Adjuvant Therapy For Gastric Cancer Research Articles

Xianglian Pill combined with 5-fluorouracil enhances antitumor activity and reduces gastrointestinal toxicity in gastric cancer by regulating the p38 MAPK/NF-κB signaling pathway

Ethnopharmacological relevancePerioperative or postoperative adjuvant chemotherapy based on 5-fluorouracil (5-FU) is a common first-line adjuvant therapy for gastric cancer (GC). However, drug resistance and the side effects of 5-FU have reduced its efficacy. Among these side effects, gastrointestinal (GI) toxicity is one of the most common. Xianglian Pill (XLP) is a Chinese patent medicine that is commonly used for the treatment of diarrhoea. It can reduce inflammation and has a protective effect on the intestinal mucosa. Recent studies have shown that many components of XLP can inhibite tumor cell growth. However, the therapeutic effect of XLP in combination with 5-FU on GC is unclear. Aim of the studyTo investigate whether the combination of XLP and 5-FU can enhance anti-GC activity while reducing GI toxicity. Materials and methodsXLP was administered orally during intraperitoneal injection of 5-FU in GC mice model. Mice were continuously monitored for diarrhea and xenograft tumor growth. After 2 weeks, the mice were sacrificed and serum was collected to determine interleukin-6 levels. Pathological changes, the expression of pro-inflammatory factors and p38 mitogen-activated protein kinase (MAPK) in GI tissue were determined by Western blot analysis. Pathological changes, apoptosis levels and p38 MAPK expression levels in xenograft tissues were also determined. ResultsThe results showed that XLP could alleviate GI mucosal injury caused by 5-FU, alleviated diarrhea, and inhibited the expression of nuclear factor (NF)-κB and myeloid differentiation primary response-88. Besides, XLP could promote the 5-FU-induced apoptosis of GC cells and enhance the inhibitory effect of 5-FU on tumor xenografts. Further study showed that XLP administration could regulate the expression of p38 MAPK. ConclusionsXLP in combination with 5-FU could alleviate its GI side effects and enhance its inhibitory effect on xenograft tumor. Moreover, these effects were found to be related to the regulation of the p38 MAPK/NF-κB pathway.

Advances in the treatment of gastric cancer: 2022-2023.

To review 2022-2023 studies in gastric cancer. Important studies report the role of laparoscopic surgery in gastric cancer, the activity of immune checkpoint inhibitors in metastatic, locally advanced and adjuvant therapy in gastric cancer, and the effectiveness of zolbetuximab in claudin 18.2-positive metastatic disease. From the Japanese JLSSG0901 Trial, equivalent survival was reported for laparoscopically assisted versus conventional open gastrectomy. Adding nivolumab to adjuvant chemotherapy in resected stage III gastric cancer failed to improve 3-year disease-free survival over chemotherapy alone. Ipilimumab and nivolumab as preoperative therapy in MSI-high gastric cancer resulted in a high rate of pathologic complete response. Trastuzumab added to chemoradiotherapy and surgery in HER2-positive locally advanced esophageal and gastroesophageal junction adenocarcinoma did not improve overall survival over chemoradiotherapy and surgery alone. Adding pembrolizumab to trastuzumab/chemotherapy in metastatic HER2-positive gastric cancer improved antitumor response rate. Addition of zolbetuximab, an antibody targeting claudin 18.2, to first-line chemotherapy in metastatic claudin 18.2-positive gastric cancer improved overall survival. Immune checkpoint inhibition has a role in locally advanced MSI-high and metastatic gastric cancer. Laparoscopic gastrectomy is acceptable in gastric cancer. Zolbetuximab in metastatic gastric cancer will emerge as a new therapy option.

