First-line Treatment For Advanced Gastric Cancer Research Articles

Safety and efficacy of apatinib in combination with chemotherapy with or without immunotherapy versus chemotherapy alone as first-line treatment for advanced gastric cancer

SummaryThe specific first-line regimen for advanced gastric cancer (GC) is still controversial. The benefit of apatinib for first-line treatment of advanced GC remains unknown and needs to be further explored. Eighty-two patients with advanced GC treated in our institution from October 2017 to March 2023 were retrospectively reviewed. All individuals had her-2 negative GC and had received at least two cycles of first-line treatment, including 44 patients in the combination treatment group (apatinib in combination with chemotherapy with or without immunotherapy) and 38 patients in the simple chemotherapy group. We evaluated the efficacy and safety of apatinib in combination with chemotherapy with or without immunotherapy in the first-line treatment of advanced GC by comparing the efficacy, progression-free survival (PFS), and adverse events in two groups of patients. The median PFS of the simple chemotherapy group was 9.25 months (95% confidence interval (CI), 6.1–11.2 months), and that of the combination treatment group was 10.9 months (95% CI, 7.9–15.8 months), which was 1.65 months longer than the simple chemotherapy group. Statistically significant differences are shown (P = 0.022). The objective response rate (ORR) of the combination treatment group was 65.9%, and 36.8% in the simple chemotherapy group. Statistically significant differences are shown (P = 0.014). No serious (Grade IV) adverse events occurred in either group. Our study indicates that apatinib in combination with chemotherapy with or without immunotherapy as first-line treatment for advanced GC exhibits good anti-tumor activity and is well tolerated by patients.

Phase I trial of apatinib and paclitaxel+oxaliplatin+5-FU/levoleucovorin for treatment-naïve advanced gastric cancer.

Chinese guidelines recommend POF (paclitaxel, oxaliplatin, and 5-FU/levoleucovorin) as first-line treatment for advanced gastric cancer (AGC). Apatinib can augment the antitumor effect of paclitaxel, oxaliplatin, or fluorouracil in preclinical studies of AGC. A phase I clinical trial was conducted to evaluate the anticancer activity and maximum tolerated dose (MTD) of apatinib plus POF in treatment-naïve patients with AGC and to establish a recommended phase II dose. Participants received escalating doses of daily oral apatinib (250, 375, 500, 625, 750, and 850 mg) plus POF every 2 weeks using a conventional "3 + 3" study design. Among 21 treated patients, one experienced a dose-limiting toxicity (grade 3 skin ulceration at 850 mg). No MTD was reached. Apatinib 750 mg plus POF was recommended for phase II study. The most common grade 3-4 adverse events (AEs) were neutropenia (33.3%), mucositis (14.3%), and hand-foot syndrome (14.3%). Median progression-free and overall survival were 10.4 months (95% CI: 6.3, 14.6) and 18.4 months (95% CI: 9.8, 28.2), respectively. Apatinib up to 850 mg coadministered with POF was well tolerated with manageable AEs. The safety and anticancer activity of this regimen warrants its further investigation as first-line treatment for AGC in a larger study.

Evaluation of neoadjuvant immunotherapy plus chemotherapy in Chinese surgically resectable gastric cancer: a pilot study by meta-analysis.

Recently, the use of immunochemotherapy in the treatment of advanced gastric cancer (GC) has been increasing and programmed cell death protein 1 (PD-1) inhibitors combined with chemotherapy has become the first-line treatment for advanced GC. However, few studies with small sample sizes have examined this treatment regimen to assess its effectiveness and safety in the neoadjuvant treatment phase of resectable local advanced GC. Herein, we systematically searched PubMed, Cochrane CENTRAL, and Web of Science for clinical trials on neoadjuvant immunochemotherapy (nICT) in advanced GC. The primary outcomes were effectiveness [evaluated by major pathological response (MPR) and pathological complete response (pCR)] and safety [assessed by grade 3-4 treatment-related adverse events (TRAEs) and postoperative complications]. A meta-analysis of non-comparative binary results was performed to aggregate the primary outcomes. Direct comparative analysis was used to compare pooled results of neoadjuvant chemotherapy (nCT) with nICT. The outcomes emerged as risk ratios (RR). Five articles with 206 patients were included, and all of them were from the Chinese population. The pooled pCR and MPR rates were 26.5% (95% CI: 21.3%-33.3%) and 49.0% (95% CI: 42.3%-55.9%), while grade 3-4 TRAEs and post-operative complication rates were 20.0% (95% CI: 9.1%-39.8%) and 30.1% (95% CI: 23.1%-37.9%), respectively. Direct comparison showed that with the exception of grade 3-4 TRAEs and postoperative complications, all outcomes including pCR, MPR, and R0 resection rate favoured nICT to nCT. nICT is a promising strategy for use as an advisable neoadjuvant treatment for patients with advanced GC in Chinese population. However, more phase III randomized controlled trials (RCTs) will be required to further consolidate the efficacy and safety of this regimen.

