of the progression-free survival on second treatment (PFS2) to the time to progression on first treatment (TTP1). Sequence benefit was defined as a GMI exceeding 1.3 (GMI-high). GMI was correlated with overall survival (OS). OS1 and OS2 were measured from first randomization and second-line failure to death. Four hundred and sixteen patients were randomized (209 in arm A, 207 in arm B). One hundred and seventy-five patients (42%) received the two sequences and were assessable for GMI (97 in arm A, 79 in arm B). The median GMI was higher in arm A than in arm B (0.62 versus 0.47, P= 0.04). Patients with a high GMI had a longer OS1 (median 14.9 versus 11.5 months, NS). Median OS2 was doubled in the GMI-high group (3.4 versus 1.6 months, NS). GMI analyses suggest that ECX followed by FOLFIRI might represent a better therapeutic strategy than FOLFIRI followed by ECX. High GMI was associated with prolonged survival.

Liposomal Paclitaxel and Albumin-bound Paclitaxel (Nanovehicle Agents) for Gastric Cancer

Gastric cancer has the third-highest cancer-related mortality rate. Paclitaxel is a microtubule stabilizer whose systemic chemotherapy regimen is widely used in clinical practice due to its major role in the chemotherapy of advanced gastric cancer. Nanovehicles are various nanoparticles with dissolved or dispersed drugs that are currently used clinically, such as nanoparticles, liposomes, and polymeric micelles. The common nanovehicle paclitaxel formulations, such as liposomal paclitaxel and albumin-bound paclitaxel, are remarkably effective in improving biocompatibility, reducing allergic reactions, and targeting and localizing drug release. Numerous studies have indicated better anticancer activity and tolerable toxicity of nanocarrier paclitaxel compared with solvent-based paclitaxel in gastric cancer, which constitutes a trendy direction in gastric cancer treatment research. This article reviews the preparation and clinical application of paclitaxel delivery by nanovehicles in gastric cancer to provide a reference for chemotherapy in patients with advanced gastric cancer.

Safety and efficacy of robotic-assisted versus laparoscopic distal gastrectomy after neoadjuvant chemotherapy for advanced gastric cancer.

Robot-assisted distal gastrectomy (RADG) has been used in the minimally invasive surgical treatment of gastric cancer, but the research on advanced gastric cancer (AGC) after neoadjuvant chemotherapy (NAC) has not been reported. This study aimed to analyze the outcomes of RADG versus laparoscopic distal gastrectomy (LDG) after NAC for AGC. This was a retrospective propensity score-matched analysis from February 2020 and March 2022. Patients who underwent RADG or LDG for AGC (cT3-4a/N +) following NAC were enrolled and a propensity score-matched analysis was performed in a 1:1 manner. The patients were divided into RADG group and LDG group. The clinicopathological characteristics and short-term outcomes were observed. After propensity score matching, 67 patients each in the RADG and LDG groups. RADG was associated with a lower intraoperative blood loss (35.6 vs. 118.8ml, P = 0.014) and more retrieved lymph nodes (LNs) (50.7 vs. 39.5, P < 0.001), more extraperigastric (18.3 vs. 10.4, P < 0.001), and suprapancreatic LNs (16.33 vs. 13.70, P = 0.042). The RADG group showed lower VAS scores at postoperative 24h (2.2 vs 3.3, P = 0.034), earlier ambulation (1.3 vs. 2.6, P = 0.011), aerofluxus time (2.2 vs. 3.6, P = 0.025), and shorter postoperative hospital stay (8.3 vs. 9.8, P = 0.004). There were no significant differences in the operative time (216.7 vs.194.7min, P = 0.204) and postoperative complications between the two groups. RADG may be a potential therapeutic option for patients with AGC after NAC considering its advantages in perioperative period compared with LDG.

Staging LaParoscopy to Assess Lymph NOde InvoLvement in Advanced GAstric Cancer (POLA)-Study protocol for a single-arm prospective observational multicenter study.

