How We Do Harm (22 page)

The idea seems exciting: a drug that kills patients in one setting might save lives in another.
You can see how important this venture from AIDS to cancer would be for Myers, Broder, and the NCI.
It would validate Broder’s idea that synergies can be found in combating cancer and AIDS.
This is important, because in January 1989, seven months after my arrival on campus, Broder is named to succeed DeVita as NCI director.

Snuffy, too, becomes increasingly important in the NCI hierarchy.
He is named chief of a new NCI branch that combines the medicine branch and the clinical pharmacology branch.
Since every fellow dreams of getting a protocol, Snuffy’s aggressive thinking strikes me as a model to emulate.

Among the warlords, Snuffy’s demeanor is uncharacteristically laid-back.
Sandy-haired and of average height, he is approachable and pleasant.
His nickname was given to him at birth.
His father, also a physician, was fond of the comic-strip character Snuffy Smith, a hillbilly from southern Appalachia who detests “flatlanders” and “revenuers.”
When I meet him, Snuffy has a long beard, just like his comic-book alter ego.

Some doctors have CVs that sound like a symphony—deep, sustained, internally consistent.
Snuffy’s is more like a series of Mozart’s piano sonatas.
Each entry is different, each one complete.
The breadth of his intellectual curiosity is astonishing, running from clinical development of the leukemia and lymphoma drug methotrexate to development of AIDS drugs.
Like everyone else at NCI, he advocates the no-guts, no-glory approach to medicine: hit the thing as hard as you can, nuke it, napalm it, and damn the consequences.

His disorganization is epic.
Papers in his office are arranged in piles several feet high, well beyond the point where anyone can credibly claim to know where anything is.
A story is told about the time Snuffy showed up in Paris only to learn that the conference where he was scheduled to speak about suramin had ended.
He gets the continent right, he gets the country right, he even gets the city right.
The date, however, is wrong.

Along the way, Snuffy ends up with something no one needs: a second nickname.

“Someone named Snoopy just called you,” a secretary reported to Daniel Ihde, then deputy chief of the Medical Oncology Branch at the National Naval Medical Center, an imposing New Deal tower across Rockville Pike from the NIH.
Puzzled, Ihde retreats into his office to review whether he knows anyone named Snoopy.
After brief pondering, Ihde reemerges from his office.

“Could it have been Snuffy?”

Snuffy, a man named after a hooting-and-hollering moonshiner, was confused with a talking, floppy-eared beagle.
That was cute.

From that point on, folks at the Naval Medical Center referred to Snuffy exclusively as Snoopy.

*

WHEN
a drug succeeds in controlling cancer, we learn about it at conferences and in scientific journals.
Stories of our fiascos, though no less instructive, are almost invisible, especially if they are cautionary tales that lay bare the fundamental flaws in the system.
Occasionally we’ll see the data from trials where a treatment that we thought would be better actually does worse than the standard of care.
Yet, in-depth analyses and narrative accounts of system failures are, almost without exception, irrevocably lost.

The story of the development of suramin has never been told in its entirety.
Yet it deserves to be told, as it demonstrates the paramount importance of honesty in experimental medicine.

I was assigned to screen patients for enrollment in Snuffy’s Phase I study of suramin for adrenal cancer.

Usually, before you decide on the method of administering a drug and set the dose, you determine how that drug behaves in the body.
You need to know how long it lingers, how long it remains active.
Typically, if a drug has a short half-life—a day—you might want to consider infusing it gradually with a pump, to keep the levels constant.
If the half-life is long—say, a month—you might hit the patient with a big dose, then maintain him at a predetermined level with small doses.

When the adrenal-cancer trial started, we had no clue about suramin’s pharmacokinetics, and I am not proud to admit that this gap in knowledge didn’t bother me.
Like Snuffy, I had bought into the war mentality.
Military intel is imperfect.
Pertinent facts will be established on the battlefield.
From the outset, suramin was to be given to adrenal-cancer patients by continuous infusion.

