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Tuesday, March 13, 2001 - Page updated at 12:00 AM

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Uninformed Consent

With a year or two to live, woman joined test in which she was misled, and died

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Dying of breast cancer at age 48, Kathryn Hamilton pinned her hopes on the wisdom of doctors at the world-renowned Fred Hutchinson Cancer Research Center in Seattle.

With conventional treatment, those doctors told her, she would live another year or two. They urged her to consider an alternative: an experimental treatment that might kill her cancer without killing her.

The experiment, labeled Protocol 681, featured new drugs that physician-researchers at "The Hutch" theorized could protect a patient's vital organs from the ravages of extraordinarily high doses of chemotherapy.

Hamilton, desperate to spend as much time as possible with her husband and three children, agreed to enlist in the clinical trial, based on what her Hutch doctors had told her.

Here's what they hadn't told her:

  • The Hutch had a financial interest in the "rescue drugs" being tested.
  • The experiment had caused the premature death of one woman, from the high-dose chemotherapy.
  • One of the rescue drugs being tested wasn't available in intravenous form, the only form Hamilton could tolerate and which they had assured her she could have.
  • There was evidence the rescue drugs might in fact do more harm than good, and Hamilton's doctors were working on a medical-journal article saying so.
The drugs didn't work.

Forty-four days after entering the hospital, weakened by failing organs and bleeding from the eyes, Hamilton grabbed her husband tightly and pleaded, "Don't you dare let me die."

Within hours, in the late afternoon of Feb. 19, 1993, she did.

The cause of death: Fred Hutchinson Protocol 681.

Six days later, Hamilton's doctors submitted the journal article documenting what they had known for more than a year: The primary rescue drug didn't work.

Hamilton's case is further evidence that doctors at The Hutch have at times failed to fully inform patients of the risks and implications of clinical trials, as required by law.

As with Protocol 126, the blood-cancer experiment described Sunday and Monday in The Seattle Times, this trial reveals a lack of accountability and communication in a system where other interests can compromise the care of patients.

The Hutch and some of its doctors had a financial stake in the drugs being tested in Protocol 681, just as they had with Protocol 126.

But the potential for profit was not as clear-cut in this instance. In fact, this experiment continued long beyond the point where any money could be made from it.

The trial appears to have taken on a life of its own, being completed for completion's sake rather than for meaningful science or for the benefit of patients. The complete findings of the study were never even published.

Ethics experts astounded

Medical-ethics experts are astounded by certain decisions made in Protocol 681.

For example, after Hamilton and the first victim died from high-dose chemotherapy, the researchers persisted - actually increasing the doses they gave other women.

Oncologists, ethicists and drug-development experts said such a decision would be extraordinary. Some said they had never heard of a clinical trial in which doses were increased after a patient had died from the drugs.

"I can't imagine such a scenario occurring," said David Lepay, who directs the scientific-investigations division of the Food and Drug Administration.

"I have never, ever heard of a trial - and I'm talking about thousands of trials here - where people would escalate the dose until people died. It would be unethical," said Bert Spilker, an expert on drug development at Pharmaceutical Research and Manufacturers of America, an industry group.

However, Spilker and other experts became more cautious when asked specifically about this Hutch experiment.

"It's a very complex answer," Spilker said. "For 99 percent of the drugs in the world, you would never escalate a dose beyond where it killed someone."

After Hamilton, at least two more women died from the treatment, according to the doctors' own notes. In all, Hutch researchers attributed four deaths out of 68 patients in this experiment to "regimen-related toxicity," meaning that the treatment rather than the cancer killed them.

Regimen-related deaths are rare in these types of cancer trials, happening in an average of one out of every 200 patients. In Protocol 681, however, the rate was nearly 12 times higher: one out of 17.

"You'd have to have a really powerful, overwhelming reason in any situation to keep pushing the dose in the face of death at lower doses," said Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania. "It's hard for me to imagine situations in which that would be morally acceptable to do."