Risk stratification for predicting postoperative recurrence of gastric cancer by grade of venous invasion

BackgroundVenous invasion (VI) in pathological examination of surgically resected gastric cancer (GC) may predict postoperative recurrence, but there are no objective criteria for VI grading.Methods157 GC patients (pathological stages I 82, II 34, and III 41) who underwent surgery with curative intent were analyzed. VI was graded in pathological examination by elastica van Gieson staining based on the number of VIs per glass slide as follows: v0, 0; v1, 1−3; v2, 4−6; and v3, ≥ 7. Filling-type invasion in veins with a minor axis of ≥ 1 mm increased the grade by 1. The association of VI grade with prognosis was statistically analyzed.ResultsRecurrence increased with VI grade (v0 1.5%, v1 29.6%, v2 41.7%, v3 78.6%). VI grade as well as pathological (p) tumor, node, metastasis (TNM) stage was a significant recurrence predictor by the multivariate Cox analysis. VI grade was implicated in hematogenous and peritoneal recurrences independent of pTNM stage but not in nodal recurrence. GC was then divided into two tiers, without indication of adjuvant chemotherapy (AC) (pStage I, pT1 and pT3N0) and with AC indication (pStages remaining II/III), based on the ACTS-GC trial, which is common in Japan and East Asia. VI grade was a significant recurrence predictor in both tiers. v2/v3 revealed a significantly worse recurrence-free survival (RFS) than v0/v1 in GC without AC indication. v0/v1 exhibited RFS rate exceeding 95% even after 5 years but that of v2/v3 fell around 70% within one year postoperatively, suggesting that AC may be considered for this tier with v2/v3. GC with AC indication exhibited dismal RFS according to the VI grade. RFS rate fell below 80% within one year postoperatively when VI was positive, while recurrence was not observed in v0, which was, however, rare in this tier (10.9%). Differentiation grade did not significantly affect postoperative prognosis in both tiers.ConclusionsVI grade was a significant predictor of postoperative GC recurrence irrespective of the AC indication based on the ACTS-GC study and this VI grading system could be applied in future studies of adjuvant therapy in GC presently deemed without AC indication in Japan.

Relative dose intensity and 1-year psoas muscle index reduction rate as prognostic factors in gastric cancer patients with postoperative adjuvant chemotherapy.

Higher relative dose intensity (RDI) of chemotherapy improves the clinical outcomes of various cancers. The psoas muscle index (PMI) is related to sarcopenia, and patients with low PMI have worse prognoses. However, few studies have demonstrated its clinical relevance in gastric cancer. This retrospective study included 188 stage II/III gastric cancer patients who had undergone curative gastrectomy between January 2013 and March 2017, 124 of whom had received postoperative S-1 adjuvant chemotherapy. Per receiver operating characteristic analysis, patients were divided into high and low RDI groups, between which relapse-free survival differed marginally significantly and disease-specific survival differed significantly. In patients who received adjuvant chemotherapy, multivariate analysis found that high RDI and low PMI reduction rate 1 year after surgery were significantly associated with better relapse-free survival. Low RDI can be predicted by a combination of low preoperative PMI and non-distal gastrectomy, whereas high PMI reduction rate at 1 year can be affected by non-distal gastrectomy. High RDI with preserved psoas muscle up to 1 year after gastrectomy may be associated with prognoses in gastric cancer requiring postoperative adjuvant chemotherapy. Since RDI and PMI reduction rate can be predicted preoperatively, respectively, interventional consideration is possible for optimal adjuvant therapy in gastric cancer.

Versican enrichment predicts poor prognosis and response to adjuvant therapy and immunotherapy in gastric cancer.