As we pump suramin into adrenal-cancer patients, on day five or so some report a numbness or tingly sensation in the lips.
The comments come almost as an afterthought: “Doctor, my lips feel funny.”

In mid-July 1988 I hear this report—the word
complaint
is too strong—about tingly lips from a young woman named Leslie Quinn.
She reports this symptom almost apologetically.
She has a terminal illness, but she is determined enough and well enough connected to get on the protocol of a drug that she hopes will be the cure.
I don’t focus on her symptom and don’t write it down.

Leslie is in her late thirties and has spectacular long, curly, dark brown hair.
Her doting husband is always at her bedside.
Her two lovely daughters, a teenager and a preteen, are there as well.
I realize that Leslie doesn’t think it’s in her interest to tell us about the side effects.
She is more invested in suramin than Snuffy.
For Snuffy, suramin’s success would be a medical breakthrough, a publication, a claim to glory.
For Leslie, it’s life itself.

Surely that feeling in the lips is nothing to worry about.
A funny feeling is not a dose-limiting toxicity, not by itself, not usually.
I am not trying to duck responsibility for the case.
I had been around the block at Case Western during my residency.
My clinical judgment during my time at NCI is the sharpest it would be in my entire career.

We keep the suramin pump on.

On the next morning’s rounds, Leslie reports that she is unable to move her feet.
She says she first had a tingling sensation in her toes, then the toes refused to take her commands.
The feet are next.
This is serious—peripheral neuropathy.
We do the only thing we can—cut the suramin and pray.
Surely, the drug is causing this reaction.
Maybe without the drug the reaction will go away.

Paralysis progresses rapidly.
By the next morning, thirty-six hours after things started to go awry, Leslie is in total body paralysis, hooked up to a ventilator.

The paralysis is either Guillain-Barré syndrome, an autoimmune disorder affecting the peripheral nervous system, or something similar to it.
Clearly the paralysis is caused by suramin.

How did we get there?
Our thinking about suramin wasn’t appreciably different from our thinking about other cancer drugs.
We surmised that if a small dose of an agent has a little activity, a great amount of the agent would have a lot of activity.
Did we get the dose right?
Is dose intensity the name of the game?
Is more
really
better?

A grunt in a firefight can’t stop to ponder the overarching military doctrine and geopolitical formations that catapult him across the seas.
But doubts, big, dark, and fundamental, creep in after the firefight, when I am able to think.
Right now I focus on keeping Leslie alive.

Our intensive care unit has no doctors.
If you take a patient there, it’s up to you to take care of her.
I take a bed in the unit and move in with my patient.
Leslie spends a week on a ventilator.
When she is weaned from the ventilator, she develops pneumonia, which requires a return to the blower.

Throughout this time, Leslie’s husband and I talk about immediate threats to her life.
We discuss her lung function, her oxygenation, her liver, her kidneys.
There is no way to predict whether she will pull through.
We take fire.
We incur casualties.
Some are wounded, some are killed.

Leslie is paralyzed for about two weeks.
She requires physical and occupational therapy to learn to move her arms and legs again.
She never regains the ability to walk independently.

Researching this book, I learned that at the time I was treating Leslie, our colleagues at the Naval hospital were horrified to hear stories about our suramin adrenal-cancer trial.
They knew that patients were ending up in the ICU with the Guillain-Barré syndrome, and that we didn’t—weren’t willing to—stop the trial and see whether we could at least get the toxicity under control.

Snuffy’s nickname Snoopy was taking deeper roots across Rockville Pike.
The image of the dog wandering onto dangerous terrain and unexpectedly encountering the fearsome Guillain-Barré syndrome (or a condition that mimics it) made observers smirk through puzzlement and sadness.

Looking back, I don’t know why we didn’t stop the trial, even temporarily.
We had good reasons to be humble.
At the time, we had no assay for measuring the levels of suramin in the blood and no way to know how long the drug stayed in the body.
Maybe we were afraid of the answers.
Maybe we thought we already had the answers.
Instead of acknowledging the limits of our knowledge, we forged ahead, blindly pushing toward what we hoped was the cure.

