Treatment Of Metastatic Gastric Cancer Research Articles

Surgical Methods in Treatment of Metastatic Gastric Cancer. Literature Review

Рак желудка представляет собой глобальную проблему здравоохранения. Несмотря на эффективность улучшенных схем химиотерапии и модернизацию хирургического вмешательства (внедрение печень-направленной терапии, конверсионной хирургии, проведение HIPEC или PIPAC в сочетании с циторедуктивной операцией), прогноз у таких пациентов по-прежнему плохой. Самыми частыми локализациями отдаленных метастазов при раке желудка являются печень, брюшина, парааортальные лимфатические узлы. В данной статье освящены итоги анализа публикаций за последние годы, посвященные хирургическим методам лечения метастатического рака желудка и выделены возможные варианты лечения в различных клинических ситуациях. По результатам проведенного исследования были сделаны следующие выводы: не во всех случаях метастатический рак желудка — это показание лишь к паллиативной химиотерапии и поддерживающей симптоматической терапии. Наиболее оптимальным и эффективным лечением является персонифицированный подход к каждому пациенту и при возможности выбор комбинированной терапии, то есть сочетания системного и местного лечения.

7799 Nesidioblastosis Concurrent with Anatomically Confirmed Metastatic Gastric Cancer

Abstract Disclosure: Y. Cho: None. K. Jo: None. J. Han: None. S. Moon: None. E. Kim: None. Background: Nesidioblastosis is a rare condition that should be considered in cases of pancreatogenic hyperinsulinemic hypoglycemia without evidence of insulinoma on imaging. We present the first case of nesidioblastosis concomitant with anatomically confirmed metastatic gastric cancer of the pancreas. Case Report A 57-year-old male presented with recurrent episodes of loss of consciousness and hypoglycemia, with a glucose level of 26 mg/dl upon arrival at the emergency room. Despite a history of advanced gastric cancer and previous chemotherapy, the patient had not been diagnosed with diabetes and was not taking medications associated with hypoglycemia. Four months prior, he underwent total gastrectomy. The fasting plasma glucose levels was 38 mg/dl, accompanied by C-peptide levels of 6.10 ng/mL, insulin levels exceeding 1000 uIU/ml, and proinsulin levels at 8.8 pmol/L. The insulin antibody level was more than 100%, and the highest cortisol level reached 15.60 ug/dL during the rapid ACTH stimulation test. The patient's postprandial 2-hour glucose level reached 233 mg/dl during the 75g glucose tolerance test. Imaging studies, including whole-body PET CT and abdominal CT, showed no evidence of suspected metastatic lesions, and the pancreas appeared normal on MRI. Endoscopic ultrasound could not be performed due to anatomical changes following the surgery. A selective arterial calcium stimulation test demonstrated a substantial over twofold increase in insulin concentrations in the gastroduodenal artery, splenic artery, and superior mesenteric artery. The patient received methylprednisolone 125 mg once daily but insulin levels remained elevated, exceeding 1000 uIU/ml, requiring continuous dextrose infusion. Octreotide therapy was initiated, resulting in an improvement in insulin levels to 589 uIU/ml, although discontinuation of dextrose fluid remained unfeasible. After consultation with the surgeon, a open subtotal pancreatectomy was performed, allowing discontinuation of dextrose on the second post-surgery day, with improved glucose and insulin levels. Histological examination showed three clusters of atypical cells with perineural infiltration. Immunostaining indicated negative synaptophysin and positive CK20, suggesting possible gastric cancer metastasis, consistent with prior gastrectomy findings. Moreover, an increased number of variable-sized Langerhans islets exhibited positive insulin and glucagon immunostaining within the islets, indicative of nesidioblastosis. Conclusion: Nesidioblastosis should be considered in cases of unexplained post-surgery hypoglycemia following metastatic gastric cancer treatment. Furthermore, given the potential link with metastatic gastric cancer, which may elude detection via imaging alone, aggressive surgical intervention should be contemplated as a nesidioblastosis treatment strategy. Presentation: 6/3/2024

What's new in gastric cancer?

