New research and encouraging findings from a clinical trial involving patients have provided new insights and hope for one of the most aggressive forms of cancer.
Gastric cancer is a serious health challenge, being the fifth most frequent type of cancer and the third primary cause of cancer-related deaths globally. Each year, it contributes to over a million new cases and almost 770,000 deaths. In Singapore, it is among the top ten causes of cancer fatalities, leading to around 300 deaths annually.
The peritoneum, which is the lining of the abdominal cavity, often gets involved in advanced cancers, including gastric, colon, pancreatic, and ovarian cancers. For gastric cancer specifically, the peritoneum is the most frequent location for metastasis, both prior to and following treatment. Patients with gastric cancer peritoneal metastases (GCPM) typically have a very poor prognosis, with dire symptoms and rapid disease advancement. The average survival is only three to six months, and the five-year survival rate generally falls below five percent, with few treatment options available.
In a significant advancement, researchers from Singapore have uncovered the complex mechanisms behind how gastric cancer spreads to the peritoneum. This pivotal study, published in the journal Gastroenterology, presents renewed optimism for those dealing with this aggressive cancer type. The team also conducted a clinical trial, documented in the journal ESMO Open, which illustrated the safety and potential effectiveness of a new treatment method for the disease.
The research was led by a group of clinicians and scientists from the National University Hospital (NUH), the National University Cancer Institute, Singapore (NCIS), the Yong Loo Lin School of Medicine at the National University of Singapore (NUS Medicine), the National Cancer Centre Singapore (NCCS), and the Duke-NUS Medical School. They utilized state-of-the-art genomic and transcriptomic technologies to analyze a large array of patient samples.
This detailed analysis has offered exceptional insights into the molecular factors that contribute to the spread of gastric cancer to the peritoneum.
Dr. Raghav Sundar, a Senior Consultant in the Department of Haematology-Oncology at NCIS, who headed the study published in Gastroenterology, stated: “Our research has revealed the intricate biological processes that facilitate the spread of gastric cancer to the peritoneum. These insights are essential for devising more effective and targeted treatments for this devastating condition.” Dr. Sundar also serves as an Associate Professor of Medicine at NUS Medicine.
Understanding the complexities of peritoneal spread
The new findings not only clarify why gastric cancer cells often metastasize to the peritoneum but also open avenues for developing novel therapies aimed at the cells and molecules around the tumor—collectively referred to as the tumor microenvironment (TME)—which could hinder cancer’s capability to flourish in the peritoneum. Key discoveries from the study include:
- Uncovering the peritoneal link: The research identified specific genetic changes and characteristics within the TME that contribute to gastric cancer’s spread to the peritoneum. The TME consists of a complex web of cells and molecules surrounding a tumor, explaining why gastric cancer cells are predisposed to peritoneal metastasis.
- The critical function of the tumor microenvironment: The study highlights the vital role of the TME in facilitating the establishment and growth of peritoneal metastases, paving the way for new treatments targeting the TME to disrupt the cancer’s growth in the peritoneum.
- Recognizing biomarkers and treatment targets: The researchers successfully pinpointed potential biomarkers that might indicate the risk of peritoneal metastasis, allowing for earlier detection and intervention. They also discovered new therapeutic targets for developing more effective treatments specifically for GCPM.
“Before our study, there was a limited understanding of the tumor microenvironment’s role in the spread of gastric cancer to the peritoneum. Most cancer patients do not succumb to their original tumors but rather due to metastases in other organs. Our findings reveal the complexities behind gastric cancer metastasis, indicating that gastric tumors can utilize distinct genetic and molecular strategies to spread to various organs,” explained Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS and a senior author of the study.
Encouraging results from a clinical trial
In a concurrent effort, the same research team undertook a clinical trial demonstrating the safety and possible effectiveness of an innovative treatment strategy for GCPM. The Phase I PIANO trial, published in ESMO Open, combined a minimally invasive surgical method known as Pressurised Intra-Peritoneal Aerosol Chemotherapy (PIPAC) with systemic immunotherapy. PIPAC delivers chemotherapy directly to the peritoneal cavity in a fine mist, while immunotherapy aids the immune system in recognizing and attacking cancerous cells.
This cutting-edge approach aims to enhance the immune system’s ability to combat cancer in the peritoneal cavity. Results from the trial were encouraging, showing that the combination treatment was well-tolerated by patients and resulted in a decrease in tumor burden for some. Notably, molecular profiling of tumor samples indicated an increase in T-cell infiltration, which is a marker of a favorable immune response against the cancer.
The trial took place from June 2020 to November 2022 and involved 18 patients across three cancer centers—two in Singapore and one in Belgium.
“The PIANO trial results are highly promising and indicate the potential of pairing targeted therapies like PIPAC with immunotherapy to enhance patient outcomes,” commented Professor Jimmy So, Senior Consultant and Head of the Division of General Surgery (Upper Gastrointestinal Surgery) at NUH, who led the trial. “This approach could transform treatment strategies for this challenging illness.” Professor So is also the Head & Senior Consultant of the Division of Surgical Oncology at NCIS and a Professor of Surgery at NUS Medicine.
Moving forward
The joint research efforts represent a significant advancement in addressing GCPM. The identification of predictive biomarkers and therapeutic targets may facilitate the development of personalized treatment strategies, customizing therapies to the distinct molecular profile of each patient’s tumor. The success of the PIANO trial signals a new age of combination therapies that harness the immune system to tackle peritoneal metastases.
“Our research has unified leading experts across various institutions focused on treating and diagnosing gastric cancer alongside clinician-scientists investigating the disease,” remarked Associate Professor Johnny Ong, Senior Consultant in the Department of Sarcoma, Peritoneal, and Rare Tumors at Singapore General Hospital and NCCS, who is a co-author of the Gastroenterology study and co-investigator of the PIANO trial. “By integrating laboratory research with clinical findings, we have illuminated the biology of gastric cancer, paving the way for urgently needed treatments for patients with peritoneal metastases.”
The studies are backed by the Singapore Gastric Cancer Consortium, a national translational research body consisting of clinicians and scientists specializing in gastric cancer research from academic medical institutions, universities, hospitals, and research centers throughout Singapore. The consortium is funded by the National Research Foundation Singapore under its Open Fund-Large Collaborative Grant, managed by the Singapore Ministry of Health’s National Medical Research Council.
