One-Off Blast of RT Triggers Immune Response in Pancreatic Cancer

Frederik Joelving

October 26, 2021

A single dose of radiation to the tumor bed immediately after pancreatic surgery not only kills cancer cells but also creates an inflammatory microenvironment that triggers antitumor immune responses, according to early findings from researchers in South Korea.

The findings suggest that intraoperative radiotherapy (IORT) "may contribute to a positive feedback loop that continuously activates immune-related cells, thereby forming an immune environment that would improve local control of pancreatic cancer," the team writes. The study was published online October 12 in BMC Cancer.

Long-term survival after curative resection of pancreatic cancers has remained dismal, and attempts to boost it with conventional external radiation have been foiled by low tolerance of the adjacent organs, note Joon Seong Park, MD, of Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea, and colleagues.

IORT has emerged as a promising alternative. One recent meta-analysis of observational studies found that local control and overall survival improved for patients with resectable pancreatic cancer.

This new study is the first, according to Park and colleagues, to use blood and peritoneal fluid "to confirm the effect of IORT on pancreatic cancer cells and the anti-cancer immune response after surgical resection."

To investigate how IORT affects the tumor microenvironment after pancreatic surgery, Park and colleagues analyzed blood and peritoneal fluid from 30 patients who underwent curative resection, either pylorus-preserving pancreatoduodenectomy, distal pancreatectomy, or total pancreatectomy. Seventeen patients received a single dose of 10 Gy at a depth of 5 mm into the tumor bed, using a mobile 50-kV x-ray source (Intrabeam, Carl Zeiss, Germany).

The authors found that several cytokines were significantly upregulated in the peritoneal fluid of patients treated with IORT, including interferon gamma, interleukin 15, platelet-derived growth factor–BB, and transforming growth factor beta.

Incubating pancreatic cancer cells with untreated peritoneal fluid stimulated cell growth, whereas IORT-treated peritoneal fluid activated cytokine-related signaling pathways PI3K-Akt and Smad2/3 and significantly reduced growth. The IORT-treated peritoneal fluid also reduced invasiveness and the ability of cancer cells to spread.

Blood samples from the two patient groups revealed significantly different trajectories of various immune cells: Cytotoxic and T-helper cell populations grew faster in the IORT group, as did natural-killer cells. The abundance of immunosuppressive Treg cells remained lower in the IORT group than in the patients who did not undergo radiotherapy.

Park and colleagues concluded that, on a molecular level, this one-off blast of radiation to the tumor cavity after surgical resection "causes apoptosis in the few remaining tumour cells and lymphocytes" and helps establish "an environment that attracts immune cells."

The authors report that 31% (5 of 16) of patients treated with IORT experienced local recurrence, vs 50% (5 of 10) of those who did not receive radiotherapy (P = .34).

Interestingly, the rate of distant recurrence was 56% in the IORT group and 30% in the non-IORT group (P=.19), but after following the patients for 2 years, the team found that the 1-year disease-free survival rate was 41.2% (7 of 17) in the IORT group and 36.4% (4 of 11) in those who did not undergo radiotherapy (P = .71). However, none of these results reached statistical significance.

The study had several limitations, including the fact that it was nonrandomized and that the sample of patients was small. Still, the researchers conclude that "IORT induces an anti-cancer immune response in patients with pancreatic cancer, ultimately aiding local control and prevention of pancreatic cancer recurrence."

The study was supported by the 2020 Research Grant of Gangnam Severance Hospital Research Committee. The authors have disclosed no relevant financial relationships.

BMC Cancer. Published online October 12, 2021. Full text

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