In the era of neoadjuvant chemotherapy in advanced gastric cancer (GC), the role of staging laparoscopy (SL) will become more established. However, despite guidelines recommendations, SL for optimal preoperative staging remains underutilized. Diagnostic value of near-infrared (NIR) / indocyanine green (ICG) guided sentinel node (SN) mapping in GC confirmed its technical feasibility, however no data exist regarding its potential role in pathological nodal staging. To the best of our knowledge, current study is the first to evaluate the role of ICG in nodal staging of advanced GC patients undergoing SL. This single-arm prospective observational multicenter study was approved by the Bioethical Committee of Medical University of Lublin (Ethic Code: KE-0254/331/2018). The protocol is registered at clinicaltrial.gov (NCT05720598), and the study results will be reported according to the Strengthening of Reporting of Observational Studies in Epidemiology (STROBE) statement. The primary endpoint of this study is the identification rate of ICG-guided SN in advanced GC patients. The secondary endpoints include pathological and molecular assessment of retrieved SNs and other pretreatment clinical variables potentially associated with SL: pattern of perigastric ICG distribution according to patients' pathological and clinical characteristics, neoadjuvant chemotherapy compliance, 30-day morbidity, and mortality. POLA study is the first to investigate the clinical value of ICG-enhanced sentinel node biopsy during staging laparoscopy in advanced GC patients in a Western cohort. Identifying pN status before multimodal treatment will improve GC staging process.

Ginseng-containing traditional medicine preparations in combination with fluoropyrimidine-based chemotherapy for advanced gastric cancer: A systematic review and meta-analysis.

Ginseng-containing traditional medicine preparations (G-TMPs) in combination with fluoropyrimidine-based chemotherapy (FBC) are well-known treatments for advanced gastric cancer (AGC), with a superior efficacy to FBC alone. However, evidence regarding their efficacy remains limited. The purpose of this meta-analysis is to evaluate the efficacy and safety of G-TMPs in combination with FBC for the treatment of AGC. Eight electronic databases were searched for randomized controlled trials (RCTs) using G-TMPs with FBC for the treatment of AGC. The primary outcome included the tumor response, while the secondary outcomes included the quality of life (QoL), proportions of peripheral blood lymphocytes, adverse drug reactions (ADRs), and levels of cancer biomarkers. The quality of evidence for each outcome was assessed using GRADE profilers. A total of 1,960 participants were involved in the 26 RCTs included. Patients treated with FBC plus G-TMPs had better objective response (risk ratio [RR] = 1.23, 95% confidence interval [CI]: 1.13 to 1.35, p < 0.00001) and disease control (RR = 1.13, 95% CI: 1.08 to 1.19, p < 0.00001) rates than those treated with FBC alone. Additionally, the combination group had a better QoL, higher proportions of CD3+ T cells, CD4+ T cells, and natural killer cells, as well as a higher CD4+/CD8+ T-cell ratio. Furthermore, lower levels of CA19-9, CA72-4, and CEA were confirmed in the combination treatment group. In addition, G-TMPs reduced the incidence of ADRs during chemotherapy. In combination with FBC, G-TMPs can potentially enhance efficacy, reduce ADRs, and improve prognosis for patients with AGC. However, high-quality randomized studies remain warranted. PROSPERO Number: CRD42021264938.

Abstract 1749: The synergic effect of cisplatin and a chemokine receptor antagonist sensitizes drug resistant gastric cancer cells and inhibits tumoroid formation