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<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.

Role of Nivolumab in the Management of First-Line Unresectable Advanced or Recurrent Gastric Cancer in Combination with Chemotherapy: Lessons from the Japanese Experience.

Recently, immune checkpoint inhibitor (ICI), such as anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) monoclonal antibodies, has provided clinical benefits in various cancer types including advanced gastric cancer (AGC). Nivolumab, a monoclonal anti-PD-1 antibody, firstly showed an improvement in the overall survival (OS) in patients with AGC in the ATTRACTION-2 trial. Recently, chemotherapy plus nivolumab, as a first-line treatment for AGC, showed both OS and progression-free survival (PFS) benefits in patients with PD-L1 combined positive score (CPS) ≥5 in the global CheckMate-649 trial, and demonstrated PFS benefit irrespective of CPS status in the Asian ATTRACTION-4 trial. Based on these results, chemotherapy plus nivolumab in a first-line treatment was approved worldwide. However, the approval requirements and recommendations are different according to the approval agent or country. Thus, this review summarized the clinical trials of chemotherapy plus anti-PD1 antibody as a first-line treatment and focused on the role of nivolumab combined with chemotherapy mainly from the viewpoint of the Japanese experience.

PD-1 inhibitors plus oxaliplatin or cisplatin-based chemotherapy in first-line treatments for advanced gastric cancer: A network meta-analysis.

BackgroundCurrently, there has been no direct comparison between programmed cell death protein 1 (PD-1) inhibitors plus different chemotherapy regimens in first-line treatments for advanced gastric cancer (AGC). This study performed a network meta-analysis (NMA) to evaluate the efficacy and safety of PD-1 inhibitors plus oxaliplatin- or cisplatin-based chemotherapy.MethodsPubMed, Embase, and the Cochrane Central Register were used to seek a series of phase III randomized controlled trials (RCTs) studying on first-line PD-1 inhibitors plus chemotherapy and phase III RCTs comparing first-line oxaliplatin and cisplatin-based chemotherapy for AGC to perform NMA. The main outcome was overall survival (OS) and other outcomes included progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (TRAEs).ResultsEight eligible RCTs involving 5723 patients were included. Compared with PD-1 inhibitors plus cisplatin-based chemotherapy, PD-1 inhibitors plus oxaliplatin-based chemotherapy could prolong the OS without statistical significance (hazard ratio [HR]: 0.82, 95% credible interval [CI]: 0.63-1.06). However, for patients with combined positive score (CPS) ≥ 1, PD-1 inhibitors plus oxaliplatin-based chemotherapy significantly prolonged the OS (HR: 0.75, 95% CI: 0.57-0.99). PFS in PD-1 inhibitors plus oxaliplatin-based chemotherapy was significantly longer than that in PD-1 inhibitors plus cisplatin-based chemotherapy (HR: 0.72, 95% CI: 0.53-0.99). Regarding safety, the incidence of ≥ 3 TRAEs was similar between PD-1 inhibitors plus oxaliplatin-based chemotherapy and PD-1 inhibitors plus cisplatin-based chemotherapy (RR: 0.86, 95% CI: 0.66-1.12). The surface under the cumulative ranking area curve (SUCRA) indicated that PD-1 inhibitors plus oxaliplatin-based chemotherapy ranked first for OS (97.7%), PFS (99.3%), and ORR (89.0%). For oxaliplatin-based regimens, there was no significant difference between nivolumab plus oxaliplatin-based chemotherapy and sintilimab plus oxaliplatin-based chemotherapy in terms of OS, PFS, ORR, and ≥3 TRAEs.ConclusionCompared with PD-1 inhibitors plus cisplatin-based chemotherapy, PD-1 inhibitors plus oxaliplatin-based chemotherapy significantly prolonged PFS. Considering both efficacy and safety, PD-1 inhibitors plus oxaliplatin-based chemotherapy might be a better option in the first-line treatment for AGC.

Improved efficacy and safety of low-dose oxaliplatin/pegylated liposomal doxorubicin/S-1 regimen in advanced gastric cancer: a cohort study.