In the locally advanced stage, multimodal therapies such as perioperative chemotherapy with FLOT or neoadjuvant radiochemotherapy are recommended. The integration of immunotherapy into these concepts could improve the prognosis. Phase II/III trials such as DANTE, KEYNOTE-585 and MATTERHORN show promising results in terms of pathological remissions but data on survival time extension for unselected patients are so far sobering. Immunotherapies and new targeted therapies offer hope in the palliative treatment of metastatic gastric cancer. Studies such as CheckMate-649 and KEYNOTE-859 show an improvement in survival and response rates. Currently, both pembrolizumab and nivolumab have been approved for the first-line treatment of tumors with positive PD-L1 expression. In HER2-positive tumors, the KEYNOTE-811 study showed that patients benefit from combination therapies with immune checkpoint inhibition and anti-HER2 therapies. The antibody-drug conjugate trastuzumab-deruxtecan is a promising second-line treatment option for HER2-positive tumors after treatment failure with trastuzumab.In addition, the bispecific antibody zanidatamab shows promising results in first-line treatment. New targeted therapies against CLDN18.2 and FGFR2b are showing promising results. The anti-claudin 18.2 (CLDN18.2) antibody zolbetuximab leads to improved survival compared to chemotherapy alone in patients with CLDN18.2 positive disease in first-line therapy, with approval expected in 2024.

Creatinine-to-cystatin C ratio and body composition predict response to PD-1 inhibitors-based combination treatment in metastatic gastric cancer.

Creatinine-to-cystatin C ratio (CCR) and body composition (BC) parameters have emerged as significant prognostic factors in cancer patients. However, the potential effects of CCR in gastric cancer (GC) remains to be elucidated. This multi-center retrospective study explored the predictive and prognostic value of CCR and BC-parameters in patients with metastatic GC receiving PD-1 inhibitors-based combination therapy. One hundred and thirteen GC patients undergoing PD-1 inhibitors-based combination therapy were enrolled at three academic medical centers from January 2021 to July 2023.A deep-learning platform based on U-Net was developed to automatically segment skeletal muscle index (SMI), subcutaneous adipose tissue index (SATI) and visceral adipose tissue index (VATI). Patients were divided into two groups based on the median of CCR or the upper tertile of BC-parameters. Logistic and Cox regression analysis were used to determine the effect of CCR and BC-parameters in predicting response rates and survival rates. The CCR was positively correlated with SMI (r=0.43; P<0.001), but not with SATI or VATI (P>0.05). Multivariable logistic analysis identified that both low CCR (OR=0.423, P=0.066 for ORR; OR=0.026, P=0.005 for DCR) and low SATI (OR=0.270, P=0.020 for ORR; OR=0.149, P=0.056 for DCR) were independently associated with worse objective response rate (ORR) and disease control rate (DCR). Patients with low CCR or low SATI had significantly lower 8-month progression-free survival (PFS) rate and 16-month overall survival (OS) rate than those with high CCR (PFS rate, 37.6% vs. 55.1%, P=0.011; OS rate, 19.4% vs. 44.9%, P=0.002) or those with high SATI (PFS rate, 37.2% vs. 53.8%, P=0.035; OS rate, 8.0% vs. 36.0%, P<0.001). Multivariate Cox analysis showed that low CCR (HR=2.395, 95% CI: 1.234-4.648, P=0.010 for PFS rate; HR=2.528, 95% CI: 1.317-4.854, P=0.005 for OS rate) and low SATI (HR=2.188, 95% CI: 1.050-4.560, P=0.037 for PFS rate; HR=2.818, 95% CI: 1.381-5.752, P=0.004 for OS rate) were both independent prognostic factors of poor 8-month PFS rate and 16-month OS rate. A nomogram based on CCR and BC-parameters showed a good performance in predicting the 12- and 16-month OS, with a concordance index of 0.756 (95% CI, 0.722-0.789). Low pre-treatment CCR and SATI were independently associated with lower response rates and worse survival in patients with metastatic GC receiving PD-1 inhibitors-based combination therapy.

Genome-wide CRISPR screen identifies ESPL1 limits the response of gastric cancer cells to apatinib

Apatinib was the first anti-angiogenic agent approved for treatment of metastatic gastric cancer (GC). However, the emergence of resistance was inevitable. Thus investigating new and valuable off-target effect of apatinib directly against cancer cells is of great significance. Here, we identified extra spindle pole bodies-like 1 (ESPL1) was responsible for apatinib resistance in GC cells through CRISPR genome-wide gain-of-function screening. Loss of function studies further showed that ESPL1 inhibition suppressed cell proliferation, migration and promoted apoptosis in vitro, and accordingly ESPL1 knockdown sensitized GC cells to apatinib. In addition, we found ESPL1 interacted with mouse double minute 2 (MDM2), a E3 ubiquitin protein ligase, and the combination of MDM2 siRNA with apatinib synergistically ameliorated the resistance induced by ESPL1 overexpression. In summary, our study indicated that ESPL1 played a critical role in apatinib resistance in GC cells. Inhibition of MDM2 could rescue the sensitivity of GC cells to apatinib and reverse ESPL1-mediated resistance.