Abstract Introduction: Gastric cancer (GC) is an important cause of death worldwide. Cisplatin (CDDP) is the most used drug in the chemotherapy of advanced GC. However, CDDP resistance reduces GC survival. The CCR5/CCL5 axis has been associated with GC development, but its role in CDDP resistance in GC has not been elucidated. The aim of this study was to determine the effects of CCR5/CCL5 axis blockade by a chemokine receptor antagonist (CRA), alone and in combination with CDDP, on in vitro and 3D tumorid models from AGS R-CDDP cells. Methodology: AGS R-CDDP cells (CDDP-resistant human gastric adenocarcinoma cells) were previously established using a stepwise drug dosing protocol and characterized. CCL5 was selected through transcriptomic analysis and its expression level was validated by qRT-PCR. Cytotoxicity assays were determined by using MTT. Apoptosis and cell cycle assays were evaluated by flow cytometry. Tumoroid formation was performed from AGS R-CDDP cells in low adhesion plates (NunclonTMSpheraTM). After 10 days in culture, tumoroid &amp;gt;150 µm in diameter were scored and pharmacological stimuli were added on days 14, 17 and 20. CRA was used alone and in combination with CDDP in all assays. Results: CRA/CDDP combination triggered a re-sensitized phenotype in AGS R-CDDP cells, decreasing cell viability but not increasing apoptosis compared to independent treatments. AGS R-CDDP cells treated with CRA/CDDP were mainly arrested in S phase. CCL5 showed a decrease in mRNA levels after the CRA/CDDP combination compared to separate treatments. AGS R-CDDP cells showed a higher potential in the ability to form tumoroids compared to AGS WT cells. Finally, CRA/CDDP combination inhibited tumoroid formation compared to independent treatments. Discussion and Conclusion: CCL5 showed a decrease in mRNA levels after the CRA/CDDP combination, possibly correlating with allosteric inhibition of the CCR5 receptor. CRA/CDDP combination has a synergic effect that sensitizes AGS R-CDDP cells and inhibits tumoroid formation. This combination could be used as a potential coadjuvant in GC therapy allowing to reduce the doses of CDDP and therefore to reduce side effects. Citation Format: Bárbara Mora-Lagos, María Elena Reyes, Lorena Lobos-Gonzalez, Matías del Campo, Carmen Gloria Ili, Kurt Buchegger, Yuselin Mora, Louise Zanella, Ismael Riquelme, Priscilla Brebi. The synergic effect of cisplatin and a chemokine receptor antagonist sensitizes drug resistant gastric cancer cells and inhibits tumoroid formation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1749.

Abstract 1082: Effect of doublet treatment versus single-agent treatment in gastric cancers with/without MET amplification or a MET exon 14 skipping mutation

Abstract Although conventional combination chemotherapy for advanced gastric cancer (GC) is associated with increased survival, it has major adverse effects, which necessitate the development of more effective, less toxic treatments. Combinations of multiple anti-cancer drugs, such as paclitaxel plus ramucirumab, have recently been used for the second-line treatment of advanced GC. This study evaluated the MET copy number variation (CNV), mutations, and gene and protein expression in human GC cells and the differential susceptibility of GC cells to single (tepotinib, ramucirumab, or paclitaxel) or doublet (tepotinib plus paclitaxel or ramucirumab plus paclitaxel) regimens. Compared to ramucirumab plus paclitaxel, tepotinib plus paclitaxel inhibited the growth of GC cells with a MET exon 14 skipping mutation and those without MET amplification but with phosphorylated MET in a dose-dependent manner with a concomitant induction of cell death. Tepotinib plus paclitaxel and ramucirumab plus paclitaxel similarly inhibited the growth of GC cells without a MET amplification or MET phosphorylation in a dose-dependent manner without inducing cell death. However, tepotinib alone or tepotinib plus ramucirumab was more effective in c-MET-positive GC cells (CNV &amp;gt; 30) than ramucirumab alone, paclitaxel alone, or ramucirumab plus paclitaxel. Our in vitro findings suggest that, compared to ramucirumab plus paclitaxel, tepotinib plus paclitaxel inhibits the growth of c-MET-positive GC cells, GC cells without a MET amplification but with phosphorylated MET, and those with MET mutations. Tepotinib alone was as effective as tepotinib plus paclitaxel in c-MET-positive GC cells. Clinical studies are required to confirm the therapeutic effects of these regimens. Citation Format: Dae Young Zang, sung-hwa sohn, Hee Jung Sul, Bum Jun Kim. Effect of doublet treatment versus single-agent treatment in gastric cancers with/without MET amplification or a MET exon 14 skipping mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1082.