Dose-limiting neurotoxicity is the major side effect caused by oxaliplatin treatment. Optimization of oxaliplatin-containing chemotherapeutic regimens may potentially benefit advanced gastric cancer (AGC) patients. We tried to reduce the dose of oxaliplatin and add a drug to compensate for the efficacy. This cohort study evaluated the efficacy and side effects of low-dose oxaliplatin combined with pegylated liposomal doxorubicin and S-1 (D-SOX) as first-line treatment for AGC. 64 AGC patients treated in our hospital between January 2015 and December 2018 were included in this study. Among them, 29 cases received standard S-1 and oxaliplatin (SOX) regimen, and 35 cases received D-SOX. Progression-free survival (PFS), overall survival (OS), response rate (RR), and safety were analyzed. The median PFS was 7.0 months [95% confidence interval (CI): 5.77 to 8.23 months] in the SOX group and 9.3 months (95% CI: 8.145 to 10.45 months) in the D-SOX group (P=0.021). The median OS was 12.5 months (95% CI: 7.00 to 17.97 months) in the SOX group and 18.7 months (95% CI: 14.485 to 22.9 months) in the D-SOX group (P=0.027). The incidence of treatment-related grade III-IV adverse events (AEs) was less than 10%. The RRs to these 2 regimens were similar (P=0.609). The incidence of neurotoxicity was significantly reduced in the D-SOX group (62.8% vs. 82.7%). Low-dose oxaliplatin combined with S-1 and pegylated liposomal doxorubicin (PLD) regimen improved OS and PFS, while exhibiting better toxicity profile as compared with standard SOX regimen for AGC.

Comparative efficacy and safety of anti-HGF/MET pathway agents plus chemotherapy versus chemotherapy alone as first-line treatment in advanced gastric cancer: a protocol for a systematic review and meta-analysis

IntroductionPhase I/II clinical trials suggested that the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition (MET) pathway-targeted agents were active in suppression of gastric cancer (GC). Randomised controlled trials (RCTs) were undertaken assessing...

Final survival results from a multicenter, randomized phase II trial of intravenous paclitaxel plus FOLFOX (ivPOF) and/or intraperitoneal paclitaxel plus FOLFOX (ipPOF) versus mFOLFOX6 as first-line treatment of advanced gastric cancer (AGC): SYLT/FNF 004.

4041 Background: Progression-free (PFS) and overall (OS) survival for SYLT/FNF 004 were previously reported in ASCO and ASCO-GI 2019. At that time, PFS was statistically significantly improved with ivPOF or ipPOF compared to mFOLFOX6 as first-line treatment of AGC; however, there were no significant between-treatment differences in OS. Herein, we report final survival results for this trial. Methods: Subjects were randomly assigned to one of three treatments: intravenous paclitaxel 135 mg/m2 + mFOLFOX6 omitting the 5-FU bolus (ivPOF); intraperitoneal paclitaxel 80 mg/m2 + mFOLFOX6 omitting the 5-FU bolus (ipPOF); or mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 followed by 5-FU 400 mg/m2 bolus and 5-FU 2400 mg/m2 as a 46-hour continuous infusion). Treatment cycles were repeated every 14 days for up to 9 cycles. Thereafter, maintenance treatment with S-1 80 mg/m2/day for 14 days every 3 weeks until disease progression, unacceptable toxicity, patient refusal, or physician decision. The original study objective was to compare ivPOF or ipPOF vs. mFOLFOX6 for PFS. Due to slow accrual, the protocol was later amended to compare POF (ivPOF and ipPOF) with mFOLFOX6 for PFS. Results: Between Nov 2015 and May 2018, 89 subjects (30 ivPOF, 29 ipPOF, 30 mFOLFOX6) were enrolled. As of the data cutoff on Dec 31, 2020, median follow-up was 41 (IQR: 37-43) months. The median number of cycles administered was 7 (IQR: 4-9) for POF; 6 (IQR: 4-9) for ivPOF; 9 (IQR: 4-9) for ipPOF; and 4 (IQR: 3-9) for mFOLFOX6. Median PFS and OS, respectively, were 6.23 (95% CI: 4.90 to 9.07) and 10.17 (95% CI: 8.97 to 16.4) months for POF and 4.55 (95% CI: 2.73 to 6.87) and 6.87 (95% CI: 5.83 to 13.6) months for mFOLFOX6. Both PFS and OS were statistically significantly better with POF, ivPOF or ipPOF versus mFOLFOX6 (Table). Safety was consistent with previous reports. Conclusions: POF, ivPOF or ipPOF improved both PFS and OS compared with mFOLFOX6, with similarly manageable adverse effects. Clinical trial information: NCT02845908. [Table: see text]

Oxaliplatin-Based Regimen is Superior to Cisplatin-Based Regimen in Tumour Remission as First-line Chemotherapy for Advanced Gastric Cancer: A Meta-Analysis.