Leslie’s symptoms and illness didn’t cause us to rethink the wisdom of continuing the trial.
Eventually, experiences such as hers helped us figure out that half the patients making the lips-feel-funny complaint didn’t progress to paralysis if the drug was stopped.
Also, experiences of patients such as Leslie helped us learn to measure the level of suramin in the blood and pinpoint the level at which the drug caused Guillain-Barré syndrome.

My work with Snuffy and the suramin trial ends in 1989.
I rotate to the Naval Medical Center and then to two years of research when I start to focus on issues of public health and cancer prevention.

I do learn a lesson from Snuffy.
He confirms the truth I learned as a kid: doctors try out things just to see whether they will work.
Here is the Great Snuffy Myers—chief of the Clinical Pharmacology Branch of the premier cancer-research institution in the world—doing what poor, illiterate factory workers in Detroit were telling me to look out for when I was nine years old.

Chapter 14

How Much Protection?

THE POWER OF CANCER
to kill is so fearsome that treating it naturally invites the metaphor of war.
As oncologists, we crave big weapons and are eager to throw them into the field.
This is our mind-set, our history, our culture.
Sometimes it’s also our folly, our madness.

Some of the key strategies that still guide us can be traced to the NCI of the 1950s and 1960s, when two young doctors with strikingly similar names—Emil “J” Freireich and Emil “Tom” Frei—performed a series of experiments on children dying of acute leukemia.

The leukemia ward at NCI at the time was terrifying.
The blood on the sheets was the first thing one noticed—children were routinely bleeding to death.
Mortality from the disease was 100 percent.

In 1955, Freireich came up with an idea for controlling the hemorrhages: give the kids platelets.
Shockingly to people who thought they understood blood, Freireich was determined to skip a step.
He didn’t want to waste time on testing his theories in animals.
He would go directly to the kids.

First, J tried thawed-out, previously frozen platelets.
When he gave this treatment to a child, the bleeding stopped, albeit for five minutes or so.
So, J decided to try fresh platelets.

Hematologists told him it was completely insane.
J’s opponents made the—seemingly logical—case that if you infuse fresh platelets even once, the patient would become sensitized, which would render the intervention impossible in the future.

J transfused platelets without formal consent, without protocols, without approval of any board responsible for monitoring ethics and safety; indeed, he did it without any formal safeguards.
This was 1955.
The concept of “informed consent” did not fully enter medicine until years later.
At that time, doctors still knew best, and no forms were required.
(Even drugs were still being approved based on their “purity.”
Proof of effectiveness was not needed.) If you owned a white coat, you could pursue your hunches.

No one knows how well these children and their parents understood the experiments and the risks.
Did the scientists conducting the experiments tell the kids or their parents that they had no earthly idea what was about to happen?
Did Freireich and Frei even understand that they had no rational way to predict the outcome?
It seems that at best the doctors explained how excited they were about their hypothesis, and permission would follow.
What else was there to do?
These were desperate parents of dying children.

Fortunately, this time skeptics in the hematology establishment were wrong and J’s approach worked.
When leukemia patients were given fresh platelets, their bleeding stopped.

After finding a way to stop the bleeding, Freireich and Frei came up with another wild idea: combine all the drugs that were at the time used to treat the disease.
They used four drugs: vincristine, amethopterin, mercaptopurine, and prednisone, abbreviated as VAMP.
This regimen was a witch’s brew, a combination of nasty drugs, each with a different mechanism of action and different side effects.
They wanted to administer it at a maximum strength, and they wanted to continue to treat their patients after the point where visible signs of disease had disappeared.

The approach of hitting the disease with multiple drugs, each with a different way of attacking the cancer, became known as combination chemotherapy.
It’s logical, sort of: if you can give multiple active drugs that attack the cancer cell at several different points of vulnerability, you get more activity than with one drug.
More activity in this case means more cancer cells dying.
Following this naturally is the idea of administering drugs at the maximum tolerated dose.
Administering large doses of chemotherapy drugs became known as dose-intensive chemotherapy.