BackgroundIncreasing evidence has revealed an important role of versican (VCAN) on various aspects of cancer progression. Here, we assessed the impact of VCAN expression on prognosis and the response to adjuvant therapy and immunotherapy in patients with gastric cancer (GC).MethodsFour independent cohorts containing 1353 patients with GC, were utilized to investigate the effect of VCAN expression on prognosis and response to adjuvant therapy in GC. Two cohorts treated with immune checkpoint blockades were included to assess the predict value of VCAN expression on response to immunotherapy. Moreover, the bulk RNA-seq and single-cell RNA-seq data were analyzed to illustrate the role of VCAN in tumor microenvironment. Clinical outcomes of patient subgroups were compared by Kaplan-Meier curves with the log-rank test.ResultHigh VCAN expression was associated with poor prognosis for patients with GC. Compared with patients with high VCAN expression, patients with low VCAN expression benefited more from adjuvant chemotherapy and adjuvant chemoradiotherapy. Moreover, patients with high VCAN expression tended to be resistant to immunotherapy, and VCAN could serve as a promising indicator for predicting the response to immunotherapy. VCANhigh tumors showed a specific microenvironment with more cancer associated fibroblasts infiltration and significant enrichment of stromal relevant signaling pathways.ConclusionVCAN could predict the response to adjuvant chemotherapy, adjuvant chemoradiotherapy and immunotherapy in GC, and designing new medicine target to VCAN might be an effective way to improve the efficacy of several treatment options for GC.

Piperlongumine combined with vitamin C as a new adjuvant therapy against gastric cancer regulates the ROS-STAT3 pathway.

ObjectiveTo investigate the effects of piperlongumine (PL) and vitamin C (VC) on signal transducer and activator of transcription 3 (STAT3) signalling in gastric cancer cell lines.MethodsIn vivo tumour xenograft anticancer assays were undertaken to confirm the anticancer activity of PL. Cell viability, flow cytometry and Western blot assays were undertaken to evaluate the anticancer effects of PL, VC and combinations of PL and VC in AGS and KATO III cells.ResultsBoth PL and VC induced apoptosis and inhibited cell proliferation in AGS and KATO III cells. These effects were dependent on reactive oxygen species (ROS). PL effectively suppressed STAT3 activation while VC caused abnormal activation of STAT3. The combination of PL and VC exhibited a stronger apoptotic effect compared with either agent alone. PL reversed the abnormal activation of STAT3 by VC, which could be a key to their synergistic effect.ConclusionsPL combined with VC exhibited a stronger anticancer effect by regulating the ROS–STAT3 pathway, suggesting that this combination might be a potential adjuvant therapy for gastric cancer.

Clinical biomarkers in adjuvant chemotherapy for gastric cancer after D2 dissection by a pooled analysis of individual patient data from large randomized controlled trials.

Adjuvant therapy for gastric cancer is a standard among the world with no regimen selection criteria. Also, prognostic factors except for tumor staging have not been established. We aimed to identify prognostic and predictive markers for gastric cancer adjuvant therapy from large randomized controlled trials with standard lymph node dissection. Three studies: ACTS-GC, CLASSIC, and SAMIT were found and selected for a pooled analysis, following PRISMA guideline. The integrity of individual participant data (IPD) was verified in the eligible 3527 patients registered, and fixed-effect model was used. The primary endpoint was relapse-free survival (RFS) and the secondary endpoint was overall survival (OS). Age was a significant prognostic factor in addition to tumor stages both in "surgery alone" and "adjuvant" groups. Adjuvant therapy was effective for every TN stage; however, it tended to be more effective in T1-2 than in T3-4. Also, it was more effective in low- or middle-BMI than in high-BMI group with Hazard ratio [HR]s: 0.58, 0.58, and 1.05, respectively. Capecitabine plus oxaliplatin (CAPOX) was more effective than S-1 for T1-2, N2-3, and differentiated type with HRs between 0.59 and 0.70, but with no difference among TNM stages. Combining histology to TN; the HRs in differentiated T1-2 N1-3 groups were between 0.29 and 0.45. For T3-4 N0-1 group, S-1 was likely to be effective, not significant. Age is a significant prognostic factor both in surgery alone and adjuvant group. CAPOX is more effective for differentiated T1-2 tumors with lymph node metastasis.