Background: This study was initially designed to examine whether oxaliplatin-based regimen was superior to cisplatin-based regimen in tumour remission as first-line chemotherapy for advanced gastric cancer (GC).Methods: Literature in EMBASE, PUBMED, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) was searched. Only phase II or III randomized controlled trials (RCTs) comparing the effectiveness and safety between oxaliplatin-based and cisplatin-based regimens as first-line treatment for advanced GC were selected. Odds ratios (ORs) with 95% confidence intervals (CIs) were reported. The primary endpoints were complete remission rate (CRR), partial remission rate (PRR), objective response rate (ORR), and disease control rate (DCR). The second endpoint was the toxicity response.Results: 2,140 patients from six phase II or III RCTs were included. Compared to cisplatin-based therapy, subjects who received oxaliplatin-based treatment had significantly higher PRR (OR: 1.25, 95%CI: 1.05-1.48, P=0.01, I2=0%), ORR (OR: 1.21, 95%CI: 1.02-1.44, P=0.03, I2=0%) and DCR (OR: 1.76, 95%CI: 1.31-2.38, P=0.0002, I2=25%), but not CRR (OR: 0.70, 95%CI: 0.37-1.31, P=0.27, I2=0%). In addition, oxaliplatin-based therapy significantly decreased all grades of leukopenia, neutropenia, anemia, febrile neutropenia, nausea, stomatitis, creatinine elevation and thromboembolism, as well as grades 3-4 of leukopenia, neutropenia, anemia and febrile neutropenia than cisplatin-based regimen. However, oxaliplatin-based treatment strikingly increased the risk of thrombocytopenia, sensory neuropathy, diarrhea, fatigue and liver dysfunction.Conclusions: Oxaliplatin-based regimen is superior to cisplatin-based regimen in tumour remission as first-line chemotherapy for advanced GC, and is associated with less toxicity and better tolerability.

Efficacy and safety of taxane-based systemic chemotherapy of advanced gastric cancer: A systematic review and meta-analysis

Taxanes are chemotherapeutic agents commonly used to treat several cancers. However, the effects of taxanes on advanced gastric cancer (AGC) are still not clear, especially when used as a first-line treatment. This systematic review and meta-analysis aims to investigate the efficacy and safety of taxanes as a first-line treatment of AGC. The quality of our included studies was assessed using the Cochrane risk of bias tool for RCTs and NOS scale for nRCTs, and the data of the included studies was of satisfactory quality to analyze. The outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and toxicity. Taxanes significantly improved OS (HR = 0.84, 95% CI 0.76–0.92, P = 0.0004) and had a slight effect on ORR (RR = 1.23, 95% CI 1.00–1.51, P = 0.05). However, taxanes may also increase the risks of neutropenia and leucopenia, similar to effects observed in other conventional chemotherapeutic treatments such as oxaliplatin and epirubicin. Therefore, patient characteristics including concomitant diseases, physical condition, and prior therapies should be considered before selecting taxane-based treatments for AGC.

Potential predictive markers of chemotherapy for advanced gastric cancer: Biomarker study in GC0301/TOP-002, randomized phase III study of irinotecan plus S-1 versus S-1.

