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Research Trifecta!
In three studies, UK team sets new worldwide standard of care for migratory cancers

by Jeff Worley

Recent headlines trumpet the bad news about cancer:FIVE-YEAR SURVIVAL FOR LUNG CANCER NO BETTER IN LAST 30 YEARS.
SKIN CANCER DANGEROUSLY ON THE RISE.
CANCER REMAINS OUR #2 KILLER.

But some cancer researchers at the University of Kentucky have been making very different headlines. In three related studies, this medical team has done nothing less than revolutionize the treatment of metastasized cancers—tumors that travel to other parts of the body—to extend the life and the quality of life for patients not only in Kentucky, but worldwide.

spinal compression illustrationSpinal metastasis typically results in compression of the spinal cord. The cancerous tumor, depicted here as a cloudy mass, first grows inside the bone and then enlarges and presses on the spinal cord.

Illustration by Tom Dolan

Roy Patchell, a professor of neurology and neurosurgery, has dedicated his 20-year career at UK to battling these cancers, a research focus that he says has generally been “unpopular” among most cancer researchers.

“Well, maybe ‘unpopular’ isn’t the best word,” says Patchell. “The truth is, our work is almost unique in the world of neuro-oncology because the prevailing thought has been that patients with serious neurological metastases aren’t going to live very long, so it’s better to focus your research efforts elsewhere.” This idea is so ingrained, there’s even a term for it, he says: therapeutic nihilism. “But we’ve been able to show that these tumors are treatable, and that if they are treated correctly and aggressively, most patients live longer, better-quality lives than if the metastases are ignored.”

Patchell stresses that this work has been a team effort. The research group through the years has included an all-star lineup of UK medical researchers: Phillip Tibbs and Byron Young in neurosurgery; William Markesbery, a neurologist, neuropathologist and longtime director of the UK Sanders-Brown Center on Aging; Mohammed Mohiuddin formerly at UK and now head of a cancer center in Pennsylvania; and William Regine, also formerly at UK and now professor of radiation oncology at the University of Maryland. Patchell also credits another member of this group, Richard Kryscio in statistics, calling him “a genius with numbers.”

Metastasized tumors begin somewhere else in the body, and through a process that’s not fully understood break out from the original site and slide into the bloodstream. They flow someplace else, attach themselves there, and—too often—begin to thrive. “Because Kentucky has a high percentage of smokers, we see a lot of metastases from lung cancer to the brain or the spinal cord,” says Patchell, who came to UK in 1985 after a neuro-oncology fellowship at Memorial Sloan-Kettering Cancer Center in New York City.

How deadly are these tumors? “If cancer did not metastasize, hardly anyone would die from it. Very few people actually die from the local tumor; but when that tumor moves and sets up camp in important places like the brain or liver, it can be deadly,” Patchell explains.

Putting Some Backbone into Spinal Cord Cancer Research
One common site where traveling cancers settle, and can cause intense pain and disability, is the spine. Spinal metastasis typically results in compression of the spinal cord, the result of the cancer first growing in the bone and then enlarging and pressing on the spinal cord.

“This is a very common complication,” says Patchell. “It happens in about 10 percent of all patients with cancer.” And Patchell has a special interest in this type of metastasis: both of his parents had spinal compressions and both died of cancer.

Spinal compression was treated early on with surgery, Patchell explains, but the wrong kind of surgery. In the 1930s, laminectomies became standard procedure to deal with cancerous spinal compression—a surgeon would remove a portion of the bony arch, or lamina, on the back side of a vertebra. This procedure, which is typically done to relieve back pain that isn’t helped by more conservative treatments, didn’t treat the tumor, though.

“So surgery had a bad name in connection with the treatment of this spine cancer,” Patchell says, “and was abandoned in favor of conventional radiation and high-dose steroids.” But the problem with radiation, he points out, is that it doesn’t work very quickly, and the tumors continued to grow. “In fact, half the patients treated with radiation got better and half didn’t improve. Frequently, people got worse.”

To help more people, surgery came back into the picture, but a different approach was tried—direct decompressive surgery—which did seem to work. “Surgeons would remove the tumor, which was in front of the spine, and this had a lot of advantages in theory,” explains Phillip Tibbs, Patchell’s longtime partner in the fight against migratory cancer. “By doing this, you relieved the compression, prevented the tumor from growing back, and could then reconstruct chewed-up bone by using metallic rods or super glue. You could rebuild the spine and make it solid. Anecdotal evidence told us that this approach was generally very effective.”

Photo of Drs. Tibbs and PatchellPhillip Tibbs (left) and Roy Patchell in the Department of Neurosurgery have teamed with other UK researchers on three clinical trials that have led to landmark changes inthe treatment of metastatic cancer.

What was needed was a clinical trial to scientifically evaluate this operation. Tibbs continues: “There had been uncontrolled clinical trials before, but, unfortunately, the patients selected for surgery in the past had good, overall prognoses anyway, and so it’s not surprising that they ended up doing well in nonrandomized studies.” In designing the UK trial, Patchell says the key concept was objectivity: “We wanted to do a randomized trial, which means people are allocated at random, by chance alone, to receive one of two clinical interventions.”