Most of the rest of the patients in the experiment died of cancer. Major studies have now shown that bone-marrow and stem-cell transplants are no better than conventional treatment at saving lives of breast-cancer patients.

The physician who supervised Protocol 681, Dr. William Bensinger, declined to discuss the study.

"I don't really have time to go back and look at the issue," he said. "I honestly don't think it's going to help me and the Hutchinson Center in any way."

Hamilton's survivors are hurt and angered by what they've learned about Protocol 681 - facts their mother never knew.

"If she would have known these things I doubt she would have gone forward" with the experiment, said her son, Chris Addicott. "It would have been suicide."

More knowledgeable than most

Kathryn Hamilton was not a typical patient.

She had a master's degree in health administration and had been coordinator for emergency medical services in Bellingham. When she came to The Hutch, she was the manager of human resources for three medical centers in Spokane.

Those who knew her describe her as strong-willed, sharp and unafraid to speak out.

Hamilton believed her cancer was caused by radiation leaked from the Hanford nuclear reservation in Eastern Washington, near where she grew up. Her father had worked at the plant, helping secretly make plutonium for the first atomic bombs.

She first detected a lump in her breast when she was 32, but it wasn't diagnosed until two years later. After a lumpectomy, radiation and chemotherapy, she thought she'd beaten the cancer.

She made it past the critical five-year mark. Then 10 years. Cancer seemed just a bad memory.

But in the 11th year, her back started to hurt. She blamed it on a bad mattress but soon was told the cancer had returned, this time to her bones. After more surgery and radiation, the cancer went away but was back two years later.

The news was devastating; it meant she was dying.

But Hamilton wouldn't go quietly. She had a lot to live for.

For one, she had become the lead plaintiff in a class-action lawsuit related to the Hanford plant, a case later consolidated into a suit on behalf of 3,000 plaintiffs. She was preparing to testify before Congress.

And there was her family - especially her 14-year-old daughter, Elisabeth, the one child still at home.

Hamilton's best hope, it seemed, was a stem-cell transplant at The Hutch, one of the leading institutions for that procedure. Bone-marrow and stem-cell transplants had been successful in treating leukemia, and researchers were experimenting on breast cancer. There was no proof it would work, but there was hope.

"She mostly wanted to do it for Elisabeth's sake," said Hamilton's mother, Mary Lee Thorpe.

Stem-cell transplants are similar to bone-marrow transplants, except that patients are infused with immature cells, taken from circulating blood, that later become bone-marrow cells.

Both types of transplants save patients by nearly killing them first. A patient is given extremely high doses of chemotherapy or radiation, killing the cancer cells but also wiping out the spongy, delicate marrow, leaving the body unable to produce new blood cells.

Without a stem-cell transplant, the patient would die.

Even with a transplant, there's a limit to how much chemo patients can withstand. The chemicals can cause other vital organs - such as the liver, kidney, heart or lungs - to fail.

As the 1990s began, The Hutch was looking for ways to protect these organs. A solution would make bone-marrow and stem-cell transplants safer and potentially useful in treating more common types of cancer.

The miracle drug that wasn't

In late 1990, two years before Kathryn Hamilton came to The Hutch, a 34-year-old researcher there wrote about a possible breakthrough in bone-marrow and stem-cell transplants.

With federal funding, Dr. James Bianco had done a preliminary study of 30 patients and concluded that an innocuous little drug used for treating leg cramps could shield the liver, kidney and soft linings of the digestive system from the toxic damage of chemotherapy.

Pentoxifylline, or PTX, held promise as a miracle drug.

The results were so amazing that not everyone at The Hutch believed them. Amazing discoveries, such as penicillin, are rare events. Lloyd Fisher, a biostatistician, said of Bianco's PTX findings, "It was awfully hard to believe that things were that good."

Fisher's instincts were right. A second study by Bianco produced far different results.