55 Background: Irinotecan plus S-1(IRI-S) achieved longer median survival than S-1 monotherapy and was well tolerated for patients with advanced gastric cancer (AGC) in GC0301/TOP-002, but it did not show significant superiority (Gastric Cancer 2011). According to subset analyses, IRI-S may have extra survival benefit in some group of patients, prompting to explore prognostic or predictive markers.We correlated expression of 5 genes related to DNA and anticancer drug metabolism (TS, DPD, Topo-I, ERCC1, TP) with outcome of patients in each arm. Methods: Paraffin-embedded primary tumor specimens before chemotherapy were available from 126 of 326 patients. mRNA expression in microdissected tumors was measured by real-time RT-PCR, and categorized into low and high using the median as a cut-off. Multivariate analysis for overall survival (OS) adjusting baseline factors, gene expression and treatment (S-1/IRI-S) was performed with a Cox regression model. Interaction tests were also carried out between gene expression and treatment. Results: Although baseline factors of the subjects were similar to the entire GC0301/TOP-002 trial, median survival seemed opposite; 13.1M for S-1 and 11.4M for IRI-S arm, p=0.192. 92 samples, 47 of S-1 and 50 of IRI-S arm, were assessable for 5 genes. Multivariate analyses showed that liver metastasis correlated with poor prognosis (HR, 2.73; 95% CI, 1.50-5.01; P=0.011), but no gene was significantly correlated with OS. There were interactions between the treatment effect for DPD and TP. HRs between high and low DPD were 3.02 in S-1 and 0.96 in IRI-S arm, p=0.012 for interaction; while those for TP were 2.98 in S-1 and 0.38 for IRI-S arm, p=0.002. In patients with low TS and high Topo-I (n=18), OS was 11.2M for S-1 and 18.6M for IRI-S arm, p=0.531. Conclusions: The correlative analyses suggest DPD and TP are predictive factor for the first-line treatment of AGC including S-1 and irinotecan. Combined biomarker analyses with the previous randomized phase III study including S-1 or irinotecan is warranted to verify these findings.

Phase III trial of a 3-weekly versus 5-weekly schedule of S-1 plus cisplatin (SP) combination chemotherapy for first-line treatment of advanced gastric cancer (AGC): SOS study.

LBA4024 Background: 5-weekly S-1 plus cisplatin (SP5: S-1 80-120 mg/body/day on D1-21, cisplatin 60 mg/m2 on D8, every 5 weeks) has become a standard first-line chemotherapy for AGC in Japan based on the SPIRITS trial (Lancet Oncol. 2008;9:215). To strengthen the low-dose intensity of cisplatin in this SP5 for greater efficacy, a 3-weekly S-1 plus cisplatin (SP3: S-1 80 mg/m2/day on D1-14, cisplatin 60 mg/m2on D1, every 3 weeks) has been developed in Korea (Cancer Chemother Pharmacol. 2008;61:837). Methods: This SOS study was a multicenter, randomized, open-label, phase III study to evaluate whether SP3 was non-inferior/superior to SP5 in terms of progression-free survival (PFS) determined by a blinded central radiology review according to RECIST v1.1. Patients (pts) with metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma and with no prior chemotherapy were randomized 1:1 to receive either SP3 or SP5 until disease progression or unacceptable toxicities. Results: Between February 2009 and January 2012, a total of 625 pts were randomized from 42 sites in Korea and Japan. Median age was 59.6 years. 99% of pts had ECOG performance status 0-1. 16% of pts had prior gastrectomy. 62% of pts had measurable lesions. With a median follow-up of 34.7 months (range, 14.2-48.8) in surviving pts, SP3 was significantly noninferior and superior to SP5 in PFS (median 5.5 months vs. 4.9 months; HR 0.82, 95% CI 0.68-0.99, p=0.0418). Overall response rate (ORR) was also better with SP3 than with SP5 (60% vs. 50%, p=0.029). However, OS of both groups was equivalent (median 14.1 vs. 13.9 months; HR 0.99, 95% CI 0.81-1.21, p=0.9068). Treatment was well tolerated in both arms, while SP3 was associated with more frequent G3/4 anemia (19% vs. 9%) and neutropenia (39% vs. 9%). Dose intensity was higher in SP3 than in SP5 for both agents (median 331 vs. 317 mg/m2/week for S-1, p<0.001; median 18 vs. 12 mg/m2/week for cisplatin, p<0.001). Conclusions: SP3 was noninferior and superior to SP5 in terms of PFS and ORR. However, considering the small benefit in PFS and no difference in OS, both SP3 and SP5 can be recommended for the first-line treatment of AGC. Clinical trial information: NCT00915382.

Impact of pretreatment systemic inflammatory response on survival in AGC patients receiving first-line chemotherapy.