Adjuvant Chemotherapy Versus Adjuvant Chemoradiation (CRT) for Gastric Cancer: 16 Years of Local Experience

Background: There is little consensus for the choice of adjuvant therapy for gastric cancer. This study aimed to compare treatment outcomes and toxicities of adjuvant capecitabine-oxaliplatin (XELOX) with adjuvant chemoradiation (CRT). Methods: Patients with resected gastric cancer stage IIA to IIIC disease treated between January 2004 and July 2018 were analysed retrospectively. Patients were treated with XELOX for eight cycles or CRT. For CRT, 5 cycles of 5-fluorouracil (5FU)/leucovorin with 45 Gy in 25 fractions radiotherapy (RT) concurrent with cycles 2 and 3 were given. Relapse-free survival (RFS) and overall survival (OS) were used to compare the effect of adjuvant chemotherapy and CRT. Acute toxicities and the pattern of relapse were also analysed. Results: 120 patients were included. 52 patients were treated with XELOX, and 68 patients were treated with CRT. Univariate analysis resulted in a five-year OS of 66% for XELOX, as compared with 48% for CRT (HR 0.706, 95% CI 0.413-1.208, p=0.202). The five-year RFS was 58% for XELOX, and 43% for CRT (HR 0.708, 95% CI 0.424-1.183, p= 0.185). On multivariate analysis, both RFS and OS favored XELOX: RFS HR 0.51 (95% CI 0.29-0.87), p=0.014; OS HR 0.45 (95% CI 0.25-0.81), p=0.007 when XELOX was compared with CRT. Patterns of failure were similar in the two groups, with distant metastases being most common. Acute toxicity grade 3/4 was seen in 42% of patients for XELOX, as compared to 65% of patients for CRT (p=0.015). Neutropenia ≥ grade 3 was more frequent in the CRT group (60% vs 21%; p <0.001).

Comparison of S-1 plus oxaliplatin (SOX) and capecitabine plus oxaliplatin (XELOX) as adjuvant chemotherapies for stage II and III gastric cancer after D2 resection: A single-center retrospective study.

BackgroundCapecitabine plus oxaliplatin (XELOX) as adjuvant therapy for gastric cancer (GC) reduces cancer recurrence and improves survival. S‐1 plus oxaliplatin (SOX) is well‐tolerated and effective against advanced GC, and also be used widely in adjuvant treatment. However, data comparing SOX and XELOX as adjuvant treatments are lacking.MethodData on treatment modalities, adverse events, recurrence and metastasis were collected from 180 patients with stage II and III GC, who received SOX or XELOX after D2 gastrectomy between January 2012 and December 2015, and analyzed retrospectively. The primary endpoint was 3‐year disease‐free survival (DFS) rate.ResultsMedian follow was 52.9 months; 3‐year DFS rate and overall survival (OS) rate were 75.2% and 67.6% (P = 0.359) and 81.2% and 83.3% (P = 0.77) in the SOX and XELOX groups, respectively. There was no significant difference in peritoneal metastasis rates in the SOX and XELOX groups (8.6% vs 15%, respectively; P = 0.232). Compound recurrent disease was associated with significantly shorter OS. Multivariate analysis identified metastatic lymph node ratio (LNR) as an independent prognostic factor for OS (P = 0.036; hazard ratio = 2.875; 95% confidence interval, 1.069–7.729); the LNR ≥17% group had inferior 3‐year OS rate to the LNR <17% group (P = 0.001). The incidence of grades 3 and 4 adverse events was similar in both groups; however, grade ≥2 hand–foot syndrome was significantly less frequent in the SOX group (P = 0.01).ConclusionSOX has similar survival benefits to XELOX and is well‐tolerated in Chinese patients with GC following D2 gastrectomy.

