Debulking Primary Disease: Does It Spur Micro-Metastases?

David J. Kerr, CBE, MD, DSc


August 07, 2023

This transcript has been edited for clarity.

I'm David Kerr, professor of cancer medicine at University of Oxford. Today, let's talk about unintended consequences. I'd like to illustrate this with a patient that we've looked after for many years in the clinic.

For more than a century, there have been empirical clinical observations that resection of a primary tumor may cause an increase in growth of any residual microscopic metastases. This implies that, in some way, there were tumor-associated factors such that when the tumor was removed or debulked, these repressor factors were removed, releasing the brake and causing a growth spurt in any residual disease that may have been left behind.

It's quite a controversial area, with arguments both for and against this conceptually. There's quite a bit of more recent mouse data suggesting that resection of the primary tumor can cause regression of at least some micrometastases. It's an area of huge controversy, but one that keeps cropping up.

How could surgical debulking of tumor be associated with growth of residual disease? Some of the factors may be to do with the perioperative state, the stress of surgery, the inflammatory insult of surgery, and psychological stress associated with debulking and the extent of primary surgery.

There may be neuroendocrine and paracrine factors. We know that, following any major operation, there can be sweeping changes in levels of cortisol, prostaglandins as part of that pro-inflammatory change, and immune factors. There's a large amount of work done looking at the immediate postoperative changes in the immune system, usually showing it being weakened.

We see increased pro-metastatic immune factors; tumor-associated macrophages; increased blood levels of interleukin (IL)-8 and IL-6; decreased anti-metastatic immunity; and reduction in natural killer (NK) cells, IL-12, and IL-10. These have all been documented and, correlated loosely with that, anti-metastatic immunity being decreased by the impact of surgery.

Of course, there's always a possibility of the changes in growth factors, such as increase in tumor necrosis factor (TNF) alpha postsurgically, decrease in anti-angiogenic factors and endostatin, and increase in pro-angiogenic factors like vascular endothelial growth factor (VEGF). There's a whole set of plausible circumstances that could be associated with a flare of growth in residual disease.

Focusing on our patient, we've looked after her for 5 years. She came initially with synchronous hepatic metastatic disease. This responded very well to conventional chemotherapy, allowing us to resect the four hepatic metastases and the primary tumor. She was well for 18 months or so and then had a recurrence in an isolated retroperitoneal lymph node.

We gave stereotactic ablative radiation (SABR) treatment. We gave focused radiation therapy for this, and she remained well. Her scans and biomarkers were normal, including carcinoembryonic antigen (CEA) and CA19-9, for another 12 months. Then she had a recurrence in the pelvic nodes, and a tumor sitting behind the bladder with one or two other peritoneal nodules. Liver and lungs were completely clear, with a rise in CEA.

We gave second-line chemotherapy and again saw a decent partial response. She wanted to go ahead with pelvic exenteration surgery, which is a major operation, including retroperitoneal lymph node dissection. She underwent this successfully with clear margins, but it was a major operation requiring a colostomy and a urinary diversion because the bladder was taken, of course.

At her first visit back to us postsurgically 2 months later, a scan showed that she had more than 15 hepatic metastases. Now, of course, these microscopic metastases would have been there. We resected the macroscopic disease that we saw all those years ago.

It just reminded me of that sense of unintended consequences of her going through a truly life-changing major operation requiring plastic surgery and so on, and after such a short period of time to come back with such devastating news, and of course, now a very limited lifespan.

We're managing her with chemotherapy. It's too early to see if it's being effective. It did remind me of that story, that sense that if we debulk primary disease, this may have this reflexive negative effect in terms of promoting more rapidly a growth spurt in any residual microscopic disease.

I'd be willing to see what you think of this. It's an area of huge controversy. The data are plausible but not compelling. The experimental data from murine models are variable, but I just wonder if any other of you practicing clinicians have come across anything similar or if you have any strong feelings one way or the other. I'd be very interested in your opinion.

Thanks for listening, as always. For the time being, Medscapers, over and out. Thank you.

David J. Kerr, CBE, MD, DSc, is a professor of cancer medicine at the University of Oxford. He is recognized internationally for his work in the research and treatment of colorectal cancer and has founded three university spin-out companies: COBRA Therapeutics, Celleron Therapeutics, and Oxford Cancer Biomarkers. In 2002, he was appointed Commander of the British Empire by Queen Elizabeth II.

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