Integration of Genomic Biology Into Therapeutic Strategies of Gastric Cancer Peritoneal Metastasis

Abstract

The peritoneum is a common site of metastasis in advanced gastric cancer (GC). Diagnostic laparoscopy is now routinely performed as part of disease staging, leading to an earlier diagnosis of synchronous peritoneal metastasis (PM). The biology of GCPM is unique and aggressive, leading to a dismal prognosis. These tumors tend to be resistant to traditional systemic therapy, and yet, this remains the current standard-of-care recommended by most international clinical guidelines. As this is an area of unmet clinical need, several translational studies and clinical trials have focused on addressing this specific disease state. Advances in genomic sequencing and molecular profiling have revealed several promising therapeutic targets and elucidated novel biology, particularly on the role of the surrounding tumor microenvironment in GCPM. Peritoneal-specific clinical trials are being designed with a combination of locoregional therapeutic strategies with systemic therapy. In this review, we summarize the new knowledge of cancer biology, advances in surgical techniques, and emergence of novel therapies as an integrated strategy emerges to address GCPM as a distinct clinical entity.

FIG 1.

Diagnosis and treatment strategies of GCPM. Various groups across the world use different strategies in the management of GCPM. This figure aims to highlight the most commonly used approaches. Major guidelines (NCCN and ESMO) recommend treatment of GCPM with systemic therapy alone, similar to patients with advanced or inoperable metastatic GC. However, academic and high-volume subspecialized tertiary centers (in SG, JP, KR, CN, FR and the US, within purple boxes) tend to deploy more aggressive and experimental approaches with peritoneal-directed therapies, which are not recommended by either NCCN or ESMO. Guidelines on staging laparoscopy not represented in the figure include those from the JGCA and the SSO. JGCA recommends weakly for staging laparoscopy to decide on the treatment plan for patients with relatively high risk of peritoneal dissemination, referring also to the results of peritoneal lavage cytology using samples that are collected at staging laparoscopy, and for patients with advanced GC (TNM not otherwise specified) who can be indicated for neoadjuvant chemotherapy. SSO guidelines recommend strong consideration for diagnostic laparoscopy before the initiation of systemic chemotherapy in all patients with proven GC. AFC, French Association for Surgery; AJCC, American Joint Committee on Cancer; CN, China; CRS, cytoreductive surgery; ESMO, European Society for Medical Oncology; FR, France; GCPM, gastric cancer peritoneal metastasis; HIPEC, hyperthermic intraperitoneal chemotherapy; IPC, intraperitoneal chemotherapy; JGCA, Japanese Gastric Cancer Association; JP, Japan; KR, Korea; NCCN, National Comprehensive Cancer Network; PCI, Peritoneal Cancer Index; PIPAC, pressurized intraperitoneal aerosol chemotherapy; SG, Singapore; SSO, Society of Surgical Oncology Chicago Consensus 2020.

FIG 2.

Biologic hallmarks of GCPM. The 11 biologic hallmarks of GCPM derived from four broad factors, including tumor-related factors, peritoneal microenvironment, paracrine factors, and biomechanical forces. Deeper understanding of these hallmarks has led to the development of novel therapeutic strategies and biomarkers. EMT, epithelial-mesenchymal transition; GCPM, gastric cancer peritoneal metastasis; MMT, mesothelial mesenchymal transition.

FIG 3.

Regulators of metastasis to the peritoneum in GC. Metastasis of the GC primary tumor to the peritoneum is a multistep process involving several pathways and networks. In this figure, we highlight some of the key regulators of this process, with factors that determine the metastatic cascade being present in the primary tumor, malignant ascites, and the peritoneal cavity. CAF, cancer-associated fibroblast; EGF, endothelial growth factor; GCPM, gastric cancer peritoneal metastasis; HGF, hepatocyte growth factor; ICAM-1, intercellular adhesion molecule-1; TGF, transforming growth factor; TNF, tumor necrosis factor; VCAM-1, vascular adhesion molecule-1; VEGF, vascular endothelial growth factor.

FIG 4.

Peritoneal-directed modalities and their roles in treatment and prophylactic strategies of GCPM. Catheter-based IPC in combination has been evaluated in both adjuvant and neoadjuvant settings in the management of GCPM. Adjuvant combination of systemic and intraperitoneal chemotherapy may help downstage PM, allowing for conversion gastrectomy, whereas the role of adjuvant early postoperative intraperitoneal chemotherapy in prevention of metachronous PM remains unclear. HIPEC is most commonly carried out in conjunction with cytoreductive surgery as a potentially curative strategy in patients with low-volume PM and potential for complete cytoreduction. A potential role exists for prophylactic HIPEC in patients with GC undergoing gastrectomy to prevent or reduce metachronous PM recurrence, with ongoing studies underway. Studies of PIPAC have thus far been limited to palliative treatment for patients with PM; the role of PIPAC in treatment of GCPM requires further evaluation and is currently limited to the settings of clinical trial. GCPM, gastric cancer peritoneal metastasis; HIPEC, hyperthermic intraperitoneal chemotherapy; IPC, intraperitoneal chemotherapy; PIPAC, pressurized intraperitoneal aerosol chemotherapy.