Comparing effectiveness and safety of paclitaxel plus raltitrexed vs. paclitaxel alone in second-line palliative chemotherapy for metastatic gastric adenocarcinoma: A randomized phase II clinical trial.

Paclitaxel (P) is a standard second-line chemotherapy in the treatment of advanced gastric cancer. This study compared the clinical outcome of a paclitaxel plus raltitrexed (RP) regimen as second-line treatment in metastatic gastric cancer (MGC) patients. An open, randomized, multi-center phase II clinical trial was conducted involving 148 patients who were randomly assigned and treated with RP [raltitrexed (3 mg/m2 on day 1) and paclitaxel (135 mg/m2 on day 1 every 3 weeks)] or P [paclitaxel (135 mg/m2 on day 1 every 3 weeks)] as 2nd-line chemotherapy. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the overall response rate (ORR), overall survival (OS), and safety. PFS had a tendency to be prolonged with RP compared to P (2.7 months vs. 1.7 months; P = 0.148). OS was also prolonged with RP compared to P (10.2 months vs. 6.1 months; P = 0.140). The ORR was equal in the RP and P groups (6.8% and 4.0%; P = 0.72). The disease control rate (DCR) in the RP and P groups was 56.2% and 36.0%, respectively. Grade 3-4 treatment-related adverse events occurred in 36.2% (RP) and 28.2% (P) of patients. Frequent grade 3-4 toxicities for RP and P were neutropenia (11.0% and 4.0%), anemia (1.4% and 4.0%), and thrombocytopenia (1.4% and 5.3%), and all grades of peripheral neurotoxicity (12.3% vs. 17.3%). All grades of hepatic toxicity were demonstrated for the RP and P groups based on elevated aminotransferase levels (27.4% and 14.1%). Subgroup analysis shows if MGC was combined with ascites or peritoneal involvement, the OS of the RP regimen was longer (P = 0.05). Second-line palliative chemotherapy with RP was shown to prolong the PFS and OS, especially among patients with ascites or peritoneal involvement, which warrants confirmation using larger sample studies.

Comparison of the Efficacy of FOLFIRI and Paclitaxel Chemotherapy Regimens in the Second Line Treatment of Metastatic Gastric Cancer

Introduction: Although the incidence of gastric cancer has shown a significant decrease over the years, it remains the fourth leading cause of cancer-related deaths, resulting in more than 700,000 annual deaths worldwide. The main goal of metastatic gastric cancer treatment is to alleviate symptoms and, if feasible, improve survival. The purpose of our study was to compare the effectiveness of two chemotherapy regimens, FOLFIRI and paclitaxel, which are commonly used in the second-line treatment of metastatic gastric cancer.&#x0D; Material and Method: Patients over the age of 18 with a diagnosis of metastatic gastric carcinoma who were treated with either FOLFIRI or paclitaxel as second-line therapy were enrolled in our study. These two treatment groups were compared in terms of overall and progression-free survival. &#x0D; Results: A total of 99 patients were included. 56 (56.6%) patients had received FOLFIRI and 43 (43.3%) had received paclitaxel. The median overall survival for the entire cohort was 9 months: 10 months for FOLFIRI and 8 months for paclitaxel, with no statistically significant difference between them. In multivariate analysis, Eastern Cooperative Oncology Group (ECOG) performance status, body mass index, and number of chemotherapy cycles were identified as independent prognostic factors.&#x0D; Conclusion: We compared two commonly used regimens in the second-line treatment of metastatic gastric cancer, FOLFIRI and paclitaxel, in terms of overall and progression-free survival. There was no statistically significant difference between the two regimens. Both regimens can be considered as reasonable second-line treatment options. According to the results of our study, the choice of chemotherapy for second-line treatment should be made on an individual basis, considering factors such as the treatment received in the first-line, side effects, medication cost, and accessibility.

A study of human epidermal growth factor receptor 2 overexpression by immunohistochemistry in patients with gastric adenocarcinoma.

