A surgeon team uses a Loop-X live medical imagery system to secure the work on the spine of a patient affected by a metastatic breast cancer at the University-affiliated hospital (CHU) in Angers, France, on June 10, 2021. (AFP via Getty Images/Loic Venance)

A simple drug regimen to diminish stress and inflammation reduced the risk of developing metastases after surgery to remove cancerous tumors, according to a recent study.

The study found that 5 years after surgery, nine of the 18 patients who received a placebo (50 percent) developed metastatic cancer, compared with only two of the 16 patients (12.5 percent) who received the drug regimen.

This first-of-its-kind clinical study was led by Shamgar Ben-Eliyahu, professor at Sagol School of Neuroscience and School of Psychological Sciences at Tel-Aviv University, and Oded Zmora, MD, a colorectal surgeon and a professor at Tel-Aviv University’s Sackler Faculty of Medicine.

The two professors have been researching this subject together for 15 years.

The research was published in the European Journal of Surgical Oncology. An overview of the theory and principles underlying the research was published in Nature Reviews Clinical Oncology in 2020.

‘The Decisive Treatment’

When a tumor without known distant metastases is detected in an organ, the standard treatment is surgery to remove the segment of the intestine that includes the tumor, Zmora told The Epoch Times.

He said it is the most important treatment, calling it “the decisive treatment that gives the highest chance of curing the disease.”

In some cases, after the patients recover, additional oncology treatments are given, such as chemotherapy.

At the time of surgery, when the primary tumor is removed, it carries the risk of recurrence. In the follow-up period, the tumor may recur either in the target organ itself or more commonly as metastases in other organs such as the liver or the lungs.

The risk of metastases after tumor removal is estimated at 30–40 percent among colon cancer patients, and about 90 percent among pancreas cancer patients, according to Zmora.

He said that while the surgery is the cornerstone in the treatment of the disease, “it also places a very heavy burden on the body, [in the form of] stress.”

Most deaths related to cancer result from metastatic recurrence after surgery. So the goal of the study was to try to reduce the recurrence rate of metastases.

The Peri-Operative Period Is Critical

“We and others have found that the short period around the surgery, a week before and a week or two after are very critical in their effect on metastatic processes of cancer,” Ben-Eliyahu told The Epoch Times.

Various interventions during this period have a much greater effectiveness than in other periods that are less critical.

Paradoxically, most of the anti-metastatic treatments such as radiotherapy, chemotherapy, and immunotherapy, are not given during this period because they interfere with the surgery, he said. Most of the treatments are not given during the peri-operative period—they end a month before it or start a month after it.

And so “one of the special things about our intervention is that we actually use this period of the surgery itself,” he said.

‘A Watershed Point in Life’

The second point is that the researchers looked for how surgery in this short peri-operative period affects metastatic processes.

They found that, during the peri-operative period, stress and inflammatory reactions each separately and together affect cancerous processes, through several mechanisms.

Being diagnosed with a tumorous disease “is a watershed point in life” said Zmora. “It is a period of time when one has to mobilize his mental resources to undergo the surgery and go through the treatments.”

The patients experience a lot of stress while waiting for surgery. Then stress and inflammation reactions occur in the body during the operation itself as well as during the physical recovery. And there is the constant anxiety at every visit for checkups, with the question of whether the cancer has come back or not.

In earlier studies with animals, Ben-Eliyahu found that the magnitude of the effect of psychological stress was no smaller than the effect of the surgery itself.

“Its weight can be more significant than we estimate,” he said.

All these mental and physiological conditions create stress responses that cause the release of stress hormones called catecholamines, such as adrenaline and noradrenaline, and inflammatory responses which cause the release of prostaglandins.

“We assume that those patients in whom the disease returns, tumor cells were implanted, seeded, back in the period when there was an original tumor before the operation and something in the body caused them to be dormant, inactive,” said Zmora.

Exposure to stress-inflammatory hormones directly affects these remaining cancer cells to become more aggressive and metastatic, said Ben-Eliyahu.

These hormones also indirectly encourage the development of metastases by suppressing anti-metastatic immune activity.