Histone chaperone CHAF1A impacts the outcome of fluoropyrimidines-based adjuvant therapy in gastric cancer by regulating the expression of thymidylate synthetase

BackgroundOutcome in adjuvant chemotherapy of gastric cancer (GC) has considerable stage-independent variability, which underscores the need for prognostic or predictive molecular markers. CHAF1A promotes tumor growth while its impact on chemotherapy outcome remains unknown. MethodsCHAF1A protein expression was measured in independent discovery and validation sets that included 86 and 325 patients respectively who received fluoropyrimidines-based adjuvant chemotherapy after radical gastrectomy. The chemosensitizing effect of CHAF1A knockdown was investigated in vitro. Bioinformatics analysis based on RNA-seq and proteome data from public database was performed to investigate the potential mechanisms and further validation was conducted. ResultsIn both the discovery and validation sets, CHAF1A expression level was an independent predictor for disease-free survival (HR = 4.25; 95% CI: 2.31–7.79; P < 0.001; and HR = 1.91; 95% CI: 1.03–3.54; P = 0.039, respectively) and overall survival (HR = 3.25; 95% CI: 1.75–6.05; P < 0.001; and HR = 2.42; 95% CI: 1.12–5.20; P = 0.024, respectively) in patients with non-cardia GC but not in those with cardia GC. In GC cells, CHAF1A knockdown significantly decreased the IC50 of 5-FU. Bioinformatics analyses indicated that CHAF1A correlated with folate metabolism and the expression of thymidylate synthetase (TS). Furthermore, CHAF1A knockdown significantly reduced TS expression in GC cells and CHAF1A positively correlated with TS protein expression in tumor tissues. Finally, ten proteins potentially relevant to the regulation of TS expression by CHAF1A were identified using online tools based on RNA-seq and proteome data. ConclusionsCHAF1A may impact adjuvant chemotherapy outcome of GC by regulating the expression of TS.

The Efficacy and Safety of (Neo)Adjuvant Therapy for Gastric Cancer: A Network Meta-analysis.

Background: Alternatives in treatment-strategies exist for resectable gastric cancer. Our aims were: (1) to assess the benefit of perioperative, neoadjuvant and adjuvant treatment-strategies and (2) to determine the optimal adjuvant regimen for gastric cancer treated with curative intent. Methods: PubMed, EMBASE, CENTRAL, and ASCO/ESMO conferences were searched up to August 2017 for randomized-controlled-trials on the curative treatment of resectable gastric cancer. We performed two network-meta-analyses (NMA). NMA-1 compared perioperative, neoadjuvant and adjuvant strategies only if there was a direct comparison. NMA-2 compared different adjuvant chemo(radio)therapy regimens, after curative resection. Overall-survival (OS) and disease-free-survival (DFS) were analyzed using random-effects NMA on the hazard ratio (HR)-scale and calculated as combined HRs and 95% credible intervals (95% CrIs). Results: NMA-1 consisted of 9 direct comparisons between strategies for OS (14 studies, n = 4187 patients). NMA-2 consisted of 16 direct comparisons between adjuvant chemotherapy/chemoradiotherapy regimens for OS (37 studies, n = 10,761) and 14 for DFS (30 studies, n = 9714 patients). Compared to taxane-based-perioperative-chemotherapy, surgery-alone (HR = 0.58, 95% CrI = 0.38–0.91) and perioperative-chemotherapy regimens without a taxane (HR = 0.79, 95% CrI = 0.58–1.15) were inferior in OS. After curative-resection, the doublet oxaliplatin-fluoropyrimidine (for one-year) was the most efficacious adjuvant regimen in OS (HR = 0.47, 95% CrI = 0.28–0.80). Conclusions: For resectable gastric cancer, (1) taxane-based perioperative-chemotherapy was the most promising treatment strategy; and (2) adjuvant oxaliplatin-fluoropyrimidine was the most promising regimen after curative resection. More research is warranted to confirm or reproach these findings.