Gastric cancer is one of the leading causes of cancer-related deaths across the world and in the Middle East. Human epidermal growth factor receptor 2 (HER2) overexpression has been observed in gastric cancers. Trastuzumab, a recombinant monoclonal antibody targeting HER2 protein, is being used for treatment of metastatic gastric cancer. To study the frequency and association of HER2 overexpression with age, gender, histopathological subtype and grade of differentiation in patients with gastric adenocarcinoma from Basra, Iraq. This cross-sectional single-center study collected demographic (age, gender), histopathological (histological subtype, grade of differentiation) and immunohistochemical (HER2 overexpression status) data from 100 consenting adult patients (male: 56) with histopathologically confirmed gastric adenocarcinoma from samples obtained through endoscopy or surgery. HER2 overexpression (ToGA score 3+) was observed in 6/100 (6%) of patients, with another 6 showing 'equivocal' HER2 expression (2+). Out of 20 patients with moderately differentiated gastric cancer, 4 (20%) showed HER2 overexpression (p=0.008). Other factors considered (age, gender, histological subtype) did not show statistically significant correlation with HER2 overexpression. More females showed HER2 overexpression than males (4 vs. 2), and more patients with intestinal type gastric cancer showed HER2 overexpression than diffuse gastric cancer (5 vs. 1), but the difference was not statistically significant in both variables. HER2 overexpression was 6% in this population; statistically significant correlation was found with histological grade. Statistically non-significant correlations were observed between HER2 overexpression and gender, age, and histological subtype.

EE276 Economic Evaluation of Trifluridine and Tipiracil Hydrochloride in the Treatment of Metastatic Gastric Cancer in the Brazilian Private Health Care Sector

The Brazilian Private Health Care Sector has first-line and second-line metastatic gastric cancer (mGC) treatment options using traditional chemotherapy and targeted therapy. Recently, trifluridine and tipiracil hydrochloride (FTD/TPI) was approved in the third-line treatment and is the only treatment option to this subgroup of patients. Our objective was to evaluate the cost-effectiveness of FTD/TPI in mGC patients, including gastroesophageal junction adenocarcinoma, who have received at least two prior therapies for metastatic disease and are eligible for third-line treatment, from the perspective of private health care sector in Brazil.

Zolbetuximab treatment in metastatic gastric cancer.

Zolbetuximab treatment in metastatic gastric cancer.

Solitary metachronous adrenal metastasis after radical resection of gastric large cell neuroendocrine carcinoma: a case report and literature review

Surgical resection is rarely employed for the treatment of metastatic gastric cancer, especially in patients with adrenal metastases, which usually indicate advanced systemic dissemination. Few published case reports have thus described the use of adrenalectomy for adrenal metastases from gastric cancer. In addition, most primary gastric malignancies are gastric adenocarcinomas, and gastric large cell neuroendocrine carcinoma (GLCNEC) is less common and has a poor prognosis. We report the case of a 71-year-old man who was diagnosed with solitary adrenal metastases 10 months after radical resection for GLCNEC and who was treated by adrenalectomy. He was followed-up for 9 months after adrenalectomy, with no further evidence of disease at his last follow-up examination. This case indicates that elective surgical resection may be feasible, even in rare cases of GLCNEC metastases to the adrenal glands, provided that the patient meets certain criteria, including solitary, metachronous tumors less than 4 cm.

A phase 1b study of the allosteric extracellular FGFR2 inhibitor alofanib in patients with pretreated advanced gastric cancer.

Alofanib is a small-molecule allosteric extracellular FGFR2 inhibitor. We report safety and preliminary efficacy from the first-in-human phase 1b study of alofanib in heavily pretreated patients with advanced gastric cancer. The standard dose-escalation design 3+3 aimed to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Alofanib was administered daily intravenously 5 days on, 2 days off. There were five dose levels (50-350 mg/m2). All patients received alofanib until disease progression or unacceptable toxicity. 21 patients were enrolled. Patients were predominantly male (71%), 67% had 2 and more metastatic sites, including liver metastases (43%), 19% had ECOG PS 2, and were heavily pretreated (86% had previous 2 and more treatment lines). During dose escalation, no dose-limiting toxicities were observed, and MTD was not defined. 15 (71.4%) patients had at least one adverse event associated with the treatment (TRAE). Grade 3 or higher TRAEs were observed in 6 patients (28.6%). The most common TRAEs included reactions immediately after administration, diarrhea, thrombocytopenia, arthralgia, and headache. The median progression-free survival and overall survival was 3.63 (95% CI 1.58-5.68) and 7.0 (95% CI 3.82-10.18) months, respectively. The 6- and 12-month overall survival rates were 57.1% and 33.3%. Disease control rate was 68% with one durable partial response. The MTD has not been reached and dose of 350 mg/m2, 5 days on, 2 days off has been declared as RP2D. Alofanib showed acceptable tolerability and preliminary signs of clinical activity in the late-line treatment of metastatic gastric cancer. (ClinicalTrials.gov identifier: NCT04071184).

Fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) regimen in the first-line treatment of metastatic gastric cancer: A single-center experience.