YpTNM staging is a potentially useful prognostic stratification tool in patients with advanced gastric cancer after preoperative chemotherapy

Although the usefulness of the ypStage in neoadjuvant chemotherapy for advanced gastric cancer (GC) has been reported, whether or not the ypStage is applicable to all GC patients who receive preoperative chemotherapy, including conversion surgery cases, is unclear. Therefore, this retrospective study evaluated the value of the ypTNM staging system in all advanced GC patients who received chemotherapy prior to gastrectomy. A total of 66 patients who underwent chemotherapy prior to gastrectomy for advanced GC at Chiba University Hospital from January 2008 to December 2020 were enrolled in the current study. The prognostic impact of the ypStage on the overall survival (OS) and relapse-free survival (RFS) were examined via univariate and multivariate analyses. The 5-year OS rates for ypStage I, II, III, and IV were 87.5%, 64.7%, 52.9%, and 28.6%, respectively, while the 5-year RFS rates were 81.3%, 57.4%, 44.4%, and 28.6%, respectively. The univariate analysis revealed that the ypStage was significantly correlated with the OS (p = 0.037) and the ypT status and ypStage showed a significant correlation with the RFS (p = 0.043 and p = 0.021, respectively). The multivariate analysis demonstrated that only the ypStage was an independent prognostic factor for the OS and RFS (p = 0.024 and p = 0.018, respectively). The ypTNM stage may be a useful tool for the risk stratification of all advanced GC patients treated with chemotherapy followed by gastrectomy, including not only neoadjuvant but also conversion surgery cases.

Doxifluridine versus Tegafur/Gimeracil/Oteracil (S-1) as adjuvant chemotherapy for patients with gastric cancer after gastrectomy: A propensity score-matched analysis

IntroductionDoxifluridine (DF), an oral 5-FU prodrug, has been used for various solid cancers due to its efficacy and low toxicity. We aim to evaluate the effect of DF as adjuvant monotherapy in advanced gastric cancer. MethodsWe retrospectively reviewed the clinical data of 263 patients with advanced gastric cancer who underwent curative gastrectomy between January 2010 and December 2013 at our institute. Since previous randomized control trials have confirmed the efficacy of S-1 as adjuvant chemotherapy in advanced gastric cancer, we analyzed the oncologic effect and patient compliance of the DF group compared to the S-1 group. After propensity score matching, 48 patients were included in each group. ResultsThere was no significant difference in 5-year overall survival (OS) and 5-year disease-free survival (DFS) between DF and S-1 groups (5-year OS; 77.1% vs 75.0%; p = 0.729, 5-year DFS; 76.6% vs 73.9%; p = 0.748). The completion rates of the DF and S-1 groups were 60.4% and 72.9%, respectively (p = 0.194). The mean relative dose intensity of the DF and S-1 groups were 76.2% and 84.2%, respectively (p = 0.195). After multivariate analysis, the chemotherapy regimen was not a risk factor for OS and DFS, whereas relative dose intensity and pathologic stage were independent prognostic factors. ConclusionThere was no significant difference in the oncologic effect and patient compliance between DF and S-1 groups. DF could be an alternative option for adjuvant chemotherapy in advanced gastric cancer. In addition, we confirmed that relative dose intensity is an important independent prognostic factor for survival.

Delta computed tomography radiomics features-based nomogram predicts long-term efficacy after neoadjuvant chemotherapy in advanced gastric cancer.