674P - The efficacy and safety of (neo)adjuvant therapy for gastric cancer: A network meta-analysis

674P - The efficacy and safety of (neo)adjuvant therapy for gastric cancer: A network meta-analysis

Updates and interpretation on NCCN clinical practice guidelines for gastric cancer 2017 version 5

The National Comprehensive Cancer Network (NCCN) issued the clinical practice guidelines for gastric cancer 2017 edition version 5, which has been fully updated for the treatment of gastric cancer, including systematic treatment, surgery and radiotherapy. This article review and summarize the updated NCCN clinical practice guidelines for gastric cancer in 2017 and try to interpret it. (1)Biomarkers: mismatch repair defect (dMMR) or high microsatellite instability (MSI-H), programmed death ligand 1 (PD-L1) and tumor Epstein Barr virus (EBV) status should be considered for patients with gastric cancer. (2)Treatment of advanced gastric cancer: the major update is the application of immunotherapy (Pembrolizumab, Nivolumab combined with Ipilimumab). (3)Adjuvant therapy after D2 resection and perioperative treatment: the guidelines recommended Capecitabine combined with Oxaliplatin as adjuvant therapy after radical operation, updated from category 2A to 1; although the 2017 edition of the NCCN guidelines have not yet been adopted, Docetaxel-based FLOT scheme has certain potential in adjuvant therapy for gastric cancer. (4) Radiotherapy: a more detailed definition of radiotherapy for gastric cancer in different locations, especially in high-risk lymphatic drainage areas, was updated. (5) Genetic risk assessment: the guidelines recommended genetic screening for gastric cancer, including hereditary diffuse gastric cancer (HDGC), Lynch syndrome, juvenile polyposis (JPS), Peutz-Jephers syndrome (PJS) and familial adenomatous polyposis (FAP). The NCCN guidelines continue to update based on new evidences, which is the embodiment of precision medicine in the treatment of gastric cancer. The biggest change in the 2017 gastric cancer guidelines is the updates of immunotherapy, which also suggests that the direction of the gastric cancer treatment began to turn to immunotherapy.

Association of Antioxidative Enzymes Polymorphisms with Efficacy of Platin and Fluorouracil-Based Adjuvant Therapy in Gastric Cancer

Background/Aims: Imbalance of oxidative/antioxidative enzymes in cells is associated with carcinogenesis and cancer cell chemoresistance. The aim of this study was to examine the clinical significance of potentially functional single nucleotides polymorphisms (SNPs) in antioxidative enzymes, GPxs and CAT, in stages II and III gastric cancer patients. Methods: A total of 591 gastric cancer patients who had radical gastrectomy were recruited. 207 patients received platinum and fluorouracil-based (PF-based) adjuvant chemotherapy and 384 patients were untreated. GPx1 rs1050450, GPx2 rs4902346, GPx3 rs736775, rs3828599 and CAT rs769218 were genotyped in the DNA samples extracted from paraffin-embedded tumor tissue. Results: CAT rs769218 was significantly correlated with the overall survival (OS) in the dominant model (P = 0.014). Multivariate analysis revealed that CAT rs769218 GA/AA (HR, 0.715; 95%CI, 0.562-0.910, P = 0.006) was an independent prognostic marker indicating improved survival. After adjustments, GPx3 rs736775 TC/CC was significantly associated with improved OS (HR, 0.621; 95%CI, 0.399-0.965; P=0.034) in patients treated with PF-based adjuvant chemotherapy, and CAT rs769218 GA/AA was significantly associated with improved OS (HR, 0.646; 95% CI, 0.482-0.864; P = 0.003) in the untreated patients. PF-based chemotherapy significantly decreased risk of death for patients carrying GPx3 rs736775 TC/CC and age ≤ 60 years or with diffused type adenocarcinoma compared to surgery alone. Conclusion: our findings suggested CAT rs769218 and GPx3 rs736775 may be considered as prognostic markers in gastric cancer. Patient stratification by GPx3 rs736775 and conventional pathological parameters may provide additional predictive information in treatment decision-making.

A review of capecitabine-based adjuvant therapy for gastric cancer in the Chinese population.