88 Background: Systemic inflammatory response plays an important role in cancer progression. However, little is known about how it affects the advanced gastric cancer (AGC) patients receiving first-line chemotherapy. We assessed the impact of pre-treatment systemic inflammatory response on survival in AGC patients receiving S-1 based first-line chemotherapy. Methods: OGSG 0402 multi-institutional phase II trial randomly assigned 102 patients with previously untreated, locally advanced and/or metastatic measurable gastric adenocarcinoma to receive S-1 plus irinotecan (SI arm) (n=51) or S1 plus paclitaxel (SP arm) (n=51) to evaluate these two S-1 based regimens as first-line treatment for AGC [ASCO-GI 2009: abstract 9.]. Among these patients, 99 patients were identified in this study excluding 2 patients who had died before receiving the allocated treatment and one patient who was lost to follow-up. All patients had performance status (PS) of 0-1 except for one with PS of 2. Pre-treatment clinical findings, such as gender, age, body mass index (BMI), tumor status (unresectable vs. recurrent, intestinal vs. diffuse), number of metastatic sites, serum levels of albumin (Alb) and C-reactive protein (CRP), neutrophil lymphocyte ratio (NLR), and platelet lymphocyte ratio (PLR), were assessed as prognostic factors for overall survival (OS) and progression-free survival (PFS) in univariate and multivariate analyses. Results: Median OS and PFS were 390 days and 175 days for SI arm, and 363 days and 140 days for SP arm, respectively. Multivariate analysis identified the CRP level of 0.5 mg/dl or above (hazard ratio 1.96, 95% confidence interval 1.08 to 3.55, P=0.026) as a significant prognosticator for poor OS, and age of 60 years or greater (hazard ratio 1.92, 95% confidence interval 1.06–3.47, P=0.032) for shorter PFS. Conclusions: Pre-treatment CRP level was a most potent prognosticator for OS, reflecting the impact of systemic inflammatory response on survival, in AGC patients receiving first-line chemotherapy.

Short-term outcomes of albumin-bound paclitaxel (abraxane)-containing chemotherapy in patients with advanced gastric cancer: a report of 14 cases

Albumin-bound paclitaxel (abraxane, ABX) has more favorable efficacy and less toxicity than conventional taxanes. However, the data of ABX in advanced gastric cancer (AGC) treatment is unavailable. The current study was designed to summarize our experience in treating AGC patients with ABX. The clinical data of patients with AGC who had received at least one cycle of ABX-based chemotherapy in Sun Yat-sen University Cancer Center from January 10th 2010 to May 14th 2012 was retrospectively analyzed.. A total of 47 cycles of ABX-containing regimens, with a median of 3 cycles (range: 1–8 cycles), were administered to 14 patients. Five (35.7%) partial responses and 6 (42.9%) stable diseases were obtained, with a disease control rate (DCR) of 78.6%. The median progression free survival (PFS) and overall survival (OS) were 3.3 and 10.8 months, respectively. Interestingly, patients in the first-line setting achieved a DCR of 100% (8/8). Neutropenia and thrombocytopenia were the main grade 3/4 adverse events with an incidence of 50% in the whole group. However, only 25% patients (2/8) experienced grade 3 neutropenia when ABX in combination with fluoropyrimidines. The activity of ABX-based regimens as first-line therapy for patients with AGC is remarkable, and the toxicity is mild when ABX combined with fluoropyrimidines. Further prospective clinical trials of ABX-based chemotherapy as first-line treatment for AGC are strongly anticipated.

Overall survival benefits for irinotecan‐containing regimens as first‐line treatment for advanced gastric cancer: An updated meta‐analysis of ten randomized controlled trials

The standard treatment for patients with advanced gastric cancer (AGC) is still debated, and the available data on the benefit of irinotecan-containing regimen as first-line treatment for those patients are controversial. We performed a systematic review and meta-analysis of randomized controlled trials to determine the survival benefits of irinotecan-containing regimens in this setting. A total of 1,837 patients from ten trials were included in the analysis. Our results showed that irinotecan-containing regimens significantly improved overall survival [OS: hazard ratio (HR) 0.86, 95% CI = 0.78-0.94, p = 0.002] and progression-free survival [HR = 0.82, 95% CI = 0.69-0.97, p = 0.026); however, the improvement of time to failure (HR = 0.90; 95% CI = 0.77-1.04, p = 0.15), 1-year survival rate [1-year SR: relative risk (RR) 1.10, 95% CI = 0.97-1.24, p = 0.13] and overall response rate (RR = 1.16, 95% CI = 0.91-1.49, p = 0.24] were nonsignificant. Equivalent frequencies of toxicities were found between the two groups excluding more Grade 3 or 4 fatigue (p = 0.001) in irinotecan-containing regimens. This updated meta-analysis provided strong evidence for a survival benefit of irinotecan-containing regimen as first-line treatment for AGC. A clear advantage of irinotecan-containing over nonirinotecan-containing regimen had not been established. These results should help to inform decisions about patient management and design of future trials.