In this study, which began in the early ’90s, 101 patients (70 UK cancer patients) with spinal cord compression caused by metastatic cancer were randomized into two groups: surgery followed by radiotherapy or radiotherapy alone. Radiotherapy is conventional radiation therapy which uses beams that are not concentrated; these beams can cover large areas if necessary. Patchell headed up this study, which also included researchers at the University of Michigan, the M.D. Anderson Cancer Center at the University of Texas, the University of Pittsburgh, and Brown University.

Patients in the study had a variety of types of cancer—including lung, breast or prostate cancer—which had spread to their bones, and had a life expectancy of at least three months. The primary measure of success in this trial was the patient’s ability to walk.

The trial yielded excellent news. Significantly more patients in the surgery group were able to walk after treatment (84 percent compared to 57 percent). Those in the surgery group also retained the ability to walk significantly longer than those with radiotherapy alone. Thirty-two patients entered the study unable to walk; over three times as many patients in the surgery group regained the ability to walk compared with patients in the radiation-only group. In addition, surgical treatment substantially reduced the use of steroids and painkillers.

“The results were so convincing that the study was ended two years early,” says Patchell, his face easing into a smile. “You have to have a hugely positive trial for that to happen.” This study, which was funded by grants from the National Cancer Institute (more than $1 million) and the National Institute for Neurological Disorders and Stroke, was published in 2005 in Lancet, one of the world’s most prestigious scientific journals.

“This trial has already changed the way that this fairly common condition is treated around the world and has made a big impact on the quality of cancer patients’ lives everywhere,” says Tibbs, who joined the UK Department of Surgery in 1980.

Revolutionizing Treatment for Brain Metastases
“Phil and I were both interested in neuroscience and just hit it off,” Patchell says, winding the clock back three decades. Patchell, then a UK med student, met Tibbs, a neurosurgery resident, in the early ’70s. “And we were both disciples of Dr. David B. Clark, a wonderful old-school neurologist who was here at the time. He launched the careers of many future neuroscientists, including Dr. William Markesbery, Phil, me, and many others.”

Tibbs adds, with a grin, “Dr. Clark was almost a godlike figure to us. His neurological skills and his patient skills were so finely-tuned that students would practically fight each other to go on Grand Rounds with him. I used to take dates along with me when I went with him on these rounds,” Tibbs chuckles. “That’s how impressive Dr. Clark was.”

Tibbs and Patchell were inspired by Clark’s example, and their work led to two landmark studies that changed the standard of care for patients with brain metastases—the most common type of migratory cancer.

In 1986, Patchell designed a study to determine if surgery was the most effective way to treat brain metastases, and he assembled a talented team at UK that included Tibbs, Markesbery and Young. Forty-eight lung cancer patients with a single brain metastasis took part in this study and were randomly assigned to either the group of 25 patients who underwent surgical removal of the tumor followed by radiotherapy, or to the radiotherapy-only group of 23 patients.

The results of this trial, published in the New England Journal of Medicine in 1990, showed conclusively the importance of surgery for patients with a metastasized brain tumor. In the surgical group, only 20 percent of patients experienced recurrence of the tumor in the brain, as opposed to 52 percent of patients in the radiation group. The length of survival was significantly longer in the surgical group, and the patients treated with surgery remained functionally independent nearly five times longer.

“This was a significant study that changed the way brain metastasis patients were treated,” says Patchell. “And this isn’t a trivial thing—metastatic brain tumors are the most common brain tumors in adults and outnumber primary brain tumors—those tumors that begin in the brain—by at least 10 to 1. Over 200,000 new brain metastases occur in patients in the United States every year. So this study has affected tremendous numbers of people in this country and worldwide.”
They had shown that surgery worked. The next question that needed to be answered was: Is postoperative radiotherapy necessary?

“I originally wanted to do this study to prove once and for all that patients didn’t need radiation therapy,” says Patchell, the study’s principal investigator. “I thought that it had long-term side-effects, and that patients would be much better off without it. Well, this just goes to show that we can be wrong in our predictions,” he says emphatically, “and shows why these trials need to be done.”

This randomized trial involved other university-affiliated cancer treatment centers and included 95 patients who had a single metastasis to the brain. Forty-nine patients were given postoperative whole-brain radiotherapy (conventional radiotherapy given to the entire brain to eliminate any residual disease), and 46 patients received no further treatment.
“The main thing we wanted to find out,” says Tibbs, “was if there would be a recurrence of a tumor anywhere in the brain.

We were also interested in length of survival, cause of death, and the patient’s ability to function independently.”  
The results showed that a brain tumor recurred far less frequently in the radiotherapy group than in the observation group (18 percent recurrence compared to 70 percent). And, it turned out, patients in the radiotherapy group were less likely to die of neurological causes than patients in the control group (14 percent died compared to 44 percent in the control group). “This trial established that radiation was a useful treatment and clearly did prevent recurrence of tumors,” says Patchell.

The study was published in the Journal of the American Medical Association (JAMA) in 1998. And Patchell points out that another study on radiotherapy for brain metastases, conducted recently in Japan and also published in JAMA, found virtually the same results nearly a decade after the landmark UK study.

“Dr. Patchell and his team have performed the most important studies on patients with metastatic cancer to the nervous system. His carefully designed trials have transformed the ‘standard of care’ worldwide,” says Jay Loeffler, chair of the Department of Radiation Oncology at Harvard Medical School.

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