How We Do Harm (24 page)

The question of benefit would have to wait till the next phases—Phase II and Phase III—of development.
Health benefits—if any—would be more likely to accrue later, most likely not to patients getting the drug in Phase I.

After putting Leslie on a ventilator, I start to wonder whether we—the researchers—are failing to tell these patients the truth.
Are we delineating what we know from what we don’t know and from what we believe?
Or are these patients not paying attention, deliberately refusing to hear?
Whatever the explanation, do these patients understand the risks they are taking?
Do they understand the likelihood of benefits?
Are they lying to themselves or are they being duped?

In 1995, researchers at the University of Chicago published a study that demonstrates just how poorly patients understand the risks and benefits of Phase I studies.
A team led by oncologist and bioethicist Christopher Daugherty surveyed thirty patients who enrolled in a Phase I trial.
Their finding was astonishing: 85 percent of patients chose the trial in pursuit of therapeutic benefit.
Worse, only a third of the patients were able to restate the purpose of the trial in which they were enrolled.
Together, these findings suggest that a minority of patients in such studies have a clear understanding of the risks they have agreed to take.

Exceedingly rarely does a physician pull a patient off a Phase I protocol for ethical reasons.
I would see it happen only once—at NCI, when an AIDS patient who had tried three courses of therapy became obsessed with the fourth.
His enthusiasm was sparked by something called a molecular sponge, or CD-4.
The idea was to fool the AIDS virus to bind to an intravenously administered receptor rather than the patient’s cells.
The Phase I protocol in this case served to uncover the maximum amount of the molecular sponge a patient could tolerate.

The patient badly wanted to receive the sponge, and he clearly not only hoped that he would get better but seemed to be
expecting
that he would get better.
He talked so much to fellows and the nurses that we went to the principal investigator on the trial and informed him of an ethical problem with putting that patient on the trial.

We cringed at the thought of contradicting the patient’s desires, but ultimately we were looking after his welfare.
This was someone who expected more than could be promised, someone who didn’t comprehend the gamble he was about to take.
Once on therapy, he could become so invested that he would not report side effects, potentially sustaining harm.
And in the end, he would almost certainly have to face the disappointment of drug failure.

Although J Freireich would have had no problem with this state of affairs, some of my NCI colleagues and I did.
The principal investigator on the trial—Robert Yarchoan, Broder’s collaborator on AIDS work—took our concerns seriously and went to see the patient.
Yarchoan tried to explain the goals and limitations of the therapy.
They spoke several times, but Yarchoan’s message didn’t seem to get through.
Finally, he decided that it would be unethical to offer the patient the molecular sponge.
This decision taught us, the fellows, an important lesson about ethics in research: it’s wrong to be anxious to put patients on trials.
Safeguards matter.

Of course, the patient was gravely disappointed.
But he was not deprived of the cure.
The therapy was ultimately shown to be ineffective.

*

THE
study of suramin in adrenal cancer went nowhere, too, but Snuffy thought of another use for the agent—prostate cancer.
With time, Snuffy and his team learned to measure the levels of the drug in the blood.
As a result, they learned that the Guillain-Barré syndrome sets in when the drug level reaches 300 mcg/ml of blood serum.

To manage toxicity, Snuffy proposed rigorous monitoring.
He called it “adaptive control with feedback.”
It was so complicated that only NCI would dare to attempt it.
Clinical pharmacologists outside NCI called the approach mumbo jumbo.
They saw it as just another case of NCI hubris, insistence that the institute’s scientists know what they are doing even if it makes no sense to anyone else in the field.

The drug seemed to have another toxicity.
It was a blood thinner, a lot like Coumadin.
Patients had to be counseled to avoid shaving or banging their fists against tables—any activity that might ordinarily result in cuts and bruises.

Snuffy also learned that suramin has an unusually long half-life—fifty days.
This means that it takes fifty days for half of the drug to be excreted from the patient’s body.
Usually, a drug with a long half-life is administered quickly with an “induction dose,” then kept up at the therapeutic level with small doses.
Yet, for reasons that surprised many of his colleagues in clinical pharmacology, Snuffy decided to keep the slow infusion regimen intact.
The objective was to get as close as possible to 300 mcg/ml because more is, of course, better.