The median survival time for metastatic gastric cancer that has a poor prognosis is usually shorter than 1 year. The fluorouracil, oxaliplatin, and docetaxel (FLOT) regimen is observed to be effective in the neo-adjuvant treatment of gastric cancer. However, data on the FLOT regimen in metastatic gastric cancer are limited. The current study aims to evaluate the safety and efficacy of the FLOT regimen in metastatic gastric cancer in real life. Retrospective study. The study was performed in an Institute of Oncology of a university and included the patients diagnosed between January 2015 and December 2020. In addition to the clinicopathological data of patients with human epidermal growth factor receptor 2 (HER-2)-negative metastatic gastric cancer, we retrospectively evaluated the survival and treatment-related toxicities. The FLOT regimen (Fluorouracil 2600 mg/m2 24 hours continuous intravenous infusion, leucovorin 200 mg/m2, oxaliplatin 85 mg/m2, and docetaxel 50 mg/m2 on day 1) every 2 weeks was used in all patients. The study included 94 patients who were followed up for a median of 11.1 (min-max: 1.5-65.8) months. The number of male patients was 60 (63.4%), and the median age was 58 (min-max: 27-78) years. The primary tumor was located in the stomach (72.3%) and gastroesophageal junction (27.7%). The objective response rate was observed in 64.8% of the patients. The median overall survival was 13.5 (95% CI: 9.2-17.8) months, whereas the progression-free survival was 7 (95% CI: 5.7-8.3) months. The 1-year survival rate was 53.6%. Complete response was detected in 7.4% of the patients. Among grade 3-4 toxicities, neutropenia (44.6%), leukopenia (27.6%), neuropathy (12.7%), and fatigue (9.5%) were the most common observed toxicities. FLOT is a highly active option in the first-line treatment of metastatic gastric cancer, with a favorable safety profile.

The Role of Lipid Metabolism in Gastric Cancer.

Gastric cancer has been one of the most common cancers worldwide with extensive metastasis and high mortality. Chemotherapy has been found as a main treatment for metastatic gastric cancer, whereas drug resistance limits the effectiveness of chemotherapy and leads to treatment failure. Chemotherapy resistance in gastric cancer has a complex and multifactorial mechanism, among which lipid metabolism plays a vital role. Increased synthesis of new lipids or uptake of exogenous lipids can facilitate the rapid growth of cancer cells and tumor formation. Lipids form the structural basis of biofilms while serving as signal molecules and energy sources. It is noteworthy that lipid metabolism is capable of inducing drug resistance in gastric cancer cells by reshaping the tumor micro-environment. In this study, new mechanisms of lipid metabolism in gastric cancer and the metabolic pathways correlated with chemotherapy resistance are reviewed. In particular, we discuss the effects of lipid metabolism on autophagy, biomarkers treatment and drug resistance in gastric cancer from the perspective of lipid metabolism. In brief, new insights can be gained into the development of promising therapies through an in-depth investigation of the mechanism of lipid metabolism reprogramming and resensitization to chemotherapy in gastric cancer cells, and scientific treatment can be provided by applying lipid-key enzyme inhibitors as cancer chemical sensitizers in clinical settings.

A phase II single-center single-arm study of PD-1 inhibitor in combination with albumin paclitaxel and apatinib as second-line treatment of metastatic gastric cancer (mGC).

e16024 Background: Immune checkpoint inhibitors have been approved for first- or third-line treatment of metastatic gastric cancer. However, pembrolizumab alone did not improve overall survival compared to second-line chemotherapy in the KEYNOTE-061 study. We aimed to explore the safety and efficacy of a three-drug regimen by carrying out a clinical study of PD-1 inhibitor combined with albumin paclitaxel and apatinib (VEGFR inhibitor) in the second-line treatment for patients with metastatic gastric cancer(mGC). Methods: This study was a single-center, single-arm phase II clinical study. patients harboring microsatellite stable (MSS) who had previously failed in first-line treatment were enrolled. The enrolled patients were given PD-1 inhibitor (PD-1 inhibitor selected according to the patients’ requirements) in combination with albumin paclitaxel (125 mg/m2 IV, D1, 8 days or 250 mg/m2 IV, D1, 250 mg and apatinib 250 or 500 mg orally for D1-21 days, every 3 weeks as a cycle). The primary endpoints were progression-free survival (PFS) and objective response rate (ORR), while the secondary endpoints were overall survival (OS) and safety (AEs), disease control rate (DCR). Results: From July 11, 2019 to December 1, 2021, a total of 23 patients were enrolled, of whom 10 had negative PD-L1 expression, 1 had PD-L1 &gt; 70% expression, and 4 had positive PD-L1 expression. Preliminary results showed 8 cases had partial response (PR), 10 cases had stable disease (SD), and 5 cases of progression disease (PD). ORR was 34.8% and DCR was 78.3%. The median PFS was 5.04 m, and the median OS was not reached. The main adverse reactions of grade 1 to 2 were bone marrow suppression (42.8%), hand-foot reaction (21.4%), hypertension (21.4%), gastrointestinal bleeding (13.0%), hypothyroidism (8.7%), and liver function damage (8.7%). No grade 3-4 adverse reactions were reported. Conclusions: PD-1 inhibitor combined with albumin paclitaxel and apatinib in the second-line treatment of metastatic gastric cancer showed certain efficacy and safety. At present, this study is ongoing to further confirm the anti-tumor effect and survival benefit of this regimen. Clinical trial information: NCT04182724.