In the first study, only 3 percent of patients taking PTX suffered kidney damage from chemotherapy. In the second, 39 percent did.

That was greater than the percentage - 36 percent - who suffered kidney damage from chemo and a placebo sugar pill. What's more, PTX patients had significantly more cases of severe kidney damage.

By January 1992, one year before Hamilton was admitted, Hutch researchers knew those results. Not only was PTX not a miracle drug, evidence indicated it might make patients sicker.

But Bianco wasn't ready to give up on PTX. He started delving into the way the drug broke down inside the body. He theorized that the key wasn't PTX but a compound created when PTX metabolized in the body. Genetic differences might explain why some patients seemed to benefit in the first study.

Bianco pulled the medical charts of patients who in addition to PTX had been given other drugs known to alter the way drugs metabolize. He found 10 patients who, in course of being treated with PTX, had also been given the antibiotic Cipro and a steroid called prednisone.

Again, he touted amazing results: None of the 10 patients had suffered damage to her kidneys, livers or lungs. These findings would be used to help justify the experiment Hamilton would enroll in a year and a half later.

By scientific standards, pulling 10 cases from files proves little. Even so, Bianco said he was so confident about the direction of the research that he and colleague Dr. Jack Singer decided to start their own company to develop this treatment.

Not everyone involved in the research was so confident. Anthony Shields, a doctor who worked side by side with Bianco and Singer on their pentoxifylline research, said, "They started the company on a drug that wasn't really panning out. I always thought that was funny."

The company was born on ferry trips to the San Juan Islands. Singer had a vacation home next to Dr. George Todaro, who had done groundbreaking research at the National Institutes of Health.

Todaro introduced Singer to New York investment banker David Blech, who, as a young entrepreneur a decade earlier, had started Genetic Systems, the company involved with Protocol 126, the leukemia experiment.

Bianco and Singer founded Combined Therapeutics Inc. in September 1991. The name, which would soon be changed to Cell Therapeutics Inc., or CTI, came from the fact that they planned to combine two drugs.

The two doctors left The Hutch three months later to work on their new company full time.

The Hutch's president, Dr. Robert Day, wanted the cancer center to be compensated for their plan to commercialize their research. A deal was cut: The Hutch would receive about $20,000 in stock shares and $50,000 a year in licensing fees. That would increase to at least $100,000 plus a percentage of sales if the company successfully sold its treatment.

The Hutch stood to make millions if the drugs worked.

Bianco also recruited two prominent doctors, both Hutch co-founders, for CTI's scientific advisory board: Dr. E. Donnall Thomas, who had just won a share of the Nobel Prize in medicine, and Dr. C. Dean Buckner, who would later become Hamilton's doctor. Both received stock options.

Review board wasn't told all

Meanwhile, another researcher, Dr. William Bensinger, was experimenting at The Hutch to see whether stem-cell transplants could save patients with advanced breast cancer.

He hadn't gotten far before a high dose of anti-cancer drugs killed two of four patients. Bensinger knew about Bianco and Singer's research and wondered whether their drug combination would allow him to safely administer high-dosage chemotherapy.

Buckner, who would soon join the Cell Therapeutics board, was working with Bensinger on Protocol 681. He said they knew PTX alone didn't work, but they hoped combining it with Cipro would make a difference.

Notably, however, proposals Bensinger submitted to The Hutch's Institutional Review Board (IRB) before beginning the new study or when making modifications to it made no mention of negative findings on PTX.

Bianco, who had left The Hutch to start CTI, was the second researcher listed on the protocol. However, he insists he was never involved in it.

In fact, he is critical of the study. There was no proof that PTX and Cipro worked, Bianco said, and until that was known, Bensinger wouldn't be able to tell whether his patients were tolerating higher doses of chemo because of the drugs or despite them.

Bianco himself quickly gave up on PTX and Cipro.