The role of S-1 in the treatment of gastric cancer

The role of S-1 in the treatment of gastric cancer Mariela A Blum, Akihiro Suzuki, Takashi Taketa, Jaffer AjaniThe University of Texas, MD Anderson Cancer Center, Division of Gastrointestinal Oncology, Houston, TX, USAAbstract: Gastric cancer is a lethal disease and continues to be the second leading cause of cancer death worldwide. Surgical resection remains the main treatment for early stages with complete resection having the potential for a cure. Recent data suggest that surgery alone is inferior to surgery plus some form of adjunctive therapy. Unfortunately, most patients with gastric cancer are diagnosed in advanced stages, rendering palliative systemic therapy as the only choice of treatment. The most common chemotherapy combination as a first-line treatment in advanced gastric cancer (AGC) includes a platinum compound, a fluoroporyrimidine and a taxane (in the United States) or an antracycline (in Europe). Fluoropyrimidines have been the backbone in the chemotherapy regimens for the treatment of gastric cancer. There has been considerable interest in oral fluoropyrimidines. S-1 is a fourth-generation oral fluoropyrimidine that combines tegafur, which is a prodrug of 5-fluorouracil (5-FU), and two biochemical modulators: (1) 5-chloro-2,4-dihydroxypyridine, a powerful but reversible inhibitor of dihydropyrimidine dehydrogenase that prevents 5-FU degradation, and (2) potassium oxonate, which reduces gastrointestinal (GI) toxicity by inhibition of 5-FU phosphorylation in the GI mucosa. S-1 has produced an advantage in the postoperative setting in a large Phase III trial and has also been evaluated as a preoperative chemotherapy in gastric cancer, but in the preoperative setting, there are no completed Phase III clinical trials. Nonetheless, S-1 is considered, as a single agent, as the standard of care in Japan for the adjuvant treatment of resected gastric cancer and in combination with cisplatin in the advanced setting based on level 1 evidence in Phase III trials. S-1 is now widely available and has been approved in 27 European countries as a first-line treatment for AGC. S-1 is generally well tolerated with a low toxicity profile. It is a novel agent that provides a convenient and safe advantage over intravenous fluoropyrimidine in AGC.Keywords: tegafur, Ftorafur, FT, 5-FU, advanced gastric cancer

Phase I study of cediranib in combination with cisplatin plus fluoropyrimidine (S-1 or capecitabine) in Japanese patients (pts) with untreated advanced gastric cancer (AGC).

111 Background: Cediranib (AZD2171) is an oral, highly potent inhibitor of VEGF signalling with activity versus all three VEGFRs and c-Kit. Combination therapy with cisplatin + oral fluoropyrimidine is commonly used as first-line treatment for AGC. This phase I study assessed cediranib in combination with cisplatin/S-1 or cisplatin/capecitabine in Japanese pts with previously untreated AGC. Methods: Eligible pts received cediranib 20 mg/day and either cisplatin 60 mg/m2 iv, day 1 + S-1 40–60 mg bd, days 1–21, q5w (Arm A) or cisplatin 80 mg/m2 iv, day 1 + capecitabine 1000 mg/m2 bd, days 1–14, q3w (Arm B). The primary endpoint was safety and tolerability. Secondary endpoints included assessment of steady-state pharmacokinetics (PK) of cediranib and chemotherapy alone and in combination. Preliminary efficacy was an exploratory objective. Adverse events (AEs) were evaluated according to CTCAE v3.0. Results: Between Aug–Dec 2009, 14 pts (median age, 60.5 [27–72] years; male, n = 9; PS 0/1, n = 7/7) were recruited to Arm A (n = 6) or Arm B (n = 8). The safety profile in both arms was consistent with that of the individual agents. There were no unexpected toxicities. All pts experienced ≥1 AE. Dose-limiting toxicities were reported in 1 pt in Arm A (decreased appetite) and 1 pt in Arm B (decreased appetite, fatigue, hyponatremia). The most common AEs in Arm A were decreased appetite, fatigue, nausea, diarrhoea, decreased weight and neutropenia (all n = 5; 83%), and decreased appetite, fatigue, nausea (all n = 8; 100%) and constipation (n = 7; 88%) in Arm B. Five (83%) pts in Arm A and 6 (75%) in Arm B experienced grade ≥ 3 AEs. Grade 3 AEs in > 1 pt were neutropenia (n = 3) in Arm A and hypokalaemia (n = 3), neutropenia, hyponatraemia and fatigue (all n = 2) in Arm B. Grade 4 syncope was reported in 1 pt in Arm A; this resolved on the same day it was observed. Preliminary efficacy and PK data will be presented. Conclusions: Cediranib 20 mg plus cisplatin/S-1 or cisplatin/capecitabine was generally well tolerated and considered suitable for further evaluation in pts with AGC. The safety profile of each regimen was comparable with the individual agents. No new toxicities were identified. [Table: see text]

Randomized phase II trial of S-1 plus irinotecan versus S-1 plus paclitaxel as first-line treatment for advanced gastric cancer (OGSG0402): Final report.