In China, the treatment of locally advanced gastric cancer (AGC) faces unique challenges. Chinese patients may harbor more unfavorable prognostic factors than western populations and, in comparison with other Asian populations such as Japan and South Korea, a higher proportion of Chinese patients are diagnosed with AGC due to inadequate early diagnosis of the malignancy. This review summarizes the use of combination chemotherapy regimens with capecitabine as adjuvant therapy in the Chinese AGC population. Based on the available domestic data in China, the review concludes that capecitabine-based chemotherapy regimens, especially XELOX, offer good efficacy following radical gastrectomy in patients with AGC, with a low incidence of adverse events, acceptable tolerance, greater patient convenience and a lower overall cost than other regimens.

Adjuvant Chemoradiotherapy After Curative Resection for Gastric Cancer

Standard adjuvant therapy for gastric cancer is either postoperative 5-fluorouracil (5-FU) and radiation therapy, or pre- and postoperative

Dosimetric Comparative Study of Static Gantry IMRT and 3D Conformal Radiotherapy for Organ at Risk in Adjuvant Therapy of Gastric Cancer

Background: Despite the benefits of postoperative radiotherapy for gastric cancer patients after publishing the results of the Intergroup 0116 (INT-0116) study, there are still the concerns of radiation-induced toxicity.Aim: To determine the radiation technique that can eliminate the dose of radiation to the organ at risk (OAR) in patients postoperatively treated for gastric cancer with three-dimensional conformal radiotherapy (3D-CRT) or intensity- modulated radiotherapy (IMRT) using dosimetric analysis.Methods: A total of 22 computerized radiation plans were reviewed. Dosimetric values for 3DCRT and IMRT technique were calculated. The following dosimetric parameters were compared for the planned target volume (PTV); the homogeneity index, maximal and minimal doses, the volumes of PTV received 95 % and 107 % of the prescribed dose. In addition, the mean dose and dose volume histogram (DVH) for the OAR as, V20 for each kidney, V30 for the liver, maximum dose (Dmax) for D1% of the spinal cord and V40 to the heart .Results: The 3D-CRT and IMRT achieved comparable PTV coverage. However, IMRT was associated with a highly significant decrease in the mean V20 value of the right kidney by 15% (P=0.001) and left kidney by 9% (P=0.01). The IMRT significantly improved sparing of the mean irradiated volume and the V30 of the liver by 12% (P=0.01) and by 10% (P=0.02) respectively compared with 3D-CRT. On the other hand, the dosimetric parameters for the spinal cord and heart were comparable for the IMRT and 3D-CRT plans.Conclusion: In gastric cancer patients receiving postoperative radiotherapy, IMRT provided better protection for the liver and kidneys when compared to 3D-CRT.

Diallyl trisulfide suppresses tumor growth through the attenuation of Nrf2/Akt and activation of p38/JNK and potentiates cisplatin efficacy in gastric cancer treatment.

Diallyl trisulfide (DATS), a garlic organosulfide, has shown excellent chemopreventive potential. Cisplatin (DDP) is widely used to treat solid malignant tumors, but causing serious side effects. In the current study, we attempted to elucidate the chemopreventive mechanisms of DATS in human gastric cancer BGC-823 cells in vitro, and to investigate whether DATS could enhance the anti-tumor efficacy of DDP and improve quality of life in BGC-823 xenograft mice in vivo. Treatment with DATS (25-400 μmol/L) dose-dependently inhibited the viability of BGC-823 cells in vitro with an IC50 of 115.2±4.3 μmol/L after 24 h drug exposure. DATS (50-200 μmol/L) induced cell cycle arrest at G2/M phase in BGC-823 cells, which correlated with significant accumulation of cyclin A2 and B1. DATS also induced BGC-823 cell apoptosis, which was accompanied by the modulation of Bcl-2 family members and caspase cascade activation. In BGC-823 xenograft mice, administration of DATS (20-40 mg·kg-1·d-1, ip) dose-dependently inhibited tumor growth and markedly reduced the number of Ki-67 positive cells in tumors. Interestingly, combined administration of DATS (30 mg·kg-1·d-1, ip) with DDP (5 mg/kg, every 5 d, ip) exhibited enhanced anti-tumor activity with fewer side effects. We showed that treatment of BGC-823 cells with DATS in vitro and in vivo significantly activated kinases such as p38 and JNK/MAPK and attenuated the Nrf2/Akt pathway. This study provides evidence that DATS exerts anticancer effects and enhances the antitumor efficacy of DDP, making it a novel candidate for adjuvant therapy for gastric cancer.