For starters, the FDA resisted the idea of combining two drugs into one. As specialists there pointed out, Bianco and Singer were trying to use one drug to change the way another drug broke down inside the body. The drugs might interact differently in different patients, so the plan to combine the drugs wasn't reliable.

What's more, using an antibiotic such as Cipro was risky. Patients might develop a resistance to antibiotics, making it more difficult to treat infections.

And there was another problem: Competing pharmaceutical companies owned PTX and Cipro, and didn't like the notion of combining them. So even if Bianco and Singer could prove the drugs worked, they might not be able to profit from them.

Cell Therapeutics was at a crossroads. At the urging of its scientific advisory board, chaired by Nobel winner Thomas, the company made a critical decision: It would dump PTX and Cipro and patent a compound that these two drugs created when mixed.

The company filed for that patent in September 1992. It called the new drug Lisofylline.

Bianco said this information was passed on to The Hutch in the company's quarterly and annual reports. Anyone on the Cell Therapeutics advisory board, such as Thomas or Buckner, would have known that Bianco was no longer backing PTX.

Others were abandoning PTX, also. On Nov. 15, 1992, the medical journal Blood published a study by Austrian and German doctors who had tried to duplicate Bianco's first PTX study on 31 patients. They concluded that the drug didn't work.

Bianco and Singer responded in the same issue. Although they knew that their own follow-up study had even worse results, they didn't mention that. Instead, they defended their first PTX study, speculating that the European study came to different results because it relied on the intravenous version of PTX, which Bianco and Singer said wasn't as effective.

The timing was critical for Cell Therapeutics. The company was wrapping up its first major stock sale, raising $38.5 million.

Investment banker Blech, who recalls skepticism over the science involved, was managing the deal.

"There were some very big claims made about a Cell Therapeutics drug," Blech said. "Half the world believed them, and half the world didn't believe them. It was a very controversial company."

Chad Waite of Olympic Venture Partners, a Seattle venture-capital firm that invested in biotechnology companies, said: "The science was controversial. There were people who just absolutely swore by it and there were people who thought it was bunk."

Cell Therapeutics would not release the documents it used to entice investors for the private stock placement. However, The Times obtained a copy of a memorandum for another stock deal in June 1993, seven months later. In it, the company reports research results that suggest that PTX and Cipro were wonder drugs.

Cell Therapeutics claimed that 74 percent of the most seriously ill patients taking these drugs lived one year after treatment, compared with 7 percent of those who didn't take the drugs. It also claimed that after two years, 75 percent of the surviving patients were cancer-free, compared with 38 percent for those who didn't take the drugs.

Robert Kupor, a stock analyst at Seattle-based Frasier & Co., said at the time, "The commercial value of such a product would be hard to overstate. Anyone who had convincing proof would have a market cap (financial backing) of a billion dollars."

But no convincing proof was ever published in medical journals. And biostatisticians say the findings defy belief.

"You don't see changes like that in cancer studies," said Geoffrey Norman, a statistician at McMasters University in Canada. "If it was that big of an effect, there's no way that it wouldn't be published."

Dr. John Nemunaitis, an oncologist who worked with Bianco and Singer on PTX-Cipro research and now practices in Dallas, said he doesn't recall any study with those findings and added, "It almost seems too good to be true."

Cell Therapeutics recently declined to comment on this research, on the advice of its attorney.

Choosing to take `a lethal dose'

So even as Cell Therapeutics was touting its PTX research, it was shutting down that research. That led to The Hutch losing its supply of the intravenous, liquid form of PTX.

The intravenous (or IV) form of PTX was not approved for use in the United States. While at The Hutch, however, Bianco had obtained permission from the FDA to use the IV form in clinical research. Bianco held onto that permission after leaving The Hutch, agreeing to supply the liquid to Hutch researchers for their continuing studies.

But on Nov. 10, 1992, Cell Therapeutics notified The Hutch that it was cutting off the IV supply of PTX.

