Phase II Study of Preoperative Intra-Arterial Epirubicin, Etoposide, and Oxaliplatin Combined with Oral S-1 Chemotherapy for the Treatment of Borrmann Type 4 Gastric Cancer

Abstract

Purpose: A phase II study was conducted to evaluate the safety and efficacy of preoperative, intra-arterial perfusion of epirubicin, etoposide, and oxaliplatin combined with oral chemotherapy S-1 (SEEOX) for the treatment of type 4 gastric cancer. Materials and Methods: A single-center, single-arm phase II trial was conducted on 36 patients with histologically proven type 4 gastric cancer without distant peritoneal or organ metastasis. Patients received 3, 21-day courses of SEEOX preoperative chemotherapy. The primary endpoint was overall survival (OS) and the secondary outcomes assessed were chemotherapeutic response, radical resection rate, pathological regression, toxicities, postoperative morbidity, and mortality. Results: All patients were at an advanced stage of cancer (stage III or IV) and completed the entire course of treatment. Based on changes in tumor volume and peritoneal metastasis, the objective response rate was 55.6% (20/36; 95% confidence interval [CI], 38.5%-72.6%) and the disease control rate was 69.4% (25/36; 95% CI, 53.6%-85.3%). The radical resection rate was 75% (27/36; 95% CI, 60.1%-89.9%) and the proportion of R0 resections was 66.7% (21/36; 95% CI, 50.5%-82.8%). The pathological response rate was 33.3%, of which 13.9% showed complete pathological regression. The median survival was 27.1 months (95% CI, 22.24-31.97 months), and the 2-year OS was 48.5% (95% CI, 30.86%-66.1%). Conclusions: Preoperative SEEOX is a safe and effective treatment for type 4 gastric cancer. Based on these preliminary data, a phase III study will be conducted to confirm the superiority of this regimen over standard treatment.

Efficacy of intra-arterial chemotherapy with sequential anti-PD-1 antibody in unresectable gastric cancer: A retrospective real-world study

“…First, oxaliplatin has been reported to induce immunogenic cell death and increase tumor-specific effector T cell infiltration ( 29 ), hence the combination of anti-PD-1 antibody with oxaliplatin-based chemotherapies might induce an additive antitumor effect, which actually has been demonstrated in ATTRACTION-4 ( 34 ) and ORIENT-16 ( 35 ) studies, whereas, pembrolizumab plus cisplatin-based chemotherapy didn’t show survival benefit ( 23 ). Second, anti-PD therapy selectively modulate immunity and function in tumor microenvironment, while intra-arterial chemotherapy also administers cytotoxic drugs via tumor supplying blood vessels directly into the tumor region ( 28 ), which could increase the local drug concentration, generate a more inflammatory tumor environment, and consequently exacerbate the antitumor effect. Additionally, intra-arterial chemotherapy per se has displayed superior clinical benefits in our previous studies ( 26 – 28 ), and a multicenter phase III study initiated by our institution comparing SEEOX and SOX regimens in the neoadjuvant setting is under investigation (NCT02338518), interim analysis has demonstrated significant better ORR and survival outcome in the intra-arterial chemotherapy group.…”

“…Second, anti-PD therapy selectively modulate immunity and function in tumor microenvironment, while intra-arterial chemotherapy also administers cytotoxic drugs via tumor supplying blood vessels directly into the tumor region ( 28 ), which could increase the local drug concentration, generate a more inflammatory tumor environment, and consequently exacerbate the antitumor effect. Additionally, intra-arterial chemotherapy per se has displayed superior clinical benefits in our previous studies ( 26 – 28 ), and a multicenter phase III study initiated by our institution comparing SEEOX and SOX regimens in the neoadjuvant setting is under investigation (NCT02338518), interim analysis has demonstrated significant better ORR and survival outcome in the intra-arterial chemotherapy group. Besides, as most untreated gastric cancer was T cell exclusion ( 20 , 25 ), it is safe to apply intra-arterial chemotherapy, with little risk of destroying infiltrated tumor-specific effector T cells at the beginning.…”

“…Enrolled participants received the combination of intra-arterial chemotherapy and anti-PD-1 antibody every 3 weeks for 3 cycles. The regimens of intra-arterial chemotherapy in our institution were described in the previous study in detail ( 28 ). Briefly, oxaliplatin (100 mg/m 2 ), etoposide (100mg/m 2 ), and epirubicin (30 mg/m 2 ) were intraarterially administrated to tumor supplying vessels via femoral artery cannulation with Seldinger method on day 1, usually super-selecting the left gastric artery for tumors in the upper and middle stomach, while the right gastroepiploic artery for tumors in the lower stomach.…”

“…Intra-arterial chemotherapy, which administrated concentration-dependent cytotoxic drugs like oxaliplatin directly into the primary tumor site via tumor supplying vessels (usually the left gastric artery or the right gastroepiploic artery) and initiated in our institution since 2002, has demonstrated excellent efficacy and superior clinical outcomes in locally advanced or advanced GC patients ( 26 – 28 ). Different from systemic intravenous infusion, high concentration of oxaliplatin concentrated in tumor site was prone to invoke immunogenic tumor cell death, then subsequent tumor antigen presentation and priming of effector T cells ( 29 ), which should be an efficient TIME modulating method and might synergize with the sequential anti-PD therapies theoretically.…”

Efforts in Bioprospecting Research: A Survey of Novel Anticancer Phytochemicals Reported in the Last Decade

“…Many drugs available in the market as anticancer agents are secondary metabolites from microbes, marine life, and plants [ 3 ]. Natural products such as vinblastine [ 4 ], vincristine [ 5 ], etoposide [ 6 ], teniposide [ 7 ], taxol [ 8 ], navelbine [ 9 ], Taxotere [ 10 ], camptothecin [ 11 ], topotecan [ 12 ], and irinotecan [ 13 ] have been approved as chemotherapy agents; all are plant-derived [ 3 , 14 ]. However, the desire for a cancer cure is not really fulfilled, as many of the drugs available have severe side effects [ 14 ].…”