Oxaliplatin and capecitabine (XELOX) plus toripalimab as perioperative treatment for locally advanced gastric or gastro-esophageal junction adenocarcinoma (Neo-Capture): A single-arm, phase 2 study.

e16001 Background: PD-1 inhibitor combined with chemotherapy showed remarkable objective response rate in the first line treatment of metastatic gastric cancer. While, the benefit of perioperative PD-1 inhibitor plus chemotherapy in locally advanced gastric or gastro-esophageal junction (G/GEJ) cancer was not clear. Therefore, we aimed to assess the efficacy and safety of perioperative XELOX plus toripalimab in the patients with locally advanced G/GEJ cancer in this study. Methods: This was a prospective single arm phase 2 study. Eligible patients were with histologically confirmed locally advanced G/GEJ (Siewert II/II type) adenocarcinoma (cT3-4 Nany M0 or T1-2 N2-3 M0). Patients received 4 preoperative and 2 postoperative cycles of XELOX plus toripalimab (oxaliplatin 130mg/m2 D1, capecitabine 1000mg/m2 bid D1-14, toripalimab 240mg D1, Q3W) followed by subsequent 2 cycles of toripalimab monotherapy. Patients underwent D2 gastrectomy after preoperative treatment. The primary endpoint was major pathological response (MPR) according to Becker TRG criteria. Secondary endpoints included safety, R0 resection rate, pathological complete response (pCR), 3-year disease free survival (DFS) and 3-year overall survival (OS). Results: From Jul, 2019, to Dec, 2021, 35 pts were recruited. The median age was 61 (34-72) years old. 80% of the pts were men. Acutally, all the pts had cT4 (cT4a [48.6%] &amp; cT4b [51.4%]) and 88.6% had cN+ by CT, MRI and ultrasound gastroscopy. 2 pts suffered disease progression during neoadjuvant treatment. 4 pts have not yet completed preoperative therapy. 29 pts had received gastrectomy and 2 pts were pathologically diagnosed with large cell neuroendocrine carcinoma. Therefore, 27 adenocarcinoma pts were included in this analysis. 3 (11.1%) pts achieved pCR (TRG1a) and 4 (14.8%) pts achieved MPR (TRG1a/b). R0 resection was achieved in 96.3% (26/27) of the pts. No patient had pT4b. The most common (≥10%) grade 1-2 treatment related adverse events (TRAEs) included leucopenia (45.7%), neutropenia (42.9%), thrombocytopenia (20%), nausea (34.1%), vomiting (14.3%), anorexia (14.3%), ALT increased (40%) and AST increased (34.3%). Only 4 (11.4%) pts experienced grade 3 neutropenia. No other ≥ grade 3 TRAEs occurred. Most of the potential immune-related adverse events were grade 1-2 including hypothyroidism (8.6%), adrenal insufficiency (2.9%) and hyperglycemia (11.4%). Only one (2.9%) patient had grade 3 hyperglycemia. No serious perioperative complication and death occurred. Conclusions: Perioperative XELOX plus toripalimab preliminarily showed a favorable R0 resection rate and acceptable MPR in cT4a/T4b locally advanced G/GEJ cancer patients with a manageable safety profile. Clinical trial information: NCT04119622.

Modified docetaxel, cisplatin, and 5-fluorouracil combination regimen and capecitabine maintenance in metastatic gastric cancer: toxicity and efficacy results.