Bianco said he no longer had a use for the IV form. But all Bensinger had to do, he said, was ask the FDA for permission to use it.

Instead, Bensinger decided to stop using the IV form of PTX in his study. He sent a revised protocol to the Hutch's Institutional Review Board, which met monthly. On Jan. 5, 1993, the board ordered mention of the IV drug to be deleted from the informed-consent papers given to patients entering the PTX study.

The next day, Kathryn Hamilton and her family met with a Hutch doctor to decide whether she should enter Protocol 681.

Hamilton was far more able to evaluate the trial than most patients. Because of her health-care background, she knew doctors at The Hutch and had persuaded them to give her a confidential document - the research protocol.

The protocol spelled out the risks involved in far greater detail than the standard-issue informed-consent paper other patients are given. Without the protocol, for example, Hamilton would not have known that high-dose chemotherapy had killed two of four breast-cancer patients in a previous experiment without the rescue drugs.

Hamilton had long discussions with her family about whether to enroll in the trial. For one thing, it would cost $265,000, of which insurance would pick up only a portion.

Hamilton asked her oldest son, Chris Addicott, then 24, to help her analyze the documents. Addicott, now a Seattle attorney, read through the protocol and was prepared to ask questions when the family met with a Hutch doctor for the informed-consent conference.

That doctor was Frederick Appelbaum, soon to be director of clinical research at The Hutch and one of the investigators on Protocol 681. He was also a co-author of two articles about PTX: one that showed promise and another, which was about to be submitted for publication, showing the drug didn't work.

According to Addicott, Appelbaum never mentioned the new findings, even though the informed-consent form incorrectly said, "Recent studies suggest that PTX (pentoxifylline) prevents kidney, lung and liver damage in patients receiving transplants."

Asked recently why this was in the document, Appelbaum looked over the form and pointed out that it also included a warning that doctors didn't know if PTX and Cipro worked when it said, "We plan to see if the combination of these drugs can prevent damage to the kidney, liver and lungs."

Appelbaum told Hamilton she would be given a large dose of anti-cancer chemicals: 18 milligrams of busulfan per kilogram of her body weight.

Addicott remembers being concerned about that amount. He thumbed through the protocol until he came across a passage explaining that five of 10 patients in two previous experiments had died when given a smaller dose, 16 milligrams. The protocol warned that even that dose was "probably too toxic."

Appelbaum's notes from the meeting make no mention of the exchange. But even if it did come up, Appelbaum said, there were too few instances to determine whether the dosage was dangerous.

Besides, the whole idea of this experiment was to see if the rescue drugs would protect the patient from toxicity.

The doctor's notes do mention that Hamilton could expect to feel quite sick from the chemotherapy.

"I explained to Kathy that the inevitable consequences of the (chemotherapy) were nausea and vomiting," the notes say.

That concerned Hamilton and Addicott. She had vomited violently during past treatments of radiation and chemotherapy. What if she could not keep down the rescue drugs, which were given in pill form?

The answer was right there in the informed-consent form: PTX "may be given through your Hickman catheter if your physician thinks you may not be absorbing the medicine when you take it."

The informed-consent papers Hamilton signed mentioned the availability of the IV version of PTX not just once or twice but three times. But in fact, as Hamilton's doctors knew - or should have known - at that point, The Hutch no longer had the IV version.

Addicott remembers telling her, "They're giving you a lethal dose of chemotherapy, and unless you get the PTX, you could die. But you should be OK because if you can't keep the pills down, they'll give you the PTX in intravenous form."

"I think that's what bothers me so much about this," Addicott says now. "She was relying on me to help interpret and understand the science of what was going on. I did that, and I think I did it correctly. But I think I was given wrong information.

"Nobody in their right mind would go into a study like this knowing they wouldn't get PTX."

