Some think breast operation triggers growth of other tumors

By David Kohn
Balitmore Sun Reporter

Could surgery to remove breast cancer tumors actually increase the risk of a relapse?

A small group of respected researchers suspects that in a significant number of women, surgery itself may trigger the rapid growth of smaller tumors elsewhere in the body.

While many cancer experts are skeptical about the controversial theory, supporters say there is growing evidence for the idea.

“With [surgical] intervention, we may in some cases make things worse,” says Michael Retsky, a researcher at Harvard Medical School and Children’s Hospital in Boston.

Retsky argues that more than half of breast cancer relapses may be accelerated by surgery and says the phenomenon may apply to surgery for other types of cancer.

Proponents of the hypothesis emphasize that breast cancer patients should not reject or put off surgery. “I would not want to discourage women from having surgery because of a fear of spreading tumors,” says Dr. Larry Norton, who nonetheless calls the hypothesis “intriguing.”

The director of breast cancer research and treatment at Memorial Sloan-Kettering Cancer Center in New York, Norton is planning lab studies to examine the effects of surgery on secondary, unremoved tumors.

If breast cancer operations do turn out to stimulate tumors, researchers will have to develop techniques to counteract the effect, perhaps with drugs that blunt the body’s response to surgery.

For decades, scientists have known surgery stimulates production of proteins and other chemicals to encourage healing.

Retsky and others argue that the process also appears to promote development of small breast cancer tumors scattered around the body — growths that had been either dormant or slow-growing.

Known as metastases, these tumors occur in many cancers. Most are tiny, sometimes just a few cells.

“When you operate on someone, you trigger a cascade of genetic signals that lead to healing. These same signals are just what a dormant cancer needs to proliferate,” says Dr. Michael Baum, a respected cancer surgeon and researcher at University College in London. He is one of the theory’s most enthusiastic advocates.

The hypothesis ties into another hot area of cancer research. In recent years, scientists have focused on the idea that tumors need a surrounding network of blood vessels to grow and spread. Many cancers persuade the body to construct these networks, allowing the tumors to thrive.

Several recent blockbuster drugs, including Genentech’s Avastin, work by shutting off the cancer’s ability to create this complex of vessels.

Baum and others believe that surgery can also spur this blood vessel growth, which is known as angiogenesis. Ironically, they say, in ramping up the body’s wound-healing machinery, an operation may also send growth signals and nutrients to tumors.

The phenomenon may have causes in addition to angiogenesis. Dr. Judah Folkman, a Harvard researcher famed for his work on angiogenesis, says that some large primary tumors may secrete substances to inhibit the growth of smaller secondary tumors.

“One tumor can suppress another one,” Folkman says. “The large tumor controls the others.” Once a large tumor is removed, this suppression wanes.

“The brakes are off,” he says.

Experiments have shown that this process occurs in mice, and Folkman suspects it also takes place in humans, too. But no studies have been conducted.The evidence for a surgical role in cancer growth is credible but not overwhelming. In a paper last year in the International Journal Of Surgery, Retsky and several colleagues mined data from a long-running study of 1,173 Italian women with breast cancer.

Retsky noted that deaths from cancer recurrence rose sharply two years after tumor removal, sooner than might otherwise be expected. He argued that the only plausible explanation for this early jump in mortality was the surgical stimulus given to the distant tumors.

And last year, researchers at the Indiana University School of Medicine in Indianapolis added some animal evidence when they surgically removed tumors from a group of mice with breast cancer. Six weeks later, almost three-quarters of the animals had significant breast cancer metastases in their lungs.

Dr. Susan E. Clare, the surgeon who led the study, notes that human physiology differs significantly from that of mice, but says the results should lead to further research in humans. “If this hypothesis is right, we could save a lot of lives,” she says.

About 211,000 women were diagnosed with breast cancer last year in this country, and more than 40,000 died from the disease.

Retsky says his research indicates that surgery-induced tumor growth may occur in over half of those deaths. “Twenty-five thousand women a year die earlier than they otherwise would have,” he says. “This is a huge effect.”