Little progress has been made, and there is an unmet medical need for treatment of metastatic gastric cancer (MGC). Docetaxel + cisplatin + 5-fluororacil (DCF) combination is an effective regimen with high rate of toxicity and is not well tolerated. We aimed to evaluate the efficacy and toxicity of a modified DCF (mDCF) combination regimen and capecitabine maintenance in MGC. Data of MGC patients were treated with first-line mDCF regimen (two weekly docetaxel 60mg/m2 day 1 iv, cisplatin 50mg/m2 day 1 iv, 5-fluouracil 400mg/m2 day 1 iv push, 2400mg/m2; day 1-day 2 iv infusion, leucovorin 400mg/m2 day 1 iv push) were recorded. Capecitabine maintenance was given as 2500mg/m2/ day 1-day 14 po, every 3weeks, to patients who do not have progressive disease and grade 3 treatment-related toxicity. A retrospective analysis was made. Forty patients were included. Mean age was 53 ± 11. Thirty-two patients had de novo metastasis. All patients' performance status was ECOG 1 or 2 (32/8). Median number of mDCF cycles given was 9 (min-max: 1-23). Overall response rate was 47.5%. Ten patients (25%) received capecitabine maintenance. Grade 3/4 toxicity was seen in 20 patients (50%). Hematologic grade 3/4 toxicity occurred in 13 patients (32.5%), and grade 3/4 neutropenia occurred in 11 patients (27.5%) and in 15 cycles. Nonhematologic grade 3/4 toxicity was seen in 7 patients (17.5%). Median follow-up time was 17.2months. Median time to progression (TTP) was 10.8 ± 1.9months (95% CI: 6.89-14.64). Median overall survival was 14.7 ± 1.73months (95% CI: 11.30-18.10). mDCF protocol was a tolerable chemotherapy regimen for the first-line treatment of MGC with higher ORR and longer TTP compared to standard DCF protocol. Capecitabine maintenance might increase TTP.

A first-in-human phase 1b study of a novel allosteric extracellular FGFR2 inhibitor alofanib in patients with refractory metastatic gastric cancer.

304 Background: FGFR2 promotes gastric cancer progression, suggesting that inhibition of FGFR2 may be an important therapeutic strategy. Alofanib (RPT835) is a small molecule, allosteric inhibitor that binds to the non-active extracellular site of IIIc and IIIb FGFR2 isoforms with IC50 &lt; 10 nM. Methods: RPT835GC1B is a Phase 1b open-label study evaluating the safety and preliminary efficacy of alofanib in patients with metastatic gastric adenocarcinoma pretreated with ≥ 1 previous lines of therapy. The standard dose-escalation part (design 3+3) aimed to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) as a primary endpoint. Secondary endpoints included pharmacokinetic (PK) parameters, rate of adverse events, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Alofanib was administered daily intravenously for 5-days followed by a 2-day interval (rest). There were five dose levels: 50, 100, 165, 250, and 350 mg/m2. All patients received alofanib until disease progression or unacceptable toxicity. Results: As of 20 September 2021, 21 patients have been enrolled in the study. Patients were Caucasian (100%), predominantly male (71%), 67% had 2 and more metastatic sites, including liver metastases (43%), 14% had ECOG PS 2, and were heavily pretreated (86% had previous 3 and more lines of therapy). All enrolled patients have been studied for safety and have not experienced any dose-limiting toxicities (DLTs) within the 28-day DLT-assessment window. 17 (81%) patients had at least one treatment-related adverse event (trAE). Grade 3 or higher trAEs (5/23.8%) have included raised ALT/AST at 50 mg/m2, neutropenia at 50 mg/m2, diarrhea at 165 mg/m2, headache at 165 mg/m2, increased serum amylase at 350 mg/m2, and reactions immediately after intravenous injections (facial flushing, dizziness, weakness, sweating, and sinus tachycardia) at 350 mg/m2. Three (14.3%) patients discontinued treatment due to trAEs. Most common Grade 1-2 adverse events included reactions immediately after intravenous injections, diarrhea, thrombocytopenia, arthralgia, and headache. Grade 1 hyperphosphatemia was found in 1 (4.8%) patient. Table summarizes efficacy data. Conclusions: The MTD has not been reached and dose of 350 mg/m2 has been declared as RP2D. Alofanib showed acceptable tolerability and preliminary signs of clinical activity in the late-line treatment of metastatic gastric cancer. Clinical trial information: NCT04071184. [Table: see text]

Review of Regional Therapies for Gastric Cancer with Peritoneal Metastases.

