August 28, 2015
This Researcher Devised His Own Low-Cost Cancer Treatment and Won
Posted on Apr 23, 2014
By Jake Bernstein, ProPublica
In 2000, Folkman’s researchers published an animal study of metronomic therapy and found that it seemed to limit tumor growth. Around the same time, a cancer researcher in the department of medical biophysics at the University of Toronto, Robert Kerbel, did an animal study that reached similar conclusions. Randomized human studies involving hundreds of European and Japanese patients who underwent a metronomic therapy have shown improved survival rates.
The approach still faces hurdles beyond just the uncertainty about how it works. One theory, Kerbel says, is that metronomic therapy triggers an immune response in addition to chemo’s traditional toxic effect on cancer cells. But pinpointing a proper dose is challenging, as are the ethics of involving patients with early stage cancers, he says. A trial could needlessly endanger patients either by exposing them to a toxic drug they didn’t need or causing them to forgo a better-established treatment.
Nonetheless, a French pediatric oncologist, Nicolas André, is trying to promote metronomic therapy in the developing world and has organized a foundation to pay for studies. “Will we ever be able to treat cancer for US$1 a day?” he asks in a recent paper. “The answer might be an absolute yes, provided we encourage scientific research and clinical studies on metronomic treatments.”
Retsky is less confident that metronomic therapy using 5-FU on early stage colon cancer will ever receive trials in the United States. “The drug was less expensive than sterile water,” he says, “so no pharmaceutical company would spend millions of dollars testing it if there was no financial reward.”
Square, Site wide
The data that led Retsky and his colleagues to recognize the two waves of relapses and the erratic growth of tumors also carried them into the fiercest dispute over breast cancer of the past 20 years: When should women have mammograms?
One of his collaborators, Baum, had helped establish the mammography program for England’s National Health Service in the 1980s. The thinking behind it was self-evident. Catch the tumor early. Save a life. But the reasoning only made sense if the tumor grew in a linear, predictable way.
It was also possible, Baum theorized, that the tumors might never progress; they might remain dormant for long periods of time or, less likely, could even shrink. By the 1990s, studies had begun to suggest that mammograms, for younger women, were not helpful and possibly were harmful. Women in their 40s who received mammograms had a slightly higher mortality rate than women who did not. Called the “mammography paradox,” the phenomenon remains controversial. Baum concluded money would be better spent on treatment rather than mammography.
The toolkit for treating aggressive breast cancer once it migrates to another part of the body remains limited. The majority of the approximately 40,000 U.S. women who die from breast cancer annually do so when the cancer reappears in another part of the body after surgery. There is no cure once the disease has gone metastatic, according to a report by the Department of Defense Breast Cancer Research Program. The median survival term for metastatic breast cancer is about three years, a number that hasn’t statistically changed in two decades.
In 1997, Retsky and Demicheli published a paper suggesting that it might be the breast cancer surgery itself that was causing the first wave of relapses they had identified. A computer simulation based on the data of Italian women Demicheli had studied suggested that removal of a primary breast tumor from premenopausal women with cancer in a lymph node triggered a cancer growth elsewhere in about 20 percent of cases. A few years later, Baum posited that the math behind tumor growth looked more like chaos theory than anything else. He, too, suggested that surgery might play a role in breast cancer recurrences. The trio, as well as Folkman and other researchers in their group, published several more papers along the same lines, but it wasn’t until 2005 that their theories entered the mainstream.
“We weren’t running to newspapers and issuing press releases,” says Retsky. “We were just looking at the data and presenting it to our colleagues in the scientific community.”
In 2005, Retsky, Demicheli and Hrushesky published a report in the International Journal of Surgery that offered surgery as a theory to explain both the mammography paradox and the first relapse wave. The paper did not propose that women forgo surgery — only that the data suggested a need for more research. But this time, an article about their report in The Wall Street Journal brought the idea to the wider public, where it was pilloried as dangerous because it might scare women from a vital treatment option.
What exactly connected surgery and the cancer recurrence remained a mystery to Retsky and his collaborators, who proposed and discarded various hypotheses. By this time, Retsky was a lecturer at Boston’s Children’s Hospital and Harvard Medical School and the author of multiple scientific papers. He was asked to review a case study out of Lebanon that had cited his work. It described a patient with advanced cancer who had bumped his head. Tumors had grown at the site of the bruise. Retsky couldn’t explain why, but a colleague at the Folkman lab suggested he look at inflammation. Animal studies showed a correlation between inflammation and cancer growth. And surgery also caused inflammation.
From there grew the idea that inflammation itself could be a facilitator of metastatic growth. Retsky and his colleagues theorized that the act of creating wounds in surgery spurred the body to growth as part of the healing process. This in turn might spread the cancer cells. If this was true, intervention to save breast cancer patients had to begin prior to surgery, the researchers concluded.
In 2010, Retsky and his collaborators came upon a paper published in the journal of the International Anesthesia Research Society by a Belgium-based anesthesiologist named Patrice Forget. He had looked at retrospective data from a Belgian surgeon whose breast cancer patients had received nonsteroidal anti-inflammatory drugs (NSAIDs) prior to surgery in the hope that they would lessen post-operative pain. Among the NSAIDs used was ketorolac.
After surgery, the patients all received the standard therapy of chemo, radiotherapy and endocrine therapy. The study size was small — 327 patients who had undergone mastectomies between February 2003 and September 2008. Of those 175 had received ketorolac.
Forget found that cancer recurred in 17 percent of patients who did not receive ketorolac and only 6 percent of those who did. The association was statistically significant and held up even when adjusted for age and other characteristics. There was no effect for the other NSAIDs although that may have been a function of not enough patients trying them, says Forget.
Clinical evidence from studies in animals and retrospectively in humans already existed suggesting that NSAIDs might help limit tumor growth. At least one other large retrospective study published in the peer-reviewed journal Cancer Causes & Control reported that NSAIDs might limit breast cancer recurrences. Forget didn’t know why ketorolac might work better than other NSAIDs, although he postulated various theories.
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