4015 Background: S-1-based regimens are commonly used for advanced gastric cancer (AGC) in Japan. Both S-1 plus irinotecan (SI) and S-1 plus paclitaxel (SP) have shown an overall response rate (ORR) of 48% in respective phase II trials. This randomized phase II trial evaluated these two S-1-based regimens in terms of ORR as first-line treatment for AGC in order to choose the optimal regimen for a phase III trial. Methods: Patients with previously untreated, locally advanced and/or metastatic measurable gastric adenocarcinoma, a performance status of < 2, and adequate organ function were randomly assigned to receive S-1 (80 mg/m2/day) for 21 consecutive days plus irinotecan (80 mg/m2) on days 1 and 15, repeated every 5 weeks for the SI arm, or the same dose of S-1 for 14 consecutive days plus paclitaxel (50 mg/m2) on days 1 and 8, repeated every 3 weeks for the SP arm. Both treatments were continued until disease progression or intolerable toxicity occurred. Study endpoints included ORR as primary, progression free survival (PFS), overall survival (OS), and toxicity. Results: Between December 2005 and November 2007, 102 patients were enrolled. The median number of cycles administered was 4 (range, 1-16) for the SI arm, and 5 (range, 1-40) for the SP arm. ORR on RECIST was 33.3% (95% CI, 20.8 to 47.9%) for the SI arm (n = 51) and 31.4% (95% CI, 19.1 to 45.9%) for the SP arm (n = 51), with no significant difference between the two. The best ORR was 37.3% (95% CI, 24.1 to 51.9%) for the SI arm and 35.3% (95% CI, 22.4 to 49.9%) for the SP arm. No treatment-related deaths occurred during the study. Both arms were well tolerated although grade 3/4 neutropenia (19% vs. 2%) and anemia (13% vs. 6%) were more frequent in the SI arm. PFS was 5.7 M (95% CI, 4.4 to 7.5 M) for the SI arm (n = 50) and 4.6 M (95% CI, 4.1 to 5.9 M) for the SP arm (n = 51), and OS was 12.4 M (95% CI, 9.2 to 15.4 M) for the SI arm (n = 50) and 11.9 M (95% CI, 10.2 to 18.0 M) for the SP arm (n = 51), with no significant difference between the two. Conclusions: Although both regimens were well tolerated in patients with AGC, neither of them could demonstrate favorable ORR, PFS or OS. Therefore, we concluded that either regimen couldn't be optimal for a phase III trial. No significant financial relationships to disclose.

Phase II study of sequential cisplatin plus 5-fluorouracil/leucovorin (5-FU/LV) followed by irinotecan plus 5-FU/LV followed by docetaxel plus 5-FU/LV in patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma

5-Fluorouracil (5-FU) plus cisplatin (C) can be considered a standard option for advanced gastric cancer (AGC). Irinotecan (Ir) and docetaxel (D) are active agents with no complete cross-resistance with C and 5-FU. Concomitant combination of Ir or D with C and 5-FU is feasible, but with substantial toxicities. A different way to include all active agents in first-line treatment of AGC may be to use them sequentially. We aimed to evaluate the activity and the safety profile of sequential chemotherapy with 5-FU-based doublets with C, Ir and D in the first-line treatment of AGC. We conducted a phase II study of first-line sequential chemotherapy in metastatic GC. Treatment consisted of 3 cycles of C + infused 5-FU and leucovorin (CFL) followed by 3 cycles of Ir + 5-FU/LV (IrFL) followed by 3 cycles of D + 5-FU/LV (DFL). Primary end-point was response rate. Forty-six patients were enrolled, median age 60 years, sites of disease (single/multiple) = 9/37, PS 0/1 = 27/19, gastric/gastro-oesophageal junction = 39/7. Median number of cycles was 9. Main grade 3-4 toxicities were neutropenia (37%), febrile neutropenia (2%), diarrhoea (4%), stomatitis (9%). Response rate after the planned 9 cycles was 45% (15 partial and 5 complete responses among 43 evaluable patients). Median PFS and OS: 6.8 and 11.1 months, respectively. This sequential treatment is feasible with a favourable safety profile and produced encouraging results in terms of activity and efficacy.