Still, most researchers and doctors express doubts about the theory. “It’s an interesting idea, but the evidence is not really compelling,” says epidemiologist Robert Smith, director of cancer screening for the American Cancer Society.

Smith also questions Retsky’s analysis of the mortality rates. He says the number of increased deaths two years after surgery was too small to be statistically significant.

The notion that surgery can exacerbate cancer has existed for centuries. In the Middle Ages, some doctors believed that exposing tumors to air could make them larger. And in recent years, many doctors have described cases in which large, metastatic tumors appeared weeks or months after surgery or other physical trauma.

But these reports aren’t solid evidence, says breast cancer expert Dr. Harold J. Burstein, an associate professor at the Harvard Medical School. “There aren’t any clinically compelling data,” he says. “There are anecdotes, but they’re not consistent.”

Retsky agrees that his hypothesis remains unproven. And even if it turns out to be right, he says, surgery will remain the cornerstone of breast cancer treatment. Without it, researchers agree, most women with breast cancer have little chance of survival.

If surgery does prove to cause secondary harm, scientists must devise a way to limit the damage from the healing response. Baum says patients might begin taking anti-angiogenic drugs such as Avastin before the operation, to minimize the subsequent stimulus.

But as Clare points out, these drugs are also likely to impede the healing of the surgical wound itself, a serious potential hitch.

Retsky says that researchers must prove or disprove the idea before they try to solve any subsequent problems.

“We want to work with the disease instead of fighting it,” he says. “Now that we are understanding the problem, it should be much easier.”
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By KATHLEEN McGRORY
NY TIMES

It was supposed to be a typical ballet class. Cynthia Toussaint, then a senior dance major at the University of California, Irvine, engaged in her usual stretching routine: she raised her left leg to the barre and slowly bent her upper body down to her right knee.

For a moment, she delighted in the long stretch. But as she returned to an upright position, she felt a sudden pop in her hamstring. “It felt like a guitar string had been plucked and it had broken,” said Ms. Toussaint, who is now 45.

An intense burning sensation followed; it felt as if her leg had been doused in gasoline and set on fire, she said. The next day, the college athletics trainer determined that she had pulled her hamstring. But even years later, the pain would not subside. It migrated to her other leg, leaving her bedridden for nearly a decade, and overtook her vocal cords, leaving her temporarily mute.

All the while, doctors puzzled over and even doubted her mysterious condition.

Ms. Toussaint now knows that she is among an estimated one million Americans living with complex regional pain syndrome, a nerve disorder formerly known as reflex sympathetic dystrophy syndrome. For patients with the disorder, a trauma as mild as a fractured wrist or a twisted ankle can cause the nerves to misfire, so much so that intense pain messages are constantly sent to the brain.

For the past 150 years, so little was known about complex regional pain syndrome that it was often diagnosed as psychosomatic. But doctors now believe that the condition complicates 1 of every 1,200 traumatic injuries. And desperate patients are turning to new, often unproven, drugs and treatments. “It is still quite a mysterious condition,” said Dr. Scott M. Fishman, a pain management specialist at the University of California, Davis, and the author of “The War on Pain.”

“It raises doubts in the eyes of doctors and the people that are looking for hard lab evidence or good imaging confirmation,” Dr. Fishman said. “With this condition, we simply don’t have that.”

Baffling as it may be, the syndrome is not new to the medical literature. It was first documented by Dr. S. Weir Mitchell, a Civil War surgeon. But few physicians are familiar with it; the average patient sees 8 to 10 doctors before a diagnosis is made, according to a recent survey by American RSDHope, a support organization.

Pain is the hallmark of the condition, which outranks cancer as the most painful disease on the McGill Pain Index. For some, the sensation remains in one place, most commonly one of the extremities. For others, it spreads throughout the body, making even a light touch or minor changes in temperature agonizing.

For Ms. Toussaint, as for many other patients, the pain was life altering. When she tore her hamstring, she was on the verge of completing her bachelor’s degree. She was also being considered for a part on the television series “Fame.” But the injury left her in debilitating pain. She could no longer stand on her own or leave her house; riding in a car on the bumpy California roads was torture.