Snuffy’s hypothesis was based on an observation of drops in PSA levels in some metastatic prostate cancer patients whose disease returns despite treatment with hormones.
Snuffy took them off hormones—at that time, flutamide—and gave them suramin and the steroid prednisone.
(The prednisone was added to replace the steroids that their bodies were unable to produce because the patients’ adrenal glands had, literally, died.) Indeed, after a while, some of these patients experienced drops in their PSA levels.

If you looked only at how you gave the patient suramin and his PSA went down, you might conclude that you had the cure.
Unless, of course, nature was giving us the middle finger and we were unable to recognize it.

Chapter 16

Saving Representative Silvio Conte

AN ARGUMENT
can be made that no one on Capitol Hill will ever believe in the War on Cancer more passionately than Congressman Silvio O.
Conte, a liberal Republican representing a largely Democratic district in the Berkshire hills of western Massachusetts.
As a ranking member of the House Appropriations Committee, Conte is among the most valuable friends NCI can ask for.

Conte is an American original.
He is a son of Italian immigrants.
He is a World War II veteran.
He is an avid hunter and fisherman.
He loves cigars.
He has grandchildren who call him Nonno.
He grows tomatoes in the backyard of his Bethesda home.
He gives away the crops.
He drives a hot-red Pontiac GTO.
He is fiercely independent.
Though a Republican, he voted against the resolution that enabled President George H.
W.
Bush to enter the first Persian Gulf War.

In 1987, Conte is diagnosed with prostate cancer.
The disease is found early enough for surgeons at Johns Hopkins University to remove his prostate.
In 1988, he gets additional surgery, to replace a knee ruined as a result of a football injury.
That surgery lands him in an electric cart, which he promptly decorates with Italian and American flags.
He is especially fond of the cart’s horn, which he blasts with abandon in the hallways of the Capitol.

The cancer progresses rapidly.
It becomes obvious that his tumor was not localized, as the surgeon had hoped.
Conte goes on a hormonal treatment.
This works for a while.
However, in December 1990, Conte is told that the treatment has failed him.
A doctor at Hopkins advises the sixty-nine-year-old congressman to get his affairs in order.

Conte’s daughter Michelle recalls her father calling her in tears.
“I just can’t believe this, I can’t believe this,” he keeps repeating.
Michelle calls the doctor at Hopkins, who repeats to her that Conte should get his house in order, and that Michelle and other family members should be guiding him in that direction.

Conte doesn’t want to give up.
First, he goes to see Fernand Labrie, a Canadian endocrinologist.
The journey in a small plane proves difficult.
After going to see Labrie, Conte calls Michelle and says, “I am so tired, it was brutal.”

The Canadian doctor sees no hope in the situation.
“I wish we had never gone,” Conte’s wife, Corinne, says to Michelle.

At the time, NCI’s Phase I/II trial of suramin is hard to miss as the final shot at hormone-refractory prostate cancer.
NCI officials trumpet the drug’s promise far and wide, and for a man in Conte’s position—that of an appropriator—the trumpeting would be deafening.

I don’t know whether that was the case with Conte, but I do know that NCI officials make special efforts to recruit sick politicians.
Conte has sharp political instincts.
Educated to think critically by Jesuits at Boston College, he has no fear of questioning accepted truths.
He is able to foresee the military quagmire of Vietnam.
He has the courage to vote his conscience on Iraq.

Why doesn’t he say no to suramin?
Does his belief in the conquest of cancer and his personal contact with the generals leading that war dull his otherwise sensitive bullshit gauge?

“He was a sitting duck for that,” daughter Michelle says.
“He firmly believed in the NCI mission.
We’ve got the best, we are cutting-edge.
He was always into the newest thing.
He had all these friends.
He was always approached as someone who could provide.
That was his position.
He was in appropriations.”

Conte has access to top-notch experts in defense, but no access to state-of-the-art clinical pharmacologists.