No effective preoperative tool is available for predicting the prognosis of advanced gastric cancer (AGC) treated by neoadjuvant chemotherapy (NAC). We aimed to explore the association between change values ("delta") in the radiomic signatures of computed tomography (CT) (delCT-RS) before and after NAC for AGC and overall survival(OS). A total of 132 AGC patients with AGC were studied as a training cohort in our center, and 45 patients from another center were used as an external validation set. A radiomic signatures-clinical-nomogram(RS-CN) was established using delCT-RS and preoperative clinical variables. The prediction performance of RS-CN was evaluated using the area under the receiver operating characteristic (ROC)curve (AUC values), time-dependent ROC, decision curve analysis(DCA) and C-index. Multivariable Cox regression analyses showed that delCT-RS, cT-stage, cN-stage, Lauren-type and the value of variation of carcinoma embryonic antigen (CEA) between NAC were independent risk factors for 3-year OS of AGC. In the training cohort, RS-CN had a good prediction performance for OS (C-Index 0.73) and AUC values were significantly better than those of delCT-RS, ypTNM-stage and tumor regression grade(TRG) (0.827 vs 0.704 vs 0.749 vs 0.571, p < 0.001). DCA and time-dependent ROC of RS-CN were better than those of ypTNM stage, TRG grade and delCT-RS. The prediction performance of the validation set was equivalent to that of the training set. The cut-off (177.2) of RS-CN score was obtained from X-Tile software, a score of > 177.2 was defined as high-risk group(HRG), and scores of ≤ 177.2 were defined as the low-risk group(LRG). The 3-year OS and disease free survival(DFS) of patients in the LRG were significantly better than those in the HRG. Adjuvant chemotherapy(AC) can only significantly improve the 3-year OS and DFS of the LRG. (p < 0.05). Our nomogram based on delCT-RS has good prediction of prognosis before surgery and helps identify patients that are most likely to benefit from AC. It works well in precise and individualised NAC in AGC.

Overview of Chemotherapy for Gastric Cancer

Gastric cancer (GC) is one of the most clinically challenging cancers worldwide. Over the past few years, new molecular-targeted agents and immunotherapy have markedly improved GC prognosis. Human epidermal growth factor receptor 2 (HER2) expression is a key biomarker in first-line chemotherapy for unresectable advanced GC. Further, the addition of trastuzumab to cytotoxic chemotherapy has extended the overall survival of patients with HER2-positive advanced GC. In HER2-negative GC, the combination of nivolumab, an immune checkpoint inhibitor, and a cytotoxic agent has been demonstrated to prolong the overall survival of GC patients. Ramucirumab and trifluridine/tipiracil, which are second- and third-line treatments for GC, and trastuzumab deruxtecan, an antibody-drug conjugate for HER2-positive GC, have been introduced in clinics. New promising molecular-targeted agents are also being developed, and combination therapy comprising immunotherapy and molecular-targeted agents is expected. As the number of available drugs increases, it is important to understand the target biomarkers and drug characteristics and select the optimal therapy for each patient. For resectable disease, differences in the extent of standard lymphadenectomy between Eastern and Western countries have led to different standard treatments: perioperative (neoadjuvant) and adjuvant therapy. This review aimed to summarize recent advances in chemotherapy for advanced GC.

CA125 kinetics as a potential biomarker of prognosis in nivolumab monotherapy for patients with advanced gastric cancer and peritoneal metastasis.

445 Background: The ascites develop in large proportion of patients during salvage-line chemotherapy for advanced gastric cancer (AGC). Serum CA125 is reported to be potential biomarker in peritoneal metastasis and associate with prognosis in first-line treatment for AGC. Therefore we aimed to clarify the association between serum CA125 and therapeutic efficacy for AGC treated with third of later-line nivolumab monotherapy (Nivo). Methods: This multicenter retrospective study comprised AGC patients who received Nivo in third line or later setting between Jun. 2015 to May 2019. Patient background and treatment outcome was assessed in CA125 elevated and non-elevated group before Nivo (cut-off, 37 U/ml). The CA125 kinetics after chemotherapy was calculated based on baseline and first measure of CA125. Further, the association between CA125 kinetics and ascites burden during chemotherapy were evaluated based on optimal cut off value calculated receiver operating characteristic (ROC) curve analysis. Results: A total 50 patients from 5 hospitals were assessable. The proportion of poor PS, moderate/severe peritoneal effusion, low albumin was significantly larger in CA125 elevated group (n=29) than those in non-elevated group. The median value of CA125 before Nivo was elevated according to ascites burden (none, 31.0 U/ml; mild, 49.4 U/ml; moderate/severe, 187.0 U/ml; p&lt;0.001). The overall survival was significantly shorter in elevated group than that in non-elevated group (median, 3.2 vs. 9.4 months, p=0.035). After Nivo, first-time measure of CA125 was performed in a median of day 27. The median change of CA125 was correlated with ascites response (CR/PR, 0.04%/day; SD, 2.06%/day; PD, 4.17 %/day, p=0.013). ROC curve analysis showed that the optimal cut-off value of CA125 kinetics for ascites progression was 2.4%/day (specificity 75%, sensitivity 70%). The progression free survival in increased group was significantly shorter than that of non-increased group in patients with peritoneal dissemination (median, 1.4 vs 3.3 months, p=0.016). Conclusions: The serum CA125 before Nivo was associated with ascites burden. Further, CA125 kinetics after Nivo was associated with prognosis in AGC patients with peritoneal dissemination.