Ms. Toussaint dropped out of school and fell into a deep depression, she said. It took 13 1/2 years for her disorder to be diagnosed. Dozens of doctors told her it was “all in her head”; one even suggested she suffered from stage fright.

Without clear clues as to what induces the syndrome or who is particularly susceptible, doctors say that treating it is a challenge. Sympathetic nerve blocks can reduce the pain, and doctors say the relief often lasts longer than the anesthetic.

More than two dozen drugs are also being used to treat the pain. But none of the medications, which range from acetaminophen and ibuprofen to morphine and methadone, have been approved by the Food and Drug Administration for this use.

“The myth is that this condition isn’t treatable, but the truth is that it responds to the same kinds of treatments that have been found effective for other neuropathic pain,” said Dr. Anne Louise Oaklander, director of the nerve injury unit at Massachusetts General Hospital and an associate professor of neurology at Harvard.

Dr. Russell K. Portenoy, chairman of the department of pain medicine and palliative care at Beth Israel Medical Center in New York, added that treatment was “a trial and error” process.

Doctors tend to use the drugs that are most commonly prescribed for other conditions before the drugs that are less commonly used,” he said. “But in many cases, doctors need to perform sequential trials to find out which drug or combination of drugs helps the most.”

Dr. Portenoy said he is a consultant for drug companies but not on work related to the syndrome or its treatment.

Another treatment is to implant an electrical stimulator near the base of the spinal cord or the injured limb. The device sends low-level electrical signals to the spinal cord or to specific nerves and blocks pain signals from reaching the brain.

Dr. Robert J. Schwartzman of the Drexel University College of Medicine in Philadelphia is skeptical of the electrical stimulators. Although he first began implanting them in patients in 1986, he no longer does. “Long term,” he said, “stimulators don’t work. From what I’ve seen, they wear out and then they stop working.”

Dr. Schwartzman treats the condition with ketamine, an anesthetic that blocks one of the body’s pain receptors. In most cases, this five-day inpatient therapy reduced the pain significantly for three to six months, he said.

In addition, a 10-day outpatient procedure — more than 1,200 people are on a waiting list for it — is being tested in a controlled experiment. Although the trial has been approved by the F.D.A., it is awaiting approval by Drexel’s institutional review board.

Dr. Schwartzman has also sent the most extreme cases — the 30 patients who were found to be intractable to all other treatments — to Germany for five days of prolonged ketamine anesthesia, enough to put them into a coma.

Ten patients were completely relieved of their pain, Dr. Schwartzman said, noting that the treatment has not been approved in the United States.

Some doctors have strong concerns about the ketamine treatments. Dr. Oaklander, for one, believes there is not enough research to support its effectiveness, especially in light of the risks.

Either way, said Ms. Toussaint, who has not had the therapy herself, “It says a lot about this disease that we are willing to be put in comas.” New research is also helping doctors understand the pain syndrome. In early 2006, a team at Massachusetts General was the first to identify organic nerve injuries in a large group of people with the disorder. The research, published in February in the journal Pain, confirmed that the syndrome was not psychosomatic, said Dr. Oaklander, who led the study.

This progress is promising for Ms. Toussaint. Since her illness was diagnosed in 1995, medications have reduced her pain, enabling her to stand and speak again. She and her partner, John Garrett, now manage For Grace, a nonprofit organization dedicated to increasing awareness of complex regional pain syndrome. Ms. Toussaint is also running for the California State Assembly on a health-based platform.

“People see me and they recognize me as the ballerina, but they don’t remember the name of my disease,” she said recently, “but that’s all about to change.”
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Those with more not as happy, survey finds

By Ronald Kotulak
Chicago Tribune science reporter

Although it might seem logical that areas with the most medical resources should offer the best health care, a nationwide survey of physicians has found that primary-care doctors in these areas are unhappier with the quality of care they provide than those working elsewhere.

“To the surprise of many, [these] doctors … perceive the quality of care to be worse on almost every dimension that we looked at,” said the study’s senior author, Dr. Elliott Fisher of Dartmouth Medical School. “Doctors are less satisfied, and they perceive the resources to be scarcer, even when they have more.”