As a fellow at NCI, I, too, was a believer in the promise of suramin, or at least enough of an agnostic that I could be involved in testing it in patients.
I was not directly involved in Conte’s care.
I think his story is illustrative of a problem in medicine, and it is told with permission of his daughter.

It’s not clear how much the Conte family knows about the risks and benefits of suramin.
“My mother was a nurse,” Michelle says in an interview nearly two decades later.
“She didn’t know the risks.”
Corinne Conte would have understood the risks, and in the close-knit Conte family, she would have told the kids.

On February 1, 1991, Conte starts to experience paralysis, and Corinne calls a military appropriations aide and an administrative assistant to help her take him to NIH.

“He was having a horrible headache and feeling weak, very weak,” Michelle says.

A CT scan reveals a blood clot near the right side of Conte’s brain.
Without doubt, this was caused by suramin, which thins the blood and increases the risk of bleeding.
Surgery is planned.

The day before surgery, Conte’s mind runs along two tracks.
There is the cheerful, positive persona.
“He was talking about going to Florida after NIH,” says Michelle.
“He thought he would make it through, and he had been working on the National Archives project in Pittsfield.”
The archives would contain his papers.
He brings a briefcase to NIH, and he works a little.

He also has an intense conversation with Corinne.
This larger-than-life American accepts that death is near.
“He had a premonition before going into that surgery about coming out,” Michelle says.
“He said to her before he went in, ‘Corinne, don’t hook me up to anything.
I want to go.
I don’t want to be hooked up to machines.’”

NIH surgeons attempt to remove the clot, but the operation fails.
Another blood clot develops almost immediately, putting Conte into a coma.

“He was never conscious,” Michelle recalls.
“They had him completely bandaged up, and there was some bleeding coming through it.
He kept twitching, his arms kept moving up and down, but I know he could hear us.”

As the appropriator’s life slips away, NCI doctors push for another surgery.
“NIH people were saying, ‘We can do it, we can keep him going.
He will come back.
We can see him driving his GTO down the road, waving.’
They were talking about keeping him on life support,” Michelle recalls.
A local urologist, a personal friend, joins the family to provide perspective, support, and sober guidance.

Michelle remembers being horrified.
These people wanted to fight, fight, fight, denying defeat.
“This was bizarre,” Michelle recalls.
“What in the heck is wrong with these people?”

Finally the urologist friend speaks up.
“If this were my father, I would let him go now.
There is no real hope of him ever having a normal life.
Half of his brain is damaged.
He will never be able to be Silvio again.”

The family, too, decides to honor Silvio’s wishes and not go through with another surgery.
The congressman dies in his hospital bed a week after being wheeled into the Clinical Center.

*

IT
took more than a decade, but science did a fine job of sorting though Snuffy’s beliefs about suramin, demonstrating that they are, without exception, wrong.
First, Snuffy’s observation that suramin decreases the PSA level in hormone-refractory prostate cancer—Conte’s disease—was incorrect.
Howard Scher, of Memorial Sloan-Kettering Cancer Center, published a paper in the
Journal of Clinical Oncology
in 1993 that struck at the heart of Snuffy’s reasoning.
Scher’s research reported that merely withdrawing hormone-refractory patients from flutamide, a hormonal therapy, decreased their PSA levels.

Here is how it works: At first, the tumor hates flutamide, but over time, it learns to like it, even grow from it.
Stop flutamide, and the disease will slow down for a while.
This was not the cure.
It was flutamide withdrawal.
Snuffy stumbled upon it and Scher described it.

The change in PSA—which Snuffy believed to be an indicator of clinical improvement—isn’t worth much.
It’s a measurement made in a lab.
It doesn’t necessarily mean anything to an actual patient.
Your PSA could go down, and you may not know the difference.
The FDA has never accepted a drop in PSA as a criterion for approving prostate-cancer drugs.

Another study compared three doses of suramin and showed conclusively that there is no relationship between intensity of the dose and the drug’s effect.
The study, by Eric Small et al., published in the
Journal of Clinical Oncology
in 2002, showed that suramin at any dose—high, intermediate, or low—produced the same impact on survival and progression of disease.
However, toxicity was more severe at high doses.
More was worse.