Hamilton signed the papers that day and was admitted immediately. At 6 p.m. Jan. 6, 1993, she took her first pink pill of PTX. That night, she became nauseated and threw up. At 7 a.m. the next day, she was given her first dose of chemo.

`I can feel it. I'm going to die'

Hamilton would finish taking the high doses of chemo within her first week in the hospital. It would then be up to a stem-cell transplant and the rescue drugs to give her her life back.

She was supposed to take PTX for 31 days, but that didn't happen. Hamilton struggled with nausea and vomiting from the first day, and nurses began noting Jan. 12 that she was throwing up the PTX virtually every time she took it.

Her husband, Allan Berman, remembered the whole pink pill would come up. She threw up almost every day, sometimes several times a day.

Addicott didn't talk about it with his mother at the time, but he would leave the room and ask nurses why she wasn't getting the IV form of PTX. They told him the FDA had withdrawn approval of the drug.

But when Addicott finally talked to a doctor in charge of the floor - he doesn't remember whom - he remembers being told not to worry. She had gotten down a little bit of the PTX, and it wasn't clear that the drug did much good anyway.

He never told this to his mother.

Appelbaum said The Hutch didn't ask the FDA for permission to use the IV form because it would have involved a lot of paperwork. However, Bianco had first obtained the liquid drug on an emergency basis by making a telephone call to the FDA. The Hutch could have done the same.

On Jan. 15, 1993, Hamilton underwent a stem-cell transplant.

Within days, she developed a fever, a sign of infection.

Berman remembers his wife's fear.

"She said, `I'm not going to live,' " he recalls. "I said, `Yes you are.' She said, `I can feel it. I'm going to die.' Every night it would be a struggle. Something would happen, then fever would come back."

Hamilton's skin became yellow, and doctors found signs of liver damage. She had problems breathing. The blood vessels in her eyes, ears and nose began leaking, causing her to bleed.

But Hamilton hung on. Then, on the evening of Feb. 18, things turned much worse. Her kidneys were failing.

The next morning, Berman talked to his wife for the last time. She pleaded with him not to let her die.

It was too late.

Bad results don't stop testing

Six days after Hamilton died, a group of 17 Hutchinson Center researchers submitted an article to the journal Blood - an article they had been working on for months. It said PTX was not effective in protecting against the toxic effects of chemotherapy. Among the authors listed on the study were Bensinger, Appelbaum, Bianco and Singer.

Yet they continued Protocol 681. The study didn't prove that PTX plus Cipro didn't work, said Buckner. And, he said, the protocol allowed them to continue even if patients died.

But that's not clear. The study was designed to find the maximum amount of chemotherapy which patients could tolerate. A dose would be tested on four women and then escalated if none of these women died or suffered life-threatening complications from the chemo. If two women died or suffered serious complications, the protocol stated, researchers must drop to a lower dose.

But the protocol didn't explicitly say what to do if one patient died.

A number of experts said that in all clinical trials they've known, a dose is considered lethal if a patient dies from it. At that point, doctors stop the trial or continue to test at a lower dose.

"I would not want to be one of those patients who received a higher dose after one of four suffered a regimen-related toxicity death," said Steve Piantadosi, an oncologist at Johns Hopkins Medical Center.

Eventually, enrollment in the study slowed. In the first three years, Bensinger and Buckner enrolled 54 women in the breast-cancer study. But in the last three, they enrolled only 14.

In 1998, Bensinger shut down the study, one week after Cell Therapeutics reported disappointing results for its drug derived from the rescue drugs used in Protocol 681.

Four women, including Kathryn Hamilton, had died from the experiment that they had hoped would cure them.

Bianco and Cell Therapeutics, meanwhile, moved on to developing other drugs. Today, the company is worth more than $764 million.

Duff Wilson's phone number is 206-464-2288. His e-mail address is dwilson@seattletimes.com.

David Heath's phone message number is 206-464-2136. His e-mail address is dheath@seattletimes.com.

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