Although the findings seem paradoxical, there appears to be an explanation, Fisher said: Abundant medical facilities lead to increased demand for resources such as hospital beds, specialists and diagnostic tests, ultimately limiting availability.

The result is a frenzied situation “where demand feeds supply, feeds demand, feeds supply in sort of a never-ending cycle,” lead author Dr. Brenda Sirovich said.

The nationwide survey, in the May issue of the Annals of Internal Medicine, involved more than 6,000 physicians who treat Medicare patients. Areas with abundant medical resources were identified by tracking medical spending.

Doctors practicing in high-spending areas–which have the most specialists, hospital beds and diagnostic equipment–reported not only that are they less able to meet the needs of their patients but also that they are less satisfied with their careers than physicians in areas where the use of medical resources is significantly lower.

The findings come at a time of growing national debate over whether the nation is spending too little on health care.

“This study focuses on whether more health spending produces happier doctors and doctors who feel that patients are getting better care and more accessible care–and they’ve shown that no, doctors don’t think that,” said Dr. Saul J. Weiner, chief of general pediatrics at the University of Illinois at Chicago Medical School.

The Dartmouth researchers found that 50 percent of physicians practicing in high-intensity health areas said they were able to obtain elective hospital admissions for their patients, compared with 64 percent of doctors in low-intensity areas. High-intensity doctors also were less likely to report obtaining adequate hospital stays for inpatients, high-quality specialist referrals and high-quality diagnostic imaging services.

Earlier studies from the Dartmouth group showed that contrary to general belief, more medical care does not mean better care. High rates of hospitalization, tests and specialist referrals, they found, lead to poorer patient outcomes when such things as degree of illness and death rates are accounted for. The researchers estimated that 30 percent of Medicare spending is wasted on unnecessary care.

“The Dartmouth studies convincingly demonstrate that expenditures under Medicare exemplify `flat-of-the-curve medicine,’ whereby incremental spending above a certain point produces no incremental health benefit or might even produce harm,” Dr. Robert Berenson of the Urban Institute wrote in an accompanying editorial.

Although unnecessary utilization of services is a key factor in wasted spending, Berenson said another factor is the exorbitant pricing for health care, the result of relatively high incomes for providers and extraordinarily high overhead costs.

“The implications [of the study] are important; it’s not that we need to pour more money into the system and it’s not that we need more hospital beds and more specialists,” said Dr. Lawrence Casalino, professor of health studies at the University of Chicago.

A major reason health-care costs continue to escalate is that the system is geared toward paying for diagnostic tests, medical procedures and other interventions and fails to reward personal contact with patients through which doctors can ascertain patients’ problems more effectively and devise effective treatments, he said.

The Dartmouth study found that Medicare spending averaged 58 percent higher in the highest-intensity areas than in the lowest-intensity areas, despite illness levels that were nearly identical.
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By PATRICK KURP
Copyright 2006 Houston Chronicle

Howard Tomlinson and his wife of 57 years, Joy, recently returned from an 11-day Caribbean cruise, with stops in Panama and Costa Rica.

The Katy couple always have enjoyed dancing, though since the onset of Parkinson’s disease about four years ago, Howard Tomlinson’s capacity for cutting a rug has been somewhat diminished.

“The music just makes you want to move. We’ve danced all over the place. You know: Harry James, country-western, waltzes, the two-step. You can always move if you have the right music,” said the 80-year-old Tomlinson, a retired electrical engineer.

Dr. Ron Tintner, a neurologist at the Methodist Neurological Institute and its Movement Disorders Clinic, hopes Tomlinson’s assessment of the link between music and movement proves correct.

He has launched a clinical study of music and its potential for improving motion in Parkinson’s patients.

“Music is a biologically mandated function. We know it makes people move. The big question for us is, are there particular rhythms that work better for these patients? Which acoustic stimuli will help Parkinson’s patients move and function better?” said Tintner, himself a musician who plays piano and guitar.