CA125 kinetics as a potential biomarker for ascites progression during taxane plus ramucirumab therapy in patients with advanced gastric cancer.

437 Background: Ascites and peritoneal metastases are major interruptive factors in sequential chemotherapy for advanced gastric cancer (AGC), although there are no established markers that predict ascites burden during treatment. Therefore, we aimed to clarify the association between serum CA125 and therapeutic efficacy for AGC treated with taxane plus ramucirumab (TAX/RAM). Methods: This multicenter retrospective study comprised AGC patients who received TAX/RAM in second or third line setting between Jun. 2015 to May 2019. Patient background and treatment outcome was assessed in CA125 elevated and non-elevated group before TAX/RAM (cut-off, 37 U/ml). The CA125 kinetics after chemotherapy was calculated based on baseline and first measure of CA125. Further, the association between early CA125 change and ascites burden during chemotherapy were evaluated based on optimal cut off value calculated receiver operating characteristic (ROC) curve analysis. Results: A total 73 patients from 5 hospitals were assessable. The proportion of poor PS, moderate/severe peritoneal effusion, low albumin was significantly larger in CA125 elevated group (n=31) than those in non-elevated group. The median value of CA125 before TAX/RAM was elevated according to ascites burden (none, 37.5 U/ml; mild, 57.9 U/ml; moderate/severe, 134.8 U/ml; p&lt;0.001). The overall survival was significantly shorter in elevated group than that in non-elevated group (median, 8.2 vs. 14.6 months, p=0.0004). Baseline CA125 elevation and peritoneal metastasis were independent prognostic factors in multivariate analysis. After TAX/RAM, first-time measure of CA125 was performed in a median of day 28. The median change of CA125 was correlated with ascites response (CR/PR, -1.86%/day; SD, 0.28%/day; PD, 2.33 %/day, p&lt;0.001). ROC curve analysis showed that the optimal cut-off value of CA125 kinetics for ascites progression was 0.0067%/day (specificity 74%, sensitivity 100%). The progression free survival in increased group was significantly shorter than that of non-increased group in patients with peritoneal dissemination (median, 2.5 vs 6.1 months, p=0.0008). Conclusions: The serum CA125 before TAX/RAM was associated with ascites burden. Further, early change of CA125 after TAX/RAM was associated with prognosis in AGC patients with peritoneal dissemination. CA125 monitoring may be biomarker in determining timing of treatment change.

Analysis of the role of tumor microenvironment on clinical outcomes of chemotherapy in patients with advanced gastric cancer using high plex digital spatial profiling.