CHK1 expression in Gastric Cancer is modulated by p53 and RB1/E2F1: implications in chemo/radiotherapy response.

Radiation has a limited but relevant role in the adjuvant therapy of gastric cancer (GC) patients. Since Chk1 plays a critical function in cellular response to genotoxic agents, we aimed to analyze the role of Chk1 in GC as a biomarker for radiotherapy resistance. We analyzed Chk1 expression in AGS and MKN45 human GC cell lines by RT-QPCR and WB and in a small cohort of human patient’s samples. We demonstrated that Chk1 overexpression specifically increases resistance to radiation in GC cells. Accordingly, abrogation of Chk1 activity with UCN-01 and its expression with shChk1 increased sensitivity to bleomycin and radiation. Furthermore, when we assessed Chk1 expression in human samples, we found a correlation between nuclear Chk1 accumulation and a decrease in progression free survival. Moreover, using a luciferase assay we found that Chk1’s expression is controlled by p53 and RB/E2F1 at the transcriptional level. Additionally, we present preliminary data suggesting a posttranscriptional regulation mechanism, involving miR-195 and miR-503, which are inversely correlated with expression of Chk1 in radioresistant cells. In conclusion, Chk1/microRNA axis is involved in resistance to radiation in GC, and suggests Chk1 as a potential tool for optimal stratification of patients susceptible to receive adjuvant radiotherapy after surgery.

Feasibility of oral administration of S-1 as adjuvant chemotherapy in gastric cancer: 4-week S-1 administration followed by 2-week rest vs. 2-week administration followed by 1-week rest.

In 2006, the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) demonstrated that S-1 is an effective adjuvant therapy for gastric cancer. Following that study, S-1 has been used as the standard adjuvant therapy for gastric cancer in Japan. However, the 1-year completion rate was only 65.8% in the ACTS-GC study and feasibility remains a critical issue. We conducted a study to evaluate the feasibility of 2 weekly administration regimens of S-1 as adjuvant chemotherapy in gastric cancer. The criteria for eligibility included histologically proven stage II (excluding T1), IIIA or IIIB gastric cancer with D2 lymph-node dissection. The patients were randomly assigned to either arm A (S-1 administration for 4 weeks followed by 2 weeks of rest) or arm B (S-1 administration for 2 weeks followed by 1 week of rest). In each arm, treatment was continued for 12 months unless recurrence or severe adverse events were observed. The primary endpoint was feasibility (protocol treatment completion rate). The secondary endpoints were safety, relapse-free survival and overall survival. A total of 47 patients were assigned to arms A or B between May, 2008 and February, 2010. During the first interim analysis, the protocol treatment completion rates in arms A and B were 83 and 100%, respectively at 6 months and 49 and 89%, respectively, at 12 months (P=0.0046). Therefore, S-1 administration for 2 weeks followed by 1 week rest was more feasible as adjuvant chemotherapy in gastric cancer. Grade 3 adverse events in arm A included fatigue (8.0%), anorexia (8.0%), nausea (4.0%), vomiting (4.0%) and hand-foot syndrome (4.0%), whereas none were observed in arm B. There were no reported grade 4 adverse events in either arm. In conclusion, the 2-week S-1 administration followed by 1-week rest regimen appears to be a more feasible oral administration regimen for S-1 as adjuvant chemotherapy in gastric cancer.