With the aid of a $25,000 grant from the Grammy Foundation — part of The Recording Academy, the organization that presents annual music awards — Tintner is researching the sorts of music most helpful for Parkinson’s patients. The ultimate goal is to develop personal audio devices that could help patients overcome the “freezing” they often experience.

“What we’re studying is the neurobiology of music,” Tintner said.

Parkinson’s disease is a progressive neurological disorder caused by the loss of dopamine-producing brain cells. The principal symptoms are tremors, rigidity, slowness of movement, and impaired balance and coordination. In the U.S., some 500,000 people have been diagnosed; about 50,000 new cases are reported annually.

For the first phase of the trial, Tintner will study people without Parkinson’s, to assess which sorts of music most stimulate them. He then will test the preliminary results on people with the disease.

Tomlinson has enrolled in this portion of the study.

Participants will be watched by supervisors trained to notice bodily changes, videotaped and electronically monitored to record physiological changes.

About five years ago, Joy Tomlinson noticed her husband was shuffling, losing energy and experiencing increased difficulty feeding himself. The average age of the onset of Parkinson’s is 60, and Tomlinson already was 75. After seeing several doctors, he was diagnosed with the disease by Tintner, who prescribed medications to replenish the dopamine in his brain.

Tomlinson felt strong enough to undertake the extended cruise, and even went ashore three times.

“Maybe what the doctor’s doing won’t help me, but if I can do something to help other people, that’ll be a good thing,” Tomlinson said.
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By SUSAN PHINNEY
P-I REPORTER

Regence BlueShield, one of the state’s major insurance companies, and nearly 500 physicians in the state are at odds over a new health plan that’s forcing patients to find new doctors.

Last week, the company sent letters to about 8,000 members of its Select Network, informing them that their current physician wasn’t part of the network and they needed to find a new doctor who was.

The letters insinuated that the 488 physicians they currently were seeing weren’t up to Regence standards.

Dr. Jeffrey Robertson, executive vice president of health services for Regence (the name for a four-state alliance of insurance companies that includes Regence BlueShield) “apologizes for the distress and confusion this has caused. We will apologize directly to the physicians,” he said in an interview Thursday.

He explained that the 488 doctors haven’t been banned by Regence. They’re just not available to members of the Select Network. They are available to members in other Regence plans.

Many of those affected are insured by The Boeing Co. When the Society of Professional Engineering Employees in Aerospace contract was negotiated last fall, a “Selections” medical plan was replaced by one named “Select Network.” The new plan still has 100 percent coverage with no monthly contribution from employees, but now there is no out-of-network coverage and a different pool of physicians.

Robertson said the company started communicating with physicians involved in January, but now as the new plan begins phasing in on July 1, people being affected are making calls.

“We have gotten a lot of feedback from employees whose doctors are now out of the network,” said Stephanie Bertholf, director of benefits policy and strategy for Boeing. Because of the timing of their health-care plan, it’s primarily affecting SPEEA members, some of the first to be phased into Select Network.

Dr. Peter Dunbar, president of the Washington State Medical Association, said physicians have been dropped from insurance companies for cost reasons in the past, but he’s never seen it done in such a defaming manner.

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“The doctors are being judged through a black-box forumula that we have no knowledge of. We’re all in favor of improving quality of care and educating physicians to practice efficiently, but this was an unexpected approach,” Dunbar said.

Physicians also have been calling in.

Dr. Rachael Gonzalez, who has a family practice in Renton, said she received a letter from Regence in February informing her that her quality and efficiency were below that of her peers so she wouldn’t be included in the Select Network.

“I am a preferred provider under all their other policies,” she said.

She wrote a letter of appeal that was denied about two months later. As a result, she will lose 70 families, people she’s cared for for many years.

Part of the problem might be a lack of consistency in assessing health care providers.

Diane Giese is a spokeswoman for the Puget Sound Health Alliance, a coalition of businesses, large employers and health organizations created about 18 months ago to create a way to measure health care.

“Regions, brokers, insurance companies are all working separately. We want to create a single measurement that would help consumers determine which medical facilities are doing the best work,” she said.
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