Simple SummaryGastric cancer is usually diagnosed at late stages and is associated with poor five-year survival rates. Metastasis to the peritoneal cavity is common and leads to even worse outcomes. Currently, the mainstay of treatment for metastatic gastric cancer is systemic chemotherapy or supportive care. These recommendations remain despite evidence that suggests systemic therapy has poor penetration into the abdominal cavity, limiting efficacy against peritoneal disease. Newer treatments have been developed to address this problem, specifically regional therapies aimed at delivering chemotherapy directly into the peritoneal cavity to eradicate tumor cells. These novel therapies include hyperthermic intraperitoneal chemotherapy, normothermic intraperitoneal chemotherapy, and pressurized intraperitoneal aerosolized chemotherapy. Regional therapies may also be combined with surgery to remove both macroscopic and microscopic disease. Although more clinical trials are needed to evaluate its efficacy, early studies have shown promising outcomes with intraperitoneal chemotherapy.Gastric cancer carries a poor prognosis and is a leading cause of cancer-related mortality worldwide. Patients with gastric cancer who develop peritoneal metastases have an even more dismal prognosis, with median survival time measured in months. Since studies have demonstrated that systemic chemotherapy has poor penetration into the peritoneum, multimodal treatment with intraperitoneal chemotherapy has been proposed for the treatment of peritoneal metastases and has become the foundation for newer therapeutic techniques and clinical trials. These include heated intraperitoneal chemotherapy (HIPEC) with cytoreductive surgery (CRS), which involves the application of heated chemotherapy into the abdomen with or without tumor debulking surgery; normothermic intraperitoneal chemotherapy (NIPEC), in which non-heated chemotherapy can be delivered into the abdomen via a peritoneal port allowing for repeat dosing; and pressurized intraperitoneal aerosolized chemotherapy (PIPAC), a newer technique of pressurized and aerosolized chemotherapy delivered into the abdomen during laparoscopy. Early results with intraperitoneal chemotherapy have shown promise in increasing disease-free and overall survival in select patients. Additionally, there may be a palliative effect of these regional therapies. In this review, we explore and summarize these different intraperitoneal chemotherapy treatment regimens for gastric cancer with peritoneal metastases.

S3715 A Leather Bottle Stomach: Rare Case of Gastric Adenocarcinoma With Signet Cell Features

Introduction: Gastric cancer is one of the most common cancers worldwide - and was previously the leader of cancer related mortality until the 1980’s. With advancements in discovery of etiologies, namely the detection of H. Pylori - incidence of gastric cancer has declined over the past decades. A common finding on imaging is the diffuse gastric wall thickening - the “leather water bottle” or Linitis Plastica. A representation of diffuse infiltration of the cancer into the wall of a hollow organ, in this case - the stomach, giving it’s rugged and preserved structural shape. We present a case of poorly differentiated gastric adenocarcinoma with signet ring cell features in setting of portal hypertensive gastropathy. Case Description/Methods: 70-year-old female with PMH of HCV (treated with SVR) and 20 pack year tobacco history presented with complaints of weight loss, decreased appetite and early satiety with no other complaints for one month. Physical exam significant for bi-temporal wasting otherwise unremarkable. Initial chemistries within normal limits. CT abdomen and pelvis revealing a prominent thickening of the wall of the stomach as well as inhomogeneous soft tissue attenuation in the omentum concerning for neoplastic disease. EGD showed evidence of portal hypertensive gastropathy with distal gastric body thickening in addition to the examined duodenum revealing duodenitis. Biopsies of the stomach revealed poorly differentiated adenocarcinoma with signet ring cell features while the duodenal mucosa was negative for significant histopathologic abnormality. H. pylori immunostain was negative. Insufficient tissue for HER2 and PDL-1 assessment. Oncology evaluation included PET CT with significant circumferential thickening and hypermetabolic activity of the stomach with additional focus of modular hypermetabolic activity at pyloric and duodenal 2nd portion suggestive of multi centric disease. Diffuse omental modularity and ascites at low level metabolic activity consistent with omental metastasis and malignant ascites. Discussion: While our patient presented late in the disease course, there are still available palliative chemotherapy opportunities. Advances have been made in molecular identification and subtypes within the gastric cancer umbrella for more targeted therapy. Recent FDA approval (April 2021) of the addition of Opdivo (immunotherapy) to FOLFOX (chemotherapy) for treatment of metastatic gastric cancer has allowed our patient to receive the most up to date treatment option.Figure 1.: Figures 1-A through C are endoscopic images of the gastric body (evidence of portal hypertensive gastropathy), the duodenal bulb (suggesting duodenitis) and the 2nd portion of the duodenum. Figure 1-D is a CT Abdomen-Pelvis with Contrast depicting the classic radiographic finding of gastric cancer - 'linitis plastica' with surrounding peri-gastric lymphadenopathy. Figures 1-E and F are NM PET scan's with evidence of diffuse hypermetabolic activity in the stomach wall with uptake of SUV max 10.1 in addition to the 2nd portion of the duodenum with uptake of SUV max 5.7 - suggestive of multi-centric disease.