456 Background: Tumor consists of not only cancer cells but also various immune cells or stromal cells. And tumor microenvironment (TME) is known to be associated with response and resistance to treatment. However, the role of TME in the response to chemotherapy in advanced gastric cancer (AGC) remains unclear. We evaluated whether TME can affect the survival in patients with AGC who received first-line chemotherapy using high plex digital spatial profiling (DSP). Methods: Patients with AGC who received first-line chemotherapy were registered. Archival tumor tissue before first-line chemotherapy were obtained and tissue microarrays (TMAs) were made. Regions of interest (ROIs) were selected on each TMA and high plex DSP including RNA transcript was performed in all ROIs using GeoMx DSP (Whole Transcriptome Atlas) after masking by cytokeratin (CK) immunofluorescence. Differentially expressed gene (DEG), geneset enrichment analysis (GSEA), gene ontology (GO) and cell subsets were analyzed separately in CK-positive and CK-negative areas, using EdgeR, mSigDb, DAVID and CIBERSORT. Results: Thirty-three tumor tissues from 33 patients and 5 normal tissues were analyzed. All patients received fluoropyrimidine and platinum doublet chemotherapy. HER2+ was 15.2% and all with HER2+ AGC received trastuzumab plus chemotherapy. Five received nivolumab plus chemotherapy. Response rate was 48.5% and progression-free survival (PFS) was 9.8 months (95% CI, 6.85-NA). In CK-positive area, high expression of PIGR (polymeric Immunoglobulin receptor gene) (FDR q=0.013) and low expression of IFNE (FDR q=0.027) were associated with long PFS. Response to interferon beta (FDR q=0.044), cytokine-cytokine receptor interaction (FDR q=0.014) and antigen processing and presentation pathway (FDR q=0.015) were less activated in patients with long PFS in GO and GSEA. Although the density of CD8+ T cell did not affect PFS (6.9 vs. 10.8, p=0.25), high density of CX3CR1+memory CD8+T cells (Tmem) showed longer PFS (18.3 vs. 6.6 months, p=0.01), compared with low density of CX3CR1+CD8+Tmem. In CK-negative area, low density of CD8+ T cells were associated with longer PFS (6.3 vs. 18.3 months, p= 0.008). Conclusions: TME particularly in CK-positive area might affect survival for chemotherapy in AGC. PIGR and CX3CR1+CD8+Tmem were suggested as good candidate markers for predicting clinical outcomes of chemotherapy, indicating further analysis of TME will be needed especially in patients with AGC who received immune checkpoint inhibitors.

Prediction of response to neoadjuvant chemotherapy in advanced gastric cancer: A radiomics nomogram analysis based on CT images and clinicopathological features.

To investigate the feasibility of predicting the early response to neoadjuvant chemotherapy (NAC) in advanced gastric cancer (AGC) based on CT radiomics nomogram before treatment. The clinicopathological data and pre-treatment portal venous phase CT images of 180 consecutive AGC patients who received 3 cycles of NAC are retrospectively analyzed. They are randomly divided into training set (n = 120) and validation set (n = 60) and are categorized into effective group (n = 83) and ineffective group (n = 97) according to RECIST 1.1. Clinicopathological features are compared between two groups using Chi-Squared test. CT radiomic features of region of interest (ROI) for gastric tumors are extracted, filtered and minimized to select optimal features and develop radiomics model to predict the response to NAC using Pyradiomics software. Furthermore, a nomogram model is constructed with the radiomic and clinicopathological features via logistic regression analysis. The receiver operating characteristic (ROC) curve analysis is used to evaluate model performance. Additionally, the calibration curve is used to test the agreement between prediction probability of the nomogram and actual clinical findings, and the decision curve analysis (DCA) is performed to assess the clinical usage of the nomogram model. Four optimal radiomic features are selected to construct the radiomics model with the areas under ROC curve (AUC) of 0.754 and 0.743, sensitivity of 0.732 and 0.750, specificity of 0.729 and 0.708 in the training set and validation set, respectively. The nomogram model combining the radiomic feature with 2 clinicopathological features (Lauren type and clinical stage) results in AUCs of 0.841 and 0.838, sensitivity of 0.847 and 0.804, specificity of 0.771 and 0.794 in the training set and validation set, respectively. The calibration curve generates a concordance index of 0.912 indicating good agreement of the prediction results between the nomogram model and the actual clinical observation results. DCA shows that patients can receive higher net benefits within the threshold probability range from 0 to 1.0 in the nomogram model than in the radiomics model. CT radiomics nomogram is a potential useful tool to assist predicting the early response to NAC for AGC patients before treatment.