“They suppress the immune elements that the immune system uses to fight cancer metastases,” he said.

So all these stress-inflammatory mechanisms taking place during the peri-operative period increase the risk of metastatic outbreak in patients, in some cases this becomes evident only years after the operation.

Once the mechanisms were understood by the researchers, it was possible to think about which type of treatment could be used to influence them.

The treatment given in the study was designed to prevent metastatic development, which may be accelerated around the time of surgery.

The Medication Treatment

The treatment included two known, inexpensive drugs that were in long-standing use in medicine for other indications, and they are available in local pharmacies.

One drug was Deralin, or propranolol, which is usually given to patients with hypertension to reduce blood pressure and to reduce anxiety.

The second drug was Etopan, or etodolac, which is used to prevent inflammation and pain.

Both drugs, which are given orally, have “a high profile safety” according to the researchers and both need to be taken at the same time.

Since both the inflammatory response and the stress response each can cause a variety of problems that ultimately converge to the same mechanisms, according to Ben-Eliyahu, blocking only one axis is not enough.

“You need to simultaneously block both the inflammatory response and the stress response when both are happening at the same time around the time of surgery,” he said.

They found in animal studies “that each of the drugs does a little bit, and both do much more than the sum of them,” he said. “This is called synergism; they have synergies between their effects.”

The 16 randomly chosen patients in the treatment group took the medication for 20 days—five days before the surgery to two weeks after the operation with minimal-to-no adverse effects.

This drug regimen showed promising results of reduced markers of metastasis in the excised tumor tissues, according to Ben-Eliyahu. Five years later, only 12.5 percent of the patients that had received the treatment developed cancer metastases, compared with 50 percent of the patients who received the placebo.

Similar results were found in a previous study with 38 breast cancer patients. The same drug regimen that was given prior to and after surgery significantly reduced markers of risk of cancer recurrence after surgery.

However, even though the results of these two studies were found to be statistically significant, a large-scale clinical study is needed to establish the beneficial effects of this treatment and to advance toward potential clinical implementation.

This Research Falls in the Gap

The next step is to repeat the study on a large scale, said Ben-Eliyahu.

“We see something very promising here.”

However, he said his concern is that it is research on a treatment protocol that pharmaceutical companies will not support.

There are many, much less-promising treatments that pharmaceutical companies will push, he added, because they present very large financial profits.

“The drugs in question are unpatented; they are generic,” said Zmora. “There is no company that has an interest in pushing such research, and it is difficult to raise funds.”

When they approach a pharmaceutical company and say there are a lot of cancer patients in the world but the treatment will only be given for 3 weeks or a month, the company is less interested because they usually want to invest in long-term therapies.

Nevertheless, the researchers have begun a large-scale study, but still don’t have the funds they need. It is already on its way in at least 4 hospitals in Israel and a few more hospitals are planning to join in.

The researchers are aiming to recruit over 300 patients but they face big financial challenges.

“There is really some scientific excitement here,” said Zmora. “At the same time, it is very, very difficult to raise funding for such research.”

“The bottleneck for us is money,” said Ben-Eliyahu. “It’s not [medical] centers that want to cooperate with us, but money to pay the hospitals … for the cost of the research.”

The researchers said they receive funding from the Israeli Ministry of Health, the Israel Ministry of Science, the Israel Cancer Research Fund, and SPARK, an innovation center at Tel Aviv University.

But the amount of money is a small fraction of what is needed.

“We need between $2–4 million to conduct research on 300 colon cancer patients,” he said. “And these bodies each give us $50,000–200,000.

“So we live from hand-to-mouth and we try to look for donors.”

Major science foundations in Israel (e.g., Israel Science Foundation) do not fund clinical trials on drugs since they are usually funded by pharmaceutical companies, Ben-Eliyahu said.

“We do it entirely on a nonprofit basis,” he said. “There is no economic profit here and, therefore, pharmaceutical companies will not push it.”

“I don’t say this as a grudge against the drug companies, I also work with them and I appreciate what they do,” said Zmora. “But that’s the way it is.”